Nephrotoxicity of dietary supplements and alternative medicine: not just an urban legend Steven Gabardi, PharmD, FAST, FCCP, BCPS Abdominal Organ Transplant Specialist Brigham and Women’s Hospital Assistant Professor of Medicine Harvard Medical School
1
Conflict of Interest • I have no financial relationships to disclose • My presentation does include discussion of off-label or investigational use
2
Has This Ever Happened to You? • The Dr. Oz Effect:
3
Forskolin FBCx (fiber) Raspberry Ketones Yakon Syrup Saffron Extract Sea Buckthorn Capsiberry Garcinia Cambogia African Mango Seed Green Coffee Bean
Complementary and Alternative Medicine •
Complementary Versus Alternative
Nearly 40% of Americans utilize health care approaches developed outside of mainstream Western, or conventional, medicine for specific conditions or overall wellbeing.
•
“Complementary” generally refers to using a non-mainstream approach together with conventional medicine.
•
“Alternative” refers to using a non-mainstream approach in place of conventional medicine.
•
True alternative medicine is uncommon. Most people use non-mainstream approaches along with conventional treatments. The boundaries between complementary and conventional medicine overlap and change with time.
•
For example, guided imagery and massage, both once considered complementary or alternative, are used regularly in some hospitals to help with pain management.
Medicinal Foodstuffs: natural products consumed as food used as either complementary or alternative therapy.
We will NOT discuss medicinal foodstuffs in much detail.
1. National Center for Complementary and Alternative Medicine. http://nccam.nih.gov/health/whatiscam 4
Focus on Natural Products •
Natural products refer to a group that includes a variety of products, such as herbs (also known as botanicals), vitamins and minerals, and probiotics. They are widely marketed, readily available to consumers, and often sold as dietary supplements.
•
2007 National Health Interview Survey
17.7% of American adults had used a non-vitamin/non-mineral natural product in the past year.
The most commonly used natural product among adults was fish oil/omega 3s
The most commonly used natural products among children was echinacea and fish oil/omega 3s
•
Some natural products have been studied in large, placebo-controlled trials, many of which have failed to show anticipated effects.
•
Research on others to determine whether they are effective and safe is ongoing.
•
While there are indications that some may be helpful, more needs to be learned about the effects of these products in the human body and about their safety and potential interactions with medicines and with other natural products.
1. National Center for Complementary and Alternative Medicine. http://nccam.nih.gov/health/whatiscam 5
Natural Product Use in the United States • A 2011 survey showed that 53% of American regularly consume natural products.
Multivitamins/multiminerals are the most commonly used dietary supplements, with approximately 40% of men and women reporting use.
• Overall, only 12% of natural product users ever seek care from a physician or licensed CAM practitioner
This implies that most people utilize natural products without consulting a healthcare provider
1. Natural Health Products Directorate. http://www.hc-sc.gc.ca/index-eng.php; 2. National Center for Complementary and Alternative Medicine. http://nccam.nih.gov/health/whatiscam 6
Natural Product Use – the Landscape • Global dietary supplements market was valued at $109.8 billion in 2013 and is expected to grow to reach an estimated value of $179.8 billion in 2020 • 15 million natural product users in the US also use at least one prescription medication on a regular basis. • 46% of natural product users consider these products to be safe and effective and perceive no potential for harm. • The American Association of Poison Control Centers reports more than 25,000 natural product-related events are reported each year. 1. Natural Health Products Directorate. http://www.hc-sc.gc.ca/index-eng.php; 2. National Center for Complementary and Alternative Medicine. http://nccam.nih.gov/health/whatiscam 7
Natural Products in the United States • Dietary Supplement Health and Education Act of 1994 stated that natural products are not required to undergo pre-market safety or efficacy testing.
• The US Food and Drug Administration treats natural products similar to food stuffs:
No requirements for product labeling to warn of known or potential adverse events
Lack of enforcement of good manufacturing practice within the natural product industry is evident by reports of product impurities and adulterations.
1. National Center for Complementary and Alternative Medicine. http://nccam.nih.gov/health/whatiscam 8
9
Natural Products and Nephrotoxicity •
The kidneys are highly susceptible to injury due to their intrinsic functions of filtration, reabsorption, metabolism and concentration.
•
Drug-induced nephrotoxicity accounts for approximately 7% of all medication-related toxicities.
•
It is reasonable to believe that some natural products are nephrotoxic.
•
Unfortunately, natural product adverse event data is limited because reporting of such events is voluntary.
•
Most information comes from case report; therefore, cause-and-effect relationships are difficult to establish.
•
In patients with chronic kidney disease (CKD), avoidance of substances that may be harmful to the kidney is one important method of reducing CKD progression.
Although many herbs commonly found in dietary supplements can cause acute kidney injury and other forms of kidney injury, they are not subject to rigorous governmental standards for content or safety for the general population or for individuals with CKD, for whom the consequences could be particularly deleterious.
1. Natural Health Products Directorate. http://www.hc-sc.gc.ca/index-eng.php 10
Evaluating the Literature •
•
Inclusion criteria
Natural products limited to only those available on the US market
Clinical studies
Case series
Single case reports
Report must have originated from a developed country or a country where large amounts of dietary supplements are imported from (i.e., India)
Exclusion criteria
•
11
Foodstuffs (i.e., Star Fruit and oxalate nephropathy, etc.)
Non-Scientific Inclusion/Exclusion Criteria: can I purchase it on Amazon or eBay?
Mechanisms of Nephrotoxicity • Direct Nephrotoxicity / Immune-Mediated Nephrotoxicity • Nephrolithiasis • Rhabdomyolysis • Hepatorenal Syndrome • Adulterants • Immunomodulators 12
Direct Nephrotoxicity / ImmuneMediated Nephrotoxicity • Bee Pollen • Chromium Picolinate • Creatine Monohydrate • Germanium • Glucosamine • L-Lysine • Larrea tridentate (Chaparral) • Pausinystalia yohimbe (Yohimbine) • Salix daphnoides (Willow Bark) • Tripterygium wilfordii hook F (Thunder God Vine) • Uncaria tomentosa (Cat’s Claw) 13
Bee Pollen • Common Uses:
Premenstrual syndrome symptom management
Appetite stimulant
Increase stamina
• Evidence of Nephrotoxicity:
49 year old male with a h/o ingesting bee pollen supplements x 5 months.
Patient presented with dyspnea, anuria, weight gain (>20 kg) and loss of appetite.
Renal biopsy confirmed AIN, including the presence of eosinophils.
Patient required HD, but renal function improved and HD was discontinued about 2 weeks after the patient stopped taking the bee pollen supplement.
1. Akiyasu, et al. Ther Apher Dial. 2010. 14
Chromium Picolinate •
•
Common Uses:
Glucose control
Lipid lowering
Weight loss
Evidence of Nephrotoxicity:
3 reported cases o
Case 1: patient w/ a 5 month h/o ingesting 1200-2400 mcg/day of chromium picolinate presenting with anemia, hemolysis, thrombocytopenia, hepatic dysfunction and acute kidney injury. •
o
Case 2: 24 year old man w/ a 2 week h/o ingesting a supplement that contained chromium picolinate who presented with AKI. •
o
Chromium levels were checked and were 3 x ULN; Abdominal ultrasound revealed enlarged kidneys and muddy brown casts were found with urine microscopy consistent with ATN; No hemodialysis was needed and the patient renal function returned to normal within a week of stopping the supplement.
Renal biopsy revealed ATN; The patient was treated with hemodialysis, plasmapheresis and corticosteroids and renal function returned to normal with a few weeks.
Case 3: patient w/ a 5 month h/o of ingesting 600 mcg/day of chromium picolinate who presented with AKI. •
Renal biopsy revealed AIN, consistent w/ heavy metal exposure; Renal function improved w/ corticosteroids.
1. Cerulli, et al. Ann Pharmacother. 1998.; 2. Wani, et al. Ann Pharmacother. 2006.; 3. Wasser, et al. Ann Intern Med. 1997 15
Creatine Monohydrate •
Common Uses:
•
Enhancement of muscle performance during brief, high-intensity exercise
Evidence of Nephrotoxicity:
2 reported cases o
o
Case 1: 20 year old male w/ a 4 week h/o ingesting 5 gm/day of creatine presenting with nausea, vomiting, and bilateral flank pain. •
Urinalysis showed proteinuria and hematuria.
•
Renal biopsy revealed AIN, tubular injury, thickened basement membrane and effacement of the foot processes.
•
Renal function recovered quickly after hydration.
Case 2: 24 year old male w/ a h/o FSGS and frequently relapsing nephrotic syndrome, presented with AKI after a 13 week h/o ingesting 2-15 gm/day of creatinine. •
A renal biopsy was not performed
•
Conservative treatment was initiated and the renal function normalized one month after discontinuation of the creatine supplement.
1. Koshy, et al. N Engl J Med. 1999.; 2. Pritchard, et al. Lancet. 1998. 16
IMPORTANT DISTINCTION Creatinine Ethyl Ester • There are two types of creatine products available:
Creatine ethyl esther
Creatine monohydrate
• Creatine ethyl esther only is converted into creatinine in the GI tract.
• Use of Creatine ethyl esther may be associated with elevated plasma creatinine levels, potentially resulting in false assumptions of renal failure. 1. Velema, et al. Neth J Med. 2011. 17
Germanium • Common Uses:
Anti-inflammatory
Immunostimulant
• Evidence of Nephrotoxicity:
10 reported cases o
Summary of the cases revealed: •
Cumulative dose of germanium ranged from 15 – 426 gm over a 2 – 36 month time period.
•
In most cases, histologic examination revealed tubular degeneration with minor glomerular abnormalities.
•
Recovery of renal function was often slow and incomplete.
1. Nagata, et al. J Toxicol Sci. 1985.; 2. Luck, et al. Nephrol Dial Transplant. 1999.; 3. Schauss. Ren Fail. 1991.; 4. Takeuchi, et al. Nephron. 1992.; 5. Matsusaka, et al. Clin Nephrol. 1988.; 6. Sanai, et al. Nephron. 1990.; 7. Asaka, et al. J Neurol Sci. 1995.; 8. Schauss. Biol Trace Elem Res. 1991.; 9. Obara, et al. Jpn J Med. 1991.; 10. van der Spoel, et al. Lancet. 1990. 18
Glucosamine •
•
Common Uses:
Osteoarthritis
Temporomandibular joint arthritis
Glaucoma
Weight loss
Evidence of Nephrotoxicity:
75 year old male with a h/o ingesting glucosamine supplements x 3 months.
Patient presented with difficulty passing urine, urgency, nocturia and hesitancy.
Renal biopsy revealed heavy mixed inflammatory cell infiltrates within the interstitium, suggestive of AIN.
Patient required HD along w/ a short course of corticosteroids, and his symptoms improved but he remained HD-dependent upon discharge.
1. Audimoolam, et al. Nephrol Dial Transplant. 2006. 19
L-Lysine • Common Uses:
Antiviral
Wound healing
• Evidence of Nephrotoxicity:
44 year old female with a h/o ingesting 3 gm/day of L-lysine supplements x 5 years.
Patient presented with Fanconi syndrome and tubulointerstitial nephritis.
Renal function never recovered and the patient progressed to CKD.
1. Lo, et al. Am J Kidney Dis. 1996. 20
Larrea tridentate (Chaparral) •
•
Common Uses:
Arthritis
Antimicrobial
Weight loss
Evidence of Nephrotoxicity:
56 year old female with a h/o ingesting chaparral supplements x 3 months.
Patient presented for routine exam approximately 18 months after stopping the chaparral supplements and was found to have an elevated SCr.
The patient was subsequently found to have bilateral renal cystic disease and RCC.
All other causes of acquired cycstic diseases were ruled out.
The authors concluded that nordihydroguaiaretic acid, in the form of chaparral, was the most likely cause of the cystic disease and RCC. o
Animal studies have found that nordihydroguaiaretic acid is present in significant quantities in chaparral and is associated with cystic nephropathy.
1. Smith, et al. J Urol. 1994.; 2. Evan, et al. Kidney Int. 1979.; 3. Goodman, et al. Lab Invest. 1970. 21
Pausinystalia yohimbe (Yohimbine) • Common Uses:
Erectile dysfunction
Sexual arousal
• Evidence of Nephrotoxicity:
42 year old male with a h/o ingesting yohimbine x 1 day.
Patient presented with progressive renal dysfunction, proteinuria, generalized erythrodermic skin eruptions, fever and pleural/pericardial effusions.
Renal biopsy was not performed.
Patient was treated with corticosteroids and regained normal renal function within 2 weeks.
The authors concluded that this was a case of yohimbine-induced SLE w/ resultant renal dysfunction.
1. Sandler, et al. Urology. 1993. 22
Salix daphnoides (Willow Bark) •
•
Common Uses:
Analgesic
Anti-inflammatory
Evidence of Nephrotoxicity:
Active constituent of willow bark is Salicin. o
Salicin, in vivo, is metabolized to saligenin, which is further metabolized to salicylate.
o
Salicylates are known to cause renal dysfunction through PG inhibition and reduced renal blood flow.
Willow bark has been implicated in the renal dysfunction diagnosed on review of the autopsy of Ludwig von Beethoven. o
His kidneys were described as normal size and shape but w/ calcareous deposits in each calyx.
o
It is believed that the deposits were necrotic papillae consistent with analgesic nephropathy.
1. Schwarz. Am J Kidney Dis. 1993. 23
Tripterygium wilfordii hook F (Thunder God Vine) • Common Uses:
Anti-inflammatory
Immunosuppressant (i.e., RA)
• Evidence of Nephrotoxicity:
36 year old male with a h/o ingesting a supplement containing Thunder God Vine x 3 days.
Patient presented with profuse nausea, vomiting, diarrhea, leukopenia, renal failure, hypotension and extensive cardiac abnormalities.
The patient died 3 days after presentation from intractable shock.
The authors could not differentiate the cause of the patient’s renal failure; postulating that it could have been supplement-induced nephrotoxicity along with the prolonged shock.
1. Chou, et al. Int J Cariol. 1995. 24
Uncaria tomentosa (Cat’s Claw) • Common Uses:
Anti-inflammatory
GI disorders
• Evidence of Nephrotoxicity:
A patient with a h/o SLE presented with renal dysfunction after ingesting Cat’s Claw.
A renal biopsy was not performed, but the patient was diagnosed with AIN.
Renal function improved after 1 month following conservative therapy and discontinuation of the Cat’s Claw supplement.
1. Hilepo, et al. Nephron. 1997. 25
Natural Products with Theoretic Nephrotoxic Potential • COX Inhibition / Altered Renal Hemodynamics:
26
Curcuma longa (turmeric)
Euterpe oleracea (açai berry)
Filipendula ulmaria (meadowsweet)
Tanacetum parthenium (feverfew)
Zingiber officinale (ginger)
Boswellia serrata (frankincense)
Camelia sinensis (green tea)
Aesculus hippocastanum (horse chestnut)
Nephrolithiasis • Ascorbic Acid • Ephedra sinica (Ma-Huang) • Vaccinium macrocarpon (Cranberry)
27
Ascorbic Acid • Common Uses:
Enhance iron absorption
Prevention of infection
Wound healing
• Evidence of Nephrotoxicity:
Ascorbic acid is metabolized to oxalate prior to elimination via filtration and tubular reabsorption.
9 case reports of oxalosis following ascorbic acid consumption have been reported. o
In all cases, oxalosis was associated with high-dose vitamin C (up to 60 gm/day), which resulted in oxalate deposition in the renal tubules with associated ATN.
o
All cases of renal failure resolved following treatment with either HD or conservative therapy.
1. Alkhunaizi, et al. J Am Soc Nephrol. 1996.; 2. Friedman, et al. Am J Nephrol. 1983.; 3. Lawton, et al. Arch Intern Med. 1985.; 4. Mashour, et al. Chest. 2000.; 5. Ono, et al. Clin Nephrol. 1989.; 6. Ponka, et al. Acta Med Scand. 1983.; 7. Pru, et al. Nephron. 1985.; 8. Swartz, et al. Ann Intern Med. 1984.; 9. Wong, et al. Aust N Z J Med. 1994. 28
Ephedra sinica (Ma-Huang) •
•
Common Uses:
Allergic rhinitis
Asthma
Hypotension
Sexual arousal
Weight loss
Evidence of Nephrotoxicity:
Over 1000 reports of ephedra-induced adverse events reported in the United States.
FDA prohibits sales of ephedra within the US; however, ephedra is quite simple to purchase online.
Ephedra is still available in Canada but only for use as a nasal decongestant.
2 case reports of nephrolithiasis associated w/ ephedra: o
Both patients were young males w/ a h/o consuming 40-3000 mg/day of ephedra for several months.
o
Analysis of kidney stones revealed the presence of ephedra, norephedrine and pseudoephedrine.
1. Powell, et al. Am J Kidney Dis. 1998.; 2. Blau. J Urol. 1998. 29
Vaccinium macrocarpon (Cranberry) •
•
Common Uses:
Antimicrobial
Urinary acidifier and deodorant
Evidence of Nephrotoxicity:
Cranberries contain oxalate o
One concentrated cranberry tablet contains approximately 180 mg of oxalate.
47 year old male with a h/o ingesting cranberry tablets daily x 6 months.
Patient presented with severe right flank pain, hematuria and elevated SCr.
o
Abdominal ultrasound reveals left and right ureteral stones.
o
The patient’s SCr normalized after stone removal (calcium oxalates present in stones).
After patient presentation the authors conducted an experiment to analyze 24-hour urine samples of 5 healthy volunteers before and after cranberry tablet consumption. o
Oxalate excretion increased by nearly 45% following cranberry tablet consumption.
1. Terris, et al. Urology. 2001. 30
Natural Products with Theoretic Nephrotoxic Potential • Nephrolithiasis (all agents listed below have been associated with stone formation when consumed as foodstuffs, but are also available as dietary supplements):
31
Rheum officinale (rhubarb)
Rumex acetosa (sorrel)
Rumex crispus (yellow dock)
Rhabdomyolysis • Artemisia absinthium (Wormwood) • Creatine Monohydrate • Glycyrrhiza glabra (Licorice)
32
Artemisia absinthium (Wormwood) •
•
Common Uses:
Anemia
Antipyretic
Appetite stimulant
Asthma
GI disorders
Evidence of Nephrotoxicity:
31year old male with a h/o ingesting 10 mL of wormwood oil presented with tonicclonic seizures.
On hospital day 2, the patient reported bilateral muscle soreness in his legs and his SCr reached its apex on hospital day 3.
With supportive care, the renal function normalized by day 17.
The authors concluded that the patient’s seizures resulted in rhabdomyolysis and subsequent AKI.
1. Weisbord, et al. N Engl J Med. 1997. 33
Creatine Monohydrate • Common Uses:
Enhancement of muscle performance during brief, highintensity exercise
• Evidence of Nephrotoxicity:
5 reported cases of AKI secondary to exercise-induced rhabdomyolysis in patients taking creatine supplements. o
Summary of the cases revealed: •
Patients consumed 5-25 gm/day of creatine.
•
All patients developed extreme muscle pain after participating in strenuous exercise and developed severe rhabdo.
Three patients required HD
Four developed compartment syndrome necessitating fasciotomy
One died of multisystem organ failure
1. Kuklo, et al. Am J Sports Med. 2000.; 2. Robinson. J am Board Fam Pract. 2000.; 3. Sandhu, et al. J Trauma. 2002. 34
Glycyrrhiza glabra (Licorice) •
•
Common Uses:
Antimicrobial
Anti-inflammatory
GI disorders
Evidence of Nephrotoxicity:
Licorice is a potent diuretic and has been associated with severe hypokalemia
2 reported cases of nephrotoxicity secondary to hypokalemia induced rhabdomyolysis following licorice consumption: o
o
Case 1: 78 year old male w/ a h/o consuming 280 mg/day of licorice for 7 years. •
Patient was hospitalized due to muscle pain, hypokalemia and AKI.
•
Initial laboratory analysis revealed elevated CPK and myoglobin levels.
Case 2: 29 year old female w/ a h/o ingesting 30 licorice tablets/day for 4 months. •
Patient presented w/ painful muscle weakness, hypokalemia and elevated CPK.
•
A renal biopsy revealed severely damaged tubular cells with intense vacuolar formations.
1. Conn, et al. JAMA. 1968.; 2. Saito, et al. Nippon Jinzo Gakkai Shi. 1994.; 3. Ishikawa, et al. Int J Eat Disord. 1999. 35
Natural Products with Theoretic Nephrotoxic Potential • Rhabdomyolysis
36
Cannabis sativa (marijuana)
Colchicum autumnale (autumn crocus)
Commiphora mukul (guggul)
Coutarea latiflora (copalchi)
Monascus purpureus (red yeast rice)
Natural Products with Theoretic Nephrotoxic Potential • Known to cause seizures, but have not been associated with rhabdomyolysis-induced renal dysfunction:
37
Aspartamine
Kava kava
Bearberry
Monkshood
Black cohosh
Water-hemlock
Ephedra
Guarana
Yohimbe
Natural Products with Theoretic Nephrotoxic Potential • Natural products with known or potential diuretic properties, but have not been associated with rhabdomyolysis-induced renal dysfunction: Aloe vera Asparagus Bladderwrack Copper Creatine Ephedra Goldenrod Horsetail l-Arginine Mistletoe Sorrel Yarrow flowers
38
Antineoplaston Astragalus Bupleurum Corn silk Dandelion Gingko Gotu kola Juniper berry Lovage Oleander Uva ursi
Artichoke Birch Burdock Couch grass Elder flower Glucosamine Green tea Kava Meadowsweet Shepherd’s purse White horehound
Hepatorenal Syndrome • Hedeoma pulegioide (Pennyroyal) • Hydrazine sulfate • Thevetia peruviana (Yellow Oleander)
39
Hedeoma pulegioide (Pennyroyal) • Common Uses:
Abortifacient
Menstrual stimulant
• Evidence of Nephrotoxicity:
Pennyroyal has been associated with renal dysfunction in the setting of hepatotoxicity. o
Two infants died of combined liver/renal failure after ingestion of preparations that contained pennyroyal. •
o
An autopsy in one child revealed hepatocellular necrosis, edematous hemorrhagic kidneys and ATN, left adrenal hemorrhage and bilateral lung consolidation.
Another report in an adult female who presented with oliguria and died of multisystem organ failure within 48 hours of pennyroyal consumption. •
A postmortem revealed acute proximal tubular degeneration.
1. Bakerink, et al. Pediatrics. 1996.; 2. Mack. NC Med. 1997.; 3. Anderson, et al. Ann Intern Med. 1996. 40
Hydrazine sulfate • Common Uses:
Anorexia and cachexia
Chemotherapeutic
• Evidence of Nephrotoxicity:
55 year old male with a h/o ingesting 180 mg/day of hydrazine sulfate x 4 months.
Patient presented with rash, pruritus, malaise and jaundice.
The patient subsequently developed hepatic encephalopathy, coagulopathy and progressive renal failure requiring HD.
Autopsy revealed autolysis of kidneys.
A similar case of multisystem organ failure was reported in a patient exposed to hydrazine for industrial purposes.
1. Sotaniemi, et al. Ann Clin Res. 1971. 41
Thevetia peruviana (Yellow Oleander) • Common Uses:
Anti-inflammatory
• Evidence of Nephrotoxicity:
4 reported cases of nephrotoxicity were seen in patients who consumed yellow oleander and consequently developed jaundice, oliguria and fever. o
Summary of the cases revealed: •
Serum bilirubin, SCr and BUN were elevated in all cases.
One patient required HD and recovered after 1 month
The remaining 3 died of multisystem organ failure » Post-mortem analysis revealed renal tubular necrosis with vacuolated areas in the glomerular spaces.
1. Samal, et al. J Assoc Physicians India. 1989. 42
Natural Products with Theoretic Nephrotoxic Potential • Hepatotoxic natural products not yet reported as causing hepatorenal syndrome:
43
Chelidonium majus (Greater Celandine)
Ephedra sinica (Ma-Huang)
Larrea tridentate (Chaparral)
Lycopodium serratum (Jin Bu Huan)
Piper methysticum (Kava)
Rhamnus purshiana (Cascara Sagrada)
Symphytum officionale (Comfrey)
Teucrium chamaedrys (Germander)
Adulterants
44
•
Adulteration of natural products occurs when supplements present a significant risk for inducing illness or injury when used as specified by product labeling, or contain an ingredient that is capable of rendering the product deleterious to human health.
•
On the basis of this definition of adulteration, contamination (unintentional or intentional) is a form of adulteration.
•
Reports of contamination of natural products are common. However, few cases of natural product adulteration have resulted in renal injury.
•
Aristolochic acid (Aristolochia serpentaria [Snakewood]) is the most welldocumented adulterant with nephrotoxic adverse events.
•
Other common contaminants, such as the heavy metals (e.g., arsenic, lead, mercury) and synthetic drugs (e.g., indomethacin, ibuprofen, phenylbutazone, mefenamic acid), may also have nephrotoxic potential.
Aristolochia serpentaria (Snakewood) •
Evidence of Nephrotoxicity:
Case reports of 9 women who presented with rapidly progressing renal failure as a result of biopsy-proven AIN. o
None of the women had any history of renal disease, but all had consumed the same weightloss supplement.
o
Chromatographic analysis of the supplement revealed that the preparation had been adulterated with Aristolochia. •
The primary constituent of Aristolochia is aristolochic acid.
•
Several case reports have demonstrated the nephrotoxic properties of aristolochic acid, leading to what is called “Chinese herb nephropathy.”
•
The major renal injury is extensive interstitial fibrosis with tubular atrophy and loss.
Some speculate that aristolochic acid may also be associated with Balkan endemic nephropathy, although a definite association remains unproven.
In a series of 39 patients (31 posttransplantation; eight HD) who developed Chinese herb nephropathy and underwent the prophylactic removal of their nonfunctioning native kidneys and ureters, 18 cases of urothelial carcinoma were found. o
In 19 of the 21 patients without carcinoma, urothelial lesions, resulting from mild to moderate dysplasia, were discovered.
o
The authors concluded that cumulative exposure to 200 g of aristolochic acid significantly increased the risk for urothelial malignancies.
1. Lord, et al. Lancet. 1999.; 2. Lord, et al. Lancet. 2001.; 3. Nortier, et al. N Engl J Med. 2000. 45
Heavy metals •
Evidence of Nephrotoxicity:
Contamination of dietary supplements with heavy metals is a common concern.
Most often, supplements are contaminated with heavy metals as a result of growth or cultivation in contaminated areas.
Heavy metals can cause significant renal damage. o
Arsenic affects the renal capillaries, tubules, and glomeruli, causing tubular necrosis and degeneration over time, yet detailed mechanisms are not well understood.
o
Chronic lead exposure can affect a variety of organ systems, including the kidneys, where it produces a chronic interstitial nephritis.
o
Mercury causes damage to the renal proximal tubule and hemebiosynthetic pathways. •
Concerns of natural products contaminated with mercury (e.g., fish oil, ephedra) and lead (e.g., calcium supplements) have been dismissed after evaluations of several products .
A single case of bladderwrack-induced nephrotoxicity has been reported with the renal injury was attributed to high levels of arsenic found within the bladderwrack. o
The presence of arsenic in kelp preparations is possibly a result of growth in contaminated water.
o
This case involved a young woman who presented with polydipsia, polyuria, proteinuria, and AKI after taking 1200 mg/day bladderwrack for 3 months.
o
Renal biopsy revealed tubular degeneration and lymphomonocytic infiltration.
o
One year after discontinuing the supplement, the patient’s renal function normalized.
1. Conz, et al. Nephrol Dial Transplant. 1998. 46
Synthetic drugs • Evidence of Nephrotoxicity:
Numerous studies that have reviewed the purity of natural products have found nonsteroidal anti-inflammatory drugs (NSAID), such as ibuprofen, phenylbutazone, and mefenamic acid, to be contaminants in products that are intended as analgesics or anti-inflammatories.
Nephrotoxicity as a results of NSAID adulteration is possibly seen in some cases involving glucosamine. o
Several cases of reversible renal dysfunction or mild proteinuria have been associated with the use of glucosamine-containing supplements.
o
Unfortunately, the authors of these case reports provided few details of the exact renal injury.
o
Many of the reporting authors concluded that the nephrotoxicity might have been due to concomitant medications or impurities/adulterants in the glucosamine preparations, although analysis of the products was never completed to confirm these conclusions.
1. Danao-Camara, et al. Arthritis Rheum. 2000. 47
Immunomodulating Natural Products • In organ transplantation, the purpose of immunosuppressive therapy is to decrease the undesirable immunologic activity of the host toward the allograft.
Conversely, it is also important that the host’s defense mechanisms continue to function.
There is often a fine line between under and over immunosuppression.
This balancing act can be disrupted by CAM that promote immunomodulation.
• Several natural products have shown immunomodulatory effects either in vitro or in vivo.
48
Immunomodulating Natural Products •
CAM Scientific Name (Common Name) – – – – – – – – – – – –
49
Apis mellifera (Royal Jelly) Arnica montana (Wolf’s Bane) Ascorbic Acid Astragalus membranaceus (Tragacanth) Baptista tinctoria (Wild Indigo) Boswellia serrata (Frankincense) Curcuma longa (Tumeric) d-Alpha Tocopherol Echinacea angustifoli (Echinacea) Eleutherococcus senticosus (Siberian Ginseng) Eupatorium perfoliatum (Feverwort) Ganoderma lucidum (Reishi Mushroom)
– Ginseng quinquefolius (American Ginseng) – Glycyrrhiza glabra (Licorice) – Grifola frondosa (Maitake) – Hydrastis canadensis (Goldenseal) – Matricaria chamomilla (Chamomile) – Medicago sativa (Alfalfa) – Oenothera biennis (Evening Primrose Oil) – Panax ginseng (Asian Ginseng) – Spirulina platensis (Spirulina) – Tripterygium wilfordii hook F (Thunder God Vine) – Viscum album (Mistletoe) – Zinc
Americans' Use of Dietary Supplements That Are Potentially Harmful in CKD • Grubbs, et al. Am J Kidney Dis. 2013:
50
Natural products are widely used in the United States despite their potential for harmful effects.
Individuals with or at risk of CKD may be particularly vulnerable to harmful effects of supplement use through direct nephrotoxicity and other renal complications, as well as decreased clearance of substances, resulting in adverse product accumulation.
This is the first study to describe the use of natural products potentially harmful in persons with and at risk of CKD in a nationally representative sample.
This study shows that approximately 1 in 12 US adults is taking at least one supplement that is potentially harmful in persons with kidney disease and that those with or at risk of CKD have a similar likelihood of taking such supplements compared with those without CKD, after accounting for important confounders.
Where can you patient’s go to get more information on dietary supplements? • Did you know that the NKF have a webpage dedicated to “Herbal Supplements and Kidney Disease”? • Do you know what’s being stated on this webpage?
51
National Kidney Foundation and Their Stance on Natural Products Which herbal supplements should I avoid if I have kidney disease? You should avoid all herbal supplements if you have kidney disease. Herbal supplements that are especially risky for patients with any stage of kidney disease, who are on dialysis or who have a kidney transplant include:
Astragalus
Barberry
Cat's Claw
Apium Graveolens
Creatine
Goldenrod
Horsetail
Huperzinea
Java Tea Leaf
Licorice Root
Nettle, Stinging Nettle
Oregon Grape Root
Parsley Root
Pennyroyal
Ruta Graveolens
Uva Ursi
Yohimbe
1. National Kidney Foundation. http://www.kidney.org/atoz/content/herbalsupp.cfm 52
National Kidney Foundation and Their Stance on Natural Products Which herbal supplements have potassium? Potassium is a mineral that may need to be limited in the diet of people with kidney disease especially for those on dialysis. Herbal supplements that have potassium include:
Alfalfa
American Ginseng
Bai Zhi (root)
Bitter Melon (fruit, leaf)
Black Mustard (leaf)
Blessed Thistle
Chervit (leaf)
Chicory (leaf)
Chinese Boxthorn (leaf)
Coriander (leaf)
Dandelion (root, leaf)
Dulse
Evening Primrose
Feverfew
Garlic (leaf)
Genipap (fruit)
Goto Kola
Japanese Honeysuckle (flower)
Kelp
Kudzu (shoot)
Lemongrass
Mugwort
Noni
Papaya (leaf, fruit)
Purslane Sage (leaf)
Safflower (flower)
Sassafras
Scullcap
Shepherd's Purse
Stinging Nettle (leaf)
Turmeric (rhizome)
Water Lotus
1. National Kidney Foundation. http://www.kidney.org/atoz/content/herbalsupp.cfm 53
National Kidney Foundation and Their Stance on Natural Products Which herbal supplements have phosphorus? Phosphorus is a mineral that may need to be limited in the diet of people with kidney disease especially for those on dialysis. Some herbal supplements that have phosphorus include:
American Ginseng
Bitter Melon
Borage (leaf)
Buchu (leaf)
Coriander (leaf)
Evening Primrose
Feverfew
Flaxseed (seed)
Horseradish (root)
Indian Sorrel (seed)
Milk Thistle
Onion (leaf)
Pokeweed (shoot)
Purslane
Shepherd's Purse
Silk Cotton Tree (seed)
Stinging Nettle (leaf)
Sunflower (seed)
Turmeric (rhizome)
Water Lotus
Yellow Dock
1. National Kidney Foundation. http://www.kidney.org/atoz/content/herbalsupp.cfm 54
National Kidney Foundation and Their Stance on Natural Products What about herbal supplements that act like a "water pill"? Some herbal supplements that act like a diuretic or "water pill" may cause "kidney irritation" or damage. These include: • Bucha Leaves • Juniper Berries • Uva Ursi • Parsley Capsules
1. National Kidney Foundation. http://www.kidney.org/atoz/content/herbalsupp.cfm 55
Conclusions • Natural does not mean safe, especially for CKD patients. • Be smart and ask your patients about natural product use. • Engage your patient about safe use of dietary supplements. • Report adverse events: http://www.fda.gov/Food/DietarySupplements/Report AdverseEvent/ 56
