Diet,Botanical Medicine,and Nutraceuticals for Chronic Kidney Disease

Abstract

Introduction

According to the Kidney Disease Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guidelines for the evaluation and management of chronic kidney disease (CKD), CKD is defined as an abnormality of kidney structure or function that has been present for more than three months and that has implications for health.¹ The main etiologies underlying CKD are diabetes and hypertension (HTN). Acute kidney injury represents an additional risk factor for CKD.

In the United States, the prevalence of kidney disease is estimated by the U.S. Renal Data System to be ∼15%. To help put this figure in perspective, more people die of kidney disease every year in the United States than of breast or prostate cancer.² Owing to lack of symptoms associated with earlier stages of CKD, many patients may be unaware that their renal function is compromised. This means that unfortunately, much of the damage associated with CKD may already be done by the time a patient becomes aware of their condition.

Per the National Institute of Diabetes and Digestive and Kidney Disease, the stages of CKD are based on estimated glomerular filtration rate (eGFR) as follows:

Stage 1: normal kidney function (eGFR ≥90 mL/min) and persistent (≥3 months) proteinuria

Stage 2: mild reduction in kidney function (eGFR 60–89 mL/min) and persistent (≥3 months) proteinuria

Stage 3: moderate reduction in kidney function (eGFR 30–59 mL/min)

Stage 4: severe reduction in kidney function (eGFR 15–29 mL/min)

Stage 5: kidney failure (eGFR <15 mL/min); CKD stage 5 that requires dialysis or transplant for survival is also known as end-stage renal disease (ESRD)

Rates of ESRD in America are not only increasing, but are also already among the highest in the world. Cardiovascular disease (CVD), including heart failure, is also common among people with ESRD.³

When approaching the case of an individual with CKD, it is important to remember the components of normal renal physiology to help appreciate and understand the sequelae of CKD. The normal functions of the kidney include:

Maintenance of fluid balance

Filtration and excretion of waste materials and toxins

Production of erythropoietin, renin, and calcitriol

Gluconeogenesis under fasting conditions

Maintenance of acid–base homeostasis

Reabsorption and regulation of urea, sodium, potassium, calcium, magnesium, and phosphate.

CKD, therefore, may lead to perturbations in any of these areas, and may result in altered levels of calcium, phosphorus, potassium, parathyroid hormone (PTH), vitamin D, uric acid, and erythropoietin, as well as changes in fluid load. In turn, these alterations can lead to anemia, electrolyte abnormalities, bone disease, gout, edema, and vascular or valvular disease including calcification. As kidney dysfunction increases, hyperlipidemia also increases.⁴ Another feature of CKD is chronic low-grade inflammation, and patients with CKD demonstrate increased inflammatory biomarkers, which are correlated with the rate of disease progression.⁵

Treatment goals in CKD are aimed toward decreasing the rate of progression to ESRD along with managing comorbidities and complications, keeping in mind that the leading cause of mortality for people with CKD is CVD. A mainstay of this approach conventionally is blockade of the renin–angiotensin–aldosterone system with either an angiotensin receptor blocker (ARB) or an angiotensin converting enzyme inhibitor (ACEI). Most patients will also be prescribed statin medication to reduce the rate of atherosclerosis or CVD. Treatment of blood pressure (BP) to maintain levels <140/90 will also be initiated to reduce renal disease progression and CVD.

Keeping these factors and treatment goals in mind can help people with CKD and their practitioner to begin to formulate an integrative plan that addresses the individual's unique needs and also takes into account how those needs may change over time.

Dietary Considerations in CKD

Nutrition is an especially important factor in people with CKD. Malnutrition may develop as CKD progresses, with muscle loss, anorexia, electrolyte changes, immune dysfunction, and micronutrient deficiencies all playing a role. In contrast, overnutrition or obesity may also contribute to poorer outcomes.⁶

Patients with CKD will generally be referred to a renal dietitian for tailored dietary recommendations. The diet should be individualized for each person, and will depend on a number of factors, including disease stage, and the presence or absence of diabetes, HTN, and proteinuria. Clinical trials have been conflicting, and the optimal diet for people with CKD is not definitively known. Many CKD patients will be recommended a diet based on the Dietary Approaches to Stop Hypertension (DASH) dietary pattern, as greater adherence to the DASH diet is associated with a reduced incidence of CKD development in people at high risk, as well as with a lower risk of ESRD in those with existing CKD.^7,8 To the author's knowledge, no prospective clinical trials have been performed assessing a DASH diet intervention in people with CKD.

A Mediterranean diet (MD) is also associated with reduced incidence of development of CKD, and greater adherence to an MD predicts survival in elderly men with CKD.⁹ In one small clinical trial, the MD was determined to be a feasible alternative to a standard low-protein diet in people with CKD, and was also found to have additional benefits for people with methylenetetrahydrofolate reductase polymorphisms.¹⁰

Although the optimal dietary pattern for people with CKD may still be a subject of debate, there are several practical considerations to keep in mind when working on nutrition with an individual with CKD. Individualized assessment of protein intake may be of benefit. KDIGO guidelines recommend that people with CKD at risk of disease progression avoid high protein intakes of >1.3 g/(kg·day). KDIGO also recommends restricting protein intake to 0.8 g/(kg·day) in people with glomerular filtration rate (GFR) <30.¹¹ Moderate protein reduction may also help reduce phosphorus intake in those people who require restriction.

Conversely, a very low protein diet would generally not be recommended. In the Modification of Diet in Renal Disease study, people who followed a very low protein diet with intakes of 0.28 g/(kg·day) not only had no benefit in terms of CKD progression, but also had a greater risk of death.¹² In addition, not just the amount of protein but also the type of protein consumed matters. It is recommended that >50% of the protein in the diet be high biological value protein.¹³ The biological value of a protein determines how efficiently the body utilizes the protein that has been consumed, and a high biological value also indicates higher levels of essential amino acids.

Although animal proteins generally have higher biological value protein content, it is also possible to achieve this recommendation with plant protein consumption, and substituting plant proteins for animal proteins may confer additional benefits (such as reductions in HTN, metabolic acidosis, and hyperphosphatemia).¹⁴ Plant-based high biological value protein powders may be a viable option for those patients who have difficulty meeting their needs with foods alone.¹⁵

Phosphorus intake may need to be restricted in CKD patients whose serum phosphate and PTH levels are elevated. The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend a phosphorus intake of 0.8–1.0 g/day. Organic phosphorus (from naturally occurring food sources) has variable absorbability, with animal foods having more readily absorbable phosphorus, and plant foods having phosphorus that is less absorbable. Favoring consumption of plant-based proteins over animal proteins may be one strategy to help a person control phosphorus intake. Inorganic phosphorus from processed foods (such as phosphate additives from soda pop or processed meats) is readily absorbed and should be avoided.¹⁶

KDOQI guidelines on potassium recommend restriction to 2–4 g/day. Serum potassium levels may be used to individualize or adjust this guideline as well. Potassium-rich herbs, such as alfalfa, dandelion leaf, or nettles, may need to be avoided in some individuals. Potassium-containing salt substitutes may need to be avoided as well.

Regarding sodium intake, KDOQI guidelines recommend restricting sodium to 2.3 g/day. A very low sodium diet is generally not recommended; the Institute of Medicine has concluded that there is insufficient evidence to recommend that people in high-risk groups (such as those with CKD) should restrict sodium to 1500 mg/day.¹⁷

These guidelines are summarized in Table 1.

Table 1.

Nutritional Guidelines in Chronic Kidney Disease

Nutrient	Guideline	Issuing body
Protein	0.8 g/(kg·day) when GFR <30	KDIGO
Phosphorus	0.8–1.0 g/day	KDOQI
Potassium	2–4 g/day	KDOQI
Sodium	≤2.3 g/day	KDOQI

GFR, glomerular filtration rate; KDIGO, Kidney Disease Improving Global Outcomes; KDOQI, Kidney Disease Outcomes Quality Initiative.

For drinking water, consider having patients with CKD strictly filter their water, especially for removal of fluoride. Although evidence is mixed, fluoride may have nephrotoxic potential, and fluoride intake is not routinely monitored in people with CKD.^18,19

Many people with CKD may enquire about caffeine or coffee consumption. A 2018 observational study provides a degree of reassurance. Bigotte Vieira et al.,²⁰ utilizing data from the National Health and Nutrition Examination Survey 1999–2010, analyzed the coffee and caffeine consumption habits of 4863 people with CKD. Utilizing both multivariable adjustment and an unadjusted analysis, the authors found that caffeine intake was inversely associated with all-cause mortality in people with CKD. There was no relationship between CKD disease stage and caffeine consumption, and the authors concluded based on this that caffeine “appears to be safe through different stages of kidney disease.” While this study is observational, and therefore does not tell us about a causative link, it may provide reassurance for CKD patients who regularly include caffeine as part of the diet.²⁰

Starfruit should be avoided in people with CKD. Starfruit is rich in oxalates and also contains a specific neurotoxin, caramboxin, which inhibits the GABAergic system. This neurotoxin undergoes renal clearance, so in people with CKD, it may fail to be properly eliminated, and may accumulate to toxic levels.²¹

Pomegranate, in contrast, may actually be beneficial for people with CKD, specifically those on dialysis treatment. A group of Israeli researchers has performed three clinical trials of pomegranate juice in dialysis patients.

In the first, they randomized 101 people with CKD to receive either 100 mL pomegranate juice, or a matched placebo, three times a week during their dialysis treatments for one year. In the group who received pomegranate juice, 25% of subjects had improvement in measures of atherosclerosis, and 5% had progression of atherosclerosis. In the placebo group, no subjects had improvement in measures of atherosclerosis, and 50% had progression of atherosclerosis. Subjects who received pomegranate juice also had a reduced incidence of hospitalizations for infection.²²

In the second trial (N = 27), a single session of pomegranate juice consumption during dialysis treatment with intravenous (i.v.) iron (compared with a placebo) was found to improve oxidative markers, potentially attenuating the increased oxidative stress that accompanies iron infusion.²³

Lastly, the same group has also examined the impact of pomegranate juice on cardiovascular risk factors in people on dialysis. One hundred one CKD patients were randomized to receive 100 mL pomegranate juice, or matching placebo, again during dialysis treatment, three times weekly for one year. The placebo consisted of a polyphenol-free juice with pomegranate artificial extract, caramel coloring, and aspartame and acesulfame artificial sweeteners. People in the pomegranate group experienced reduced systolic BP, and improved triglycerides (TGs) and high-density lipoprotein (HDL) levels than those in the placebo group (P = 0.001, P < 0.001, and P = 0.05, respectively). These effects were most pronounced in people with existing HTN, hypertriglyceridemia, and low HDL levels.²⁴

Note that a later trial of either pomegranate extract (supplement) or juice conducted in the United States in 2015 failed to show any impact on oxidative stress markers or BP in dialysis patients.²⁵ Another 2015 trial, utilizing a pomegranate extract supplement at a dose of 1000 mg daily for six months versus placebo, found that the extract improved a measure of antioxidant status, but failed to have any impact on BP or cardiovascular factors.²⁶ Perhaps additional trials comparing pomegranate supplements with juice will provide additional clarification in the future.

Botanical Medicine and CKD

The choice of a particular botanical medicine for a person with CKD will depend on the individual's health goals, disease stage, and comorbidities, among other factors. As already mentioned, potassium-rich herbs may need to be avoided in some people with CKD, especially those on dialysis. Many individuals with CKD, whether on dialysis or not, may wish to avoid diuretic herbs as well. These herbs are often marketed as being “kidney cleansing,” but may simply force the kidneys to work harder.

Panax ginseng may represent a good option for those with early stage kidney disease. In a study conducted in China, 197 subjects with stage 2 or stage 3 CKD were randomly assigned to receive either a Panax ginseng extract (ginsenoside Rb1) at a dose of 500 mg daily, or a placebo, for six months. A total of 177 people completed the study, 91 in the ginseng group and 86 in the placebo group. Subjects in the ginseng group had significantly alleviated measures of renal function compared with subjects in the placebo group. In addition, people who received ginseng had reduced oxidative stress and inflammation than people in the placebo group.²⁷ Ginseng, of course, is a well-known traditional remedy for fatigue; since fatigue is quite common in people with CKD,²⁸ ginseng may perhaps offer additional practical benefits.

The Indian plant Salacia oblonga, traditionally used to treat people with type 2 diabetes, may also benefit people with early stage CKD. In a randomized single-blind prospective placebo controlled trial, the effect of Salacia was examined in people with CKD with and without diabetes (the authors did not specify whether these subjects had type 1 or type 2 diabetes). Criteria for enrollment included serum creatinine >1.5 mg/dL but <5 mg/dL, and subjects could not be taking ACEI or ARB medications. Initially, 67 subjects were enrolled in the trial and allocated to one of four groups. Group A1 consisted of nondiabetic CKD patients randomized to receive Salacia whereas group A2 consisted of nondiabetic CKD patients randomized to placebo. Group B1 consisted of diabetic CKD patients randomized to receive Salacia whereas group B2 consisted of diabetic CKD patients randomized to placebo. The dose of Salacia used in the trial was 1000 mg twice a day, although the authors did not specify the form of the plant utilized.²⁹

A total of 60 subjects completed the 6-month trial, 15 in each treatment group. Both diabetic and nondiabetic subjects who received the herbal treatment had significantly better preservation of renal function at the six-month time point, as evidenced by stabilization of creatinine clearance (P = 0.04 and P = 0.05, respectively). Subjects who received herbal treatment also experienced a reduction in TGs, with a 17% reduction in TG levels in diabetic CKD patients, and a 24% reduction in nondiabetic CKD patients. Subjects treated with Salacia experienced a significant reduction in C-reactive protein (CRP) levels (P = 0.03 for diabetic subjects and P = 0.002 for nondiabetic subjects). Furthermore, diabetic subjects in the herbal treatment group also had a significant reduction in interleukin-6 (IL6) and cholesterol compared with diabetic subjects in the placebo group (P = 0.0003 and P = 0.0001, respectively).²⁹

It is thought that Salacia may exert its effects through inhibition of α-glucosidase enzymes, antioxidant and anti-inflammatory actions, and improvement of cardiac lipid metabolism.^30

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As already mentioned, CKD may involve chronic inflammation. Two small trials have examined the use of a combination of curcumin and Boswellia serrata (frankincense) to help address inflammation in people with CKD.

In the first, Moreillon et al.³⁴ randomly gave 16 participants with stages 1–5 CKD either a curcumin and B. serrata supplement or a placebo for 8 weeks. The supplement contained 824 mg turmeric extract from Curcuma longa, standardized to 95% curcuminoids, and 516 mg B. serrata extract, standardized to 10% 3-acetyl-11-keto-β-boswellic acid, and was given at a dose of one capsule twice daily (b.i.d). A significant time effect and time x compliance interaction effect were for IL6 (P = 0.03 and P = 0.04, respectively), with levels decreasing in the herbal supplement group, and increasing in the placebo group. There was no significant difference seen between groups for plasma glutathione peroxidase, CRP, or tumor necrosis factor-α. The authors speculated that the lack of effect for these other variables may have been influenced by the small sample size or by the short period of supplementation.³⁴

Shelmadine et al.³⁵ performed a second trial on curcumin and B. serrata in people with CKD. In their study, 16 subjects with stages 2 and 3 CKD were randomized to receive either the herbal supplement or a placebo. The supplement utilized and dosage taken were identical to those found in Moreillon's trial mentioned, and subjects received eight weeks of supplementation. Eicosanoid metabolite levels were assessed as markers of inflammation. A significant difference was seen in prostaglandin E₂ levels for subjects who received the herbal supplement compared with placebo (P = 0.05). There was no significant difference for additional eicosanoid metabolites 5-hydroxyicosatetraenoic acid, 12-hydroxyicosatetraenoic acid, 15-hydroxyicosatetraenoic acid, or 13-hydroxyoctadecadienoic acid in this very small study.³⁵ As these studies specifically looked at inflammatory markers, effects on creatinine clearance or proteinuria were not assessed.

Astragalus membranaceus may also be a worthwhile consideration. Several studies have been performed on A. membranaceus root for people with CKD, including subjects both on dialysis and not on dialysis. A 2014 Cochrane review summarized these studies. A total of 22 studies with 1323 subjects were included. Of these 1323 subjects, 241 were on dialysis. Of the 22 studies included as part of this review, 16 studies utilized an i.v. infusion of the herb, 1 study utilized a slow i.v. injection, 1 study administered the herb as part of the dialysis solution, 2 studies administered the herb as an intramuscular injection, and 2 studies utilized a decoction of the herb administered orally. The authors did not specify the range of dosages utilized in these studies and various preparations. Astragalus was found to significantly increase creatinine clearance (4 studies, 306 subjects: mean difference [MD] 5.75 mL/min, 95% confidence interval [CI] 3.16 to 8.34; statistical heterogeneity [I²] = 0%). Astragalus also significantly decreased serum creatinine, especially in people with a baseline creatinine level <133 μmol/L (3 studies, 187 subjects: MD −2.52 μmol/L, 95% CI −8.47 to 3.42; I² = 0%). Astragalus supplementation resulted in significantly reduced proteinuria (10 studies, 640 subjects; MD −0.53 g/24 hours, 95% CI −0.79 to −0.26; I² = 90%) and increased serum albumin levels (9 studies, 522 subjects: MD 3.55 g/L, 95% CI 2.33 to 4.78; I² = 65%) both in subjects on dialysis and not on dialysis.³⁶

Astragalus also led to significantly increased hemoglobin levels, especially in subjects receiving dialysis (3 studies, 142 subjects: MD 11.20 g/L, 95% CI 5.81 to 16.59; I² = 0%). BP reductions were also significant among those receiving Astragalus. Included studies utilized crude Astragalus herb root, or Astragalus root extract. The authors noted that risk of bias was unclear in 16 studies, and risk of bias was found to be high in 6 studies. Only 6 studies observed for adverse effects, and no adverse effects were reported. The remaining 16 studies did not observe or report adverse effects. There were errors and omissions both in reporting and in study methods, which may have affected results seen in these studies. The quality of studies overall was, therefore, determined to be low.³⁶ The results from these trials certainly seem promising, but future studies should be of good methodological quality to provide more informative results.

Nutraceuticals and Nutritional Supplements and CKD

There are a number of nutritional supplements that may be helpful options for people in varying stages of CKD. These include l-carnitine, probiotics, activated charcoal (AC), and N-acetylcysteine (NAC).

l-carnitine

As a conditionally essential amino acid, l-carnitine plays an important role in cellular energy production. Carnitine also functions as an antioxidant and free radical scavenger.³⁷ The kidneys play a key role in maintaining carnitine levels in the body by reabsorbing filtered carnitine in the renal tubules, and, to a lesser extent, by synthesizing carnitine (carnitine biosynthesis also occurs in the liver).³⁸ As a result, CKD can lead to significant changes in carnitine homeostasis, with a reduction in skeletal muscle carnitine stores and free plasma carnitine. Patients on dialysis are at special risk of carnitine deficiency.³⁹

Carnitine repletion or supplementation may have a number of benefits for people with CKD. Oral supplementation for eight weeks at a rather modest dose of 250 mg three times daily (t.i.d) has been found to significantly reduce total cholesterol (P < 0.01), TG levels (P < 0.001), and LDL levels (P < 0.01) in CKD patients on dialysis, compared with patients in a control group.⁴⁰ Oral supplementation at a dose of 10 mg/kg three times per week for 12 months has also been shown to reduce left ventricular volume in dialysis patients (P < 0.01), and to result in a 31% reduction in erythropoietin requirements.⁴¹ This would work out to a dose of 770 mg three times a week for the average American woman at a weight of 77 kg, or 900 mg three times a week for the average American man at a weight of 90 kg (again, quite modest doses).

Although oral supplementation clearly has many advantages, keep in mind that i.v. supplementation may be even more efficacious at helping patients maintain higher carnitine levels.⁴² In a randomized, double-blind placebo-controlled multicenter trial of CKD patients on dialysis, six months of i.v. carnitine at a dose of 20 mg/kg administered at the rinse-back cycle at the completion of each dialysis treatment was compared with an equal volume of saline administered as placebo. Participants who received carnitine experienced a reduction in hypotension and muscle cramping during dialysis treatment, and also had significant improvement in maximal oxygen consumption measured by a progressive work exercise test (P < 0.03). Carnitine therapy was also found to result in significant reductions in predialysis levels of serum urea nitrogen (BUN), creatinine, and phosphorus (P < 0.004) compared with placebo. Mid-arm muscle circumference was also boosted in carnitine group subjects, while remaining the same in placebo group subjects (P = 0.05). Global clinical status improved in carnitine group subjects compared with those who received placebo (P < 0.005).⁴³ This same dose of carnitine (20 mg/kg at the end of each dialysis treatment) given for eight weeks has also been found to improve quality-of-life (QOL) measures, as well as hemoglobin and albumin levels.⁴⁴

Probiotics

Probiotics have also been the subject of clinical trials in people with CKD. In people with CKD, uremic toxins may diffuse from the bloodstream to the gastrointestinal tract, and may be found in bile, as well as in gastric and intestinal contents.⁴⁵ Among the numerous potential immunologic, digestive, and anti-inflammatory benefits of probiotics, some beneficial bacteria may also utilize nitrogenous uremic toxins as growth nutrients. This results in an overall reduction in levels of uremic toxins as they are consumed by probiotic microbes. Of the various probiotics that have been studied, a proprietary formulation containing Streptococcus thermophilus (KB19), Lactobacillus acidophilus (KB27), and Bifidobacterium longum (KB31) is perhaps the best researched for its effects on people with CKD, with four clinical trials having been performed.

The first two studies of this probiotic were pilot-scale trials. A 2009 trial of subjects with stage 3 or stage 4 CKD randomized participants to receive either the probiotic at a dose of 90 billion colony forming units (CFU) daily or a placebo containing wheat germ and psyllium husk for three months. After three months, a crossover was made, and the first group took the placebo whereas the second received the probiotic for an additional three months. This was a small trial, with 16 subjects enrolled and 13 completing the study. At the completion of the trial, there were significant improvements in BUN levels during probiotic treatment compared with placebo (P = 0.002). Uric acid levels were also significantly improved during probiotic treatment versus placebo (P = 0.050). There were no significant differences in CRP or creatinine. Results from this trial may have been impacted by the very small sample size.⁴⁶

A 2010 pilot-scale trial used a design similar to the 2009 trial mentioned. This study was a randomized double-blind placebo-controlled crossover trial in 62 people with stage 3 or stage 4 CKD. Subjects were randomized to receive placebo or the probiotic at a dose of 90 billion CFU daily for 3 months, and then crossover was made and subjects switched groups for an additional 3 months. Of the 62 subjects enrolled, 46 completed the trial. Compared with the placebo period, BUN levels were lower in 63% of subjects during the probiotic treatment period (P < 0.05). Creatinine and uric acid levels were not significantly lower during probiotic treatment. Higher measures of QOL were reported by 85% of subjects during the probiotic intervention compared with the placebo period of the trial (P < 0.05). The probiotic supplement was generally well tolerated, with 10 participants reporting bloating, flatulence, or diarrhea that occurred during the first 3 weeks of probiotic supplementation and that did not recur after that.⁴⁷

Two additional small trials utilizing the same proprietary probiotic formulation have been performed. A 2013 six-month open-label study examined the effects of probiotics in escalating doses. Thirty-one subjects with stages 3 and 4 CKD were enrolled, of whom 28 completed the trial. Participants were initiated on the probiotic at 90 billion CFU daily for one month. The dose was then increased to 180 billion CFU daily for another month. The dose was then increased to 270 billion CFU daily for two months. After two months of supplementing at the maximum dosage, probiotics were discontinued for two months. Participants then returned for a follow-up completion visit.⁴⁸

All subjects tolerated the maximum dosage, with the exception of one person who reported nausea. Participants experienced several benefits in this trial. Significant changes were seen in creatinine and CRP levels from months 2 to 6 (P < 0.05 and P < 0.05, respectively). Significant changes were also seen in hemoglobin at several time points, including from baseline to six months (P < 0.01) and from months 2 to 6 (P < 0.0001). Subjects also had improved QOL measures for physical functioning from baseline to month 6 (P < 0.05). There were no significant changes in mental, emotional, or social functioning.⁴⁸

Lastly, a 2014 trial was performed in 22 CKD patients receiving dialysis. This was a six-month randomized double-blind placebo-controlled crossover trial. Twenty-two subjects were randomized to receive either a 180 billion CFU probiotic daily or a placebo containing cream of wheat and psyllium husk. After two months of supplementation, participants discontinued and began a two-month washout period. At the four-month mark, participants were then crossed over and received the opposite intervention for a total of two months. Although trends were seen for reductions of white blood cell counts, CRP, and indoxyl glucuronide (a uremic toxin), none of these results reached statistical significance. The study's small sample size may have impacted these results, as may have the fact that patients were in a more advanced disease state, and only supplemented with probiotics for two months in total.⁴⁹

Clinically, many patients with CKD seem to benefit on multiple levels from probiotic supplementation. Constipation, for example, is very common in people with CKD, and interestingly both the presence and severity of constipation have been linked to incident CKD.^50,51 It would be very helpful to see larger trials supplementing probiotics for longer time periods in people with CKD, including those on dialysis, to help us better understand the many effects these supplements may have.

Activated charcoal

As already mentioned, uremic toxins may diffuse from the blood into the gastrointestinal tract. Oral adsorbents such as AC may ameliorate CKD by adsorbing these toxins in the gut. AC may also impact hyperphosphatemia as well as vascular calcification (the most important factor in development of CVD for these patients).

A trial from earlier this year examined these effects. This study included two phases and enrolled patients with stage 3 or stage 4 CKD. During phase 1, all subjects (who had normal baseline phosphorus levels) were randomized to receive either AC at 0.6–1.2 g t.i.d, taken with food, or a placebo. The authors did not further specify how this dose (0.6–1.2 g) was determined for participants who took AC. Subjects were followed for 12 months and had measurements of serum phosphorus, PTH, and calcium performed every three months.

When a patient developed hyperphosphatemia, they then entered phase 2 of the trial. During phase 2, patients underwent coronary artery computed tomography. They were then randomized to one of three groups. Group 1 subjects continued to receive AC t.i.d, and also received calcium carbonate and vitamin D supplements as needed to maintain normal serum calcium levels. Group 2 subjects received calcium carbonate and group 3 subjects received lanthanum carbonate (a calcium-free phosphate binder), with both groups receiving respective supplementation in accordance with KDIGO guidelines. A total of 97 patients enrolled, and 50 entered phase 2 of the trial (developed hyperphosphatemia).

During phase 1 of the trial, subjects who took AC had decreased phosphorus levels compared with those who took placebo, with this effect starting after three months of supplementation and continuing to the end of the trial (P = 0.000). Also significant, 28.6% of subjects in the AC group developed hyperphosphatemia, whereas 79.2% of subjects in the placebo group did (P = 0.000). During phase 2 of the trial, measures of coronary calcification were significantly better for patients who received AC versus those who received calcium carbonate or lanthanum carbonate supplements at the 12-, 18-, and 24-month marks (P < 0.01, P < 0.01, and P < 0.05, respectively). The authors concluded that vascular calcification could be delayed in CKD patients with the use of AC supplements.⁵²

A bothersome symptom experienced by many people with ESRD is uremic pruritus, estimated to affect >50% of people on dialysis. The exact reason this pruritus occurs is not well elucidated, but it is thought that chronic inflammation experienced by these patients, or immune system dysfunction, may play a role.⁵³ Oral AC at a dose of 6 g daily has been found to reduce pruritus in CKD patients on dialysis. In one trial, 20 out of 23 patients (87%) responded to AC supplementation, with 10 out of the 23 experiencing complete relief of pruritus (43.5%), and an additional 10 out of 23 achieving partial relief (43.5%).⁵⁴ In another trial, 10 out of 11 patients (91%) had relief of pruritus with 8 weeks of AC supplementation.⁵⁵

An important practical consideration to keep in mind when supplementing with AC is that as an adsorbent, it may also adsorb any drugs that are administered concomitantly, theoretically preventing intestinal absorption of medications. Oral AC has been shown to have varying effects on absorption of medications such as amlodipine, phenobarbital, and aspirin for example.⁵⁶ This may be especially important in people with CKD, for whom polypharmacy is common. When recommending AC, consider the absorption rate for medications a patient may be taking, and also consider separating the administration of medications and charcoal by two (or more) hours as appropriate.

N-acetylcysteine

NAC is a well-known antioxidant and nephroprotectant, and is widely used to reduce the risk of nephropathy in people receiving imaging contrast dyes (although there is controversy regarding the efficacy of this practice). NAC has been the subject of several studies in patients receiving dialysis.

Ahmadi et al.⁵⁷ examined the effect of NAC supplementation on residual renal function in dialysis patients. Fifty-four patients were enrolled and 47 completed the trial. Subjects were randomized to either a treatment group, receiving NAC at a dose of 1200 mg b.i.d in addition to usual care, or a control group receiving usual care only. After three months, GFR in the NAC group patients improved, whereas GFR in control patients declined, with the difference being statistically significant (P = 0.004). There were no differences in renal Kt/V (a measure of dialysis adequacy) between groups.⁵⁷ Likewise, Feldman et al.⁵⁸ also examined the effect of NAC on residual renal function in people receiving dialysis, also supplementing at a dose of 1200 mg b.i.d. This was a nonrandomized pilot trial of 2 weeks duration, with 20 patients enrolled. Two weeks of NAC use was found to significantly increase urine volume (P < 0.01), Kt/V (P < 0.01), and GFR levels (P < 0.01).⁵⁸

In addition to helping preserve renal function in those receiving dialysis, NAC may potentially improve inflammation or oxidative stress. A small 2014 trial (N = 24) found that dialysis patients who supplemented with NAC at a dose of 600 mg b.i.d for three months had significant improvements in CRP (P = 0.001), IL6 (P = 0.005), PTH (P = 0.037), ferritin (P = 0.007), and erythrocyte sedimentation rate (P < 0.001).⁵⁹ Another small trial (N = 40), this one conducted in 2016, found that dialysis patients who supplemented with NAC 600 mg b.i.d for six weeks had increased serum antioxidant capacity compared with patients who took a placebo (P = 0.000).⁶⁰

Conclusions

As already mentioned, an estimated 15% of Americans have CKD. This means that close to 50 million people in the United States are living with chronic renal disease. Not only are these people facing a host of difficult complications as a result of CKD, including CVD, but they are also at increased risk for progression to ESRD and an eventual need for dialysis or transplantation.

Whether someone is in the early stages of this illness, or in later stages or receiving dialysis, there are many areas where integrative medicine may step in to offer support. Many of the conditions that contribute to the development or progression of CKD, such as diabetes or HTN, are also important targets for integrative therapies, since they are frequently lifestyle related. A balanced approach that takes into account each CKD patient's individual needs will help that person achieve the best possible health while living with CKD. ▪

References

Stevens

, Levin

, Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: Synopsis of the kidney disease: Improving global outcomes 2012 clinical practice guideline. Ann Intern Med, 2013; 158:825–830.

, Murphy

, Kochanek

, et al. National Vital Statistics Reports 2018;67. Online document at: www.cdc.gov Accessed April 8, 2019 .

Saran

, Robinson

, Abbott

, et al. US renal data system 2018 annual data report: Epidemiology of kidney disease in the United States. Am J Kidney Dis, 2019; 73:A7–A8.

Thomas

, Kanso

, Sedor

. Chronic kidney disease and its complications. Prim Care, 2008; 35:329–344, vii.

Amdur

, Feldman

, Gupta

, et al. Inflammation and progression of CKD: The CRIC study. Clin J Am Soc Nephrol, 2016; 11:1546.

Kumar

, Henderson

, Cameron

, et al. Malnutrition, obesity, and undernutrition in chronic kidney disease. In: Goldsmith D, ed. Oxford Textbook of Clinical Nephrology. Oxford, UK: Oxford University Press, 2018:830–831.

Banerjee

, Crews

, Tuot

, et al. Poor accordance to a DASH dietary pattern is associated with higher risk of ESRD among adults with moderate chronic kidney disease and hypertension. Kidney Int, 2019; 95:1433–1442.

Yuzbashian

, Asghari

, Mirmiran

, et al. Adherence to low-sodium Dietary Approaches to Stop Hypertension-style diet may decrease the risk of incident chronic kidney disease among high-risk patients: A secondary prevention in prospective cohort study. Nephrol Dial Transplant, 2018; 33:1159–1168.

Huang

, Jiménez-Moleón

, Lindholm

, et al. Mediterranean diet, kidney function, and mortality in men with CKD. Clin J Am Soc Nephrol, 2013; 8:1548–1555.

10.

Di Daniele

, Di Renzo

, Noce

, et al. Effects of Italian Mediterranean organic diet vs. low-protein diet in nephropathic patients according to MTHFR genotypes. J Nephrol, 2014; 27:529–536.

11.

Org

, Kasiske

, City

. Kidney disease: Improving global outcomes guideline on CKD. 2014. Online document at: www.kdigo.org Accessed June 3, 2019 .

12.

Menon

, Kopple

, Wang

, et al. Effect of a very low-protein diet on outcomes: Long-term follow-up of the modification of diet in renal disease (MDRD) study. Am J Kidney Dis, 2009; 53:208–217.

13.

Zha

, Qian

. Protein nutrition and malnutrition in CKD and ESRD. Nutrients, 2017; 9:pii:E208.

14.

Joshi

, Shah

, Kalantar-Zadeh

. Adequacy of plant-based proteins in chronic kidney disease. J Ren Nutr, 2019; 29:112–117.

15.

Berue

. Vegan protein powder supplements of high biological value. J Ren Nutr, 2012; 22:e39–e41.

16.

Kalantar-Zadeh

, Gutekunst

, Mehrotra

, et al. Understanding sources of dietary phosphorus in the treatment of patients with chronic kidney disease. Clin J Am Soc Nephrol, 2010; 5:519–530.

17.

McGuire

. Institute of Medicine. 2013. “Sodium intake in populations: Assessment of evidence.” Washington, DC: The National Academies Press, 2013. Adv Nutr, 2014; 5:19–20.

18.

Dharmaratne

. Exploring the role of excess fluoride in chronic kidney disease: A review. Hum Exp Toxicol, 2019; 38:269–279.

19.

Schiffl

. Fluoridation of drinking water and chronic kidney disease: Absence of evidence is not evidence of absence. Nephrol Dial Transplant, 2007; 23:411–411.

20.

Bigotte Vieira

, Magriço

, Viegas Dias

, et al. Caffeine consumption and mortality in chronic kidney disease: A nationally representative analysis. Nephrol Dial Transplant, 2019; 34:974–980.

21.

Oliveira

ESM de

, Aguiar

AS de

, Oliveira

ESM de

, et al. Why eating star fruit is prohibited for patients with chronic kidney disease?. J Bras Nefrol, 2015; 37:241–247.

22.

Shema-Didi

, Sela

, Ore

, et al. One year of pomegranate juice intake decreases oxidative stress, inflammation, and incidence of infections in hemodialysis patients: A randomized placebo-controlled trial. Free Radic Biol Med, 2012; 53:297–304.

23.

Shema-Didi

, Kristal

, Ore

, et al. Pomegranate juice intake attenuates the increase in oxidative stress induced by intravenous iron during hemodialysis. Nutr Res, 2013; 33:442–446.

24.

Shema-Didi

, Kristal

, Sela

, et al. Does pomegranate intake attenuate cardiovascular risk factors in hemodialysis patients?. Nutr J, 2014; 13:18.

25.

Rivara

, Mehrotra

, Linke

, et al. A pilot randomized crossover trial assessing the safety and short-term effects of pomegranate supplementation in hemodialysis patients. J Ren Nutr, 2015; 25:40–49.

26.

P-T

, Fitschen

, Kistler

, et al. Effects of pomegranate extract supplementation on cardiovascular risk factors and physical function in hemodialysis patients. J Med Food, 2015; 18:941–949.

27.

, Lu

, Wu

, et al. Impact of extended ginsenoside Rb1 on early chronic kidney disease: A randomized, placebo-controlled study. Inflammopharmacology, 2017; 25:33–40.

28.

Joshwa

, Campbell

. Fatigue in patients with chronic kidney disease: Evidence and measures. Nephrol Nurs J, 2017; 44:337–343.

29.

Singh

, Rathore

, Wani

, et al. Effects of Salacia oblonga on cardiovascular risk factors in chronic kidney disease patients: A prospective study. Saudi J Kidney Dis Transpl, 2015; 26:61–66.

30.

Collene

, Hertzler

, Williams

, et al. Effects of a nutritional supplement containing Salacia oblonga extract and insulinogenic amino acids on postprandial glycemia, insulinemia, and breath hydrogen responses in healthy adults. Nutrition, 2005; 21:848–854.

31.

Heacock

, Hertzler

, Williams

, et al. Effects of a medical food containing an herbal α-glucosidase inhibitor on postprandial glycemia and insulinemia in healthy adults. J Am Diet Assoc, 2005; 105:65–71.

32.

Ismail

, Gopalakrishnan

, Begum

, et al. Anti-inflammatory activity of Salacia oblonga Wall. and Azima tetracantha Lam. J Ethnopharmacol, 1997; 56:145–152.

33.

Huang

TH-W

, Yang

, Harada

, et al. Salacia oblonga root improves cardiac lipid metabolism in Zucker diabetic fatty rats: Modulation of cardiac PPAR-α-mediated transcription of fatty acid metabolic genes. Toxicol Appl Pharmacol, 2006; 210:78–85.

34.

Moreillon

, Bowden

, Deike

, et al. The use of an anti-inflammatory supplement in patients with chronic kidney disease. J Complement Integr Med, 2013; 10:pii:/j/jcim.2013.

35.

Shelmadine

, Bowden

, Moreillon

, et al. A pilot study to examine the effects of an anti-inflammatory supplement on eicosanoid derivatives in patients with chronic kidney disease. J Altern Complement Med, 2017; 23:632–638.

36.

Zhang

, Lin

, Xu

, et al. Astragalus (a traditional Chinese medicine) for treating chronic kidney disease. Cochrane Database Syst Rev, 2014; 10:CD008369.

37.

Arockia Rani

, Panneerselvam

. Carnitine as a free radical scavenger in aging. Exp Gerontol, 2001; 36:1713–1726.

38.

Tanphaichitr

, Leelahagul

. Carnitine metabolism and human carnitine deficiency. Nutrition, 1993; 9:246–254.

39.

Katalinic

, Krtalic

, Jelakovic

, et al. The unexpected effects of L-carnitine supplementation on lipid metabolism in hemodialysis patients. Kidney Blood Press Res, 2018; 43:1113–1120.

40.

Argani

, Rahbaninoubar

, Ghorbanihagjo

, et al. Effect of carnitine on the serum lipoproteins and HDL-C subclasses in hemodialysis patients. Nephron Clin Pract, 2005; 101:c174–c179.

41.

Sakurabayashi

, Miyazaki

, Yuasa

, et al. L-carnitine supplementation decreases the left ventricular mass in patients undergoing hemodialysis. Circ J, 2008; 72:926–931.

42.

Suzuki

, Sakai

, Hashimoto

, et al. Kinetics of carnitine concentration after switching from oral administration to intravenous injection in hemodialysis patients. Ren Fail, 2018; 40:196–200.

43.

Ahmad

, Robertson

, Golper

, et al. Multicenter trial of L-carnitine in maintenance hemodialysis patients. II. Clinical and biochemical effects. Kidney Int, 1990; 38:912–918.

44.

Rathod

, Baig

, Khandelwal

, et al. Results of a single blind, randomized, placebo-controlled clinical trial to study the effect of intravenous L-carnitine supplementation on health-related quality of life in Indian patients on maintenance hemodialysis. Indian J Med Sci, 2006; 60:143–153.

45.

Sparks

. Review of gastrointestinal perfusion in the treatment of uremia. Clin Nephrol, 1979; 11:81–85.

46.

Ranganathan

, Friedman

, Tam

, et al. Probiotic dietary supplementation in patients with stage 3 and 4 chronic kidney disease: A 6-month pilot scale trial in Canada. Curr Med Res Opin, 2009; 25:1919–1930.

47.

Ranganathan

, Ranganathan

, Friedman

, et al. Pilot study of probiotic dietary supplementation for promoting healthy kidney function in patients with chronic kidney disease. Adv Ther, 2010; 27:634–647.

48.

Bohdan Pechenyak

, Pechenyak

, Vyas

, et al. Dose escalation, safety and impact of a strain-specific probiotic (Renadyl^™) on stages III and IV chronic kidney disease patients. J Nephrol Ther, 2013; 3:1–9.

49.

Natarajan

, Pechenyak

, Vyas

, et al. Randomized controlled trial of strain-specific probiotic formulation (Renadyl) in dialysis patients. Biomed Res Int, 2014; 2014:568571.

50.

Sumida

, Molnar

, Potukuchi

, et al. Constipation and incident CKD. J Am Soc Nephrol, 2017; 28:1248.

51.

Lee

, Lambert

, Byrne

, et al. Prevalence of constipation in patients with advanced kidney disease. J Ren Care, 2016; 42:144–149.

52.

Gao

, Wang

, Li

, et al. Effects of oral activated charcoal on hyperphosphatemia and vascular calcification in Chinese patients with stage 3–4 chronic kidney disease. J Nephrol, 2019; 32:265–272.

53.

Mettang

, Weisshaar

. Pruritus: Control of itch in patients undergoing dialysis. Skin Therapy Lett, 2010; 15:1–5.

54.

Giovannetti

, Barsotti

, Cupisti

, et al. Oral activated charcoal in patients with uremic pruritus. Nephron, 1995; 70:193–196.

55.

Pederson

, Matter

, Czerwinski

, et al. Relief of idiopathic generalized pruritus in dialysis patients treated with activated oral charcoal. Ann Intern Med, 1980; 93:446–448.

56.

Tanaka

, Ohtani

, Tsujimoto

, et al. Brief report/drug interactions effects of dosing interval on the pharmacokinetic interaction between oral small spherical activated charcoal and amlodipine in humans. J Clin Pharmacol, 2007; 47:904–908.

57.

Ahmadi

, Abbaszadeh

, Razeghi

, et al. Effectiveness of N-acetylcysteine for preserving residual renal function in patients undergoing maintenance hemodialysis: Multicenter randomized clinical trial. Clin Exp Nephrol, 2017; 21:342–349.

58.

Feldman

, Shani

, Sinuani

, et al. N-acetylcysteine may improve residual renal function in hemodialysis patients: A pilot study. Hemodial Int, 2012; 16:512–516.

59.

Saddadi

, Alatab

, Pasha

, et al. The effect of treatment with N-acetylcysteine on the serum levels of C-reactive protein and interleukin-6 in patients on hemodialysis. Saudi J Kidney Dis Transpl, 2014; 25:66–72.

60.

Shahbazian

, Shayanpour

, Ghorbani

. Evaluation of administration of oral N-acetylcysteine to reduce oxidative stress in chronic hemodialysis patients: A double-blind, randomized, controlled clinical trial. Saudi J Kidney Dis Transpl, 2016; 27:88–93.