Factors that Compromise Kidney Health
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).
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 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 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).
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 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).
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).
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 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 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).