You may be surprised to learn that until 2002, no standard definition for chronic kidney disease (CKD) existed within the medical community (Medscape, 2010). Before then, conflicting classifications had created a state of confusion as to how many Americans were afflicted with this progressive, life-threatening condition.

Once proper categorization of the various phases of CKD was established, the stark and daunting scale of this modern epidemic emerged.

We now know that as many as 26 million Americans currently suffer from some form of chronic kidney disease (US Renal Data System 2009; National Kidney Foundation 2009). Aging individuals are especially vulnerable (Coresh 2003).

When you consider that the risk of cardiovascular mortality in CKD sufferers is 30 times that of the general population (Galil 2009), the steady increase in kidney disease rates seen today amounts to a public health disaster. Unfortunately, public awareness of this threat remains low.

Life Extension has long emphasized the need for vigilance through routine testing (at least once a year) to monitor kidney health. In addition to the standard tests for measuring kidney function (i.e., creatinine, albumin, and BUN/creatinine ratio), certain individuals should insist that their doctor test for cystatin-C, a largely overlooked blood marker providing a far more precise measure of renal function (Shlipak 2005). Optimal levels are below .91 mg/L.

Individuals should keep a record of their test results. Once any sign (such as an increase in creatinine) of disease is detected, it is imperative that immediate steps be taken to halt its progress, as kidney function can decline precipitously and kidney damage may be irreversible. Fortunately, Life Extension customers are already taking a variety of nutrients that support kidney health.

In this protocol, you will discover recent scientific advances in our understanding of how CKD unfolds, the specific risk factors that contribute to its progress, and how to bring them under control.

You will also learn of safe, low-cost, natural interventions that have been shown to stop CKD in its tracks, long before end-stage renal disease (ESRD) renders either dialysis, kidney transplant, or both as the only option(s).

The formation of advanced glycation end-products (AGE's) is a well-established factor in the onset and progression of kidney disease. Nutrients that have been conclusively shown to mitigate the effects of these lethal agents constitute a front line, low-cost intervention.

A formidable AGE antagonist is the vitamin B6 compound pyridoxamine. A plethora of research confirms its power to halt formation of AGE's (Voziyan 2005; Ahmed 2007; Williams 2006). Evidence has also emerged that pyridoxamine drastically limits formation of equally deadly advanced lipoxidation end-products (ALE's)—another catalyst for kidney disease (Alderson 2004; Metz 2003(a,b)).

A team of biochemists at the University of South Carolina were able to show that pyridoxamine traps the reactive molecules formed during lipid (fat) peroxidation and accompanies them harmlessly into the urine (Metz 2003a; Onorato 2000).

Their colleagues subsequently found that neutralizing AGE's and ALE's can prevent kidney disease and lipid profile abnormalities in diabetic rats (Degenhardt 2002). They found that rats supplemented with pyridoxamine had lower levels of albumin (protein) in their urine, lower plasma levels of the waste product creatinine, and less dramatically elevated blood lipids than the placebo-treated rats, all directly related to the reduction of AGE/ALE's.

They subsequently examined whether similar results could be obtained in non-diabetic rats (Alderson 2003). Three groups of rats were studied:

1. Lean (healthy)
2. Obese without treatment
3. Obese treated with pyridoxamine.

As expected, AGE and ALE formation underwent a two- to three-fold increase in obese, untreated rats as compared to lean rats. Conversely, those increases were absent in obese rats treated with pyridoxamine. Treated rats also experienced a smaller increase in plasma triglycerides, cholesterol, and creatinine levels as compared to the obese, untreated rats (Alderson 2003).

In an equally compelling development, hypertension in the rats treated with pyridoxamine resolved, as did thickening of blood vessel walls. Untreated rats displayed urinary evidence of renal disease (albuminuria) that in contrast had been nearly normalized in supplemented rats. This provides powerful evidence of pyridoxamine’s multi-targeted protective effect against CKD (Alderson 2003).

In 2004, the same research team made a landmark discovery. While studying the relative effects of pyridoxamine (along with a variety of additional natural antioxidants) on the progression of kidney disease in diabetic rats, they decided to examine how these natural compounds stacked up against enalapril, a standard pharmaceutical intervention used to prevent CKD (Alderson 2004). Enalapril is an ACE inhibitor, one of a class of drugs commonly used to control blood pressure and kidney disease.

They found that pyridoxamine therapy was the most effective at preventing the progression of kidney disease, followed by vitamin E and lipoic acid. Enalapril, the prescription drug, proved to be the least effective intervention. Pyridoxamine also limited lipid profile abnormalities as well as the formation of AGE's and ALE's, offering a far broader spectrum of preventive effects than enalapril (Alderson 2004).

Researchers at the University of Miami advanced these findings by treating diabetic mice with both pyridoxamine and enalapril (Zheng 2006). Again they found that pyridoxamine alone provided substantial benefit, cutting albuminuria and damage to the glomeruli (capillaries which carry blood within the kidneys). Combining enalapril with pyridoxamine reduced kidney disease mortality in these animals as well, leading the researchers to suggest that the ACE-inhibitor (enalapril)/pyridoxamine combination might be useful.

A convincing body of research on pyridoxamine therapy in humans with CKD has emerged. In 2007, a team of researchers at Harvard University set out to determine optimal interventions to halt the progression of kidney disease in diabetics (Williams 2007). They conducted two 24-week multicenter placebo-controlled trials in patients with known diabetic nephropathy—treatment of which is known to delay the onset of end-stage renal disease in diabetics. Doses of pyridoxamine ranged from 50 to 250 mg twice daily.

Pyridoxamine significantly inhibited the rise in blood levels of the waste product creatinine, one of the key biomarkers of kidney dysfunction and a predictor of kidney failure. Urinary levels of inflammatory cytokines were also significantly lower in the treated group compared to controls.

Pyridoxamine has been firmly established as a front line, safe, low-cost intervention in CKD caused or exacerbated by AGE's and ALE's. Further, this natural vitamin B6 compound has been shown to significantly improve outcomes of experimental kidney transplants and other forms of kidney disease (Murakoshi 2009; Tanimoto 2007; Waanders 2008).

It therefore borders on the criminal that in January of 2009, the FDA classified this potent, entirely safe CKD therapeutic as a drug, putting it out of reach for many Americans suffering from this deadly condition. No one should be forced to bear the outrageous burden of costly pharmaceuticals and their toxic side effects when a perfectly safe alternative exists.

Fortunately, there is another equally safe option available—another form of vitamin B6 known as pyridoxal-5-phosphate (P5P) that also exerts potent anti-AGE effects. It has been shown to prevent the progression of diabetic kidney disease in pre-clinical models (Nakamura 2007). In fact, as far back as 1988, P5P was used by a German research group to reduce blood lipids in humans with chronic kidney disease (Kirsten 1988).

Coenzyme Q10

Because of the tremendous blood flow and high concentration of metabolic toxins continuously circulating through the kidneys, they are the site of extraordinary oxidative stress, which is known to contribute to progressive kidney damage and its complications (i.e., high LDL and increased cardiovascular disease risk) (Gazdikova 2000).

Coenzyme Q10 (CoQ10) fortifies the body’s natural antioxidant capacity and reduces levels of oxygen free radicals, indicating an important defense against CKD. As it happens, CoQ10 has been used experimentally to control hypertension and kidney disease in laboratory animals since the early 1970s (Igarashi 1974; Morotomi 1975).

Human studies have shown that CoQ10 levels substantially decline, while markers of oxidation such as malondialdehyde are dramatically elevated in kidney disease patients with even mild renal dysfunction (Yao 2007). These decreased CoQ10 levels make circulating lipoproteins (such as LDL) more vulnerable to oxidative damage. This in turn increases risk for further cardiovascular damage, adding to the renal burden and substantially increasing the risk of kidney disease (Lippa 2000).

In 2001, a team of European researchers published compelling evidence for how effective nutritional intervention can be in patients with established kidney disease (Gazdikova 2001). Subjects received antioxidant therapy with vitamins C, E, and riboflavin (vitamin B2) for one month preceding the addition of CoQ10 therapy for 2 months. Following supplementation, CoQ10 levels in the blood increased from just one-quarter to nearly four times the normal reference levels. The study was too brief to demonstrate any change in kidney function. However, evidence from animal trials the same year showed that increasing CoQ10 levels in tissues of diabetic rats resulted in a reversal of oxidative stress markers in the kidney, heart, and liver (Rauscher 2001).

By 2004, definitive evidence of the benefits of CoQ10 in human kidney disease patients was demonstrated by European researchers working with transplant recipients. Transplant recipients undergo tremendous oxidative stress and as a result, typically have marked disturbances in lipid profiles. The researchers provided their patients with 30 mg of CoQ10 three times daily for four weeks, and monitored levels of oxidation factors (such as malondialdehyde), natural antioxidant enzymes in the body, and lipid profiles (Dlugosz 2004).

Significant improvements were seen after just four weeks, with reduction in LDL, increase in beneficial HDL, and a decrease in presence of inflammatory cells noted. These results suggest a potentially dramatic improvement in both quality of life and survival rates for patients with early-stage kidney disease as well as those requiring dialysis or transplantation.

Animal studies have also shown that CoQ10 can protect kidney tissue from numerous nephrotoxic drugs, including gentamicin, a powerful antibiotic with a notorious propensity for causing kidney damage (Farswan 2005; Upaganlawar 2006). These findings are significant not only because they offer protection in patients who might be exposed to such drugs, but they teach us about CoQ10’s potent ability to combat the extreme oxidant stress that the kidney faces as it deals with a variety of foreign chemicals.

Silymarin

Silymarin is extracted from milk thistle (Silybum marianum), a plant rich in the following flavonolignans (natural phenols composed of flavonoid and lignin): silychristin, silydianin, silybin A, silybin B, isosilybin A and isosilybin B -- collectively known as the silymarin complex.

This safe, natural compound has a long history as a traditional therapy for liver and kidney conditions (Post-White 2007; Wojcikowski 2007). It has been used in Western medicine for more than a quarter of a century, owing to its potent antioxidant and nephron-protective effects, as the treatment of choice for kidney injury resulting from severe mushroom poisoning (Floersheim 1978). In fact, we’ve known since 1979 that kidney injury (via mushroom poisoning) in animals who are pre-treated with silymarin can be almost entirely preventable (Vogel 1979). This makes it a natural choice for protection against drug-induced kidney damage since so many drugs can act like poisons, exerting extreme oxidant stress on kidney tissue.

Mushroom poisons (mycotoxins) are among the most deadly natural toxins known. Their kidney toxicity is surpassed only by some of the most aggressive chemotherapy agents. Physicians have therefore looked to silymarin as a potential “renoprotective” agent for patients undergoing chemotherapy.

Silymarin is also protective against several classes of nephrotoxic drugs, in particular cisplatin and Adriamycin®, two of the most potent and damaging (owing to oxidative damage and severe inflammation) chemotherapeutic drugs (Launay-Vacher 2008; Machado 2008; Yao 2007). Researchers around the world have found that silymarin and its components reduce and often prevent the kidney damage caused by these drugs (Bokemeyer 1996; Gaedeke 1996; Karimi 2005; El-Shitany 2008).

Silymarin’s ability to protect against the oxidative stress produced by potent drugs suggests that it may be useful in protecting against more subtle, chronic injury by free radicals -- particularly those generated by chronic blood glucose elevations. German researchers, for instance, have found that silymarin could prevent injury to renal cells incubated with elevated glucose concentrations while blocking production of oxidative stress markers (Wenzel 1996).

Silymarin’s protective power also extends to ischemia/reperfusion injury (restoration of blood supply following restriction of blood flow). Turkish researchers demonstrated that by pre-treating animals with silymarin, they could completely prevent visible and functional damage to kidney structures exposed to this kind of injury (Senturk 2008; Turgut 2008). Studies such as these suggest that by maintaining optimal antioxidant function through supplementation, we may be able to prevent much (if not most) of the chronic oxidative damage to which our kidneys are exposed on a daily basis. As a result, they have huge implications for the general population.

Resveratrol

The considerable advance in our understanding of the cyclical relationships between oxidative stress, endothelial dysfunction, inflammation, atherosclerosis, and chronic kidney disease points to resveratrol as an intervention in the chain of events that ultimately lead to renal failure (Caimi 2004).

Italian researchers are among the leaders in resveratrol research. Early in this century, one group published research demonstrating the impact of resveratrol on preserving kidney structure and function in rats exposed to ischemia/reperfusion injury (Bertelli 2002; Giovannini 2001).

Japanese and Indian urologists followed that up with reports detailing the mechanisms by which resveratrol combats oxidative damage following reperfusion, markedly reducing kidney dysfunction (Saito 2005; Chander 2006(a,b); Chander 2005(a,b)). Bacterial infection (sepsis) is a common cause of kidney failure in the intensive care unit and following surgery or trauma. Turkish physiologists demonstrated that resveratrol can reduce or prevent both kidney and lung injury in septic rats (Kolgazi 2006).

Resveratrol, due to its antioxidant and anti-inflammatory potential, has been utilized in studies to prevent drug-induced kidney damage. The following results were noted when rats, exposed to antibiotic gentamicin, were treated with resveratrol: 1) nephrotoxicity was significantly reduced, 2) more rapid healing of injured kidney tissue was attained, and 3) a dramatic reduction in markers of oxidant injury was observed (Silan 2007). A team of toxicologists in Brazil demonstrated its protective power against cisplatin, the powerful chemotherapy agent responsible for so much drug-induced kidney damage (Do Amaral 2008). Finally, Indian pharmacologists were successful in protecting animal kidneys from damage caused by cyclosporine A (another common chemotherapy and immune suppressant drug) by pre-treating the animals with resveratrol (Chander 2005(b)).

Since diabetes is the leading cause of kidney disease—and because the damage it inflicts is largely mediated by free radical production resulting from destructive alteration of proteins by glucose (glycation)—researchers have explored resveratrol as a preventive in diabetic kidney damage. Promising results have come from Indian pharmacologists who significantly attenuated kidney damage in rats with experimentally induced diabetes, even 4 weeks after the diabetes was induced (Sharma 2006).

In the researchers’ own words, “The present study reinforces the important role of oxidative stress in diabetic kidney disease and points towards the possible antioxidative mechanism being responsible for the renoprotective action of resveratrol.”

Lipoic Acid

Like resveratrol, lipoic acid is a powerful antioxidant with few known side effects (Amudha 2006). Lipoic acid has been successfully employed in the laboratory to block the oxidative damage caused by ischemia/reperfusion injury, thereby opening the door to another effective treatment for this common cause of acute kidney failure (Takaoka 2002). In 2008, researchers showed that they could reverse all adverse effects on renal function and lab abnormalities following experimental ischemia/reperfusion injury in animals (Sehirli 2008).

Lipoic acid has been comprehensively studied worldwide for its power to prevent or mitigate drug-induced kidney damage. We know that lipoic acid is an effective kidney-protective agent against damage inflicted by Adriamycin® (Malarkodi 2003(a,b)), the immunosuppressive drug cyclosporine A (Amudha 2006; Amudha 2007(a,b)), and even against acute toxic doses of the pain reliever acetaminophen (Abdel-Zaher 2008). In studies examining the protective benefits of lipoic acid against cyclosporine toxicity, it helped to normalize blood lipid abnormalities (Amudha 2007b).

Nephrologists at Georgetown University examined lipoic acid in the context of diabetic kidney disease. Their results showed that it can improve renal function in diabetes by lowering sugar levels (Bhatti 2005).

They also demonstrated that lipoic acid lowers protein loss in urine and improves kidney structure and function by reducing oxidative stress in diabetic laboratory animals (Bhatti 2005).

In yet another compelling study, Korean researchers showed that they could improve kidney patients’ responses to the vasodilator (blood vessel relaxer) nitric oxide (NO) by supplementing them with lipoic acid (Chang 2007). Loss of endothelial responsiveness to NO is a cause of vascular disease in diabetics. A chemical called asymmetric dimethylarginine (ADMA) is a sensitive marker and predictor of cardiovascular outcome in patients with end-stage renal disease. Fifty patients on hemodialysis were treated with 600 mg lipoic acid daily for 12 weeks. ADMA levels remained unchanged in the control group but fell significantly in the treatment group, suggesting that lipoic acid may reduce the risk of cardiovascular complications in this group of patients.

L-carnitine, an amino acid-derived nutrient crucial to cellular energy management, may play a vital role in kidney disease prevention and management (Kendler 1986; Matera 2003). Carnitine deficiency is itself a known causative factor in the development of kidney disease. Conversely, patients with kidney disease frequently develop carnitine deficiency, especially those on dialysis. Carnitine therapy is known to lead to improvements in many kidney disease-related complications including cardiovascular disease, anemia, decreased exercise tolerance, weakness, and fatigue (Matera 2003).

As noted earlier, CKD sufferers are at very high risk for developing cardiovascular complications, including heart attacks and heart failure. This is thought to be related in part to the massive oxidative stress induced by kidney disease and in part to inadequate energy management in cardiac tissues induced by carnitine deficiency (Calo 2006). The frequent result of these interrelated factors is a massive deterioration in energy, exercise tolerance, quality of life—and perhaps, longevity (Schreiber 2006).

Based on patient reported outcomes, scientists in Kentucky discovered that supplementation with L-carnitine could improve general health, vitality, and physical function in people on dialysis (Sloan 1998). In 2001, research by clinicians at Los Angeles Medical Center showed that L-carnitine given intravenously to dialysis patients could reduce fatigue and preserve exercise capacity (Brass 2001). A literature review by nephrologists at Vanderbilt University indicated that L-carnitine supplementation should be used to improve red blood cell count in dialysis patients whose anemia doesn’t respond to therapy with the hormone erythropoietin (Golper 2003). Finally, data from Italy demonstrated that L-carnitine supplements could help suppress levels of the inflammatory marker C-reactive protein, potentially reducing cardiovascular risk in dialysis patients (Savica 2005).

Additional Nutrients that May Benefit CKD

Folic acid is well known for its capacity to reduce levels of the metabolite homocysteine, which is strongly associated with cardiovascular disease and dramatically elevated in individuals with kidney disease or kidney failure (Alvares Delfino 2007; Bostom 2006; Menon 2005; Nanayakkara 2007).

Omega-3 fatty acids have been shown to help improve cardiovascular risk factors (Farmer 2001; Hartweg 2009; Moreira 2007) and kidney function in patients with established kidney disease (Miller 2009; Parinyasiri 2004). Research published in 2009 suggests that diets rich in omega-3s may actually prevent kidney disease (Bell 2009; Garman 2009).

Through its powerful antioxidant effects, vitamin E may help prevent the onset of CKD. Vitamins E and C may mitigate the development of cardiovascular and other complications in patients with chronic kidney disease (Abdel-Naim 1999; Boaz 2000; Khajehdehi 2001; Mune 1999; Ramos 2005; Tain 2007).

Sodium-glucose cotransporter-2 (SGLT2) inhibitor drugs like dapagliflozin (Farxiga), canagliflozin (Invokana), and empagliflozin (Jardiance) are drugs used to treat type 2 diabetes. SGLT2 inhibitors reduce sodium and glucose reabsorption in the kidneys, resulting in increased glucose and sodium excretion in the urine (Tuttle 2021; Layton 2018).

SGLT2 inhibitors have been shown in large clinical trials to improve kidney-related outcomes in people with diabetes and those without diabetes. These benefits appear to be independent of these drugs’ glucose-lowering effects (Rosenberg 2021; Heerspink 2017; Fernandez-Fernandez 2020; Zelniker 2019). Among the proposed mechanisms for these benefits are a reduction in kidney workload and improvement in oxygen dynamics; lowering of blood pressure in the kidneys (leading to reduction in hyperfiltration); anti-inflammatory and antifibrotic effects within the kidneys; and diuretic effects (Tuttle 2021; Miyata 2021; Tian 2021).

A randomized controlled trial including 4,304 participants with CKD with or without type 2 diabetes, from 21 different countries, examined the effect of dapagliflozin (10 mg once daily) or placebo on renal function over a median period of 2.4 years (Heerspink, Stefansson, Correa-Rotter 2020). Subjects were already being treated with blood pressure medications known as angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), unless the treatment was not tolerated. The primary outcome was a composite of the following: a prolonged decline of at least 50% in estimated glomerular filtration rate (eGFR), the onset of ESRD, or death from renal or cardiovascular causes. Participants treated with dapagliflozin had a 39% relative risk reduction in the primary outcome compared with placebo. These benefits were similar in people of different ages, races, genders, baseline eGFR, and with or without a type 2 diabetes diagnosis. Subjects with type 2 diabetes experienced a relative risk reduction of 36%, whereas those without diabetes experienced a 50% risk reduction. Participants treated with dapagliflozin also experienced a 31% risk reduction in all-cause mortality compared with placebo. No occurrences of severe hypoglycemic events or diabetic ketoacidosis were observed in patients without diabetes. This trial was stopped early due to clear evidence of efficacy for the composite primary outcome (Heerspink, Stefansson, Correa-Rotter 2020; Heerspink, Stefansson, Chertow 2020).

A different double-blind, randomized, controlled trial enrolled 4,401 participants with type 2 diabetes and CKD. The subjects were treated with canagliflozin (100 mg daily) or placebo over a median of 2.62 years. Again, patients were stable on ACE inhibitor or ARB treatment prior to randomization. The primary outcome was a composite of the development of ESRD, a doubling of serum creatinine level, or death from renal or cardiovascular causes. The relative risk of the primary outcome was 30% lower in the treatment group compared with placebo. Those taking canagliflozin also had a 20% reduced risk of cardiovascular death, heart attack, or stroke. This trial was also stopped early due to clear evidence of efficacy of canagliflozin on the composite primary outcome (Perkovic 2019).

A 2021 meta-analysis examined results from seven studies with over 1,700 type-2 diabetic subjects in which SGLT2 inhibitors were combined with blood pressure medications known as renin-angiotensin system blockers (eg, ARBs and ACE inhibitors). Compared with the blood pressure drugs alone, the combination resulted in greater reductions in systolic and diastolic blood pressure and body weight, and greater improvement in kidney function and hemoglobin A1C. However, the combination therapy increased the risk of hypoglycemia (Tian 2021).

Although SGLT2 inhibitors have demonstrated impressive efficacy and a robust safety profile in trials, there are caveats to their use which include an increased risk of potentially serious urinary tract infections, genital mycotic (fungal) infections, and hypovolemia. In diabetics already taking other drugs that increase risk of hypoglycemia, add-on therapy with an SGLT2 inhibitor may increase this risk, but SGLT2 inhibitors generally do not cause hypoglycemia on their own (Tian 2021; Menne 2019; Lega 2019; Singh 2019; Hopf 2021). A systematic review and meta-analysis of 112 randomized trials and four observational studies, totaling approximately 180,000 patients, found an increased incidence in adverse events of hypovolemia in individuals treated with SGLT2 inhibitors (Menne 2019). SGLT2 treatment is also associated with an increased relative risk of a rare condition, euglycemic diabetic ketoacidosis (Wang 2019; Menghoum 2021). Careful monitoring for adverse effects is important, particularly in older individuals and those using diuretics or non-steroidal anti-inflammatory drugs (NSAIDs). It is important for those taking these medications to be compliant with their treatment regimen and remain mindful of their own signs and symptoms to reduce the risk of adverse effects.

SGLT2 inhibitors are also linked to a three- to four-fold increase in genital mycotic (fungus, usually the yeast Candida albicans) infections (Aggarwal 2019). Female gender and prior genital mycotic infections are associated with higher risk, whereas circumcised males are at lower risk. It is thought that the increased urinary excretion of glucose in these patients contributes to this increased susceptibility; emphasizing personal hygiene can decrease the risk of genital mycotic infections. When these candida infections occur as a result of treatment with SGLT2 inhibitors, they are generally mild, respond well to treatment, and do not require medication discontinuation (Engelhardt 2021).