Herbal Therapies and the Patient with Kidney Disease

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Herbal Therapies and the Patient with Kidney Disease

The primary importance of the passage of urine for maintenance of health was recognized by early students of physiology, including Dioscorides and Pliny the Elder, 1st century scholars with broad knowledge of medicinal plants.( 1, 2) Dioscorides mentioned 12 plants which could be used for treatment of diseases of the kidneys in his De Materia Medica, while Pliny details 130 plants in his famous treatise Naturalis Historia. Unfortunately, we have not progressed much in our knowledge of the place for botanical therapy in renal diseases since that time.

In this article, I will attempt to briefly review the main function(s) of the kidneys, and then discuss the potential hazards of using herbs in patients with compromised renal function. Finally, I will discuss potential benefits which could be derived from using herbs in this population and the data (meager that it is) which supports my contentions.

Review of Kidney Function

The two kidneys, which together weigh 200 to 320 grams, are truly the seat of homeostasis in the body. Kidney damage leads to disorders, not only of salt and water, but of blood and bone as well.( 3) Kidney function can be broken clown into several parts: control of salt and water balance, filtration of solute, and maintenance of acid-base equilibrium and endocrine functions (see Table 1). Each function can be affected separately by therapies or, in the case of disease or toxic insult, all three may be affected.

Salt and Water Balance

The basic working unit of the kidney is the nephron, which contains a tuft of capillaries, called the glomerulus, and a system of tubules. Plasma is ultrafiltered across the glomerular surfaces at a rate of 135 to 180 L/day, which would result in death by dehydration if it were not largely reabsorbed. Initially, the ultrafiltrate enters the first part of the tubules, the proximal tubule, where 70% of the filtered water and sodium are reabsorbed. Further regulation occurs at the loop of Henle, where more sodium is reabsorbed and finally, at the collecting system, the final regulation of salt and water balance occurs. Sodium can be reabsorbed in the cortical collecting duct until almost none remains in the urine, and, under the control of antidiuretic hormone (ADH), water can be reabsorbed or allowed to remain in the ultrafiltrate, resulting in either a concentrated or dilute urine.

Abnormal volume regulation is a major component of most renal diseases, resulting in fluid overload with secondary hypertension and, often, edema. Many herbs which have been used historically to treat diseases of the kidneys, including dandelion leaves and/or root (Taraxacum officinale), bearberry (Archtostaphylus uvaursi), parsley (Petroselinum crispum), and broom (Cytisus scoparius) have diuretic properties and probably function through alteration of sodium reabsorption or ADH action. Interestingly, dandelion root contains large quantities of inulin, an insoluble carbohydrate which is cleared similarly to creatinine (see below) and could act as an osmotic diuretic. Broom is known to contain scoparin, a glycoside which is believed to be responsible for its diuretic action.( 4)

Filtration of Solute/Maintenance of Acid-Base Balance

The glomerular capillary wall serves as a barrier which determines which solutes are filtered. Filtration is determined by size-selectivity, as well as ionic charge. Solutes smaller than molecular weight of 6,000 are freely filtered, whereas those as large as albumin (or bound to albumin) are not (M.W. 70,000), unless the glomerulus becomes diseased. Filtration of highly negatively charged substances, regardless of size, is retarded by electrostatic repulsion due to the anionic charge on sialoproteins which are present in the glomerular basement membrane and epithelial foot processes. The glomerular filtration rate (GFR) determines the clearance, not only of sodium, but also of toxic waste products of metabolism including blood urea nitrogen (BUN) and creatinine which, in addition to filtration, undergoes active secretion at the proximal tubule.

Control of GFR is multifactorial, depending on the hydrostatic pressure gradient within the glomerulus which drives fluid out (and which in turn depends on renal plasma flow rate), the plasma oncotic pressure, which counteracts the hydrostatic forces, as well as surface area of the glomerular capillary tuft and its permeability characteristics. If any of these factors are altered, through disease or administration of a drug or herb, the GFR will fall, eventually leading to renal insufficiency and retention of waste products.

The kidney plays an important role in maintenance of acid-base balance. Ninety percent of filtered bicarbonate is reabsorbed in the proximal tubule through a complex series of steps involving active transport of hydrogen ions into the lumen of the tubule. The remainder is reabsorbed in the distal tubule and collecting duct. Anything which deranges tubular function (substances which are toxic or cause fibrosis) may cause acidosis through loss of bicarbonate in the urine.

Control of potassium secretion occurs both in the distal tubule and (predominantly) in the collecting duct. Potassium secretion is mediated through the actions of the adrenal hormone aldosterone which is under the control of renin (see below) and serum potassium concentration. Damage to the collecting tubules rendering them insensitive to aldosterone, decreased aldosterone release due to adrenal disease or deficient renin release and decreased GFR all can cause hyperkalemia which can be life-threatening. For this reason, it is imperative to AVOID potassium-containing botanical products in patients with known tendency toward hyperkalemia. Conversely, overuse of diuretics can contribute to hypokalemia through increased delivery of sodium to the distal and collecting tubules.

The kidney also controls levels of phosphate, calcium (both mediated in part via the actions of parathyroid hormone), magnesium, uric acid and various arnino acids through complex mechanisms which are beyond the scope of this article, but which, when deranged, can lead to abnormal concentrations of these substances in the blood and/or urine.

Endocrine Functions of the Kidney

The glomerular blood flow is under auto-regulatory control via at least two substances: renin, released from the juxtaglomerular apparatus, and prostaglandins, which have important effects on moderating regional renal blood flow. Renin, which is stimulated in situations where renal blood flow is decreased (decreased renal mass, hypotension, renal artery stenosis, heart or liver failure, true volume depletion) acts on renin-substrate to produce angiotensin I, which is converted to angiotensin II via angiotensin-converting enzyme (ACE). Renal prostaglandins have many effects on kidney function, which differ depending on the prostaglandin type involved, and also serve to maintain GFR when renal blood flow is compromised by preferentially shunting blood to the renal cortex, which has the highest concentration of glomeruli. The result is that any substance, be it a pharmaceutical agent or herb, that depresses either angiotensin conversion or prostaglandin synthesis, can decrease renal function in the settings of compromised renal function or severe volume depletion.

The proximal tubule plays a role in the maintenance of red cell volume and the conversion of vitamin D to its active metabolite. Specialized tubule cells secrete a hormone, erythropoietin, which stimulates the erythroid progenitor cells of the bone marrow to mature in response to anemia or hypoxia.( 5) Inadequate synthesis secondary to kidney disease results in anemia, and requires replacement by the synthetic recombinant hormone. Vitamin D (cholecalciferol), following synthesis in the skin, undergoes 25-hydroxylation in the liver, followed by conversion to 1,25-cholecalciferol in the proximal convoluted tubule of the kidney. Synthesis of active vitamin D is stimulated by parathyroid hormone and hypophosphatemia and when it is insufficient, hypocalcemia can occur, predominantly because of deficient absorption from the intestine.

Treatment of Kidney Diseases

Diseases which affect the kidney are many and varied (see Table 2), as can be surmised by its myriad functions. Diseases of the glomerulus are either glomerulonephritides, which may be accompanied by blood in the urine, hypertension and inflammatory response within the kidney and glomerulonephroses, which are always accompanied by loss of protein into the urine, often accompanied by hypertension and edema. The former diseases usually result in a loss of kidney function which may or may not be reversible, while the latter are more variable in their effect on kidney function, but carry a great morbidity due to accompanying hypoalbuminemia.

Diseases of the tubules are generally secondary to toxic insult, ischemia or interstitial inflammation (interstitial nephritis) which can follow exposure to pharmaceutical agents, most commonly antibiotics and nonsteroidal anti-inflammatory agents (NSAIDs). Diseases of the collecting system tend to be infectious or neoplastic in nature, or mechanical, such as obstruction by stone or blood clot.

Because the kidney is a highly vascular organ, diseases of the blood vessels (vasculitides) can also affect the kidney, compromising blood flow. Constriction of the blood vessels leading to the glomerulus can alter kidney function, as can decreased blood flow due to volume depletion, sepsis, heart failure or other shock situations.

Unfortunately, traditional allopathic medicine has little to offer once kidney disease occurs. Some glomerular diseases are treated with highly toxic immunosuppressive medications, but few respond. Most tubular diseases will either get better on their own, or the patient will develop end-stage renal disease (ESRD). Once ESRD occurs, the patient is given an option of hemodialysis, which requires attachment to a machine which passes the blood by a dialysis membrane through which dialysate flows in a counter-current direction. This requires on average, three to four hours per session, three times weekly. The patient may also undergo peritoneal dialysis, in which case a special catheter is implanted into the patient's peritoneal cavity and dialysate solution instilled and removed up to six times daily. Neither hemo- nor peritoneal dialysis restores the endocrine functions of the kidneys, which requires the patient to take medications for maintenance of calcium balance and avoidance of anemia. Finally, the patient may undergo transplantation of a cadaveric or living-donor kidney, which requires continuous immunosuppression, but restores all of the functions of the patient's native kidneys.

Until the 1960s, there was no treatment for ESRD and all patients died from the buildup of toxic waste products which accumulated in the blood. Since that time dialysis and transplantation have become readily available in the United States, but very few references are available which address using herbal therapy to prevent progression of kidney disease. In many areas throughout the world today, however, including the Caribbean, South America and most of Asia, dialysis is only available for the wealthy or politically connected, and a strong tradition of treating renal disease with herbal medicines exists. Unfortunately for us, the treatments have been known mostly to local shamans or practitioners of traditional herbal medicine who closely guard their "prescriptions."

Herbal Therapies

In a recent review of the data available on "Medline" there were only seven references which appeared upon cross-search in "kidney" or "renal" and "herbs." Four of these references were negative and discussed recent outbreaks of severe interstitial fibrosis in a Belgian population following ingestion of a Chinese "slimming herb" mixture.( 6, 7, 8) The other references were published in Chinese journals and hinted at the possibility of affecting not only nephroses (see above) but also slowing the progress of established kidney disease.( 9, 10) The dearth of modern research stands in contrast to the interest expressed historically by herbologists; in the previously mentioned work by Pliny the Elder with 130 herbs and in a compendium of herbal medicines published in 1931, no fewer than 99 herbs were listed for the treatment of "kidney disorders or dropsy" (edema). Even a recent review of the NAPRALERT database revealed 28 herbs or classes or herbs with purported "antinephritic" or "antinephrotoxic" effects.( 11)

In the sections which follow, I will discuss specific concerns which must be borne in mind when faced with a patient with compromised kidney function as well as potential areas of use for herbs in patients with kidney disease. At this point, I would state that, because of the complexity of the interplay of the kidney and many other body systems, unless one has been trained in nephrology, an herbalist or herbal practitioner should NOT prescribe herbs for a patient with renal insufficiency without discussion with the patient's primary physician.

Potential Hazards of Using Botanicals in the Patient with Renal Disease

As can be surmised from a review of peer-reviewed literature, there have been no controlled research projects focusing on the use of botanicals in the treatment of kidney disease, at least in the English literature. Part of the problem lies in the potential hazards of using botanicals in this population (Table 3), which are unique to the patient with renal impairment. Because the pharmacokinetic characteristics of many herbal products are not readily available, it is impossible to know whether the major route of elimination is through hepatic metabolism or renal excretion. In the latter situation, overdosing could occur once the patient has developed renal insufficiency, because of retention of metabolites or parent compounds.

Many patients with renal disease, especially those who have received a kidney transplant, are on potent medications. Any herb (or drug for that matter) which affects the hepatic cytochrome p450 system, will alter the level of the fungal immuno-suppressants, cyclosporine or tacrolimus, with potentially disastrous results. Again, for that reason, a transplant physician should always be aware when an herb is administered to a transplant recipient, so that drug levels can be monitored and doses adjusted if needed.

Herbs can have direct toxicity for kidney tissue. The aforementioned "Chinese herb nephropathy" is believed to result from progressive fibrosis of the renal interstitium believed to be secondary to aristolochic acid affecting intrarenal DNA.( 7) Herbs which have not been widely used, or are used in high doses, should definitely be avoided in the renal population. In addition, renal function could be affected by changes in intrarenal autoregulatory hemodynamics (see above), similar to the effects of NSAIDS or angiotensin-converting enzyme (ACE) inhibitors, resulting in loss of kidney function. Theoretically, as some herbs may have anti-inflammatory properties mediated through alteration of prostaglandin synthesis, and even affect ACE inhibition, patients who unwittingly take large quantities of herbs with these properties might experience a decline in renal function.

It should be remembered that most renal patients are taking a variety of pharmaceutical agents for blood pressure, and often for blood glucose control. Any herb which might potentiate the effects of the patient's medications, although it may be beneficial in allowing the patient to taper pharmaceutical agents, should be used with caution, and with the knowledge of the patient's primary physician. This is especially true in the case of patients with diabetes, whose insulin requirements fall as uremia (kidney failure) approaches due to the decreasing ability of the kidney to metabolize insulin.( 12)

As mentioned previously, patients whose kidneys are failing or who are on dialysis often have a host of electrolyte abnormalities. Many of the herbs which have traditionally been used in the treatment of kidney disorders have diuretic properties, and some (e.g. dandelion leaf) are high in potassium. Ingestion of licorice (Glycyrrhiza glabra) has been associated with pseudo-hyperaldosteronism, manifested by decreased potassium levels, sodium and water retention and hypertension.( 13) It is imperative that patients taking such herbs have serum electrolytes measured at routine intervals in order to avoid potentially fatal hyper- or hypokalemia.

A special concern of patients who are already on dialysis is the unpredictable effect dialysis will have on the clearance of the herb itself. Large substances (M.W. 500 to 40,000 daltons) and charged smaller substances are not cleared well by the dialysis membrane and may accumulate, but smaller substances, especially if they are water soluble, will be rapidly cleared, leading to unpredictable plasma levels.( 14)

Finally, patients who have received a kidney transplant must be concerned not only with alteration of essential drug metabolism but also with potential hepatotoxicity, as the fungally derived immunosuppressants, cyclosporine and tacrolimus, have hepatotoxic properties, especially when administered at high doses. ( 15) These patients should also be concerned with any herb which might stimulate the immune system. Although graft rejection occurs, for the most part through alloantigen recognition and activation of helper T-cells, B-cells and macrophages also play a role in antigen presentation and theoretically herbs such as Echinacea purpurea or Japanese mushrooms, such as shiitake, maitake and reishi, could be detrimental, especially in the immediate post-transplant period.

Potential Benefits of Using Herbs in the Patient with Renal Disease

Despite these concerns, I believe that botanical products could produce tremendous benefit in the patient with renal impairment/failure, if used judiciously, and in conjunction with a sympathetic allopathic kidney specialist. Table 4 lists areas in which herbs might be of benefit. Table 5 lists specific herbs which have been studied or have been reported to have renoprotective effects.

As the progressive nature of many renal diseases is believed to be secondary to inflammatory responses and platelet activation,( 16) herbs which act as anti-inflammatory agents could have long-term beneficial effects. This is believed to be the mode of action (if the preliminary data can be reproduced) of the combination of Astragalus sp. and Rehmannia glutinosa (Men-shen-ling) which has been used to treat chronic glomerulonephritis in China.( 9) Other herbs such as wintergreen contain methyl salicytate, which has anti-inflammatory properties.( 4)

The herbs which have been traditionally used, as listed in early herbals such as the 1931 A Modern Herbal of Mrs. Grieve,( 4) or the more "modern" herbals such as the CD-ROM developed by Genusys( 17) or the NAPRALERT database, ( 11) have unclear activity (if any). Theoretically, herbs with ACE-inhibitory effects might be used to decrease proteinuria, and other herbal preparations could be used as adjunctive therapy for diabetes, such as those used in diabetic patients without kidney disease( 18) (see also Case Report 2) or hypertension and hyperlipidemia,( 19) which often accompany kidney disease.

Herbal therapies, including corn silk (Zea mays) and marshmallow (Althea officinalis), which are used as demulcents, and the aptly named gravel root (Eupatorium purpureum) and stone root (Collinsonia canadensis), as well as ellitory of the wall (Parietaria officinalis) which are purported to have "anti-lithic" and diuretic properties, have long been employed in the treatment of renal stones.( 20) These may have tremendous potential in the treatment of these disorders. Unfortunately, the efficacy of these herbs in the treatment of various stone disorders (calcium based vs. uric acid vs. struvite) has not been systematically studied, nor are the mechanisms of action known. In a rat model, Verbena officinalis, Lithospermum officianale, Taraxacum officianale, Equisetum arvense, Arctostaphylos uva-ursi and Arctium lappa were found to have mild antibacterial action and the ability to alkalinize the urine, which resulted in solvent action on uric acid stones.( 21) For patients with stone disease accompanied by renal insufficiency, it would probably be wise to avoid herbal therapies because of uncertainty regarding the pharmaco-compounds which undergo renal excretion (or they wouldn't act on renal stones!).

For hemodialysis patients, botanical approaches may turn out to be excellent substitute therapies in this population, which requires multiple pharmaceutical agents with frequent side effects. Adjunctive therapy for blood pressure control (both for hypo- and hypertension), improvement of uremic bruising via improvement of capillary fragility using bilberry (Vaccinium myrtillus) or other herbs rich in bioflavonoids, improvement or maintenance of energy levels with adaptogens or identification of herbs which enhance iron or calcium absorption might be fruitful areas for research. One of my colleagues reports that he has used 150 mg of a standardized (0.5% essential oils) extract of valerian root (VaIeriana officinalis) to calm overly anxious patients during hemodialysis and allow them to complete the procedure without the drowsiness which occurs following benzodiazepine use.

In renal transplant recipients, I have successfully used bilberry extract (see Case Report 1) for the treatment of prednisone-associated bruising. Cyclosporine-treated patients are at increased risk for gout, which is extremely resistant to treatment. As NSAIDs are typically contraindicated in this population because of the potential for decreasing renal function, we have utilized botanical products rich in linolenic acid (e.g. oil of evening primrose or flaxseed oil), without untoward effects (see Case Reports 2 and 3). Again, the "adaptogenic" potential of the ginsengs might be of use in these patients who undergo chronic corticosteroid therapy, although the potential for immune stimulation must be borne in mind, and such therapy should probably be reserved for stable patients in the late post-transplant period (see Case Report 2).

An interesting and potentially beneficial herb for renal transplant recipients with hepatitis B or C is milk thistle (Silybum marianum). I have used this herb, at a dose of 420 mg (80% silymarin content) taken in three divided doses, in several patients. In one patient we observed a complete reversal of her liver dysfunction, which is very uncommon in immunosuppressed patients (Case Report 3). As this herb has proven hepatoprotective effects,( 22) and the drugs cyclosporine and tacrolimus undergo extensive hepatic metabolism and have hepatotoxic properties,( 15) it might be prudent to include milk thistle extract in every patient's regimen.

Renal transplant recipients commonly develop urinary tract infection, and may require chronic antibiotic prophylaxis. Use of herbs which have antibacterial or demulcent activity (e.g. cranberry, corn silk) may be helpful in this regard.

Finally, the drugs which we use as primary immunosuppressants, cyclosporine and tacrolimus, have nephrotoxic effects.( 15) An isolate of ginkgolides from Ginkgo biloba, BN52063, has been shown in a rat model to protect against acute cyclosporine nephrotoxicity.( 23) In addition, the same isolate has been reported to decrease the incidence of early delayed graft function in a human trial.( 24) It is not known whether a standardized ginkgo extract would be as effective.

Finally, several herbs( 25, 26, 27) have been shown to be renoprotective in animal models of drug toxicity. After administration of a tubulotoxin such as cisplatinum or cyclosporine, it is believed that tubule cells die and the medulla becomes ischemic, resulting in the generation of free radicals by the remaining viable cells.( 28) Herbs such as the ones mentioned above, and other with potent antioxidant properties, may be able to prevent damage by oxygen radicals in known situations where nephrotoxicity may result (e.g. administration of nephrotoxic drugs, exposure to radiocontrast agents).

Summary and Conclusions

Obviously, botanical medicine use in the patient with kidney disease is a potentially fruitful area for research. In reviewing the data available for this paper and in talking with many patients and colleagues, several observations become apparent. Although herbs have been used both in this country and in others for centuries for the treatment of kidney diseases, actual data regarding efficacy and safety are close to nonexistent. As Pliny the Elder astutely observed almost 2,000 years ago, "Experience, the most efficient teacher of all things especially in medicine, gradually degenerated into mere words and verbage. For it was pleasanter to sit diligently listening in lecture-rooms than to go into the fields and look for different plants at different seasons of the year."

As the potential for patient benefit and the interest on the part both of patients and nephrologists alike are both tremendous, ideally, nephrologists, nurses, naturopaths, pharmacognosists, herbalists and others with an interest in both herbs and kidney patients will form a collaboration in order to answer some of the questions I have raised here and allow us to judiciously use herbs in this very complex patient population. Until that time, I will close by advising that the practitioner trained in herbal medicine should not consider administering botanicals to a patient with renal disease without collaborating with the patient's primary physician. I would also advise renal specialists to become familiar with herbs so that we can carefully begin to enlarge our clinical and research experience for the benefit of our patients.

References
(1) De Matteis Tortora M. Some plants described by Dioscorides for the treatment of renal diseases. Am I Nephrology 1994; 14:418-22.

(2) Aliotta G, Pollio A. Useful plants in renal therapy according to Pliny the Elder. Am I Nephrology 1994; 14:399-411.

(3) Rose B. Clinical Physiology of Acid-Base and Electrolyte Disorders. New York McGraw-Hill Company, 1984.

(4) Greive M. A Modern Herbal, Vols. 1, 2. New York Dover Publications, 1971.

(5) Dunn CJ, Markham A. Epoetin beta. A review of its pharmacologic properties and clinical use in the treatment of anaemia associated with chronic renal failure. Drugs 1996; 51(2):299-318.

(6) Depierrieux M, Van Damme B, Vanden Houte K, Vanherweghem JL. Pathologic aspects of a newly described nephropathy related to the prolonged use of Chinese herbs. Am J Kidney Dis 1994; 24(2):172-80.

(7) Schmeiser HH, Bieler CA, Wiessler M, van Ypersele de Strihou C, Cosyns JP. Detection of DNA adducts formed by aristolochic acid in renal tissue from patients with Chinese herbs nephropathy. Cancer Res 1996; 56(9):2025-8.

(8) Cosyns JP, Jadoul M, Squifflet JP, De Plaen IF, Ferluga D, van Ypersele de Strihou C. Chinese herbs nephropathy: a clue to Balkan endemic nephropathy? Kidney Int 1994; 45(6):1680-88.

(9) Su ZZ, He YY, Chen G. [Clinical and experimental study on effects of man-shen-ling oral liquid in the treatment of 100 cases of chronic nephritis] [Chinese]. Chiung-Kuo Chung Hsi Chieh Ho Tsa Chih 1993; 13(5):269-72, 259-260.

(10) Li L, Wang H, Zhu S. [Hepatic albumin's m-RNA in nephrotic syndrome rats treated with Chinese herbs] [Chinese]. Chung-Hua Hsueh Tsa Chih [Chinese Medical Journal] 1995; 75(5):276-9.

(11) NAPRALERT database. A natural products database maintained at the Program for Collaborative Research in the Pharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL 60612.

(12) DeFronzo RA, Castellino P. Metabolic and endocrine disturbances in uremia. In: Massry SG, Glassock RJ, eds. Textbook of Nephrology, 2nd ed. New York Williams and Wilkins, 1989, 1221-7.

(13) Anon. Medical Letter on Drugs and Therapeutics 1979; 21 (7):30.

(14) Van Stone JC, Daugirdas IT. Physiologic principles. In: Daugirdas IT, Ing TS, eds. Handbook of Dialysis. New York Little Brown Publishing, 1994, 13-35.

(15) Gruber SA, Chan GLC, Canafax DM, Matas AI. Immunosuppression in renal transplantation. Clin Transplantation 1991; 5:65-85.

(16) Couser WG, Johnson RJ. Mechanisms of progressive renal disease in glomerulonephritis. Am J Kidney Diseases 1994; 23(2):193-8.

(17) Genusys Pharmacopoeia of Herbs, CD-ROM, publishers Genusys labs, Solebury, PA 18963, 1996.

(18) Sotaniemi EA, Hapakoski E, Rautio A. Ginseng therapy in non-insulin-dependent diabetic patients. Diabetes Care 1995; 18:1373-5.

(19) Silagy C, Neil A. Garlic as a lipid-lowering agent: a meta-analysis. J Royal College Physicians London 1994; 28(1):39-45.

(20) Hoffman D. The Complete Illustrated Holistic Herbal. Rockport, MA: Element Books, 1996.

(21) Grases F, Melero G, Costa-Bauza A, Prieto R, March JG. Urolithiasis and phytotherapy. Int Urol Nephrol 1994; 26(5):507-11.

(22) Palasciano G, Portincasa P. The effect of silymarin on plasma levels of malondealdehyde in patients receiving long-term treatment with psychotropic drugs. Curr Ther Res 1994; 55:537.

(23) Priotzky E, Colliez P, Guilmard C, Schaeverbeke J, Braquet P. Cyclosporine-induced nephrotoxicity: preventive effect of a PAF-acether antagonist, BN 52063. Trans Proc 1988; 20(suppl 3):665-9.

(24) Grino JM. BN 52021: a platelet activating factor antagonist for preventing post-transplant renal failure. Ann Intern Med 1994; 121(5):345-7.

(25) Inselmann G., Blohmer A., Kottny W, Nellessen U, Hanel H, Heidemann HT. Modification of cisplatin-induced renal p-aminohippurate uptake alteration and lipid peroxidation by thiols, Ginkgo biloba extract, deferoxamine and torbafylline. Nephron 1995; 70:425-9.

(26) Xuan W, Dong M, Dong M. Effects of a compound injection of Pyrola rotundifolia and Astragalus membranaceus Bge on experimental guinea pigs' gentamycin ototoxicity. Ann Otology Rhinol Laryngol 1995; 104(5):374-80.

(27) Gaedeke J, Fels LM, Bokemeyer C, et al. Cisplatin nephrotoxicity and protection by silibinin. Nephrol Dial Transplant 1996; 11:55-62.

(28) Baliga R, Ueda N, Walker PD, Shah SV. Oxidant mechanisms in toxic acute renal failure. Am J Kidney Diseases 1997; 29(3):465-77

Table 1: Functions of the normal kidneys (summarized)

Maintenance of blood pressure

Filtration and reabsorption of sodium

Maintenance of appropriate volume (water balance)

Synthesis of active hormones and autocoids (renin, kinins, prostaglandins)

Maintenance of electrolyte homeostasis

Filtration, reabsorption and secretion of potassium

Filtration and reabsorption of magnesium, chloride and other electrolytes

Maintenance of acid-base balance (bicarbonate reabsorption, hydrogen ion secretion)

Filtration and elimination of metabolic waste products (BUN, creatinine -- also secreted)

Filtration, secretion and reabsorption of other solutes (amino acids, glucose)

Maintenance of calcium and phosphorous balance

Final hydroxylation (activation) of vitamin D Filtration and reabsorption of phosphate and calcium (PTH dependent) Maintenance of hematocrit/hemoglobin Synthesis of erythropoietin

Table 2: General diseases of the kidneys (by no means all-inclusive)

Glomerulopathies

Glomerulonephritis

Acute glomerulonephritis

Rapidly progressive glomerulonephritis

Chronic glomerulonephritis

Nephrotic syndrome (nephrosis)

Tubulopathies

Toxic insult (drugs, poisons, radiocontrast dye)

Ischemia (hypotension, blood loss, volume depletion)

Allergic interstitial nephritis

Vasculopathies

Vasculitis (e.g., systemic lupus, polyarteritis nodosa, primary vasculitis)

Hemodynamic disorders

Thrombosis of the renal artery or vein

Renal artery stenosis

Overuse (or misuse) of NSAIDs or ACE inhibitors

Hepatorenal syndrome

Obstructive disorders

Infection

Renal stones

Papillary necrosis (diabetes, pyelonephritis, sickle cell anemia)

Tumors (extrinsic or intrinsic)

Prostate disease

Table 3: Potential hazards of using botanicals in patients with renal disease

General:

Unpredictable pharmacokinetics (under- or overdosing)

Interactions with patient's pharmaceutical agents

Negative effect on kidney function

Toxicity for kidney tissue

Hemodynamic alterations leading to decreased GFR

Unpredictable effects on blood pressure or blood glucose

Potentiation of electrolyte abnormalities (especially herbs with high potassium content or diuretic function)

Dialysis patients (in addition to general concerns):

Potential dialyzability of active compounds or metabolites -- under- or overdosing

Renal transplant recipients (in addition to general concerns):

Unpredictable effects on immune function

Synergistic hepatotoxicity

Table 4: Areas in which herbs might benefit patients with renal disease

General:

Decreased inflammatory response

Decreased proteinuria

Control of hypertension, hyperglycemia and/or hyperlipidemia

Decreased rate of progression to end-stage renal disease

Improved diuresis

Management of renal stone disease

Treatment of chronic urinary tract infection

Dialysis patients:

Improved blood pressure control (hypo- or hypertension)

Decreased uremic bruising

Increased energy

Maintenance of calcium and iron balance

Anti-anxiety therapy during hemodialysis treatment

Renal transplant recipients: (in addition to general benefits)

Decreased prednisone-induced bruising

Treatment of gout

Adaptogen effect in chronic steroid use

Adaptogen effect in chronic steroid use

Hepatoprotection during use of fungally derived immunosuppressants

Treatment of hepatitis B and C

Case Reports

Case 1

Ms. F, a 61 year old woman with Addison's disease (adrenal insufficiency), history of a myocardial infarction, type I diabetes and a living-related kidney transplant over 15 years previously was plagued with severe bruising secondary to prolonged corticosteroid use and low dose aspirin. She had normal coagulation parameters (prothrombin and partial-thromboplastin time) and platelet count. Three weeks after starting bilberry extract (250 mg twice daily), she experienced lessening of her bruising. Now almost six months later, she has minimal bruising and has experienced no untoward effects of the bilberry. She also takes azathioprine, furosemide, losartan, amlodipine, erythropoietin, lovastatin, calcium, magnesium and zinc supplements.

Case 2

Mr. F, a 40 year old man, with type I diabetes since childhood, received a cadaveric kidney with excellent renal function. Despite tapering the doses of his medications, his blood glucose control was erratic and he was frustrated and felt unwell at two years post-transplant. He was started on Asian ginseng extract (100 mg twice daily) and Gingko biloba extract (30 mg twice daily). Within one month, his blood glocuses improved, with glycosylated hemaglobin dropping from 8.6% to 7.9%. Two months later he developed worsening of his blood glucose after "running out of the herbs." Resumption of therapy resulted again in improvement in his blood sugars and well-being. In addition to taking the ginseng on a six week on, two week off schedule, as well as the ginkgo, he takes garlic (1500 mg softgel), vitamin E (400 IU) and lecithin (1200 mg). He takes the lecithin for gout. He also takes prednisone, cyclosporine, furosemide, enalapril, cisapride, ranitidine, insulin and simvastatin. We have noted no interactions between his pharmaceutical and his botanical products.

Case 3

Ms. G, a 36 year old woman, developed fulminant hepatitis C after receiving a cadaveric kidney transplant. She was given interferon but did not tolerate it and slowly recovered hepatic function, with bilirubins in the 2.5 to 3.5 mg/dl range. Her transaminases remained elevated continuously. At 11 months post-transplant, she was started on milk thistle extract standardized to 80% silymarin (175 mg twice daily). Within nine months, her transaminases normalized and her albumin increased from 2.9 to 3.4 mg/dl (despite nephrotic range proteinuria). One year following initiation of therapy with milk thistle, her bilirubins and transaminases were normal and her gastroenterologist sent her blood for a measurement of viral load and found that hepatitis C was no longer detectable in her serum. She has remained on cyclosporine and prednisone throughout the time and not required a change in her dose of cyclosporine in order to maintain adequate levels. In addition to milk thistle, she takes Ginkgo biloba extract standardized to 24% ginkgo flavone glycosides (50 mg twice daily), 1,000 mg of flaxseed oil (standardized to contain 594 mg alpha-linolenic acid, 144 mg linolenic acid, and 165 mg oleic acid) once daily for gout, which has been incapacitating and for which she also takes lecithin ( 1,000 mg), vitamin E (400 IU), and selenium (50 mcg). Pharmaceutical agents taken by the patient, in addition to immunosuppressive drugs, include erythropoietin, furosemide and clonidine. She also takes an iron preparation, magnesium and calcium supplementation and feels well at this time.

Natural Product Research Consultants, Inc.

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By Mariana S. Markell

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