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 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 (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).
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).
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).
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 (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).
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).
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).
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).