by Subhuti Dharmananda, Ph.D., Director, Institute for Tradi...
Salvia has been used in treatment of chronic renal insufficiency in China for at least thirty yea...
China had limited ability to provide dialysis or renal transplant until recently, primarily due ...
oxidant agents are emerging as particularly promising therapeutic approaches (18); salvia and rhubarb are
examples of herb...
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  1. 1. THE USE OF SALVIA FOR PATIENTS WITH RENAL FAILURE by Subhuti Dharmananda, Ph.D., Director, Institute for Traditional Medicine, Portland, Oregon BACKGROUND Renal failure is increasingly common, primarily because of high rates of diabetes and hypertension (1). Despite ongoing public alerts about essential dietary controls and exercise requirements for maintaining health, there is heavy reliance on risk-reducing and disease modifying drugs as well as surgical interventions for dealing with the adverse impact of modern lifestyle problems. Renal failure also occurs as the result of systemic autoimmune disorders (e.g., lupus), chronic use of certain nephrotoxic drugs, repeated or severe renal infections, and primary kidney disorders, such as glomerulonephritis and polycystic kidney disease. Except for cases of temporary decline in renal function that may occur from several causes, kidney disease is usually progressive once a significant fraction of nephrons are damaged, and the disorder becomes end- stage renal disease (ESRD). A summary of the incidence and primary causes of ESRD have been monitored and reported. The U.S. data available at this writing comes from reports produced up from 1999 to 2005. Here are the basic statistics showing the increasing frequency of ESRD and the primary causes (2): Incidence (annual new cases) of ESRD: 89,252 (1999); 93,327 (2001); 106,912 (2005) Prevalence (existing cases) of ESRD: 361,031 cases (1999); 392,023 cases (2001); 485,012 cases (2005) 3/4 of the cases attributed to these primary diseases (number of cases indicated): Diabetes: >179,000 Hypertension: >117,000 Glomerulonephritis: >78,000 The cost of treating people with ESRD has been estimated to be $32 billion dollars per year, as of 2005. Most patients are treated by in-center hemodialysis, and to a much lesser extent via other dialysis techniques, and then, when possible, by kidney transplant. The first hemodialysis center was established in Seattle in 1962 and this method became routine in the U.S. in the 1970s; kidney transplantation became a routine procedure in the 1980s. According to the Annual Report of the Organ Procurement and Transplantation Network (3), the kidney transplant waiting list more than doubled in the decade from 1993 and 2003 to over 50,000, and reached 79,000 by the end of 2007. The number of kidney transplants performed in the U.S. increased from less than 10,000 per year before 1990 to over 16,000 per year in 2004. The combined number of those on waiting lists, those who receive transplants, and those in need of transplants but not on the list, now comes to about 100,000 per year. About 2/3 of transplanted kidneys are from cadavers (mainly from auto accidents and other sudden causes of death); the other one-third are from living donors. Both kinds of transplants require immunosuppression, but matched family donors can provide organs that need minimal suppression. During dialysis (e.g., hemodialysis, peritoneal dialysis) and after renal transplant, there is considerable concern about foods, beverages, drugs, nutritional supplements, and herbs that might be taken, since the potential action of their constituents on the remaining kidney function or on other physiological responses that might influence the kidney condition (such as immune system effects) are often unknown or poorly known. Nonetheless, some patients desire assistance with herbs and other natural therapies. An herb of interest is salvia (Chinese: danshen), which has been used in China for patients with early renal failure, for those who are on dialysis, and after renal transplant. Rhubarb (Chinese: dahuang) has also been used for preventing progression of early renal failure and treatment of patients who could not access dialysis or transplant.
  2. 2. SALVIA AND RENAL FAILURE Salvia has been used in treatment of chronic renal insufficiency in China for at least thirty years. In 1978, an article in the Shanghai Journal of Traditional Chinese Medicine reported on this application (4). In 1989, Japanese researchers reported on isolation of a constituent of salvia responsible for promoting renal function, which was identified as lithospermate B (5). This ingredient, like the whole root of salvia, was reported to enhance plasma blood flow and reduce glomerular filtration rate in the kidneys of laboratory animals suffering renal failure; it was later shown to be of potential benefit for diabetic nephropathy (6) and for improving renal microcirculation (7). In 1993, Chinese researchers in Hangzhou reported on the effect of salvia injection in patients undergoing peritoneal dialysis for renal failure, claiming it could markedly increase the clearance rate and ultrafiltration rate of creatinine, urea nitrogen, and uric acid (8). A study in Japan published in 2000 further noted that salvia inhibited nitrogen oxide (NO) production which was thought to be a contributor to both acute and chronic renal failure (9), while a study in Korea published in 2004 suggested that scavenging of free radicals was part of the mechanism of action for both salvia and its component lithospermate B (10) Salvia has also been used in the treatment of patients who have undergone organ transplants to help prevent rejection and aid longevity of the transplants. Pharmacological studies appeared to confirm the value of this application (11). A review of its use in renal transplant patients was published in 2004 (12). Claimed benefits included improvement in nearly all blood parameters that monitor renal function, improved recovery from the transplant, and better protection of the kidney. In a summary statement, the authors noted: According to TCM theory, many symptoms of patients after renal transplantation belong to the category of blood stasis. Many animal experiments proved that salvia has the actions of activating blood circulation and removing blood stasis; it could ameliorate renal ischemia, improve blood circulation and microcirculation in the kidney, thereby enhancing the oxygen utilization ability of the graft’s tissue and accelerating its repair process, which is favorable to preventing rejection. In observing the effect of salvia in treating acute vascular rejection after renal transplantation (Wu Kun et al.,), 81 allograft recipients were treated in two groups: methylprednisolone impulse (control group) and methylprednisolone impulse plus salvia (treated group). Salvia was administered by adding 30 ml of salvia injection in 5% glucose saline (250 ml) for IV dripping. The total therapeutic course was 14 days. Seven parameters—blood urea nitrogen, serum creatinine, creatinine clearance rate (CCr), urine albumin, N-aceytl-D- glucosamine (NAGase), D-dimer (DD), and antineutrophil cytoplasm antibody—were observed and the efficacy of treatment was estimated as effective when the SCr of the recipients decreased by more than 20% or the CCr rose by more than 20%, or when the clinical symptoms were relieved or disappeared; the other cases were considered ineffective. Results showed that the levels for all seven parameters were significantly improved in both groups. Comparisons between the effects in the two groups showed that the results for the treated group were superior to that of the control group in the total effective rate and in the improvement of the levels of NAGase and DD. The authors concluded that salvia could enhance the curative effect of methylprednisolone impulse in controlling acute vascular rejection. Further study showed that DD, as the simplest degradation product of fibrin monomers, increased in vascular rejection, suggesting that a hypercoagulative state and hyperfibrinolysis might affect the microcirculation of the allograft and result in microthrombus formation in the allograft. NAGase is a renal tubular lyosomal enzyme; increase in its activity reflects the damage to the renal parenchyma. Salvia treatment could reduce the titer of the two parameters, the mechanism is related to its effects in regulating capillary tension, improving hemorrheological properties, impacting activity of fibrinolysis, suppressing platelet aggregation, reducing blood viscosity, inhibiting the excessive expression of nitrogen monoxide (NO) and peroxide, and improving microcirculation, and thus improving function of the transplanted kidney. Huang Zufa, et al., also reported that salvia is able to enhance the curative effect of immunosuppressant, protect renal tubular epithelial cells, and accelerate the recovery of renal function of the graft. 2
  3. 3. RHUBARB AND RENAL FAILURE China had limited ability to provide dialysis or renal transplant until recently, primarily due to economic conditions. Herbal therapies were devised to treat patients with early renal failure. The common ingredient in virtually all the treatments was rhubarb root; it could be used alone, but was usually incorporated into formulas, and it might be given by retention enema, IV injection, or in decoctions given orally. A difficulty with rhubarb treatment is that it usually produced loose stool or diarrhea. This method of treatment persisted into the 1990s, but is used less now that dialysis and transplantation are available. Still, it is worth investigating, because low to moderate doses of rhubarb may provide some benefits. The traditional medicine rationale for using rhubarb in treatment of patients with renal failure is that the disease is marked by an underlying condition of deficiency (which allows the deterioration) and an overlay of excess, namely stagnation of blood and accumulation of damp and turbidity. Rhubarb is applied to address the excess through its purgative and diuretic qualities, as well as its blood-vitalizing activity. While alleviating this secondary condition, therapies for the underlying deficiencies might be applied, relying mainly on tonic formulas that address the specific types of deficiency (e.g., yin deficiency, qi deficiency, etc.). In a study published in 1995 (13), patients with chronic renal failure were treated by traditional Chinese medicine according to standard methods of differential diagnosis; tonic formulas selected accordingly, but each prescription was also accompanied by rhubarb, with 8–12 grams in a daily decoction. The dosage of rhubarb was adjusted so that the patients experienced no more than two soft stools daily, thus avoiding electrolyte imbalances or other problems from the purgative action of the herb. Both the herb-treated patients and a control group were provided modern medical therapies, such as restricting protein intake and treating specific disorders with drugs (e.g., infections, hypertension). Patients were not undergoing dialysis. According to the authors, the herb therapies resulted in slowed or partially reversed disease progression in about 82% of cases. Some researchers focused on use of specific formulas along with rhubarb, rather than multiple formulas. For example, in a study of herb therapy for patients with chronic renal failure, the well-known traditional formula Xiao Chaihu Tang was used with addition of rhubarb (6 grams per day) and leonurus. Xiao Chaihu Tang belongs to the harmonizing group of herbal therapies. The case was made that this combined therapy (harmonizing plus rhubarb) could alleviate several factors that contribute to progression of chronic renal failure, including hypertension, high blood viscosity, and immune attack against nephrons. Use of the formula led to the observed result of slowed progression of the disease (14). Another approach described in the literature is to use herbs that invigorate spleen function to remove accumulated dampness and turbidity, along with rhubarb and other herbs to activate circulation and reduce excess (15, 16). A treatment was devised based on Liu Junzi Tang, a traditional formula for the spleen weak and damp syndrome, adding rhubarb (15 grams/day) and several blood vitalizing herbs such as sparganium, zedoaria, tang-kuei, and cnidium. This study was long-term (patients treated for 10–18 months) and involved patients with chronic glomerulonephritis (15). Another long-term study (treatment duration 10–22 months) relied on a qi tonic and damp-eliminating formula with astragalus, pseudostellaria, hoelen, alisma, and pinellia, along with rhubarb (10 grams/day) and blood vitalizing herbs: red peony, cnidium, and millettia (14). All patients were treated with modern medicine as appropriate, but no dialysis was utilized; the control group did not receive the herb therapies. As with the other studies, improvements in blood markers were found and progression of the disease was reported to be notably slowed in the herb group. A formula with salvia and rhubarb, plus tonic herbs (such as astragalus, cordyceps, and codonopsis) was reported to display nephroprotective effects in an animal model (17). OTHER MEASURES In presenting potentially useful herbal interventions, it is important to note that there are other important considerations in treatment of patients with renal failure, some of them were prominently mentioned in the study reports cited above, including low-protein diets and blood pressure control as the primary concerns. Other interventions, such as the administration of lipid-lowering agents, anti-inflammatory drugs, and anti- 3
  4. 4. oxidant agents are emerging as particularly promising therapeutic approaches (18); salvia and rhubarb are examples of herbs that may contribute all these potentially useful benefits. REFERENCES 1. Meguid El Nahas A and Bello AK, Chronic kidney disease: the global challenge, Lancet 2005; 365(9456); 331–340. 2. National Kidney and Urological Diseases Information Clearing House, Kidney and Urologic Diseases Statistics for the United States; 3. Organ Procurement and Transplantation Network, Scientific Registry of Transplant Recipients Data Reports,, 2007 Annual Report; 4. Chang HM and But PPH (editors), Pharmacology and Applications of Chinese Materia Medica, 1986 World Scientific, Singapore. 5. Yokozawa T, et al., Isolation of a renal function-facilitating constituent from the Oriental drug, Salvia miltiorrhiza root, Japanese Journal of Nephrology, 1989 31(10): 1091–1098 6. Lee GT, et. al., Delayed treatment with lithospermate B attenuates experimental diabetic renal injury. Journal of the American Society of Nephrology 2003; 14: 709−720. 7. Chen CG and Wang YP, Magnesium lithospermate B ameliorates renal cortical microperfusion in rats, Acta Pharmacologica Sinica, 2006; 27(2):217–222. 8. Xu ZC, Effect of injection Salvia miltiorrhizae on peritoneal dialysis, Chinese Journal of Integrated Traditional and Western Medicine, 1993;13(2): 74–6, 67. 9. Yokozawa T, Chen CP, Role of Salvia miltiorrhiza root extract and its compounds in enhancing nitric oxide expression, Phytomedicine. 2000;7(1): 55–61. 10. Kang DG, et al., Lithospermic acid B isolated from Salvia miltiorrhiza ameliorates ischemia/reperfusion- induced renal injury in rats, Life Sciences, 2004; 75(15): 1801–1816. 11. Zhuang HM, Zhu HY, and Qin ZL, Effect of Salvia miltiorrhiza on the survival time of a heart allograft in experimental animals, Chinese Journal of Integrated Traditional and Western Medicine, 1988; 8(1): 29–30, 6. 12. Zhang Zhiguo, Yin Xiaoling, and Xia Suisheng, Application of Chinese traditional medicine in kidney transplantation, Chinese Journal of Integrated Traditional and Western Medicine, 2004; 10 (4): 310–314. 13. Ye Rengao, Li Yanchun, and Sun Duo, Clinical study of the therapeutic effects of rhubarb a main drug in the treatment of chronic renal failure, Chinese Journal of Integrated Traditional and Western Medicine, 1995; 1(2): 104–107. 14. Zhan Yongli, Zhou Jingyuan, and Huo Baomin, Study on the effect of mediation principle in retarding the progress of chronic renal failure, Chinese Journal of Integrated Traditional and Western Medicine, 1997; 3(1): 2–5. 15. Yu Yueming, et al., Chinese drugs that invigorate spleen to remove dampness and activate blood circulation to eliminate turbidity for retarding progression of chronic renal failure, Chinese Journal of Integrated Traditional and Western Medicine, 2001; 7(3): 183–185. 16. Yin Dehai, Dai Xiwen, and Rao Xiangrong, Yishen Huanshuai Fang retards progression of chronic renal failure, Chinese Journal of Integrated Traditional and Western Medicine, 2000; 6(1): 10–13. 17. Ngai HH, Sit WH, and Wan JM, The nephroprotective effects of the herbal medicine preparation, WH30+, on the chemical-induced acute and chronic renal failure in rats, American Journal of Chinese Medicine, 2005; 33(3): 491–500. 18. Locatelli F, Vecchio LD, and Pozzoni P, The importance of early detection of chronic kidney disease, Nephrology, Dialysis, and Transplantation 2002; 17(Sup. 11): 2–7. March 2007 4