Kidney Health

Kidney Health

1 Overview

Summary and Quick Facts

  • The kidneys support many critical functions, including filtering waste products out of the blood, regulating fluids and blood pressure and forming urine. Roughly 10% of American adults live with some degree of chronic kidney disease, which oftentimes goes undetected until it reaches an advanced stage.
  • In this protocol you will learn how kidneys function and what factors, including use of common over-the-counter medications, can lead to chronic kidney disease. You will also discover simple tests used to detect kidney disease and many dietary and lifestyle strategies for supporting healthy kidney function. Several nutritional supplements shown to decrease risk of kidney disease are covered, as well.
  • The strategies in this protocol, in combination with physician supervised treatment, can provide a well-rounded approach to ensuring optimal kidney health.
  • Vitamin D has been shown in both clinical and observational studies to improve multiple parameters of kidney function in patients with chronic kidney disease.

The kidneys are one of the body’s critical filters, supporting water and fluid balance, blood pressure regulation, and waste elimination. Maintaining good kidney health is of the utmost importance if one’s goal is to live a long and healthy life.

Natural interventions like vitamin D, coenzyme Q10 (CoQ10) and N-acetyl L-cysteine (NAC) help protect the kidneys.

Common Diseases of the Kidney

  • Chronic kidney disease (most commonly caused by high blood pressure and diabetes)
  • Acute kidney injury
  • Kidney stones

Note: Most people do not think twice about taking non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen (Tylenol). But overuse of these drugs can cause severe acute kidney injury or lead to progression of chronic kidney disease.

Factors that Compromise Kidney Health

  • Diabetes, metabolic syndrome, and insulin resistance
  • High blood pressure (see note about telmisartan [Micardis])
  • Obesity
  • Dysbiosis (imbalance of good and bad intestinal microorganisms)

Note: Telmisartan is a unique drug for high blood pressure. Not only does it help reduce blood pressure, but it also activates peroxisome proliferator-activated receptor gamma (PPAR-γ), which helps regulate glucose and lipid metabolism and insulin sensitivity. Additionally, telmisartan provides antioxidant and anti-inflammatory action in the kidneys.

Monitoring Kidney Health

Laboratory evaluation may be the only way that poor kidney function and disease can be discovered in their initial phases.

  • Blood tests include:
    • Glomerular filtration rate (GFR), the most important measure of kidney function and one that declines with age
    • Creatinine and blood urea nitrogen (BUN)
    • Cystatin C, a more sensitive indicator of GFR than creatinine that Life Extension reported on nearly a decade ago
  • Urine tests include:
    • Urine output, osmolality, and specific gravity: designed to measure how much urine is made and how concentrated it is
    • Urine protein, as the presence of elevated amounts in patients with diabetes, hypertension, or other diseases is a powerful predictor of chronic kidney disease progression

Dietary and Lifestyle Considerations

  • Avoid or minimize the use of NSAIDs by using the lowest effective dose for the shortest period of time
  • Eat a Mediterranean-style diet or the DASH (Dietary Approaches to Stop Hypertension) diet that is low in animal protein and high-glycemic carbohydrates, and high in vegetables, fruits, unsaturated fats, and fiber
  • Increase dietary potassium and decrease dietary sodium
  • Make sure to get enough vitamin D, vitamin B6, and vitamin B12

Note: Patients with advanced kidney disease should consult with their physician before making any dietary changes.

Integrative Interventions

  • Vitamin D: Vitamin D may exert a protective effect on the kidneys. Clinical trials in chronic kidney disease patients who received vitamin D showed improved kidney and heart function.
  • Omega-3 Fatty Acids: Omega-3 fatty acid supplementation in humans will decrease the prevalence of chronic kidney disease, as well as reduce blood pressure, excess protein in the urine, and inflammation and triglycerides in those with kidney disease.
  • Coenzyme Q10 (CoQ10): CoQ10 helps keep blood pressure levels healthy and decrease hemoglobin A1c (HbA1c), both strong risk factors for kidney disease.
  • Pre- and Probiotics: Improving the balance of bacteria and microorganisms in the digestive tract has shown promise in preventing formation and assisting removal of toxins that promote kidney disease from the blood. A trial of a combination of pre- and probiotics is currently underway in patients with moderate-to-severe chronic kidney disease.
  • N-Acetyl L-Cysteine (NAC): In a group of hemodialysis patients, NAC resulted in significant reductions in some serum markers of inflammation, possibly through an enhancement of renal glutathione.

2 Introduction

In recent years, chronic kidney disease (CKD) incidence has doubled among older individuals, owing partly to increasing prevalence of conditions such as diabetes and hypertension that damage the delicate blood vessels of the kidneys (Liu 2010). One in ten American adults is now living with some degree of CKD, and kidney disease is the ninth leading cause of death in the United States (NKUDIC 2012; Arora 2014).

The kidneys are two bean-shaped, fist-sized organs located in the back of the abdominal cavity on both sides of the spine near the base of the ribcage. They represent one of the body’s critical biological filtration systems. The kidneys cleanse the blood and ensure the components of the circulatory milieu stay within the narrow ranges necessary to support normal physiology. Impairment of kidney function can beget potentially grave systemic consequences, so maintaining good kidney health is of the utmost importance if one’s goal is to live a long and healthy life (Al-Awqati 2012; Baynes 2014). Although some causes of kidney damage, such as acute kidney injury, can cause rapid onset of severe symptoms, many people with subclinical CKD are unaware of their condition for years until it becomes symptomatic or is revealed by blood tests. CKD is often not detected until it has reached an advanced stage (NIH 2008; NKF 2013a; NKF 2013b).

One of the biggest threats to kidney health can be found in the medicine cabinets of most Americans, or on the shelves of any pharmacy. Most of us do not think twice about taking non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen (Tylenol) for even minor aches and pains. But overuse of these pervasive and seemingly innocuous drugs can cause severe acute kidney injury or lead to progression of chronic kidney disease (Gooch 2007; Downie 1991; Pai 2015; Rahman 2014; Le Vaillant 2013; Ozkaya 2010).

Back in 1985, the National Kidney Foundation recommended that labels of over-the-counter NSAIDs display a warning about their potential to cause kidney damage (NKF 1985), but these drugs are often still considered benign by consumers (Jang 2014; LaCivita 2009; Pai 2015). Today, NSAIDs are among the most common medications inappropriately prescribed to older Americans, and have accounted for over 70 million prescriptions and more than 30 billion over-the-counter purchases (Jang 2014). For many years, Life Extension has sounded the alarm about the risk of kidney damage posed by NSAIDs and acetaminophen (Faloon 2004). Sadly, a study published in late 2014 found that nearly half of patients at high risk for the development of acute kidney injury concurrently used NSAIDs, and that “risk for [chronic kidney disease] and [acute kidney injury] is not routinely assessed among those for whom NSAIDs are prescribed” (Jang 2014).

The good news is that kidney health can easily be monitored with inexpensive blood and urine tests. Even for aging individuals without obvious symptoms of kidney disease, novel blood tests such as cystatin C can help identify subclinical kidney impairment (Lassus 2012; Oh 2014; Arimoto 2005; Shlipak, Mattes 2013).

In this protocol, you will learn about the structure and function of the kidneys and the causes of kidney dysfunction. You will also read about the most common diseases of the kidney and how they are typically treated. In addition, you will discover several simple preventive tests that can be used to detect kidney disease early in its course, and a number of dietary and lifestyle considerations to support optimal kidney health, such as avoiding long-term use of NSAIDs, will be reviewed. Integrative interventions that may support kidney health will be discussed as well. Finally, those reading this protocol should also read the Acetaminophen and NSAID Toxicity protocol, which outlines strategies to avoid the detrimental effects of acetaminophen and NSAIDs, since overuse of these drugs is a major contributor to kidney impairment.

3 Understanding the Structure and Function of the Kidneys

The kidneys are charged with many important tasks in water and fluid balance, blood pressure regulation, and waste elimination (Li 2011; Navar 1997; Baynes 2014). Kidneys are highly active organs, and they receive about one-quarter of cardiac output for their blood supply (Al-Awqati 2012; Baynes 2014).

The main functional unit of the kidney is the nephron; each kidney has approximately 1 million of these independently functioning units (Baynes 2014).

The nephron has two distinct parts. The glomerulus is a microscopic blood filter that allows electrolytes, small molecules, and water to pass while preventing blood cells and large proteins from leaving the bloodstream (Szczepańska-Konkel 2014; Al-Awqati 2012).

Molecules that pass through the glomerulus enter the renal tubule, a convoluted channel lined with specialized transport proteins that can either reabsorb needed electrolytes or excrete unwanted small molecules (Szczepańska-Konkel 2014; Al-Awqati 2012).

Finally, renal tubules empty into collecting ducts, which channel the unabsorbed water and electrolytes toward the ureters and eventually the bladder. Microscopic molecular pores in the collecting ducts can selectively allow water to be pulled out of the ducts and retained in the body (Baynes 2014; Khalifeh 2009; Al-Awqati 2012; Agre 2002).

Urine, the output of the collecting ducts, is a solution of released electrolytes, nitrogen compounds, and other metabolic waste. Normally, the kidneys excrete about 1–2 L of urine per day (Baynes 2014; Khalifeh 2009; Al-Awqati 2012).

The kidneys help regulate several aspects of normal physiology:

Blood pressure regulation. When blood pressure is low, a collection of cellular sensors in the kidney release the hormone renin, which initiates a series of reactions to produce the hormone angiotensin II. Angiotensin II constricts blood vessels, which increases blood pressure (Wackenfors 2004). Renin also promotes the release of the hormone aldosterone from the adrenal glands (Underwood 2013). Aldosterone causes the kidney to reabsorb sodium and water, which also increases blood volume and pressure (Epstein 2001; Genazzani 2007; Al-Awqati 2012).

Water balance (hydration) and electrolyte balance. By retaining or excreting water and electrolytes, healthy kidneys maintain blood volume and optimal hydration of tissues (Baynes 2014; Al-Awqati 2012). When dehydration is detected by the central nervous system, antidiuretic hormone causes the kidneys to retain water (Al-Awqati 2012). Likewise, when the blood contains too much water, antidiuretic hormone secretion is suppressed, and the extra water is excreted in urine (Baynes 2014).

Muscular contraction, nerve impulses, skeletal integrity, and a variety of metabolic reactions depend on very specific concentrations of electrolytes—particularly sodium, potassium, chloride, magnesium, calcium, and bicarbonate (Rizzoli 2014; Saric 2005; Prieto 1993; Turnberg 1970; Dempsher 1981; Adelstein 1987). The renal tubules selectively absorb, excrete, or exchange electrolytes to maintain the proper balance of electrolytes in the blood (Al-Awqati 2012; Baynes 2014).

Hormone secretion and activation. The kidneys are involved in the activation and secretion of several important hormones:

  • Activation of vitamin D - The kidneys activate vitamin D (calcitriol or 1,25-dihydroxyvitamin D) from calcidiol or 25-hydroxyvitamin D (Al-Awqati 2012; Baynes 2014). Activated vitamin D is a hormone that acts at multiple tissue sites throughout the body (Norman 2008).
  • Erythropoietin - The kidneys secrete erythropoietin, a hormone that signals bone marrow to produce new red blood cells (Baynes 2014).
  • Renin - This hormone, secreted by the kidneys, is an essential part of the renin-angiotensin system that helps regulate sodium, fluid levels, and blood pressure (GHR 2015; Hawley 2015).

pH maintenance. The pH of the blood must be maintained within a very narrow range. pH is maintained by both the lungs (by retaining or removing carbon dioxide) and kidneys (by secreting acid and absorbing bicarbonate [HCO3-] from the filtrate in the renal tubules) (Al-Awqati 2012; A.D.A.M. 2013a; Seifter 2011; Walker 1990a; Walker 1990b).

Waste excretion. Nitrogen from broken down proteins is converted to a biologically inactive compound called urea in the liver and is excreted by the kidneys (Bankir 1996; Vilstrup 1980; Karsai 1982). The kidneys filter and also enable the ultimate excretion of other waste, such as excess hormones, vitamins, toxins, and drug metabolites (Al-Awqati 2012; Baynes 2014).

Drug and toxin metabolism. Cells of the renal tubules contain many of the same detoxification enzymes as liver cells (Jancova 2010). See Life Extension’s Metabolic Detoxification protocol for a detailed discussion of detoxification enzymes and their mechanisms.

Glucose production (gluconeogenesis). Only the kidneys, liver, and intestine are able to produce glucose from non-sugar compounds in humans (Baynes 2014; Mithieux 2009; Mithieux 2005; Mithieux, Andreelli 2009). After an overnight fast, the kidneys produce about one-quarter of the glucose released into the blood. Insulin suppresses kidney glucose production whereas epinephrine stimulates gluconeogenesis (Baynes 2014).

4 Common Diseases of the Kidneys

Chronic Kidney Disease

CKD is a progressive decline in renal function, demonstrated by an estimated glomerular filtration rate under 60 for three or more months, resulting in a buildup of waste products in the blood, and in electrolyte imbalances and anemia. Albumin to creatinine ratio may also be used to establish a diagnosis of CKD. Other blood, urine, and kidney imaging tests may also indicate CKD (Cohen 2010; Ferri 2014c).

Features of CKD include progressive retention of nitrogenous waste products in the blood (uremia), electrolyte imbalance, metabolic acidosis, and anemia (Duranton 2012). While prolonged exposure to acute insults such as drugs or infection are capable of causing CKD, chronic conditions such as diabetes mellitus and hypertension are more commonly the cause (Mehdi 2009; Cohen 2010).

Acute Kidney Injury

Acute kidney injury is a rapid impairment of renal function that occurs in a matter of hours or days. Acute kidney injury can result from insults within the kidney itself (renal causes), reduction of blood flow into the kidney (prerenal causes), or damage to the lower urinary tract that causes the backup of uremic toxins into the kidney (postrenal causes) (Ferri 2014a; NKF 2013b).

Blood flow to the kidneys can be reduced by hemorrhage, dehydration, heart failure, pulmonary embolism, sepsis (a systemic inflammatory response caused by infection of the blood), excessive blood calcium, and some drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs) (Ferri 2014a).

The kidneys may be directly damaged by autoimmune disease, lymphoma, infection, certain medications, and conditions that lead to rapid tissue breakdown (Ferri 2014a).

The urinary tract can be damaged by obstruction of the ureters, bladder, or urethra by stones, tumors, prostatic hyperplasia, trauma, or infection (Ferri 2014a; Elsevier BV 2012).

Kidney Stones

Kidney stone(s), a condition also known as nephrolithiasis, is one of the most common kidney diseases. There are several types of kidney stones, each composed of an accumulation of a different type of compound naturally present in the body, and having different risk factors for their formation. Calcium oxalate stones are the most common kidney stones in humans, accounting for 76% of stones; their most common cause is high urine calcium levels (Finkielstein 2006). Other relatively common stones include calcium phosphate, usually due to high urine pH; uric acid, common in cases of acidic urine and patients with gout or metabolic syndrome; struvite, often the result of urinary tract infections; and cystine, resulting from genetic disorders of amino acid transport (Elsevier BV 2012).

5 Factors that Compromise Kidney Health

Diabetes

Diabetes mellitus is a common cause of CKD and end-stage renal disease in the United States and other developed countries. Diabetic kidney disease, which is characterized by increased urinary albumin excretion in a person with diabetes mellitus, represents a significant and increasingly relevant medical and public health problem worldwide (Stanton 2014; Radbill 2008; Cohen 2010). Diabetic kidney disease has been estimated to occur in 20–40% of diabetes mellitus patients (Radbill 2008; Park 2014).

Glycated hemoglobin (HbA1c) levels and the concentration of circulating advanced glycation end products (AGEs) are the source of many complications of diabetes mellitus (Leslie 2009; Zoungas 2012). Controlling glycated hemoglobin (HbA1c) levels, blood pressure, and urine albumin levels can slow the progression of diabetic kidney disease (Stanton 2014). There is substantial evidence showing that HbA1c level is a primary risk factor contributing to the development of small blood vessel (microvascular) complications in patients with type 1 and type 2 diabetes mellitus, a risk that increases exponentially as HbA1c levels rise (Penno 2013).

AGEs, the formation of which is promoted by high blood sugar levels, are compounds formed when sugars chemically modify proteins, lipids, and nucleic acids (Forbes 2003; Davis 2014; Busch 2010). AGEs have pro-inflammatory and pro-oxidative effects; they play a key role in the development of diabetic nephropathy. AGEs can damage the delicate cells in the glomerulus, leading to kidney dysfunction (Thomas 2005; Linden 2008; Bohlender 2005). In preclinical studies, inhibition of AGE formation, or interventions that break their cross-linked structure, have been shown to delay the development of nephropathy, even without directly impacting blood sugar control (Forbes 2003).

Hypertension 

High blood pressure is the second leading cause of chronic kidney disease (Sanghavi 2014). High blood pressure is present in over 80% of patients with chronic kidney disease, and is a factor in the progression towards end-stage kidney disease (Toto 2005). High blood pressure damages blood vessels in the kidneys and compromises filtration. Damaged kidneys are then less capable of regulating blood pressure, further exacerbating hypertension (AHA 2014a).

Telmisartan: Renal Benefits beyond Blood Pressure Control

Controlling blood pressure is an important goal for patients with chronic kidney disease. One class of medication often used for this purpose is angiotensin II receptor blockers or ARBs.

These medications have been shown to effectively lower blood pressure and reduce urinary protein excretion in CKD patients with hypertension (Weinberg 2006). Use of ARBs has also been associated with increased survival among individuals with CKD (Molnar 2014). In addition, long-term use of ARBs does not appear to cause significant side effects in CKD patients (Weinberg 2006; Weinberg 2004).

Several ARBs are available and have been studied in the context of kidney health and disease. However, few are as intriguing as telmisartan (Micardis).

Telmisartan is a unique ARB; not only does it help reduce blood pressure, but it also activates a nuclear receptor called peroxisome proliferator-activated receptor gamma or PPAR-γ (Yamagishi 2007; Kurtz 2005).

Upon activation, PPAR-γ helps regulate glucose and lipid metabolism, and insulin sensitivity, which are of critical importance for those with diabetes-related kidney disease (Kurtz 2005). Additionally, telmisartan exerts anti-inflammatory and antioxidant action in the kidneys (Balakumar 2012; Schmieder 2011). In fact, one group of researchers remarked “telmisartan provides renal benefit at all stages of the renal continuum in patients with type 2 diabetes” (Schmieder 2011).

Clinical evidence supports the notion that telmisartan’s positive effects go beyond blood pressure control, suggesting meaningful benefits for patients with kidney disease. Telmisartan was compared to the blood pressure-lowering medication enalapril (Vasotec), which belongs to another class of blood pressure-lowering drugs called angiotensin-converting enzyme inhibitors (Santos 2009), in a group of patients with CKD. After 12 months, telmisartan led to more robust reductions in urinary markers of kidney dysfunction compared with enalapril. The researchers concluded that this effect did not depend on telmisartan’s ability to lower blood pressure (Nakamura 2010).

On the basis of good safety data for telmisartan (Zhu 2004) and the evidence of robust benefits for kidney health, individuals seeking a strategy to help control their blood pressure and keep their kidneys healthy should speak with their healthcare provider about telmisartan.

Obesity

Obesity is a risk factor for CKD, independent of diabetes or hypertension (Hall 2014; Kumar 2013), and has been referred to as the number one preventable risk factor for chronic kidney disease(Wickman 2013). Several studies have shown that obesity is an independent risk factor for the onset of CKD as well as its severity; predicts poor outcomes in patients with CKD; and is associated with a more rapid progression to CKD. Some of the kidney-related changes caused by obesity may be reversible with weight loss (Eknoyan 2011; Kopple 2010; Guarnieri 2010). More information on weight loss is available in Life Extension’s Weight Loss protocol.

Metabolic Syndrome and Insulin Resistance

Metabolic syndrome is a cluster of conditions that increase the risk of cardiovascular as well as kidney disease (Watanabe 2010; Salerno 2011; Guarnieri 2010). Metabolic syndrome comprises abdominal obesity; high blood pressure; high fasting blood glucose and triglycerides; and low levels of beneficial high-density lipoprotein (HDL) cholesterol (IDF 2006; MedicineNet 2014). Metabolic syndrome is also accompanied by insulin resistance (Kaur 2014). Insulin resistant cells—particularly those of muscle and fat tissue—no longer use insulin efficiently to remove glucose from the bloodstream, which predisposes to diabetes and high blood pressure (Reaven 1988; Laville 2009). Both metabolic syndrome and insulin resistance may be predictors of kidney disease progression, even in the absence of high blood sugar levels (Kumar 2013). The components of metabolic syndrome have been independently associated with incidence and progression of chronic kidney disease (Raimundo 2011); increased albumin elimination in the urine; and decreased glomerular filtration rate (Nashar 2014). Studies have estimated that metabolic syndrome may double the risk of CKD (Chen 2004; Thomas 2011; Kumar 2013). The mechanisms by which metabolic syndrome leads to kidney disease are not completely understood, but inflammation, insulin resistance, oxidative stress, and dysfunction of the small blood vessels of the kidney are involved (Raimundo 2011).

Hypothyroidism

Hypothyroidism is associated with several derangements in kidney function, including decreased renal blood flow, filtration, and sodium reabsorption, and may be associated with progression of CKD (Kim, Lee 2014). Thyroid replacement therapy in CKD patients with low thyroid hormone (even those not showing clinical signs of hypothyroidism) may improve glomerular filtration (Shin, Lee 2012; Hataya 2013). More information about thyroid health is available in Life Extension’s Thyroid Regulation protocol.

Age and Race

Kidney function declines with age. Population-based studies among elderly populations estimate the prevalence of kidney dysfunction or CKD at 11–35%. Also, individuals of African descent are at greater risk for developing kidney disease (Bolignano 2014).

Medication Usage

Certain medications are capable of damaging the kidneys, most commonly as a result of overuse. Some of the more notable kidney-damaging medications include:

Nonsteroidal anti-inflammatory drugs. Kidney damage resulting from chronic use of pain medication is estimated to afflict 4 in 100 000 individuals (NKUDIC 2010). A comprehensive review of seven studies with well over 1.5 million participants found a 26% increased risk of accelerating CKD progression with habitual use of high-dose NSAIDs (Nderitu 2013).

NSAIDs reduce the flow of blood through the kidneys and can impair glomerular filtration in individuals susceptible to kidney injury. This effect is mediated by a reduction in the synthesis of prostaglandins, which are cell-signaling molecules derived from the omega-6 fatty acid arachidonic acid via the action of the cyclooxygenase enzymes (Downie 1991; Whelton 1999; Marnett 1999; Pai 2015; Rahman 2014). In the context of impaired renal function, such as occurs in chronic kidney disease and during aging, prostaglandins play an important role in the maintenance of blood flow through the kidneys. Inhibition of renal prostaglandin synthesis can lead to a variety of detrimental effects if kidney function is less than optimal, including fluid and electrolyte disorders, acute renal dysfunction, nephrotic syndrome, interstitial nephritis, and renal papillary necrosis. Also, NSAIDs can adversely influence blood pressure regulation by interfering with renal prostaglandin synthesis, especially when used concurrently with angiotensin-converting enzyme (ACE) inhibitors, diuretics, and β-blockers (Whelton 1999; Murray 1993; Pai 2015; Rahman 2014).

Those reading this protocol should also read the Acetaminophen and NSAID Toxicity protocol, which outlines strategies to avoid the detrimental effects of acetaminophen and NSAIDs.

Chemotherapy agents. Kidney toxicity is a common side effect of some chemotherapy drugs such as cisplatin (Platinol), doxorubicin (Adriamycin), and oxaliplatin (Eloxatin) (Lahoti 2012; Lameire 2011; Joybari 2014). For example, kidney toxicity due to cisplatin occurs in about one-third of patients undergoing treatment (Wensing 2013). Many chemotherapy drugs are metabolized and excreted through the kidneys, exposing the kidneys to their toxic effects. Thus, kidney toxicity is one of the most important challenges for individuals receiving chemotherapy (Di Vito 2011; Vogelzang 1991).

Antibiotics. Certain antibiotics have been associated with kidney toxicity; vancomycin (Vancocin) is the best characterized, with an incidence ranging from < 1% to > 40% in different studies. Vancomycin nephrotoxicity has been associated with high-dosage, extended duration of use, or combination therapies with other nephrotoxic drugs (Gupta 2011). Other antimicrobials associated with acute kidney injury include aminoglycosides, rifampin (Rifadin), penicillin, cephalosporins, amphotericin B, and fluoroquinolones (Bird 2013; Ferri 2014a).

Radiocontrast Media

Radiocontrast media are commonly used in certain radiographic (X-ray) imaging. However, they can be toxic to renal cells and affect renal blood flow, both of which lead to kidney injury (Michael 2014). Contrast-induced nephropathy is the third most common cause of hospital-acquired kidney failure (Michael 2014).

Dietary Net Acid Load

One of the kidneys’ chief roles is excreting excess acid to keep the pH of blood in the narrow, slightly alkaline range necessary to support normal metabolic function (Hamm 1987; Unwin 2001; Schwalfenberg 2012). Because most typical diets produce a slightly net acid excess, the kidney must continuously excrete this acid residue. As kidneys age and gradually lose some of their functional capacity, they become less efficient at eliminating this acid so more of it remains in the bloodstream (Amodu 2013; Frassetto 1996). Also, because nephron number and functional capacity are decreased in CKD, this additional workload may cause further damage to the kidneys (Scialla 2013; Meyer 1989; Frassetto 1996; Amodu 2013; Fenton 2011; Frassetto 2001).

Correcting low-grade systemic metabolic acidosis with alkali salts, such as sodium bicarbonate or potassium citrate, corrects some of these biochemical consequences (Hazard 1982; Starke 2012; Frassetto 2001; Vormann 2006; Alpern 1997; Rylander 2009). A diet higher in alkaline elements from fruits and vegetables also neutralizes this acidic condition, making it a potential therapeutic strategy in CKD (Scialla 2011; Kanda 2013).

Other Toxins

Some metals can accumulate in the tubules of the kidney and cause functional and structural damage. These include metals such as cadmium, mercury, lead, uranium, platinum, and others (Sabolić 2006). Organic toxins such as pesticides and solvents have also been associated with acute kidney injury and CKD (Pozzi 1985; Siddharth 2012; Sato 1988). While some evidence for this effect is for acute high-dose exposure (Yadla 2013; Ordunez 2014; Bashir 2013), chronic low-level exposure has also been implicated (Siddarth 2014; Jacob 2007; Siddharth 2012; Ordunez 2014). One study found higher levels of pesticides in the blood of CKD patients compared to healthy controls, and noted that higher levels of total pesticides correlated with impaired kidney function (Siddharth 2012).

See Life Extension’s Heavy Metal Detoxification and Metabolic Detoxification protocols for more information.

Genetic Diseases

Genetic diseases, such as polycystic kidney disease (Ferri 2014b) and Alport syndrome, may damage the kidneys and lead to CKD (Quigley 2012; Heidet 2009). Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder affecting about 400 000 people in the United States. ADPKD is among the most common polycystic kidney diseases. This condition causes fluid-filled cysts to grow typically in both kidneys, displacing healthy kidney tissue. Over time, this leads to reduced kidney function and can eventually cause kidney failure. Once the kidneys fail, people with ADPKD require dialysis or a kidney transplant. High blood pressure is one of the most common consequences of ADPKD, and about half of individuals with ADPKD develop end-stage kidney disease by age 60 (NHGRI 2013).

Genetic testing can assist with the early identification of people at risk of developing ADPKD. Mutations in two genes, PKD1 or PKD2, lead to ADPKD. Although there is no curative treatment available for ADPKD, people with known PKD1 and PKD2 mutations can initiate diet and lifestyle changes—especially keeping blood pressure under control—that may slow the onset of symptomatic polycystic kidney disease (NHGRI 2013).

Adrenal Function

Adrenal function can have a profound effect on kidney function. Hyperadrenocorticism (Cushing’s syndrome), the oversecretion of the hormone cortisol by the adrenal gland, can cause water and sodium retention in the kidney (leading to hypertension) and a number of urine abnormalities; and can increase the occurrence of kidney stones (Smets 2010). Oversecretion of aldosterone (hyperaldosteronism) by the adrenal glands can also interfere with water and sodium retention by the kidney and has been associated with treatment-resistant hypertension (Calhoun 2013; Magill 2014). Life Extension’s Adrenal Disorders protocol provides more information on Cushing’s syndrome and related health problems.

Diabetes Insipidus

Diabetes insipidus is a condition that is different from diabetes mellitus. In diabetes insipidus the kidneys are unable to effectively reabsorb water due to a failure in the production of or response to antidiuretic hormone. Patients with diabetes insipidus produce large quantities (up to 20 L per day) of dilute urine and are in danger of severe dehydration. Diabetes insipidus can be congenital or acquired (Sands 2006).

The Gut Microbiome-Kidney Health Connection

The bacterial microbiome within the human gastrointestinal tract has important implications for kidney health. When the intestinal microbiome is perturbed, a phenomenon known as dysbiosis, uremic toxins such as p-cresyl sulfate can accumulate and promote CKD progression; these toxins may also promote insulin resistance (Montemurno 2014; Evenepoel 2009; Koppe 2013; Soulage 2013).

Uremic toxins also increase intestinal permeability, allowing bacteria and bacteria-derived toxins to enter the bloodstream, which is associated with chronic inflammation, cardiovascular risk, and immune dysregulation. Intestinal permeability in CKD contributes to the progression of CKD; CKD also results in dysbiosis and increased intestinal permeability (Ramezani 2014; Sabatino 2014; Anders 2013; Vaziri 2012).

The microorganisms found in the gut are highly influenced by their host’s diet. Some evidence suggests that a high fiber, plant-based diet modelled on the Mediterranean diet could help improve kidney function and slow down the progression of CKD (Montemurno 2014).

Probiotics and prebiotics may help eliminate uremic toxins (Evenepoel 2009; Vitetta, Gobe 2013; Vitetta, Linnane 2013; Ramezani 2014). A randomized controlled trial has been proposed to co-administer prebiotics and probiotics to individuals with moderate-to-severe CKD to target p-cresyl sulfate and indoxyl sulfate synthesis, with a wide range of biomarkers being studied to measure the clinical effects of the treatment (Rossi 2014).

6 Monitoring Kidney Health

Kidney disease patients may have few symptoms, or even none at all, early in the course of the condition. Laboratory evaluation may be the only way that poor kidney function and disease can be discovered in their initial phases. Detecting disease before it progresses may allow intervention to have the greatest effect (Rosner 2006). There are many tests that give important insight into kidney function.

Blood Tests

Glomerular filtration rate. Glomerular filtration rate (GFR) is the most important measure of kidney function. GFR is the volume of blood plasma that the kidney clears of a given substance each minute. In practice, it is indirectly measured by comparing blood and urine levels of the metabolite creatinine (Baynes 2014).

GFR decreases with age and renal disease, and is higher in men, pregnant women, and some disease states (eg, diabetes, obesity) (Rosner 2006; Baynes 2014). Average GFR is 120 mL/min in men and 100 mL/min in women (Baynes 2014), though lab reports usually do not provide exact values when GFR is above 60 mL/min (NKDEP 2012). Direct measurement of GFR requires both a urine and blood sample; an estimation based on serum creatinine, and incorporating adjustments for age, sex, and body size, is often used and referred to as estimated GFR (eGFR). eGFR can also be calculated using other metabolites (Rosner 2006; Levey 1999).

Creatinine and blood urea nitrogen. Creatinine is a breakdown product of phosphocreatine from muscle (Baynes 2014). It is released by muscle cells into the blood at a fairly constant rate and filtered from the blood by the kidneys and nearly completely excreted (Rosner 2006; Baynes 2014). Because its level in the blood is almost entirely dependent on the kidneys, it is a sensitive marker of renal function and is used to estimate GFR (Levey 1999).

Blood urea nitrogen (BUN) is a measure of the amount of urea in the blood (A.D.A.M. 2013b). Since excess nitrogen (a breakdown product of amino acid degradation) is removed from the body via the kidneys as urea, increases in BUN can indicate decreased kidney function (Gowda 2010). It is not as specific an indicator of kidney function as creatinine and GFR, so these values are often considered together when assessing kidney function (Lyman 1986; Qin 2013).

Cystatin C. Cystatin C is a newer blood marker of kidney function and has numerous advantages over standard tests. Unfortunately, it is not currently part of the standard blood chemistry panel, but it is available upon request from several labs. While mainstream medicine is just beginning to incorporate cystatin C testing into the clinic, Life Extension reported on the value of this novel blood test back in 2006 (Wagner 2006), and customers can purchase a cystatin C blood test through the Life Extension website.

Compared with creatinine, cystatin C is less influenced by age, gender, body composition, diet, or preexisting infection or cancer, so its blood levels are more consistent across different patient populations (Lassus 2012; Shlipak, Matsushita 2013). This may make it a more sensitive indicator of GFR, and thus of kidney disease (Newman 1995; Mussap 2002). Indeed, a large analysis of pooled data from 11 general population studies involving 90 750 subjects and five additional studies of CKD patients involving 2960 subjects found that cystatin C is a better predictor of declining kidney function than creatinine. Whereas creatinine-based estimates of GFR are able to predict risks associated with declining kidney function when eGFR levels fall to 60 mL/min/1.73m2 or less, GFR estimates based on cystatin C level are predictive at approximately 85 mL/min/1.73m2. In other words, cystatin C-based estimates of GFR are able to predict risk when the magnitude of the decline in kidney function is less pronounced than that necessary for creatinine-based GFR estimates to be predictive. Although chronic kidney disease is not diagnosed until the eGFR reaches 60 mL/min, being able to detect earlier, less-significant decrements in kidney function is important, as the period of subclinical kidney dysfunction before overt kidney disease can be diagnosed based on creatinine may last one to two decades (Rush-Monroe 2013; Shlipak, Matsushita 2013).

Another advantage of cystatin C over creatinine is that while creatinine production is highly variable across populations, cystatin C production is more uniform. Since creatinine is a byproduct of muscle metabolism, individuals with greater muscle mass, those who engage in more physical activity, or those generally in better health produce more creatinine than people with lower muscle mass, physical activity levels, and poorer overall health. Thus, determining GFR based on creatinine levels requires that doctors approximate the rate of creatinine generation, which may not take all variables into account (Shlipak, Mattes 2013).

Current recommendations suggest that cystatin C measurement be used in combination with creatinine testing to confirm kidney disease diagnosis in patients with reduced GFR (45–59 mL/min) but no other signs of kidney damage (Shlipak, Mattes 2013).

Cystatin C is a better indicator of kidney function in elderly patients and predicts outcomes more accurately than creatinine (Hojs 2004; Fliser 2001). Compared with GFR, cystatin C has a stronger association with death from cardiovascular or any other cause in those with advanced CKD (Menon 2007; Ferri 2014c).

Cystatin C appears to offer novel applications beyond kidney function. In patients with normal kidney function, it was strongly and significantly associated with the risk of venous thromboembolism (Brodin 2012). Moreover, cystatin C has recently emerged as a promising predictor of cardiovascular risk (Salgado 2013; Angelidis 2013; Lassus 2012). Although more research is needed before cystatin C can be widely used to assess cardiovascular risk, studies so far suggest cystatin C testing may be a reliable measure of risk of incident or recurrent cardiovascular events and adverse outcomes. Also, cystatin C has been shown to be predictive of heart failure development, and increased levels have been associated with increased mortality in both acute and chronic heart failure (Lassus 2012).

Importantly, there are some populations in whom cystatin C may not provide accurate measurements of kidney function. These include people with uncontrolled thyroid disease and those using corticosteroids. These individuals should discuss the best kidney function testing options with their healthcare provider (Shlipak, Mattes 2013).

Electrolytes and albumin. For individuals with kidney disease, standard blood chemistry panels may reveal abnormalities in electrolytes. Kidney injury can cause increases in blood potassium and phosphate and decreases in bicarbonate, sodium, and calcium; blood pH may also become more acidic, a metabolic condition known as acidosis (Ferri 2014a).

Levels of the blood protein albumin, as it is lost in the urine, can also be reduced in certain types of kidney disease (Bolisetty 2011; Kaysen 1998).

Homocysteine. Homocysteine is a modified amino acid generated as a byproduct of protein metabolism. Elevated blood levels of homocysteine have been associated with cardiovascular risk; this link is attributable to the detrimental effect of homocysteine on the endothelial cells that line the inside of blood vessels (van Dijk 2013; Debreceni 2014; Cacciapuoti 2012; Pushpakumar 2014; Sipkens 2013; Lee 2013). Homocysteine is also highly correlated with eGFR and is elevated in 85–100% of patients with end-stage kidney disease. A large study in individuals with heart disease found that homocysteine was significantly and markedly predictive of risk of death from CKD. In this study, patients with CKD who were in the lower third of homocysteine levels had the same mortality rate as those with normal renal function, while those in the top third of homocysteine levels had a seven-fold mortality risk (van Guldener 2006; Shishehbor 2008).

Another study showed that homocysteine levels correlated with the stage of CKD in individuals with type II diabetes (Pastore 2014). Similarly, a study on children with CKD showed that increased plasma concentrations of homocysteine were associated with advanced stages of CKD (Fadel 2014). Yet another study demonstrated a strong association between high homocysteine levels and CKD. In fact, the likelihood of having CKD increased over five-fold among subjects whose homocysteine levels were high compared with subjects whose levels were normal. Moreover, higher serum homocysteine levels were associated with lower eGFR in this study (Chao 2014).

More information about homocysteine is available in Life Extension’s Homocysteine Reduction protocol.

Complete blood count. A count of blood cells in a patient with kidney disease may reveal reduced numbers of red blood cells (anemia) due to decreases in production of the hormone erythropoietin or may show blood concentration/dehydration due to the kidney’s inability to prevent water loss (Ferri 2014a).

Urinalysis

Urine output, osmolality, specific gravity. Urine output can be decreased in acute kidney injury. For instance, a 24-hour urine output of < 20.5 mL in a 150-lb adult meets the criteria for “Failure” according to the RIFLE (Risk, Injury, Failure, Loss of Kidney Function, and End-stage kidney disease) classification system (Bellomo 2004).

Urine specific gravity and osmolality measure the ability of the kidneys to concentrate urine (A.D.A.M. 2013c). When water intake is low, healthy kidneys produce concentrated urine by excreting less water, thus keeping the body hydrated. In kidney diseases such as renal tubular disease or diabetes insipidus, urine remains dilute, which results in low urine specific gravity or osmolality, as the kidney loses its ability to concentrate urine (Hamilton 2000; Rosner 2006).

Urine protein. The presence of elevated amounts of protein in the urine (proteinuria; > 150 mg/day) represents a loss in the ability of the glomeruli in the kidney to selectively retain blood proteins, which ultimately leads to difficulties maintaining blood volume and is a powerful predictor of kidney failure (Cravedi 2013; Johnson 2012). Urine protein measurements can be either total protein or, specifically, the blood protein albumin. Urine protein measurements can be standardized to the amount of creatinine in the urine (to compensate for differences in urine concentration) and are expressed as urine protein to creatinine ratio or urine albumin to creatinine ratio (UACR). Slightly high UACR (2.5–25 mg/mmol in men or 3.5–35 mg/mmol in women) is called microalbuminuria; a level above these values is called macroalbuminuria (Johnson 2012). Changes in UACR may be used to track disease progression or response to therapy (Marre 2003; Younes 2010).

Imaging

Abdominal X-rays or CT scans may be taken if kidney, ureter, or bladder stones are suspected. Ultrasound can evaluate kidney size; acutely injured kidneys may be enlarged on ultrasound whereas chronically diseased kidneys are usually smaller than normal. Ultrasound can also detect urinary tract obstruction, and can be used to detect abnormalities in renal blood flow (Meola 2012; Ferri 2014a; Cohen 2010).

Other Testing

Blood pressure is usually monitored in patients with kidney disease, as it both contributes to and results from diminished kidney function. Electrolyte changes, especially increased blood potassium levels, may affect heart rhythm, so electrocardiogram (ECG or EKG) is sometimes used to monitor for arrhythmia (Ferri 2014a).  

7 Dietary and Lifestyle Considerations to Promote Kidney Health

Avoidance of Nonsteroidal Anti-inflammatory Drugs

Use of nonsteroidal anti-inflammatory drugs (NSAIDs) for the treatment of pain and inflammation can increase the risk of NSAID-induced kidney damage. The lowest effective dose should be used; shorter durations of use may also be protective. Regular follow-up with a clinician, including testing for kidney function, and discontinuation of the drug if signs of toxicity develop are advised (Curiel 2013).

Evidence for the impact of aspirin on kidney health is mixed. One study showed that regular use of aspirin actually slowed the progression of CKD in individuals over a 5–7 year period (Evans 2009). Also, an earlier study, published in the New England Journal of Medicine, showed that acetaminophen and NSAID use was associated with risk of end-stage kidney disease, but aspirin use was not (Perneger 1994). Conversely, 150 mg of aspirin daily was associated with deterioration of creatinine clearance, compared with clopidogrel (Plavix), in a study of preventive anti-platelet therapy in individuals with type 2 diabetes and CKD (Dash 2013). In addition, a study in 1884 CKD patients receiving 100 mg aspirin daily for cardiovascular prevention found that usage doubled serum creatinine levels and incidence of renal death (Kim, Lim 2014). Similarly mixed results have come from studies on the use of low-dose aspirin in elderly patients (Akinwusi 2013; Segal 2006). On the basis of currently available evidence, those with existing kidney disease should consult their healthcare provider before initiating a low-dose aspirin regimen. Such individuals on low-dose aspirin therapy should have regular testing for kidney function (Curiel 2013; Akinwusi 2013).

“Western-style” vs. Mediterranean-style Diets

Compared with a standard “Western-style” diet, a Mediterranean-style diet is lower in animal protein and high-glycemic carbohydrates, and higher in vegetables, fruits, unsaturated fats, and fiber—thus, it contains less of the dietary factors that contribute to kidney disease. A “Western-style” diet rich in high-glycemic carbohydrates and excess salt increases the risk of hypertension and metabolic syndrome, which increase CKD risk (Odermatt 2011).

A study examined the degree of adherence to a Mediterranean diet among 597 men, 42% of whom had a GFR < 60 and were thus considered to have CKD. Study participants were divided into three degrees of adherence to Mediterranean diet: low, medium, and high. Subjects with medium and high adherence were 23% and 42% less likely, respectively, to have CKD compared with those with low adherence. Compared with those with low Mediterranean diet adherence, medium and high adherence were associated with a 25% and 23% lower mortality risk, respectively (Huang, Jimenez-Moleon 2013). Another study found that creatinine clearance score, a measure of healthy kidney function, was positively correlated with fruit and moderate alcohol consumption (moderate alcohol consumption is an aspect of Mediterranean-style diet). The same study also found that higher consumption of potatoes, red meat, and poultry decreased creatinine clearance scores, and thus was correlated with diminished kidney function (Chrysohoou 2010).

A Mediterranean-style diet has been shown to decrease cardiovascular risk in chronic renal failure patients (Mekki 2010). One group of authors proposed a novel mechanism for the beneficial effects of a Mediterranean-style diet on kidney function, suggesting it promotes a healthy gut microenvironment, which prevents the accumulation of uremic toxins (Montemurno 2014).

The DASH Diet

The DASH (Dietary Approaches to Stop Hypertension) diet decreases blood pressure, improves blood lipid levels, and reduces the risk for cardiovascular disease. The DASH diet is based on studies supported by the US National Institutes of Health. Two important characteristics of the DASH diet are that it does not require special types of food and the recipes are easy to follow (PubMed Health 2014).

The DASH diet places emphasis on vegetables, fruits, and low-fat or fat-free dairy products; it includes fish, poultry, whole grains, and nuts; and it limits sodium, sweets, sweet drinks, and red meat. It can be implemented together with medical therapies and other lifestyle interventions in most patient populations (Tyson 2012).

The DASH diet was shown to lower blood pressure in individuals with prehypertension and stage I hypertension (Tyson 2012). A subgroup analysis from the Nurses’ Health Study revealed that the DASH-style diet was associated with an almost 50% decreased risk of rapid eGFR decline (Lin 2011). A prospective cohort study that enrolled over 88 000 nurses  and followed them for 24 years reported a 27% decrease in total coronary heart disease and a 34% decrease in fatal heart disease (Fung 2008; McCarron 2008).

Potassium Salts/Sodium Chloride Balance

Both low and high blood concentrations of potassium are associated with increased risk of dying in chronic kidney disease and end-stage renal disease patients (Kovesdy 2013). Sodium chloride (table salt and the salt in processed foods) is a known risk factor for high blood pressure, which is a risk factor for CKD. Sodium chloride appears to affect some people more than others, but in the general population only amounts over 2300 mg per day are conclusively linked with hypertension (Jin 2014; AHA 2014b).

Restriction of sodium in patients with CKD, to 6 g/day, also enhances the activity of angiotensin-converting enzyme (ACE) inhibitor medications, one of the standard therapies for CKD (Bellizzi 2013). Lowering dietary sodium chloride and increasing dietary potassium salts may also decrease chronic low-level acidosis, which may be associated with bone loss and muscle loss, and progression of nephropathy (Frassetto 2007; Frassetto 2001; Goraya, Simoni 2012; Scialla 2013; Goraya 2013).

Simple Carbohydrates

Sugar consumption, particularly from sweetened beverages, has been postulated to contribute to the incidence of CKD in the United States (Karalius 2013). One study demonstrated a statistically significant link between consumption of sugar-sweetened soda and CKD (Cheungpasitporn 2014). In another study, higher levels of dietary fructose consumption were significantly associated with CKD (Yuzbashian 2014). Fructose, a sugar present in sucrose (table sugar) and high-fructose corn syrup, may increase uric acid levels, which may contribute to hypertension and kidney disease (Karalius 2013).

See Life Extension’s Gout and Hyperuricemia protocol for more information on associations between uric acid and these diseases.

Saturated vs. Unsaturated Fats

Diets high in polyunsaturated fats were shown to significantly decrease risk of CKD in two observational studies (Yuzbashian 2014; Gopinath 2011). On the other hand, a large population study showed that those who ate the most saturated fat had significantly higher protein loss from their kidneys compared with those who ate the least saturated fat (Odermatt 2011; Lin 2010).

Diets rich in monounsaturated fats may reduce many risk factors associated with CKD; these fats promote healthy blood lipid profiles, improve hypertension, and may improve glycemic control and reduce obesity risk (Kumar 2013).

Phosphate Restriction

High blood phosphate levels have been associated with reduced kidney function and progression to renal failure in CKD patients. Even in healthy individuals, elevated blood phosphate (> 4 mg/dL) is an independent predictor of future CKD. Phosphorus from meat is more easily absorbed than phosphorus from plant-based foods; therefore, animal protein is a larger contributor to dietary phosphorus than vegetable protein. Dietary calcium may mitigate negative consequences of phosphorus, as a lower ratio of calcium to phosphorus intake appears to increase the chance of negative outcomes, regardless of the level of dietary phosphorus (Uribarri 2013).

Protein Restriction

Animal proteins generally, and high-sulfur protein sources specifically, yield acidic metabolites that must be excreted by the kidneys (Scialla 2013; Goraya, Wesson 2012; Frassetto 2001). Thus, protein restriction, if undertaken judiciously, may be an effective strategy for slowing CKD and preserving kidney function (Eyre 2008; Mandayam 2006).

At the same time, patients who restrict protein may tend to eat more alkaline vegetables and fruits, thus further relieving systemic acidity (Frassetto 2001). The success of adherence to the plant-based Mediterranean diet for preserving kidney function may derive from this mechanism (Chrysohoou 2010).

Protein restriction may slow progression of CKD (Kovesdy 2013; Bellizzi 2013), and it also appears that increased consumption of animal protein and low consumption of vegetables and fruit contribute to acidosis in renal transplant recipients (van den Berg 2012). A protein-restricted diet may enhance the blood pressure-lowering and antiproteinuric effect of angiotensin-receptor blockers (ARBs), a standard therapy for hypertension and kidney diseases that cause proteinuria (Bellizzi 2013). In one study, healthy individuals who consumed plant-based rather than animal protein had less risk of developing CKD (Yuzbashian 2014).

Adequate protein intake for individuals with CKD has been estimated at 0.55 g/kg/day, provided caloric requirements are met (Bellizzi 2013).

Vitamin Sufficiency

Kidney disease is associated with poor vitamin status. This is especially well documented in the case of vitamin D (which is activated in the kidneys), so individuals with kidney disease should test their blood level of 25-hydroxyvitamin D. Kidney disease has also been associated with vitamin B6 and B12 deficiency (Mariani 2014; Lacour 1983; Saifan 2013).

8 Integrative Interventions to Help Maintain Kidney Health

Integrative interventions for addressing hypertension and diabetes, the two most significant risk factors for CKD, can be found in Life Extension’s High Blood Pressure and Diabetes protocols, respectively. Interventions for environmental toxicity, a risk for acute kidney injury and CKD, may be found in Life Extension’s Metabolic Detoxification and Heavy Metal Detoxification protocols.

Potassium Citrate

Potassium citrate is, like sodium bicarbonate, a base-forming salt (Minich 2007; Fjellstedt 2001). In an animal model of polycystic kidney disease, it has successfully preserved GFR, apparently through its alkalinizing effect (Tanner 1998; Tanner 2000). In a study in older adults, up to 9 g a day of potassium bicarbonate showed an ability to attenuate some urinary effects of protein consumption (Ceglia 2009).

Pyridoxal 5’-Phosphate

Pyridoxal 5’-phosphate (P5P) is a form of vitamin B6 (Fortin 1999). It is a metabolite of pyridoxamine, a form of vitamin B6 that is a potent inhibitor of advanced glycation end product (AGE) formation, which is one of the features of diabetic kidney disease. Pyridoxamine is currently being investigated for maintaining kidney function in patients with diabetic kidney disease (Shepler 2012). P5P itself may help maintain kidney health in diabetics; in animal models of diabetes, P5P administration inhibited AGE formation, protein loss in the urine, fibrosis of kidney tissue, and development of diabetic kidney disease (Nakamura 2007).

Vitamin D

The kidneys play a role in converting vitamin D to its active form, and kidney disease can lead to vitamin D deficiency. Vitamin D may also exert a protective effect on the kidneys: studies in animal models suggest the active form of vitamin D may suppress kidney inflammation, fibrosis, and cell death; and protect against toxicity from cisplatin. In humans, this treatment may reduce protein loss in urine and improve immune function (Kim, Kim 2014). In observational studies, CKD and dialysis patients who received calcitriol or synthetic vitamin D analogs (active forms of vitamin D that do not require the kidney for activation) exhibited reduced cardiovascular and all-cause mortality (Zheng 2013). Clinical trials in CKD patients who received synthetic vitamin D analogs or calcitriol showed lower protein loss in the urine, lower albumin-to-creatinine ratio, and improved heart function (Zoccali 2014; Moe 2010; Kim, Kim 2014; Wesseling-Perry 2009).

L-Carnitine

Patients undergoing kidney dialysis can develop a functional carnitine deficiency known as dialysis-related carnitine disorder, a condition that includes anemia that responds poorly to erythropoietin treatment; low blood pressure during dialysis; cardiomyopathy; and muscle dysfunction, the main symptom of which is overall fatigability. This disorder results from the removal of a significant amount of carnitine during dialysis. The National Kidney Foundation recommends treatment of dialysis-related carnitine disorder symptoms with intravenous L-carnitine at 20 mg/kg of total body weight after each dialysis procedure (Eknoyan 2003). L-carnitine may have additional benefits for the dialysis patient: a meta-analysis of 49 clinical trials involving 1734 kidney dialysis patients found a significant decrease in C-reactive protein (a marker of inflammation) and low-density lipoprotein in patients taking carnitine. Thirty-seven trials included in this literature review administered L-carnitine intravenously while 12 trials used oral L-carnitine (Chen 2014).

Coenzyme Q10

A small study on 55 predialysis patients assessed levels of oxidative stress markers and coenzyme Q10 (CoQ10) in the subjects’ blood. While levels of the oxidative stress marker malondialdehyde were increased, levels of CoQ10 were decreased in subjects with mildly decreased creatinine clearance rates. These two results were significantly correlated, and the authors concluded that oxidative stress is an early event in the progression of kidney disease (Gazdíková 2001).

Another important way that CoQ10 may benefit kidney health is by helping to keep blood pressure levels healthy. A meticulous literature analysis in which data from three separate trials were pooled and analyzed found that CoQ10 supplementation for 4–12 weeks led to highly clinically and statistically significant reductions in systolic blood pressure of 11 mm Hg and diastolic pressure of 7 mm Hg. The doses of CoQ10 used in the studies analyzed ranged from 100–120 mg daily (Ho 2009). In a randomized controlled trial in type 2 diabetics, 200 mg of CoQ10 daily for 12 weeks significantly decreased both systolic and diastolic blood pressure, by 6.1 mm Hg and 2.9 mm Hg, respectively. Hemoglobin A1c levels, a measurement of long-term blood glucose control, also decreased by 0.37% (Hodgson 2002). These findings point to an important role of CoQ10 in protecting kidney health, since both high blood pressure and elevated glucose are strong risk factors for kidney disease.

In addition, animal studies have shown that CoQ10 can protect kidney tissue from numerous nephrotoxic drugs, including gentamicin, cisplatin, and cyclosporine (Upaganlawar 2006; Fouad 2010; Sato 2013; Ishikawa 2012).

Omega-3 Fatty Acids

Omega-3 fatty acids from fish oil have been shown to significantly reduce blood pressure (a risk factor for CKD) in several clinical trials on patients with hypertension (Hartweg 2007; Geleijnse 2002). Omega-3 fatty acid supplementation at a dose of 4 g daily reduced blood pressure in patients with CKD in a double-blind trial (Mori 2009). Other evidence has shown that omega-3 fatty acids could reduce proteinuria in patients with CKD, and reduce inflammation and triglycerides in dialysis patients. Eating more oily fish with a plant-based diet low in saturated fats may benefit patients who have CKD or those at risk of developing it (Huang, Lindholm 2013). A study of over 3000 individuals showed that among those with greater adherence to a Mediterranean-type diet, greater long-term fish consumption was associated with improved kidney function (Chrysohoou 2010).

Prebiotics and Probiotics

Improving the balance of bacteria and microorganisms in the digestive tract has shown promise in preventing formation and assisting removal of uremic toxins from the blood. Because these toxins negatively affect kidney function, they are implicated in kidney damage in CKD (Montemurno 2014; Ramezani 2014; Evenepoel 2009; Vitetta, Linnane 2013; Vitetta, Gobe 2013). Rodent studies have demonstrated that a prebiotic­—food for beneficial probiotic bacteria—was capable of preventing CKD-associated insulin resistance. This ability was caused by a reduction in the accumulation of uremic toxins (Soulage 2013; Koppe 2013). A trial of a combination of pre- and probiotics is currently underway in patients with moderate-to-severe CKD (Rossi 2014).

N-Acetyl Cysteine

N-acetyl cysteine (NAC) is a sulfur-containing compound that helps counteract the damaging effects of heavy metal toxicity (Patrick 2006; De la Fuente 2011). In animal models, NAC enhanced the renal excretion of chromium and lead, and lowered kidney concentrations of mercury (Samuni 2013). In a rat model of salt-sensitive hypertension, NAC reduced renal protein loss and tubular damage and improved GFR and renal blood flow, possibly through an enhancement of renal glutathione (Tian 2006). In a group of 24 hemodialysis patients, 600 mg of NAC twice daily for three months resulted in significant reductions in some serum markers of inflammation, including interleukin-6 and C-reactive protein. The investigators remarked that “This suggests that patients with [end-stage renal disease] may benefit from the anti-inflammatory effects of NAC” (Saddadi 2014). Other evidence suggests that NAC may be useful in treating nephrotoxicity caused by the chemotherapeutic drug ifosfamide (Ifex) in children (Hanly 2013).

Magnesium

High blood pressure can considerably compromise kidney health (Rasu 2007), and magnesium has been shown to reduce blood pressure at intake levels of 500–1000 mg daily (Houston 2011). Moreover, magnesium improves the performance of blood pressure-lowering drugs and may improve the function of the important lining of blood vessels, the endothelium (Barbagallo 2010; Houston 2011; Kisters 2011). Magnesium deficiency is associated with diabetes and metabolic syndrome, both of which are risk factors for kidney disease (Kurella 2005; Kabir 2012; Chaudhary 2010; Munekage 2012; Dong 2011; Mirmiran 2012). In addition, magnesium-potassium citrate has been studied as a urinary alkalinizer to prevent renal stone formation (Jaipakdee 2004). However, the kidneys are the major route by which excess magnesium is excreted from the body. Magnesium levels may increase when the eGFR falls below approximately 30 mL/min. It is not as certain what the impact of less severe kidney impairment (eg, eGFR > 30) will be, so individuals with existing kidney disease should consult with their healthcare provider before taking magnesium (Cunningham 2012; Mountokalakis 1990).

Vitamin E

In individuals undergoing coronary imaging studies, seven days of prophylactic (preventive) treatment with 350 mg alpha-tocopherol or 300 mg gamma-tocopherol, along with intravenous saline, reduced the incidence of contrast-induced acute kidney injury (Tasanarong 2013). Vitamin E supplementation, in combination with pravastatin (Pravachol) and a homocysteine-lowering combination of the B vitamins folic acid, B6, and B12, improved measures of cardiovascular health and reduced albumin loss from the kidneys compared with a control group (Veringa 2012). In a pilot trial in patients with non-diabetic CKD, vitamin E reduced asymmetric dimethylarginine, an inhibitor of endothelial nitric oxide synthase that is elevated in patients with CKD and a proposed cardiovascular risk factor (Saran 2003).

Additional Interventions

The agents described in this section have been the focus of preclinical research aimed at determining whether they have the potential to support kidney health. However, these agents have not yet been studied in human clinical trials specifically in the context of kidney health.

Silymarin. Silymarin is extracted from the seeds and fruit of milk thistle (Silybum marianum), a plant rich in the flavonolignans silychristin, silydianin, and silybin, which are collectively known as the silymarin complex(Kohno 2002; Abenavoli 2010). Silymarin has antioxidant, toxin-blocking properties, and is recognized as a safe and well-tolerated natural compound (Post-White 2007; Wojcikowski 2007).

In experimental models, silymarin, when administered in doses equivalent to about 220 mg to 2.2 g daily for an adult human, protected kidney cells and rat kidneys from damage caused by toxin overdose (Rastogi 2001; Soto 2010). Similarly, silymarin protected against ischemia-reperfusion injury, a pro-oxidative state and a major contributor to acute kidney injury, when given to rats at a dose equivalent to about 567 mg for an adult human (Senturk 2008). Also, researchers found that silymarin could entirely prevent injury to renal cells incubated with elevated glucose concentrations while blocking production of oxidative stress markers (Wenzel 1996).

Silymarin is also protective against several classes of nephrotoxic drugs, in particular cisplatin and doxorubicin. These are two of the most potent chemotherapeutic drugs, but also two of the most damaging to the kidney owing to the oxidative damage and severe inflammation they produce (Launay-Vacher 2008; Machado 2008; Yao 2007). Several research groups have found that, in animal models, silymarin and its components reduce and can even entirely prevent the kidney damage caused by these drugs (Bokemeyer 1996; Gaedeke 1996; Karimi 2005; El-Shitany 2008).

Resveratrol. Resveratrol, a natural phytochemical, belongs to a class of compounds known as polyphenols. Sources of resveratrol include Polygonum cuspidatum (Japanese knotweed), grapes, peanuts, berries, and red wine (Tang 2014). Resveratrol may hold promise as a treatment for CKD via modulation of several cellular pathways involved in kidney damage. For example, resveratrol inhibits nuclear factor-kappa B, a major coordinator of inflammatory processes, which are involved in kidney damage. Also, resveratrol is a potent inhibitor of oxidative stress, which is also an important contributor to kidney damage (Saldanha 2013). In animal models, resveratrol treatment, at a dose roughly equivalent to 56 mg for an adult human, has been shown to inhibit renal oxidative stress, improve kidney circulation, and increase survival in sepsis-related acute kidney injury (Holthoff 2012). Resveratrol has also been shown to reduce ischemia-reperfusion injury in rat kidneys (Bertelli 2002). In diabetic rats, resveratrol doses corresponding to about 56 mg for an adult human normalized creatinine clearance (a measure of renal function), attenuated several markers of oxidative damage in kidney tissue, and improved levels of antioxidant enzymes and vitamins C and E (Palsamy 2011). Human equivalent doses of resveratrol ranging from about 90–227 mg have been shown to reduce acute kidney injury due to cisplatin, doxorubicin, gentamicin, or arsenic toxicity in laboratory and animal models (Zhang 2014; Valentovic 2014; Oktem 2012; Silan 2007). Other evidence from animal models shows that resveratrol can protect against drug-induced and sepsis-related kidney injury as well as kidney injury related to ureteral obstruction (Kitada 2013).

Green tea. Green tea, in the form of the beverage or an extract, as well as the isolated green tea polyphenol epigallocatechin gallate (EGCG), have reduced the nephrotoxicity of the medications gentamycin, cisplatin, and cyclosporine in animal models. Doses used in these studies ranged from the equivalent of about 1.1 g to about 3.4 g of green tea for an adult human (Abdel-Raheem 2010; Khan 2009; Shin, Kwon 2012; Sahin 2010). In addition, green tea was shown to protect against kidney damage in rats with diabetic nephropathy (Yokozawa 2005). EGCG combined with alpha-lipoic acid reduced inflammatory changes induced by AGEs in human kidney cells (Leu 2013).

Curcumin. Curcumin, an extract from the spice turmeric, has been shown to reduce the nephrotoxicity of the medications gentamycin, cisplatin, doxorubicin, chloroquine (Aralen), and cyclosporine, as well as the heavy metals cadmium and mercury in animal models. In animal models of diabetic nephropathy, a dose of curcumin equivalent to about 1.1 g for an adult human prevented the progression of renal disease (Trujillo 2013).

Alpha-lipoic acid. Sulfur-containing compounds can form complexes with toxic heavy metals. Alpha-lipoic acid, a sulfur-containing antioxidant, has been shown to aid in the removal of a number of toxic metals such as cadmium, lead, cobalt, and nickel in laboratory models (Patrick 2002). Alpha-lipoic acid injections reduced cadmium-catalyzed oxidative stress and increased the activity of the antioxidant enzyme catalase in rat kidneys (Veljkovic 2012). Alpha-lipoic acid reduces the nephrotoxicity of chemotherapy medications like cisplatin and doxorubicin in animal models (Malarkodi 2003; Bae 2009), and helps preserve renal function in animal models of diabetic nephropathy (Feng 2013). It may also protect against acute kidney injury caused by sepsis in animal models (Li 2014).

Benfotiamine. Benfotiamine, a fat-soluble form of thiamine (vitamin B1), inhibits the formation of AGEs. Benfotiamine has been studied, mostly in laboratory settings and in animals, for its ability to mitigate the effects of high blood sugar on the nervous system, kidneys, and eyes (Balakumar 2010). In animals, it has been demonstrated to reduce AGE formation and content in the kidneys at doses ranging from a human equivalent of about 795 mg to about 1.1 g daily (Karachalias 2010; Kihm 2011); protect against kidney damage during peritoneal dialysis (Kihm 2011); and diminish the nephrotoxic effects of the chemotherapy drug cisplatin (Harisa 2013). In diabetic rodents, benfotiamine inhibited the development of microalbuminuria (Babaei-Jadidi 2003).

Taurine. Taurine is a sulfur-containing amino acid. In animal models, taurine has been shown to reduce renal toxicity caused by cadmium, acetaminophen, and AGEs associated with diabetes (Das 2012). Evidence from an animal model suggest that taurine may protect kidney tissue from injury induced by alcohol metabolism (Latchoumycandane 2014). Another animal experiment showed that taurine protected rat kidneys from damage caused by 21 days of nicotine injections. The dose of taurine used in this study corresponded to roughly 567 mg for an adult human (Sener 2005).

Arginine. Arginine is a natural precursor to nitric oxide, a compound that promotes blood flow and is often deficient in CKD patients. This deficiency may be a result of ineffective arginine synthesis in chronically damaged kidneys. Supplementation with arginine in a rat model of hypertension has improved endothelial function (Johnson 2005).

A.D.A.M. MedlinePlus web page. Acidosis. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0002164/. Last updated 11/7/2013a. Accessed 10/21/2014.

A.D.A.M. MedlinePlus web page. BUN – blood test: Blood urea nitrogen. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0003945/. Last updated 4/29/2013b. Accessed 10/21/2014.

A.D.A.M. MedlinePlus web page. Urine concentration test. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/003608.htm. Last updated 8/25/2013c. Accessed 10/21/2014.

Abdel-Raheem IT, El-Sherbiny GA, Taye A. Green tea ameliorates renal oxidative damage induced by gentamicin in rats. Pakistan journal of pharmaceutical sciences. Jan 2010;23(1):21-28.

Abenavoli L, Capasso R, Milic N, Capasso F. Milk thistle in liver diseases: past, present, future. Phytother Res. 2010;24(10):1423-32.

Adelstein RS, Sellers JR. Effects of calcium on vascular smooth muscle contraction. The American journal of cardiology. Jan 30 1987;59(3):4b-10b.

Agre P, King LS, Yasui M, Guggino WB, Ottersen OP, Fujiyoshi Y, . . . Nielsen S. Aquaporin water channels--from atomic structure to clinical medicine. The Journal of physiology. Jul 1 2002;542(Pt 1):3-16.

AHA. American Heart Association. Kidney Damage and High Blood Pressure. Available at: http://www.heart.org/HEARTORG/Conditions/HighBloodPressure/WhyBloodPressureMatters/Kidney-Damage-and-High-Blood-Pressure_UCM_301825_Article.jsp. Last updated 9/11/2014a. Accessed 8/10/2014.

AHA. American Heart Association. Myths About High Blood Pressure. Available at: http://www.heart.org/HEARTORG/Conditions/HighBloodPressure/AboutHighBloodPressure/Myths-About-High-Blood-Pressure_UCM_430836_Article.jsp. Last updated 8/12/2014b. Accessed 10/21/2014.

Akinwusi PO, Oluyombo R, Ogunro PS, Adeniji AO, Okunola OO, Ayodele OE. Low dose aspirin therapy and renal function in elderly patients. International journal of general medicine. 2013;6:19-24.

Al-Awqati Q, Barasch J, Goldman L (ed.), SchaferAI  (ed.). Goldman's Cecil Medicine, Twenty-Fourth Edition. Chapter 117: Structure and Function of the Kidneys; 716-720. Copyright 2012 Saunders, an imprint of Elsevier, Inc. Available at: www.clinicalkey.com Accessed: 6/9/2014.

Alpern RJ, Sakhaee K. The clinical spectrum of chronic metabolic acidosis: homeostatic mechanisms produce significant morbidity. American journal of kidney diseases : the official journal of the National Kidney Foundation. Feb 1997;29(2):291-302.

Amodu A, Abramowitz MK. Dietary acid, age, and serum bicarbonate levels among adults in the United States. Clinical journal of the American Society of Nephrology : CJASN. Dec 2013;8(12):2034-2042.

Anders HJ, Andersen K, Stecher B. The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease. Kidney international. Jun 2013;83(6):1010-1016.

Angelidis C, Deftereos S, Giannopoulos G, Anatoliotakis N, Bouras G, Hatzis G, . . . Cleman MW. Cystatin C: an emerging biomarker in cardiovascular disease. Current topics in medicinal chemistry. 2013;13(2):164-179.

Arimoto T, Takeishi Y, Niizeki T, et al. Cystatin C, a novel measure of renal function, is an independent predictor of cardiac events in patients with heart failure. J. Card. Fail. 2005;11(8):595–601

Arora P. Medscape. Chronic Kidney Disease. Available at: http://emedicine.medscape.com/article/238798-overview. Last updated 2/18/2014. Accessed 6/18/2014.

Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, and Thornalley PJ. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes. 2003;52(8):2110–20

Bae EH, Lee J, Ma SK, et al. alpha-Lipoic acid prevents cisplatin-induced acute kidney injury in rats. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 2009;24(9):2692–700

Balakumar P, Bishnoi HK, Mahadevan N. Telmisartan in the management of diabetic nephropathy: a contemporary view. Current diabetes reviews. May 2012;8(3):183-190.

Balakumar P, Rohilla A, Krishan P, Solairaj P, and Thangathirupathi A. The multifaceted therapeutic potential of benfotiamine. Pharmacol. Res. 2010;61(6):482–8

Bankir L, Bouby N, Trinh-Trang-Tan MM, Ahloulay M, Promeneur D. Direct and indirect cost of urea excretion. Kidney international. Jun 1996;49(6):1598-1607.

Barbagallo M, Dominguez LJ, Galioto A, Pineo A, Belvedere M. Oral magnesium supplementation improves vascular function in elderly diabetic patients. Magnesium research : official organ of the International Society for the Development of Research on Magnesium. Sep 2010;23(3):131-137.

Bashir B, Sharma SG, Stein HD, Sirota RA, D'Agati VD. Acute kidney injury secondary to exposure to insecticides used for bedbug (Cimex lectularis) control. American journal of kidney diseases : the official journal of the National Kidney Foundation. Nov 2013;62(5):974-977.

Baynes JW, Dominiczak MH. Medical Biochemistry, Fourth Edition. Chapter 23: Role of Kidneys in Metabolism; 309-319. Copyright 2014, Elsevier Limited. Available at: www.clinicalkey.com. Accessed 6/9/2014.

Bellizzi V. Low-protein diet or nutritional therapy in chronic kidney disease? Blood purification. 2013;36(1):41–6

Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P. Acute renal failure - definition, outcome measures, animal models, fluid therapy and information technology needs: the Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Critical care (London, England). Aug 2004;8(4):R204-212.

Bertelli AAE, Migliori M, Panichi V. Resveratrol, a component of wine and grapes, in the prevention of kidney disease. Ann N Y Acad Sci. 2002;957:230–8

Bird ST, Etminan M, Brophy JM, Hartzema AG, Delaney JA. Risk of acute kidney injury associated with the use of fluoroquinolones. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. Jul 9 2013;185(10):E475-482.

Bohlender JM, Franke S, Stein G, and Wolf G. Advanced glycation end products and the kidney. American journal of physiology. Renal physiology. 2005;289(4):F645–59

Bokemeyer C, Fels LM, Dunn T, Voigt W, Gaedeke J, Schmoll HJ, . . . Lentzen H. Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity. British journal of cancer. Dec 1996;74(12):2036-2041.

Bolignano D, Mattace-Raso F, Sijbrands EJG, and Zoccali C. The aging kidney revisited: a systematic review. Ageing Res Rev. 2014;14:65–80

Bolisetty S, Agarwal A. Urine albumin as a biomarker in acute kidney injury. American journal of physiology. Renal physiology. Mar 2011;300(3):F626-627.

Brodin EE, Braekkan SK, Vik A, Brox J, Hansen JB. Cystatin C is associated with risk of venous thromboembolism in subjects with normal kidney function--the Tromso study. Haematologica. Jul 2012;97(7):1008-1013.

Busch M, Franke S, Ruster C, and Wolf G. Advanced glycation end-products and the kidney. Eur J Clin Invest. 2010;40(8):742–55

Cacciapuoti F. Lowering homocysteine levels may prevent cardiovascular impairments? Possible therapeutic behaviors. Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis. Dec 2012;23(8):677-679.

Calhoun DA. Hyperaldosteronism as a common cause of resistant hypertension. Annu. Rev. Med. 2013;64:233–47

Ceglia L, Harris SS, Abrams SA, Rasmussen HM, Dallal GE, Dawson-Hughes B. Potassium bicarbonate attenuates the urinary nitrogen excretion that accompanies an increase in dietary protein and may promote calcium absorption. The Journal of clinical endocrinology and metabolism. Feb 2009;94(2):645-653.

Chao MC, Hu SL, Hsu HS, Davidson LE, Lin CH, Li CI, . . . Lin WY. Serum homocysteine level is positively associated with chronic kidney disease in a Taiwan Chinese population. Journal of nephrology. Jan 16 2014.

Chaudhary DP, Sharma R, Bansal DD. Implications of magnesium deficiency in type 2 diabetes: a review. Biological trace element research. May 2010;134(2):119-129.

Chen J, Muntner P, Hamm LL, et al. The Metabolic Syndrome and Chronic Kidney Disease in U.S. Adults. Ann Intern Med. 2004;140(3):167–74

Chen Y, Abbate M, Tang L. L-Carnitine supplementation for adults with end-stage kidney disease requiring maintenance hemodialysis: a systematic review and meta-analysis. American Journal of Clinical Nutrition. 2014;99(2):408–22

Cheungpasitporn W, Thongprayoon C, OA OC, Edmonds PJ, Kittanamongkolchai W, Erickson SB. Associations of Sugar and Artificially Sweetened Soda and Chronic Kidney Disease: A Systematic Review and Meta-analysis. Nephrology (Carlton, Vic.). Sep 23 2014.

Chrysohoou C, Panagiotakos DB, Pitsavos C, Skoumas J, Zeimbekis A, Kastorini CM, Stefanadis C. Adherence to the Mediterranean diet is associated with renal function among healthy adults: the ATTICA study. Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. May 2010;20(3):176-184.

Cohen D, Goldberg M, Gulati A, and Ferri FF. First Consult. Chronic kidney disease. Available at: www.clinicalkey.com. Last updated 5/5/2010. Accessed 6/12/2014. 2010; Available at: [Accessed August 3, 2014].

Cravedi P, Remuzzi G. Pathophysiology of proteinuria and its value as an outcome measure in chronic kidney disease. Br J Clin Pharmacol. 2013;76(4):516–23

Cunningham J, Rodríguez M, Messa P. Magnesium in chronic kidney disease Stages 3 and 4 and in dialysis patients. Clinical Kidney Journal. 2012;5(Suppl 1):i39-i51.

Curiel RV, Katz JD. Mitigating the cardiovascular and renal effects of NSAIDs. Pain Med. 2013;14 Suppl 1:S23–8

Das J, Roy A, Sil PC. Mechanism of the protective action of taurine in toxin and drug induced organ pathophysiology and diabetic complications: a review. Food Funct. 2012;3(12):1251–64

Dash A, Maiti R, Bandakkanavar TK, Bhaskar A, Prakash J, Pandey BL. Prophylactic Add-on Antiplatelet Therapy in Chronic Kidney Disease With Type 2 Diabetes Mellitus: Comparison Between Clopidogrel and Low-dose Aspirin. International journal of preventive medicine. Aug 2013;4(8):902-910.

Davis KE, Prasad C, Vijayagopal P, Juma S, Imrhan V. Advanced Glycation End Products, Inflammation, and Chronic Metabolic Diseases:Links in a Chain? Critical reviews in food science and nutrition. Sep 26 2014.

De la Fuente M, Hernanz A, Viniegra S, Miquel J. Sulfur-containing antioxidants increase in vitro several functions of lymphocytes from mice. International immunopharmacology. Jun 2011;11(6):661-669.

Debreceni B, Debreceni L. The role of homocysteine-lowering B-vitamins in the primary prevention of cardiovascular disease. Cardiovascular therapeutics. Jun 2014;32(3):130-138.

Dempsher J. The nerve impulse in the axon--a new theory. Acta biotheoretica. 1981;30(2):121-137.

Di Vito R, Sirolli V, Amoroso L, Bonomini M. [Nephrotoxicity induced by chemotherapy]. Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia. May-Jun 2011;28(3):296-304.

Dong JY, Xun P, He K, Qin LQ. Magnesium intake and risk of type 2 diabetes: meta-analysis of prospective cohort studies. Diabetes care. Sep 2011;34(9):2116-2122.

Downie WW. Prostaglandins and NSAID in the kidney. The Journal of rheumatology. Supplement. Mar 1991;28:19-21.

Duranton F, Cohen G, De Smet R, Rodriguez M, Jankowski J, Vanholder R, Argiles A. Normal and pathologic concentrations of uremic toxins. Journal of the American Society of Nephrology : JASN. Jul 2012;23(7):1258-1270.

Eknoyan G. Obesity and chronic kidney disease. Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia. 2011;31(4):397-403.

Eknoyan G, Latos DL, Lindberg J, National Kidney Foundation Carnitine Consensus Conference. Practice recommendations for the use of L-carnitine in dialysis-related carnitine disorder. National Kidney Foundation Carnitine Consensus Conference. Am J Kidney Dis. 2003;41(4):868–76.

Elsevier BV. First Consult. Nephrolithiasis. Available at: www.clinicalkey.com. Last updated 7/13/2012. Accessed 6/12/2014.

El-Shitany NA, El-Haggar S, El-desoky K. Silymarin prevents adriamycin-induced cardiotoxicity and nephrotoxicity in rats. Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association. Jul 2008;46(7):2422-2428.

Epstein M. Aldosterone as a determinant of cardiovascular and renal dysfunction. Journal of the Royal Society of Medicine. Aug 2001;94(8):378-383.

Evans M, Fored CM, Bellocco R, Fitzmaurice G, Fryzek JP, McLaughlin JK, . . . Elinder CG. Acetaminophen, aspirin and progression of advanced chronic kidney disease. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. Jun 2009;24(6):1908-1918.

Evenepoel P, Meijers BK, Bammens BR, Verbeke K. Uremic toxins originating from colonic microbial metabolism. Kidney international. Supplement. Dec 2009(114):S12-19.

Eyre S, Attman PO, Haraldsson B. Positive effects of protein restriction in patients with chronic kidney disease. Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. May 2008;18(3):269-280.

Fadel FI, Elshamaa MF, Essam RG, Elghoroury EA, El-Saeed GS, El-Toukhy SE, Ibrahim MH. Some amino acids levels: glutamine,glutamate, and homocysteine, in plasma of children with chronic kidney disease. International journal of biomedical science : IJBS. Mar 2014;10(1):36-42.

Faloon W. FDA Approves Deadly Drugs, Delays Lifesaving Therapies. Life Extension Magazine. http://www.lifeextension.com//Magazine/2004/5/awsi/Page-01. May 2004. Accessed 1/26/2015.

Feng B, Yan X-F, Xue J-L, Xu L, and Wang H. The Protective Effects of α-Lipoic Acid on Kidneys in Type 2 Diabetic Goto-Kakisaki Rats via Reducing Oxidative Stress. Int J Mol Sci. 2013;14(4):6746–56

Fenton TR, Tough SC, Lyon AW, Eliasziw M, Hanley DA. Causal assessment of dietary acid load and bone disease: a systematic review & meta-analysis applying Hill's epidemiologic criteria for causality. Nutrition journal. 2011;10:41.

Ferri FF. Ferri's Clinical Advisor. Chronic Kidney Disease. Available at: www.clinicalkey.com. Copyright © 2014c. Accessed 6/12/2014.

Ferri FF. Ferri's Clinical Advisor. Acute Kidney Injury. Available at: www.clinicalkey.com. Copyright © 2014a. Accessed 6/12/2014.

Ferri FF. Ferri's Clinical Advisor. Polycystic Kidney Disease. Available at: www.clinicalkey.com. Copyright © 2014b. Accessed 6/12/2014.

Finkielstein VA, Goldfarb DS. Strategies for preventing calcium oxalate stones. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne. May 9 2006;174(10):1407-1409.

Fjellstedt E, Denneberg T, Jeppsson JO, Tiselius HG. A comparison of the effects of potassium citrate and sodium bicarbonate in the alkalinization of urine in homozygous cystinuria. Urological research. Oct 2001;29(5):295-302.

Fliser D, Ritz E. Serum cystatin C concentration as a marker of renal dysfunction in the elderly. American journal of kidney diseases : the official journal of the National Kidney Foundation. Jan 2001;37(1):79-83.

Forbes JM, Cooper ME, Oldfield MD, Thomas MC. Role of advanced glycation end products in diabetic nephropathy. Journal of the American Society of Nephrology : JASN. Aug 2003;14(8 Suppl 3):S254-258.

Fortin MC, Amyot SL, Geadah D, Leblanc M. Serum concentrations and clearances of folic acid and pyridoxal-5-phosphate during venovenous continuous renal replacement therapy. Intensive care medicine. Jun 1999;25(6):594-598.

Fouad AA, Al-Sultan AI, Refaie SM, and Yacoubi MT. Coenzyme Q10 treatment ameliorates acute cisplatin nephrotoxicity in mice. Toxicology. 2010;274(1-3):49–56

Frassetto L, Morris RC, Jr., Sellmeyer DE, Todd K, Sebastian A. Diet, evolution and aging--the pathophysiologic effects of the post-agricultural inversion of the potassium-to-sodium and base-to-chloride ratios in the human diet. European journal of nutrition. Oct 2001;40(5):200-213.

Frassetto LA, Morris RC, Jr., Sebastian A. Effect of age on blood acid-base composition in adult humans: role of age-related renal functional decline. The American journal of physiology. Dec 1996;271(6 Pt 2):F1114-1122.

Frassetto LA, Morris RCJ, and Sebastian A. Dietary sodium chloride intake independently predicts the degree of hyperchloremic metabolic acidosis in healthy humans consuming a net acid-producing diet. American journal of physiology. Renal physiology. 2007;293(2):F521–5

Fung TT, Chiuve SE, McCullough ML, Rexrode KM, Logroscino G, Hu FB. Adherence to a DASH-style diet and risk of coronary heart disease and stroke in women. Archives of internal medicine. Apr 14 2008;168(7):713-720.

Gaedeke J, Fels LM, Bokemeyer C, Mengs U, Stolte H, Lentzen H. Cisplatin nephrotoxicity and protection by silibinin. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. Jan 1996;11(1):55-62.

Gazdíková K, Gvozdjáková A, Kucharská J, Spustová V, Braunová Z, and Dzúrik R. Oxidative stress and plasma concentrations of coenzyme Q10, alpha-tocopherol, and beta-carotene in patients with a mild to moderate decrease of kidney function. Nephron. 2001;88(3):285

Geleijnse JM, Giltay EJ, Grobbee DE, Donders ART, and Kok FJ. Blood pressure response to fish oil supplementation: metaregression analysis of randomized trials. J. Hypertens. 2002;20(8):1493–9

Genazzani AR, Mannella P, Simoncini T. Drospirenone and its antialdosterone properties. Climacteric : the journal of the International Menopause Society. Feb 2007;10 Suppl 1:11-18.

GHR. Genetics Home Reference. Conditions page. Renal tubular dysgenesis. Available at: http://ghr.nlm.nih.gov/condition/renal-tubular-dysgenesis. 1/5/2015. Accessed 1/6/2015. 2015.

Gooch K, Culleton BF, Manns BJ, Zhang J, Alfonso H, Tonelli M, . . . Hemmelgarn BR. NSAID use and progression of chronic kidney disease. The American journal of medicine. Mar 2007;120(3):280.e281-287.

Gopinath B, Harris DC, Flood VM, Burlutsky G, and Mitchell P. Consumption of long-chain n-3 PUFA, α-linolenic acid and fish is associated with the prevalence of chronic kidney disease. Br J Nutr. 2011;105(9):1361–8

Goraya N, Simoni J, Jo C, Wesson DE. Dietary acid reduction with fruits and vegetables or bicarbonate attenuates kidney injury in patients with a moderately reduced glomerular filtration rate due to hypertensive nephropathy. Kidney international. Jan 2012;81(1):86-93.

Goraya N, Wesson DE. Dietary management of chronic kidney disease: protein restriction and beyond. Current opinion in nephrology and hypertension. Nov 2012;21(6):635-640.

Goraya N, Wesson DE. Does correction of metabolic acidosis slow chronic kidney disease progression? Current opinion in nephrology and hypertension. Mar 2013;22(2):193-197.

Gowda S, Desai PB, Kulkarni SS, Hull VV, Math AA, Vernekar SN. Markers of renal function tests. North American journal of medical sciences. Apr 2010;2(4):170-173.

Guarnieri G, Zanetti M, Vinci P, Cattin MR, Pirulli A, Barazzoni R. Metabolic syndrome and chronic kidney disease. Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. Sep 2010;20(5 Suppl):S19-23.

Gupta A, Biyani M, and Khaira A. Vancomycin nephrotoxicity: myths and facts. Neth J Med. 2011;69(9):379–83

Hall ME, do Carmo JM, da Silva AA, Juncos LA, Wang Z, Hall JE. Obesity, hypertension, and chronic kidney disease. International journal of nephrology and renovascular disease. 2014;7:75-88.

Hamilton KL, Butt AG. The molecular basis of renal tubular transport disorders. Comparative biochemistry and physiology. Part A, Molecular & integrative physiology. Jul 2000;126(3):305-321.

Hamm LL, Simon EE. Roles and mechanisms of urinary buffer excretion. The American journal of physiology. Oct 1987;253(4 Pt 2):F595-605.

Hanly L, Rieder MJ, Huang SH, Vasylyeva TL, Shah RK, Regueira O, Koren G. N-acetylcysteine rescue protocol for nephrotoxicity in children caused by ifosfamide. Journal of population therapeutics and clinical pharmacology = Journal de la therapeutique des populations et de la pharamcologie clinique. 2013;20(2):e132-145.

Harisa GI. Benfotiamine enhances antioxidant defenses and protects against cisplatin-induced DNA damage in nephrotoxic rats. J. Biochem. Mol. Toxicol. 2013;27(8):398–405

Hartweg J, Farmer AJ, Holman RR, and Neil HAW. Meta-analysis of the effects of n-3 polyunsaturated fatty acids on haematological and thrombogenic factors in type 2 diabetes. Diabetologia. 2007;50(2):250–8

Hataya Y, Igarashi S, Yamashita T, and Komatsu Y. Thyroid hormone replacement therapy for primary hypothyroidism leads to significant improvement of renal function in chronic kidney disease patients. Clinical and experimental nephrology. 2013;17(4):525–31

Hawley MA. The Kidney Transplant/Dialysis Association Patient Handbook. Chapter 1: Normal and Abnormal Kidney Function. Available at: http://msl1.mit.edu/ESD10/kidneys/HndbkHTML/ch1.htm. Accessed 1/6/2015. 2015.

Hazard PB, Griffin JP. Calculation of sodium bicarbonate requirement in metabolic acidosis. The American journal of the medical sciences. Jan-Feb 1982;283(1):18-22.

Heidet L, Gubler M-C. The renal lesions of Alport syndrome. J. Am. Soc. Nephrol. 2009;20(6):1210–5

Ho MJ, Bellusci A, Wright JM. Blood pressure lowering efficacy of coenzyme Q10 for primary hypertension. Cochrane Database Syst Rev. 2009;(4):CD007435

Hodgson JM, Watts GF, Playford DA, Burke V, and Croft KD. Coenzyme Q10 improves blood pressure and glycaemic control: a controlled trial in subjects with type 2 diabetes. Eur J Clin Nutr. 2002;56(11):1137–42

Hojs R, Bevc S, Antolinc B, Gorenjak M, Puklavec L. Serum cystatin C as an endogenous marker of renal function in the elderly. International journal of clinical pharmacology research. 2004;24(2-3):49-54.

Holthoff JH, Wang Z, Seely KA, Gokden N, and Mayeux PR. Resveratrol improves renal microcirculation, protects the tubular epithelium, and prolongs survival in a mouse model of sepsis-induced acute kidney injury. Kidney Int. 2012;81(4):370–8

Houston M. The role of magnesium in hypertension and cardiovascular disease. Journal of clinical hypertension (Greenwich, Conn.). Nov 2011;13(11):843-847.

Huang X, Lindholm B, Stenvinkel P, Carrero JJ. Dietary fat modification in patients with chronic kidney disease: n-3 fatty acids and beyond. Journal of nephrology. Nov-Dec 2013;26(6):960-974.

Huang X, Jimenez-Moleon JJ, Lindholm B, et al. Mediterranean diet, kidney function, and mortality in men with CKD. Clinical journal of the American Society of Nephrology: CJASN. 2013;8(9):1548–55

IDF. International Diabetes Federation. The IDF consensus worldwide definition of the METABOLIC SYNDROME. Available at: http://www.idf.org/webdata/docs/IDF_Meta_def_final.pdf. Copyright 2006. Accessed 9/19/2014.

Ishikawa A, Homma Y. Beneficial effect of ubiquinol, the reduced form of coenzyme Q10, on cyclosporine nephrotoxicity. International braz j urol : official journal of the Brazilian Society of Urology. Mar-Apr 2012;38(2):230-234; discussion 234.

Jacob S, Hery M, Protois JC, Rossert J, Stengel B. Effect of organic solvent exposure on chronic kidney disease progression: the GN-PROGRESS cohort study. Journal of the American Society of Nephrology : JASN. Jan 2007;18(1):274-281.

Jaipakdee S, Prasongwatana V, Premgamone A, Reungjui S, Tosukhowong P, Tungsanga K, . . . Sriboonlue P. The effects of potassium and magnesium supplementations on urinary risk factors of renal stone patients. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. Mar 2004;87(3):255-263.

Jancova P, Anzenbacher P, Anzenbacherova E. Phase II drug metabolizing enzymes. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010;154(2):103–16

Jang SM, Cerulli J, Grabe DW, Fox C, Vassalotti JA, Prokopienko AJ, Pai AB. NSAID-Avoidance Education in Community Pharmacies for Patients at High Risk for Acute Kidney Injury, Upstate New York, 2011. Preventing chronic disease. 2014;11:E220.

Jin J, Sugerman DT. Salt in the Diet. JAMA. 2014;311(12):1265.

Johnson FK, Johnson RA, Peyton KJ, Durante W. Arginase inhibition restores arteriolar endothelial function in Dahl rats with salt-induced hypertension. American journal of physiology. Regulatory, integrative and comparative physiology. Apr 2005;288(4):R1057-1062.

Johnson DW, Jones GR, Mathew TH, et al. Chronic kidney disease and measurement of albuminuria or proteinuria: a position statement. Med J Aust. 2012;197(4):224–5

Joybari AY, Sarbaz S, Azadeh P, Mirafsharieh SA, Rahbari A, Farasatinasab M, Mokhtari M. Oxaliplatin-induced renal tubular vacuolization. The Annals of pharmacotherapy. Jun 2014;48(6):796-800.

Kabir MS, Dutta PK, Islam MN, Hasan MJ, Mondol G. Prevalence of risk factors of chronic kidney disease in adults. Mymensingh medical journal : MMJ. Oct 2012;21(4):605-610.

Kanda E, Ai M, Yoshida M, Kuriyama R, Shiigai T. High serum bicarbonate level within the normal range prevents the progression of chronic kidney disease in elderly chronic kidney disease patients. BMC nephrology. 2013;14:4.

Karachalias N, Babaei-Jadidi R, Rabbani N, and Thornalley PJ. Increased protein damage in renal glomeruli, retina, nerve, plasma and urine and its prevention by thiamine and benfotiamine therapy in a rat model of diabetes. Diabetologia. 2010;53(7):1506–16

Karalius VP, Shoham DA. Dietary sugar and artificial sweetener intake and chronic kidney disease: a review. Advances in chronic kidney disease. 2013;20(2):157–64

Karimi G, Ramezani M, Tahoonian Z. Cisplatin nephrotoxicity and protection by milk thistle extract in rats. Evidence-based complementary and alternative medicine : eCAM. Sep 2005;2(3):383-386.

Karsai T, Elodi P. Urea cycle enzymes in human liver: ontogenesis and interaction with the synthesis of pyrimidines and polyamines. Molecular and cellular biochemistry. 1982;43(2):105-110.

Kaur J. A comprehensive review on metabolic syndrome. Cardiology research and practice. 2014;2014:943162.

Kaysen GA. Albumin turnover in renal disease. Mineral and electrolyte metabolism. 1998;24(1):55-63.

Khalifeh N, Haider D, Horl WH. Natriuretic peptides in chronic kidney disease and during renal replacement therapy: an update. Journal of investigative medicine : the official publication of the American Federation for Clinical Research. Jan 2009;57(1):33-39.

Khan SA, Priyamvada S, Khan W, Khan S, Farooq N, and Yusufi ANK. Studies on the protective effect of green tea against cisplatin induced nephrotoxicity. Pharmacol. Res. 2009;60(5):382–91

Kihm LP, Müller-Krebs S, Klein J. Benfotiamine protects against peritoneal and kidney damage in peritoneal dialysis. J. Am. Soc. Nephrol. 2011;22(5):914–26

Kim AJ, Lim HJ, Ro H, Ko KP, Han SY, Chang JH, . . . Jung JY. Low-dose aspirin for prevention of cardiovascular disease in patients with chronic kidney disease. PloS one. 2014;9(8):e104179.

Kim CS, Kim SW. Vitamin D and chronic kidney disease. Korean J Intern Med. 2014;29(4):416

Kim EO, Lee IS, Choi YA, et al. Unresolved subclinical hypothyroidism is independently associated with progression of chronic kidney disease. Int J Med Sci. 2014;11(1):52–9

Kisters K. Oral magnesium supplementation improves borderline hypertension. Magnesium research : official organ of the International Society for the Development of Research on Magnesium. Mar 2011;24(1):17; author reply 18.

Kitada M, Koya D. Renal protective effects of resveratrol. Oxid Med Cell Longev. 2013;2013:568093.

Kohno H, Tanaka T, Kawabata K, Hirose Y, Sugie S, Tsuda H, Mori H. Silymarin, a naturally occurring polyphenolic antioxidant flavonoid, inhibits azoxymethane-induced colon carcinogenesis in male F344 rats. International journal of cancer. Journal international du cancer. Oct 10 2002;101(5):461-468.

Koppe L, Pillon NJ, Vella RE, Croze ML, Pelletier CC, Chambert S, . . . Soulage CO. p-Cresyl sulfate promotes insulin resistance associated with CKD. Journal of the American Society of Nephrology : JASN. Jan 2013;24(1):88-99.

Kopple JD. Obesity and chronic kidney disease. J Ren Nutr. 2010;20(5 Suppl):S29-30.

Kovesdy CP. Traditional and novel dietary interventions for preventing progression of chronic kidney disease. Journal of renal nutrition: the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2013;23(3):241–5

Kumar PA, Chitra PS, Reddy GB. Metabolic syndrome and associated chronic kidney diseases: nutritional interventions. Reviews in endocrine & metabolic disorders. 2013;14(3):273–86

Kurella M, Lo JC, Chertow GM. Metabolic syndrome and the risk for chronic kidney disease among nondiabetic adults. Journal of the American Society of Nephrology : JASN. Jul 2005;16(7):2134-2140.

Kurtz TW. Treating the metabolic syndrome: telmisartan as a peroxisome proliferator-activated receptor-gamma activator. Acta diabetologica. Apr 2005;42 Suppl 1:S9-16.

LaCivita C, Funkhouser E, Miller MJ, Ray MN, Saag KG, Kiefe CI, . . . Allison JJ. Patient-reported communications with pharmacy staff at community pharmacies: the Alabama NSAID Patient Safety Study, 2005-2007. Journal of the American Pharmacists Association : JAPhA. Sep-Oct 2009;49(5):e110-117.

Lacour B, Parry C, Drüeke T, et al. Pyridoxal 5'-phosphate deficiency in uremic undialyzed, hemodialyzed, and non-uremic kidney transplant patients. Clin. Chim. Acta. 1983;127(2):205–15

Lahoti TS, Patel D, Thekkemadom V, Beckett R, Ray SD. Doxorubicin-induced in vivo nephrotoxicity involves oxidative stress-mediated multiple pro- and anti-apoptotic signaling pathways. Current neurovascular research. Nov 2012;9(4):282-295.

Lameire N, Kruse V, Rottey S. Nephrotoxicity of anticancer drugs--an underestimated problem? Acta clinica Belgica. 2011;66(5):337–45

Lassus J, Harjola VP. Cystatin C: a step forward in assessing kidney function and cardiovascular risk. Heart Fail Rev. 2012;17(2):251–61

Latchoumycandane C, Nagy LE, McIntyre TM. Chronic ethanol ingestion induces oxidative kidney injury through taurine-inhibitable inflammation. Free radical biology & medicine. Apr 2014;69:403-416.

Launay-Vacher V, Rey JB, Isnard-Bagins C, et al. Prevention of cisplatin nephrotoxicity: state of the art and recommendations from the European Society of Clinical Pharmacy Special Interest Group on Cancer Care. Cancer Chemother Pharmacol. 2008;61(6):903-9.

Laville M, Nazare JA. Diabetes, insulin resistance and sugars. Obesity reviews : an official journal of the International Association for the Study of Obesity. Mar 2009;10 Suppl 1:24-33.

Le Vaillant J, Pellerin L, Brouard J, Eckart P. [Acetaminophen (paracetamol) causing renal failure: report on 3 pediatric cases]. Archives de pediatrie : organe officiel de la Societe francaise de pediatrie. Jun 2013;20(6):650-653.

Lee JT, Peng GS, Chen SY, Hsu CH, Lin CC, Cheng CA, . . . Lin JC. Homocysteine induces cerebral endothelial cell death by activating the acid sphingomyelinase ceramide pathway. Progress in neuro-psychopharmacology & biological psychiatry. Aug 1 2013;45:21-27.

Leslie RD, Cohen RM. Biologic variability in plasma glucose, hemoglobin A1c, and advanced glycation end products associated with diabetes complications. Journal of diabetes science and technology. Jul 2009;3(4):635-643.

Leu J-G, Lin C-Y, Jian J-H, Shih C-Y, and Liang Y-J. Epigallocatechin-3-gallate combined with alpha lipoic acid attenuates high glucose-induced receptor for advanced glycation end products (RAGE) expression in human embryonic kidney cells. An. Acad. Bras. Cienc. 2013;85(2):745–52

Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Annals of internal medicine. Mar 16 1999;130(6):461-470.

Li H, Weatherford ET, Davis DR, Keen HL, Grobe JL, Daugherty A, . . . Sigmund CD. Renal proximal tubule angiotensin AT1A receptors regulate blood pressure. American journal of physiology. Regulatory, integrative and comparative physiology. Oct 2011;301(4):R1067-1077.

Li G, Gao L, Jia J, Gong X, Zang B, and Chen W. α-Lipoic acid prolongs survival and attenuates acute kidney injury in a rat model of sepsis. Clin. Exp. Pharmacol. Physiol. 2014;41(7):459–68

Lin J, Fung TT, Hu FB, Curhan GC. Association of dietary patterns with albuminuria and kidney function decline in older white women: a subgroup analysis from the Nurses' Health Study. American journal of kidney diseases : the official journal of the National Kidney Foundation. Feb 2011;57(2):245-254.

Lin J, Judd S, Le A, et al. Associations of dietary fat with albuminuria and kidney dysfunction. American Journal of Clinical Nutrition. 2010;92(4):897–904

Linden E, Cai W, He JC, Xue C, Li Z, Winston J, . . . Uribarri J. Endothelial dysfunction in patients with chronic kidney disease results from advanced glycation end products (AGE)-mediated inhibition of endothelial nitric oxide synthase through RAGE activation. Clinical journal of the American Society of Nephrology : CJASN. May 2008;3(3):691-698.

Liu H, Peng Y, Li J, Liu Y, Cheng M, Yuan F, Liu F. [Stages of 3,547 patients with chronic kidney disease and relevant factor analysis]. Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences. May 2010;35(5):499-510.

Lyman JL. Blood urea nitrogen and creatinine. Emergency medicine clinics of North America. May 1986;4(2):223-233.

Machado V, Cabral A, Monteiro P, et al. Carvedilol as a protector against the cardiotoxicity induced by anthracyclines (doxorubicin). Rev Port Cardiol. 2008;27(10):1277-96.

Magill SB. Pathophysiology, diagnosis, and treatment of mineralocorticoid disorders. Comprehensive Physiology. Jul 2014;4(3):1083-1119.

Malarkodi KP, Balachandar AV, Sivaprasad R, and Varalakshmi P. Prophylactic effect of lipoic acid against adriamycin-induced peroxidative damages in rat kidney. Ren Fail. 2003;25(3):367–77

Mandayam S, Mitch WE. Dietary protein restriction benefits patients with chronic kidney disease. Nephrology (Carlton, Vic.). Feb 2006;11(1):53-57.

Mariani LH, White MT, Shults J, et al. Increasing use of vitamin D supplementation in the chronic renal insufficiency cohort study. Journal of renal nutrition: the official journal of the Council on Renal Nutrition of the National Kidney Foundation. 2014;24(3):186–93

Marnett LJ, Rowlinson SW, Goodwin DC, Kalgutkar AS, Lanzo CA. Arachidonic Acid Oxygenation by COX-1 and COX-2: MECHANISMS OF CATALYSIS AND INHIBITION. Journal of Biological Chemistry. August 13, 1999 1999;274(33):22903-22906.

Marre M, Garcia Puig J, Kokot F, Fernandez M, Jermendy G, Opie L, . . . Asmar R. Effect of indapamide SR on microalbuminuria--the NESTOR study (Natrilix SR versus Enalapril Study in Type 2 diabetic hypertensives with micrOalbuminuRia)--rationale and protocol for the main trial. Journal of hypertension. Supplement : official journal of the International Society of Hypertension. Mar 2003;21(1):S19-24.

McCarron DA. Dietary sodium and cardiovascular and renal disease risk factors: dark horse or phantom entry? Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. Jul 2008;23(7):2133-2137.

MedicineNet. Metabolic Syndrome: How is metabolic syndrome defined? Available at: http://www.medicinenet.com/metabolic_syndrome/article.htm#how_is_metabolic_syndrome_defined. 9/19/2014. Accessed 9/19/2014.

Mehdi U, Toto RD. Anemia, diabetes, and chronic kidney disease. Diabetes care. Jul 2009;32(7):1320-1326.

Mekki K, Bouzidi-bekada N, Kaddous A, Bouchenak M. Mediterranean diet improves dyslipidemia and biomarkers in chronic renal failure patients. Food & function. Oct 2010;1(1):110-115.

Menon V, Shlipak MG, Wang X, Coresh J, Greene T, Stevens L, . . . Sarnak MJ. Cystatin C as a risk factor for outcomes in chronic kidney disease. Annals of internal medicine. Jul 3 2007;147(1):19-27.

Meola M, Petrucci I. [Ultrasound and color Doppler in nephrology. Acute kidney injury]. Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia. Sep-Oct 2012;29(5):599-615.

Meyer BR. Renal function in aging. Journal of the American Geriatrics Society. Aug 1989;37(8):791-800.

Michael A, Faga T, Pisani A, and Riccio E. Molecular mechanisms of renal cellular nephrotoxicity due to radiocontrast media. 2014;2014:249810

Minich DM, Bland JS. Acid-alkaline balance: role in chronic disease and detoxification. Alternative therapies in health and medicine. Jul-Aug 2007;13(4):62-65.

Mirmiran P, Shab-Bidar S, Hosseini-Esfahani F, Asghari G, Hosseinpour-Niazi S, Azizi F. Magnesium intake and prevalence of metabolic syndrome in adults: Tehran Lipid and Glucose Study. Public health nutrition. Apr 2012;15(4):693-701.

Mithieux G, Andreelli F, Magnan C. Intestinal gluconeogenesis: key signal of central control of energy and glucose homeostasis. Current opinion in clinical nutrition and metabolic care. Jul 2009;12(4):419-423.

Mithieux G, Misery P, Magnan C, Pillot B, Gautier-Stein A, Bernard C, . . . Zitoun C. Portal sensing of intestinal gluconeogenesis is a mechanistic link in the diminution of food intake induced by diet protein. Cell Metab. Nov 2005;2(5):321-329.

Mithieux G. A novel function of intestinal gluconeogenesis: central signaling in glucose and energy homeostasis. Nutrition (Burbank, Los Angeles County, Calif.). Sep 2009;25(9):881-884.

Moe SM, Saifullah A, LaClair RE, Usman SA, Yu Z. A randomized trial of cholecalciferol versus doxercalciferol for lowering parathyroid hormone in chronic kidney disease. Clinical journal of the American Society of Nephrology : CJASN. Feb 2010;5(2):299-306.

Molnar MZ, Kalantar-Zadeh K, Lott EH, Lu JL, Malakauskas SM, Ma JZ, . . . Kovesdy CP. Angiotensin-converting enzyme inhibitor, angiotensin receptor blocker use, and mortality in patients with chronic kidney disease. Journal of the American College of Cardiology. Feb 25 2014;63(7):650-658.

Montemurno E, Cosola C, Dalfino G, Daidone G, De Angelis M, Gobbetti M, Gesualdo L. What Would You Like to Eat, Mr CKD Microbiota? A Mediterranean Diet, please! Kidney & blood pressure research. Jul 29 2014;39(2-3):114-123.

Mori TA, Burke V, Puddey I, et al. The effects of [omega]3 fatty acids and coenzyme Q10 on blood pressure and heart rate in chronic kidney disease: a randomized controlled trial. J. Hypertens. 2009;27(9):1863–72

Mountokalakis TD. Magnesium metabolism in chronic renal failure. Magnesium research : official organ of the International Society for the Development of Research on Magnesium. Jun 1990;3(2):121-127.

Munekage E, Takezaki Y, Hanazaki K. [Shortage and metabolic disturbance of magnesium in diabetic patients and significance of magnesium replacement therapy]. Clinical calcium. Aug 2012;22(8):1235-1242.

Murray MD, Brater DC. Renal toxicity of the nonsteroidal anti-inflammatory drugs. Annual review of pharmacology and toxicology. 1993;33:435-465.

Mussap M, Dalla Vestra M, Fioretto P, Saller A, Varagnolo M, Nosadini R, Plebani M. Cystatin C is a more sensitive marker than creatinine for the estimation of GFR in type 2 diabetic patients. Kidney international. Apr 2002;61(4):1453-1461.

Nakamura T, Fujiwara N, Kawagoe Y, Sugaya T, Ueda Y, Koide H. Effects of telmisartan and enalapril on renoprotection in patients with mild to moderate chronic kidney disease. European journal of clinical investigation. Sep 2010;40(9):790-796.

Nakamura S, Li H, Adijiang A, Pischetsrieder M, and Niwa T. Pyridoxal phosphate prevents progression of diabetic nephropathy. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 2007;22(8):2165–74

Nashar K, Egan BM. Relationship between chronic kidney disease and metabolic syndrome: current perspectives. Diabetes, metabolic syndrome and obesity : targets and therapy. 2014;7:421-435.

Navar LG. The kidney in blood pressure regulation and development of hypertension. The Medical clinics of North America. Sep 1997;81(5):1165-1198.

Nderitu P, Doos L, Jones PW, Davies SJ, Kadam UT. Non-steroidal anti-inflammatory drugs and chronic kidney disease progression: a systematic review. Family practice. Jun 2013;30(3):247-255.

Newman DJ, Thakkar H, Edwards RG, Wilkie M, White T, Grubb AO, Price CP. Serum cystatin C measured by automated immunoassay: a more sensitive marker of changes in GFR than serum creatinine. Kidney international. Jan 1995;47(1):312-318.

NHGRI. National Human Genome Research Institute. Health page. Learning About Autosomal Dominant Polycystic Kidney Disease. Last updated 4/18/2013. Accessed 1/6/2015.

NIH. National Institutes of Health. MedlinePlus. Kidney Disease: Early Detection and Treatment. Available at: http://www.nlm.nih.gov/medlineplus/magazine/issues/winter08/articles/winter08pg9-10.html. Copyright 2008. Accessed 9/19/2014.

NKDEP. National Kidney Disease Education Program. Laboratory Evaluation page. Reporting GFR. Available at: http://nkdep.nih.gov/lab-evaluation/gfr/reporting.shtml. Last updated 6/6/2012. Accessed 10/21/2014.

NKF. National Kidney Foundation. About Chronic Kidney Disease. Available at: http://www.kidney.org/kidneydisease/aboutckd. Copyright 2013a. Accessed 9/19/2014.

NKF. National Kidney Foundation. Acute Kidney Injury. Available at: http://www.kidney.org/news/kidneyCare/fall10/AcuteKidneyInjury. Copyright 2013b. Accessed 9/19/2014.

NKF. National Kidney Foundation. Statement on the release of ibuprofen as an over-the-counter medicine. Ad Hoc Committee for the National Kidney Foundation. American journal of kidney diseases : the official journal of the National Kidney Foundation. Jul 1985;6(1):4-6.

NKUDIC. National Kidney and Urologic Diseases Information Clearinghouse. Kidney Disease Statistics for the United States. Available at: http://kidney.niddk.nih.gov/kudiseases/pubs/kustats/#1. Last updated 11/15/2012. Accessed: 6/16/2014.

NKUDIC. National Kidney and Urologic Diseases Information Clearinghouse. Analgestic Nephropathy (Painkillers and the Kidneys). Available at: http://kidney.niddk.nih.gov/kudiseases/pubs/analgesicnephropathy/. Last updated 9/9/2010. Accessed 9/19/2014.

Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health. The American journal of clinical nutrition. August 1, 2008 2008;88(2):491S-499S.

Odermatt A. The Western-style diet: a major risk factor for impaired kidney function and chronic kidney disease. AJP: Renal Physiology. 2011;301(5):F919–31

Oh MY, Lee H, Kim JS, et al. Cystatin C, a novel indicator of renal function, reflects severity of cerebral microbleeds. BMC neurology. 2014;14(1):127

Oktem G, Uysal A, Oral O. Resveratrol attenuates doxorubicin-induced cellular damage by modulating nitric oxide and apoptosis. Exp. Toxicol. Pathol. 2012;64(5):471–9

Ordunez P, Martinez R, Reveiz L, Chapman E, Saenz C, Soares da Silva A, Becerra F. Chronic Kidney Disease Epidemic in Central America: Urgent Public Health Action Is Needed amid Causal Uncertainty. PLoS neglected tropical diseases. Aug 2014;8(8):e3019.

Ozkaya O, Genc G, Bek K, Sullu Y. A case of acetaminophen (paracetamol) causing renal failure without liver damage in a child and review of literature. Renal failure. 2010;32(9):1125-1127.

Pai AB. Keeping kidneys safe: The pharmacist's role in NSAID avoidance in high-risk patients. Journal of the American Pharmacists Association : JAPhA. Jan 1 2015;55(1):e15-25.

Palsamy P, Subramanian S. Resveratrol protects diabetic kidney by attenuating hyperglycemia-mediated oxidative stress and renal inflammatory cytokines via Nrf2-Keap1 signaling. Biochim Biophys Acta. 2011;1812(7):719–31

Park CW. Diabetic kidney disease: from epidemiology to clinical perspectives. Diabetes & metabolism journal. Aug 2014;38(4):252-260.

Pastore A, Noce A, Di Giovamberardino G, De Stefano A, Calla C, Zenobi R, . . . Di Daniele N. Homocysteine, cysteine, folate and vitamin B status in type 2 diabetic patients with chronic kidney disease. Journal of nephrology. Aug 6 2014.

Patrick L. Lead toxicity part II: the role of free radical damage and the use of antioxidants in the pathology and treatment of lead toxicity. Altern Med Rev. 2006;11(2):114–27

Patrick L. Mercury toxicity and antioxidants: Part 1: role of glutathione and alpha-lipoic acid in the treatment of mercury toxicity. Altern Med Rev. 2002;7(6):456–71

Penno G, Solini A, Bonora E, Fondelli C, Orsi E, Zerbini G, . . . Pugliese G. HbA1c variability as an independent correlate of nephropathy, but not retinopathy, in patients with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study. Diabetes care. Aug 2013;36(8):2301-2310.

Perneger TV, Whelton PK, Klag MJ. Risk of kidney failure associated with the use of acetaminophen, aspirin, and nonsteroidal antiinflammatory drugs. The New England journal of medicine. Dec 22 1994;331(25):1675-1679.

Post-White J, Ladas EJ, Kelly KM. Advances in the use of milk thistle (Silybum marianum). Integrative cancer therapies. Jun 2007;6(2):104-109.

Pozzi C, Marai P, Ponti R, Dell'Oro C, Sala C, Zedda S, Locatelli F. Toxicity in man due to stain removers containing 1,2-dichloropropane. British journal of industrial medicine. Nov 1985;42(11):770-772.

Prieto J, Qian C, Garcia N, Diez J, Medina JF. Abnormal expression of anion exchanger genes in primary biliary cirrhosis. Gastroenterology. Aug 1993;105(2):572-578.

PubMed Health. DASH Eating Plan. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0063068/. Last updated 6/11/2014. Accessed 10/21/2014.

Pushpakumar SB, Kundu S, Sen U. Endothelial dysfunction: The link between homocysteine and hydrogen sulfide. Current medicinal chemistry. Jul 6 2014.

Qin J, Wang H, Rets A, Harari S, Alexis H, Eid I, Pincus MR. Stability of BUN and creatinine determinations on the Siemens Advia 1800 analyzer. Journal of clinical laboratory analysis. Nov 2013;27(6):435-437.

Quigley R. Chronic kidney disease: highlights for the general pediatrician. International journal of pediatrics. 2012;2012:943904.

Radbill B, Murphy B, LeRoith D. Rationale and strategies for early detection and management of diabetic kidney disease. Mayo Clinic proceedings. Dec 2008;83(12):1373-1381.

Rahman S, Malcoun A. Nonsteroidal antiinflammatory drugs, cyclooxygenase-2, and the kidneys. Primary care. Dec 2014;41(4):803-821.

Raimundo M, Lopes JA. Metabolic syndrome, chronic kidney disease, and cardiovascular disease: a dynamic and life-threatening triad. Cardiology research and practice. 2011;2011:747861.

Ramezani A, Raj DS. The gut microbiome, kidney disease, and targeted interventions. Journal of the American Society of Nephrology : JASN. Apr 2014;25(4):657-670.

Rastogi R, Srivastava AK, Rastogi AK. Long term effect of aflatoxin B(1) on lipid peroxidation in rat liver and kidney: effect of picroliv and silymarin. Phytother Res. 2001;15(4):307–10

Rasu RS, Crawford T, Manley HJ, Balkrishnan R. Treatment of hypertension and diabetes mellitus in patients with chronic kidney disease: a review. Expert opinion on pharmacotherapy. Oct 2007;8(15):2543-2551.

Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. Dec 1988;37(12):1595-1607.

Rizzoli R. Dairy products, yogurts, and bone health. The American journal of clinical nutrition. May 2014;99(5 Suppl):1256s-1262s.

Rosner MH, Bolton WK. Renal function testing. Am. J. Kidney Dis. 2006;47(1):174–83

Rossi M, Johnson DW, Morrison M, Pascoe E, Coombes JS, Forbes JM, . . . Campbell KL. SYNbiotics Easing Renal failure by improving Gut microbiologY (SYNERGY): a protocol of placebo-controlled randomised cross-over trial. BMC nephrology. 2014;15:106.

Rush-Monroe K. Kidney Function Can Be Assessed by Measuring Cystatin C in Blood. University of California, San Francisco. http://www.ucsf.edu/news/2013/09/108666/relationship-kidney-function-estimates-risk-improves-measuring-cystatin-c-blood. 9/4/2013. Accessed 1/27/2015.

Rylander R, Tallheden T, Vormann J. Acid-base conditions regulate calcium and magnesium homeostasis. Magnesium research : official organ of the International Society for the Development of Research on Magnesium. Dec 2009;22(4):262-265.

Sabatino A, Regolisti G, Brusasco I, Cabassi A, Morabito S, Fiaccadori E. Alterations of intestinal barrier and microbiota in chronic kidney disease. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. Sep 4 2014.

Sabolić I. Common mechanisms in nephropathy induced by toxic metals. Nephron Physiol. 2006;104(3):p107–14

Saddadi F, Alatab S, Pasha F, Ganji MR, Soleimanian T. The effect of treatment with N-acetylcysteine on the serum levels of C-reactive protein and interleukin-6 in patients on hemodialysis. Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia. Jan 2014;25(1):66-72.

Sahin K, Tuzcu M, Gencoglu H, et al. Epigallocatechin-3-gallate activates Nrf2/HO-1 signaling pathway in cisplatin-induced nephrotoxicity in rats. Life Sci. 2010;87(7-8):240–5

Saifan C, Samarneh M, Shtaynberg N, Nasr R, El-Charabaty E, and El-Sayegh S. Treatment of confirmed B12 deficiency in hemodialysis patients improves Epogen® requirements. Int J Nephrol Renovasc Dis. 2013;6:89–93

Saldanha JF, Leal Vde O, Stenvinkel P, Carraro-Eduardo JC, and Mafra D. Resveratrol: why is it a promising therapy for chronic kidney disease patients? Oxid Med Cell Longev. 2013;2013:963217

Salerno MP, Piselli P, Rossi E, Favi E, Gargiulo A, Spagnoletti G, . . . Citterio F. Metabolic syndrome and cardiovascular disease in kidney transplantation. Transplantation proceedings. May 2011;43(4):1067-1068.

Salgado JV, Souza FL, Salgado BJ. How to understand the association between cystatin C levels and cardiovascular disease: Imbalance, counterbalance, or consequence? Journal of cardiology. Dec 2013;62(6):331-335.

Samuni Y, Goldstein S, Dean OM, and Berk M. The chemistry and biological activities of N-acetylcysteine. Biochim Biophys Acta. 2013;1830(8):4117–29

Sands JM, Bichet DG, American College of Physicians, American Physiological Society. Nephrogenic diabetes insipidus. Ann Intern Med. 2006;144(3):186–94

Sanghavi S, Vassalotti JA. Practical use of home blood pressure monitoring in chronic kidney disease. Cardiorenal medicine. Aug 2014;4(2):113-122.

Santos EL, de Picoli Souza K, da Silva ED, Batista EC, Martins PJ, D'Almeida V, Pesquero JB. Long term treatment with ACE inhibitor enalapril decreases body weight gain and increases life span in rats. Biochemical pharmacology. Oct 15 2009;78(8):951-958.

Saran R, Novak JE, Desai A. Impact of vitamin E on plasma asymmetric dimethylarginine (ADMA) in chronic kidney disease (CKD): a pilot study. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 2003;18(11):2415–20

Saric M, Piasek M. [Effects of sodium chloride on bone health]. Arhiv za higijenu rada i toksikologiju. Mar 2005;56(1):39-44.

Sato A, Yonekura I, Kaneko T, Koizumi T. [Renal disorders induced by organic solvents]. Sangyo igaku. Japanese journal of industrial health. Mar 1988;30(2):85-96.

Sato T, Ishikawa A, Homma Y. Effect of reduced form of coenzyme Q10 on cyclosporine nephrotoxicity. Exp Clin Transplant. 2013;11(1):17–20

Schmieder RE, Bakris G, Weir MR. Telmisartan in incipient and overt diabetic renal disease. Journal of nephrology. May-Jun 2011;24(3):263-273.

Schwalfenberg GK. The alkaline diet: is there evidence that an alkaline pH diet benefits health? Journal of environmental and public health. 2012;2012:727630.

Scialla JJ, Anderson CA. Dietary acid load: a novel nutritional target in chronic kidney disease? Advances in chronic kidney disease. Mar 2013;20(2):141-149.

Scialla JJ, Appel LJ, Astor BC, Miller ER, 3rd, Beddhu S, Woodward M, . . . Anderson CA. Estimated net endogenous acid production and serum bicarbonate in African Americans with chronic kidney disease. Clinical journal of the American Society of Nephrology : CJASN. Jul 2011;6(7):1526-1532.

Segal R, Lubart E, Leibovitz A, Iaina A, Caspi D. Renal effects of low dose aspirin in elderly patients. The Israel Medical Association journal : IMAJ. Oct 2006;8(10):679-682.

Seifter JL. Acid-base disorders. Chapter 120. Pages 741-753. In: Goldman’s Cecil Medicine. Published 12/31/2011. Available at: www.clinicalkey.com. Accessed 10/21/2014.

Sener G, Sehirli O, Ipci Y, Cetinel S, Cikler E, Gedik N, Alican I. Protective effects of taurine against nicotine-induced oxidative damage of rat urinary bladder and kidney. Pharmacology. Apr 2005;74(1):37-44.

Senturk H, Kabay S, Bayramoglu G, et al. Silymarin attenuates the renal ischemia/reperfusion injury-induced morphological changes in the rat kidney. World J Urol. 2008;26(4):401–7

Shepler B, Nash C, Smith C, Dimarco A, Petty J, and Szewciw S. Update on potential drugs for the treatment of diabetic kidney disease. Clin Ther. 2012;34(6):1237–46

Shin BC, Kwon YE, Chung JH, and Kim HL. The antiproteinuric effects of green tea extract on acute cyclosporine-induced nephrotoxicity in rats. Transplant. Proc. 2012;44(4):1080–2

Shin DH, Lee MJ, Kim SJ, et al. Preservation of renal function by thyroid hormone replacement therapy in chronic kidney disease patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 2012;97(8):2732–40

Shishehbor MH, Oliveira LP, Lauer MS, Sprecher DL, Wolski K, Cho L, . . . Hazen SL. Emerging cardiovascular risk factors that account for a significant portion of attributable mortality risk in chronic kidney disease. The American journal of cardiology. Jun 15 2008;101(12):1741-1746.

Shlipak MG, Matsushita K, Arnlov J, Inker LA, Katz R, Polkinghorne KR, . . . Gansevoort RT. Cystatin C versus creatinine in determining risk based on kidney function. The New England journal of medicine. Sep 5 2013;369(10):932-943.

Shlipak MG, Mattes MD, Peralta CA. Update on cystatin C: incorporation into clinical practice. American journal of kidney diseases : the official journal of the National Kidney Foundation. Sep 2013;62(3):595-603.

Siddarth M, Datta SK, Mustafa M, Ahmed RS, Banerjee BD, Kalra OP, Tripathi AK. Increased level of organochlorine pesticides in chronic kidney disease patients of unknown etiology: role of GSTM1/GSTT1 polymorphism. Chemosphere. Feb 2014;96:174-179.

Siddharth M, Datta SK, Bansal S, Mustafa M, Banerjee BD, Kalra OP, Tripathi AK. Study on organochlorine pesticide levels in chronic kidney disease patients: association with estimated glomerular filtration rate and oxidative stress. Journal of biochemical and molecular toxicology. Jun 2012;26(6):241-247.

Silan C, Uzun O, Comunoğlu NU, Gokçen S, Bedirhan S, and Cengiz M. Gentamicin-induced nephrotoxicity in rats ameliorated and healing effects of resveratrol. Biol. Pharm. Bull. 2007;30(1):79–83

Sipkens JA, Hahn N, van den Brand CS, Meischl C, Cillessen SA, Smith DE, . . . Niessen HW. Homocysteine-induced apoptosis in endothelial cells coincides with nuclear NOX2 and peri-nuclear NOX4 activity. Cell biochemistry and biophysics. Nov 2013;67(2):341-352.

Smets P, Meyer E, Maddens B, and Daminet S. Cushing's syndrome, glucocorticoids and the kidney. Gen. Comp. Endocrinol. 2010;169(1):1–10

Soto C, Pérez J, García V, Uría E, Vadillo M, and Raya L. Effect of silymarin on kidneys of rats suffering from alloxan-induced diabetes mellitus. Phytomedicine. 2010;17(14):1090–4

Soulage CO, Koppe L, Fouque D. Protein-bound uremic toxins...new targets to prevent insulin resistance and dysmetabolism in patients with chronic kidney disease. Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation. Nov 2013;23(6):464-466.

Stanton RC. Clinical challenges in diagnosis and management of diabetic kidney disease. American journal of kidney diseases : the official journal of the National Kidney Foundation. Feb 2014;63(2 Suppl 2):S3-21.

Starke A, Corsenca A, Kohler T, Knubben J, Kraenzlin M, Uebelhart D, . . . Ambuhl PM. Correction of metabolic acidosis with potassium citrate in renal transplant patients and its effect on bone quality. Clinical journal of the American Society of Nephrology : CJASN. Sep 2012;7(9):1461-1472.

Szczepańska-Konkel M, Dominiczak MH, JW B. Medical Biochemistry, Fourth Edition. Chapter 23: Role of Kidneys in Metabolism; 309-319. Copyright 2014, Elsevier Limited. Available at: www.clinicalkey.com Accessed 6/9/2014.

Tang PC, Ng YF, Ho S, Gyda M, Chan SW. Resveratrol and cardiovascular health - Promising therapeutic or hopeless illusion? Pharmacological research : the official journal of the Italian Pharmacological Society. Dec 2014;90c:88-115.

Tanner GA, Tanner JA. Citrate therapy for polycystic kidney disease in rats. Kidney international. Nov 2000;58(5):1859-1869.

Tanner GA. Potassium citrate/citric acid intake improves renal function in rats with polycystic kidney disease. Journal of the American Society of Nephrology : JASN. Jul 1998;9(7):1242-1248.

Tasanarong A, Vohakiat A, Hutayanon P, and Piyayotai D. New strategy of α- and γ-tocopherol to prevent contrast-induced acute kidney injury in chronic kidney disease patients undergoing elective coronary procedures. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 2013;28(2):337–44

Thomas MC, Forbes JM, Cooper ME. Advanced glycation end products and diabetic nephropathy. American journal of therapeutics. Nov-Dec 2005;12(6):562-572.

Thomas G, Sehgal AR, Kashyap SR, Srinivas TR, Kirwan JP, and Navaneethan SD. Metabolic syndrome and kidney disease: a systematic review and meta-analysis. Clinical journal of the American Society of Nephrology: CJASN. 2011;6(10):2364–73

Tian N, Rose RA, Jordan S, Dwyer TM, Hughson MD, and Manning RDJ. N-Acetylcysteine improves renal dysfunction, ameliorates kidney damage and decreases blood pressure in salt-sensitive hypertension. J. Hypertens. 2006;24(11):2263–70

Toto RD. Treatment of hypertension in chronic kidney disease. Seminars in nephrology. Nov 2005;25(6):435-439.

Trujillo J, Chirino YI, Molina-Jijon E, Anderica-Romero AC, Tapia E, and Pedraza-Chaverri J. Renoprotective effect of the antioxidant curcumin: Recent findings. Redox biology. 2013;1(1):448–56

Turnberg LA, Bieberdorf FA, Morawski SG, Fordtran JS. Interrelationships of chloride, bicarbonate, sodium, and hydrogen transport in the human ileum. The Journal of clinical investigation. Mar 1970;49(3):557-567.

Tyson CC, Nwankwo C, Lin PH, Svetkey LP. The Dietary Approaches to Stop Hypertension (DASH) eating pattern in special populations. Current hypertension reports. Oct 2012;14(5):388-396.

Underwood PC, Adler GK. The renin angiotensin aldosterone system and insulin resistance in humans. Current hypertension reports. Feb 2013;15(1):59-70.

Unwin RJ, Capasso G. The renal tubular acidoses. Journal of the Royal Society of Medicine. May 2001;94(5):221-225.

Upaganlawar A, Farswan M, Rathod S, and Balaraman R. Modification of biochemical parameters of gentamicin nephrotoxicity by coenzyme Q10 and green tea in rats. Indian J. Exp. Biol. 2006;44(5):416–8.

Uribarri J. Dietary phosphorus and kidney disease. Ann N Y Acad Sci. 2013;1301:11–9

Valentovic MA, Ball JG, Brown JM. Resveratrol attenuates cisplatin renal cortical cytotoxicity by modifying oxidative stress. Toxicol In Vitro. 2014;28(2):248–57

van den Berg E, Engberink MF, Brink EJ, van Baak MA, Joosten MM, Gans RO, . . . Bakker SJ. Dietary acid load and metabolic acidosis in renal transplant recipients. Clinical journal of the American Society of Nephrology : CJASN. Nov 2012;7(11):1811-1818.

van Dijk SC, Smulders YM, Enneman AW, Swart KM, van Wijngaarden JP, Ham AC, . . . van der Velde N. Homocysteine level is associated with aortic stiffness in elderly: cross-sectional results from the B-PROOF study. Journal of hypertension. May 2013;31(5):952-959.

van Guldener C. Why is homocysteine elevated in renal failure and what can be expected from homocysteine-lowering? Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association - European Renal Association. 2006;21(5):1161–6.

Vaziri ND. CKD impairs barrier function and alters microbial flora of the intestine: a major link to inflammation and uremic toxicity. Current opinion in nephrology and hypertension. Nov 2012;21(6):587-592.

Veljkovic AR, Nikolic RS, Kocic GM, et al. Protective effects of glutathione and lipoic acid against cadmium-induced oxidative stress in rat's kidney. Ren Fail. 2012;34(10):1281–7

Veringa SJE, Nanayakkara PWB, van Ittersum FJ. Effect of a treatment strategy consisting of pravastatin, vitamin E, and homocysteine lowering on arterial compliance and distensibility in patients with mild-to-moderate chronic kidney disease. Clin. Nephrol. 2012;78(4):263–72

Vilstrup H. Synthesis of urea after stimulation with amino acids: relation to liver function. Gut. Nov 1980;21(11):990-995.

Vitetta L, Gobe G. Uremia and chronic kidney disease: the role of the gut microflora and therapies with pro- and prebiotics. Molecular nutrition & food research. May 2013;57(5):824-832.

Vitetta L, Linnane AW, Gobe GC. From the gastrointestinal tract (GIT) to the kidneys: live bacterial cultures (probiotics) mediating reductions of uremic toxin levels via free radical signaling. Toxins. Nov 2013;5(11):2042-2057.

Vogelzang NJ. Nephrotoxicity from chemotherapy: prevention and management. Oncology (Williston Park, N.Y.). Oct 1991;5(10):97-102, 105; disc. 105, 109-111.

Vormann J, Goedecke T. Acid-Base homeostasis: Latent acidosis as a cause of chronic diseases. SCHWEIZERISCHE ZEITSCHRIFT FUR GANZHEITS MEDIZIN. 2006;18(5):255.

Wackenfors A, Pantev E, Emilson M, Edvinsson L, Malmsjo M. Angiotensin II receptor mRNA expression and vasoconstriction in human coronary arteries: effects of heart failure and age. Basic & clinical pharmacology & toxicology. Dec 2004;95(6):266-272.

Wagner E. Life Extension Magazine; In The News. Cystatin C Valuable in Detecting Kidney Dysfunction. http://www.lifeextension.com//Magazine/2006/12/itn/Page-01. 2006. Accessed 1/27/2015.

Walker HK, Hall WD, Hurst JW (ed.). Chapter 196: Serum Total Carbon Dioxide. In: Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990a. Available at: http://www.ncbi.nlm.nih.gov/books/NBK308/. Accessed 10/21/2014.

Walker HK, Hall WD, Hurst JW (ed.). Chapter 49: Arterial Blood Gases. In: Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990b. Available at: http://www.ncbi.nlm.nih.gov/books/NBK371/. Accessed 10/21/2014.

Watanabe H, Obata H, Watanabe T, Sasaki S, Nagai K, Aizawa Y. Metabolic syndrome and risk of development of chronic kidney disease: the Niigata preventive medicine study. Diabetes/metabolism research and reviews. Jan 2010;26(1):26-32.

Weinberg AJ, Zappe DH, Ashton M, Weinberg MS. Safety and tolerability of high-dose angiotensin receptor blocker therapy in patients with chronic kidney disease: a pilot study. American journal of nephrology. May-Jun 2004;24(3):340-345.

Weinberg AJ, Zappe DH, Ramadugu R, Weinberg MS. Long-term safety of high-dose angiotensin receptor blocker therapy in hypertensive patients with chronic kidney disease. Journal of hypertension. Supplement : official journal of the International Society of Hypertension. Mar 2006;24(1):S95-99.

Wensing KU, Ciarimboli G. Saving ears and kidneys from cisplatin. Anticancer Res. 2013;33(10):4183–8

Wenzel S, Stolte H, Soose M. Effects of silibinin and antioxidants on high glucose-induced alterations of fibronectin turnover in human mesangial cell cultures. J Pharmacol Exp Ther. Dec 1996;279(3):1520-1526.

Wesseling-Perry K, Salusky IB. Is replacement therapy with nutritional and active forms of vitamin D required in chronic kidney disease mineral and bone disorder? Current opinion in nephrology and hypertension. Jul 2009;18(4):308-314.

Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. The American journal of medicine. 1999;106(5):13S-24S.

Wickman C, Kramer H. Obesity and kidney disease: potential mechanisms. Seminars in nephrology. Jan 2013;33(1):14-22.

Wojcikowski K, Stevenson L, Leach D, Wohlmuth H, Gobe G. Antioxidant capacity of 55 medicinal herbs traditionally used to treat the urinary system: a comparison using a sequential three-solvent extraction process. Journal of alternative and complementary medicine. Jan-Feb 2007;13(1):103-109.

Yadla M, Yanala SR, Parvithina S, Chennu KK, Annapindi N, Vishnubhotla S. Acute kidney injury in endosulfan poisoning. Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia. May 2013;24(3):592-593.

Yamagishi S, Nakamura K, Matsui T. Potential utility of telmisartan, an angiotensin II type 1 receptor blocker with peroxisome proliferator-activated receptor-gamma (PPAR-gamma)-modulating activity for the treatment of cardiometabolic disorders. Current molecular medicine. Aug 2007;7(5):463-469.

Yao X, Panichpisal K, Kurtzman N, et al. Cisplatin nephrotoxicity: a review. Am J Med Sci. 2007;334(2):115-24.

Yokozawa T, Nakagawa T, Oya T, Okubo T, and Juneja LR. Green tea polyphenols and dietary fibre protect against kidney damage in rats with diabetic nephropathy. J. Pharm. Pharmacol. 2005;57(6):773–80

Younes N, Cleary PA, Steffes MW, de Boer IH, Molitch ME, Rutledge BN, . . . Dahms W. Comparison of urinary albumin-creatinine ratio and albumin excretion rate in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Clinical journal of the American Society of Nephrology : CJASN. Jul 2010;5(7):1235-1242.

Yuzbashian E, Asghari G, Mirmiran P, Hosseini FS, Azizi F. Associations of dietary macronutrients with glomerular filtration rate and kidney dysfunction: Tehran lipid and glucose study. Journal of nephrology. Jun 5 2014.

Zhang W, Liu Y, Ge M. Protective effect of resveratrol on arsenic trioxide-induced nephrotoxicity in rats. Nutr Res Pract. 2014;8(2):220–6

Zheng Z, Shi H, Jia J, Li D, Lin S. Vitamin D supplementation and mortality risk in chronic kidney disease: a meta-analysis of 20 observational studies. BMC nephrology. 2013;14:199.

Zhu JR, Bai J, Cai NS, Tang B, Fan WH, Guo JZ, . . . Cheng NN. Efficacy and safety of telmisartan vs. losartan in control of mild-to-moderate hypertension: a multicentre, randomised, double-blind study. International journal of clinical practice. Supplement. Dec 2004(145):46-49.

Zoccali C, Curatola G, Panuccio V, Tripepi R, Pizzini P, Versace M, . . . Mallamaci F. Paricalcitol and endothelial function in chronic kidney disease trial. Hypertension. Nov 2014;64(5):1005-1011.

Zoungas S, Chalmers J, Ninomiya T, Li Q, Cooper ME, Colagiuri S, . . . Woodward M. Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds. Diabetologia. Mar 2012;55(3):636-643.