Renal Failure, 1716). 759-764 (1995)

CASE REPORT

Renal Failure Associated With Alternative Medical Therapies

John Farrell, MRCPI, Eileen Campbell, PhD, and John Joseph Walshe, FACP

National Kidney Centre Beaumont Hospital Dublin 9. Ireland

ABSTRACT

Because the kidnrj is tile major exrrrton organjbr drugs and toxins, it is especially susceptible to damage,from such agents. While alternative medical therapies appear to he on an increase $vorldwide, there have been few case reports regarding their rirphrotoxicitj. However we huLse recently observed three patients who developed irreversible renal impairment, which we believe was due to such therupies.

INTRODUCTION

Over the last two decades, there has been increased recognition of the role of drugs and toxins in the development of renal disease, and a number of different histological lesions have been described (1,2). In recent times, there also has been an upsurge in the practice of alternative medicine (3, 4), despite scientific doubts about its effectiveness (5, 6). Of concern in this regard are reports ofcardiotoxicity (7) and hepatic failure (8) due to the use of such therapies.

Herein we describe three female patients who developed irreversible renal impairment, which we believe can only be attributed to the use of alternative medical therapies. The implications of these observations are discussed.

Address correspondence to: Prof. J. .I. Wilshe, National Kidney Centre, Beaumont Hospital, Dublin 9, Ireland.

759

Copyright 0 1995 by Marcel Dekker. Inc.

Ren

Fai

l Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

UB

Kie

l on

11/0

7/14

For

pers

onal

use

onl

y.

760 Farrell, Campbell, and Walshe

CASE NO. 1

A 59-year-old female was admitted to hospital with generalized myalgia. Ten days previously, she had lacerated her thumb and was treated with homeopathic doses of oral hypericum and ledum. She was a 52-kg female with no known risk factors for renal disease and had taken no other medications. Her blood pressure was 130190, pulse 88lmin in sinus rhythm, and she was afebrile. Physical examination was unremarkable. Repeated wound, blood, and urine cultures were negative. Urinalysis: pH 6.0,20-50 WBC/HPF, + 1 protein. There were no RBC casts. Her hemoglobin (Hgb) was 13.7 g/dL, with a normal white cell and platelet count. Serum Creatinine (sCr) was elevated at 129 pmol/L (n 80-120). Her electrolytes were within normal limits. Autoantibody screen was negative.

Complement levels were within normal limits. Blood and urine toxicology screens were negative. Her kidneys measured 12 cm on ultrasonography. Over the next 7 days, she became oliguric and her sCr rose to 490 FmolL. She was commenced on hemodialysis. A renal biopsy was performed. This showed an inflammatory infiltrate, which consisted mainly of lymphocytes and plasma cells. The tubular membrane stained strongly for C3. There was minimal interstitial fibrosis. The overall picture was of a severe acute tubuloin- terstitial nephritis (Fig. 1). She was given methylprednisone 500 mg i.v. for 5 days. During the following 14 days, her renal function improved and dialysis was stopped. She was discharged with a sCr of 230 pmol/L. Two years on, her sCr remains steady at 217 pmol/L.

CASE NO. 2

A 32-year-old female presented to the renal department in July 1992 with a sCr of 559 pmol/L. Review of previous checkups showed her sCr to be 80 FmolL in January 1990. In May of that year, she was commenced on an 18-month course of mesotherapy for weight reduction. Mesotherapy is a form of alternative medical therapy used in the treatment of osteoarticular disease (9), but which has recently been employed in slimming regimes (10, 11). For this patient, mesotherapy involved weekly intradermal injections of artichoke and euphyllin, and oral medications comprising substances prescribed by her doctor and made up by a pharmacist. These included fenfluramine, Fucus extract, meprobamate, belladonna,

Figure 1. Acute tubulointerstitial nephritis (renal biopsy, Case 1)

Ren

Fai

l Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

UB

Kie

l on

11/0

7/14

For

pers

onal

use

onl

y.

Renal Failure in Alternative Therapies 761

diethylpropion, Cascara powder. acetazolamide, pancreas extract, Laminaria powder and the Chinese herbs Stephania tetranda and Magnolia ofJrciiia1i.s. On this therapy, she lost 15 kg. By November 1991, her sCr had risen to 196 pmol/L. Her past history was unremark- able, and from May 1990 to July 1992 she had not been taking any other medications. Physical examination including her blood pressure was normal. Urinalysis: 6-8 WBC/HPF + 1 protein, no RBC casts. Urine cultures-negative.

She had a normochromic, normocytic anemia with a Hgb of 7.9 gidL. Her white cell and platelet counts were within normal limits. sCr-559 pmol/L. Serum potassium-5.6 pmol. Autoantibody screen-negative. Complement levels were within normal limits. Blood and urine toxicology screens were negative. On ultrasound, she had bilateral small kidneys (8 cm). Renal histology revealed 30 glomeruli, of which 12 were sclerosed. The nonsclerosed glomeruli were well preserved. There was an advanced degree of tubular loss and atrophy, with compensatory hypertrophy and dilatation of the surviving tubules. There was a marked interstitial fibrosis with minimal inflammatory cell infiltrate (Fig. 2). The overall clinical picture was of a subacute tubulointerstitial fibrosis. The patient progressed to end-stage renal failure and in August 1992 was started on hemodialysis.

CASE NO. 3

A 62-year-old female was referred with acute renal failure in December 1993. In September 1993, her sCr was 130 pmol/L. Two months prior to admission, she underwent a course of chelation therapy with intravenous EDTA (300 mg) on a weekly basis for 6 weeks for coronary artery disease. She had taken no other medications. Physical examination was unremarkable. Her blood pressure was 110/80. Urinalysis: 10-15 WBC, 1-3 RBC/HPF, trace protein. Urine cultures-negative. Her Hgb was 8.4 g/dL. White cell and platelet counts were within normal limits. sCr was 1093 pmol/L. Serum potassium-6.1 pmol/L. Blood lead, copper, and iron levels were all within normal limits. Autoantibody screen was negative. Blood and urine toxicology screens were negative. Her kidneys measured 10.5 cm on ultrasonography. Renal histology revealed normal glomeruli with marked tubular dam- age, consistent with acute tubular necrosis. The patient was commenced on hemodialysis.

Figure 2. Subacute tubulointerstitial nephritis (renal biopsy, Case 2).

Ren

Fai

l Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

UB

Kie

l on

11/0

7/14

For

pers

onal

use

onl

y.

762 Farrell, Campbell, and Walshe

Hemodialysis was stopped as her renal function gradually improved, and six months on her sCr was 188 wmol/L.

DISCUSSION

As physicians have become more aware of the ever-expanding number of drugs and toxins that can cause renal failure, the diagnosis of drug-induced acute tubulointerstitial nephritis (ATIN) has greatly increased. This condition now accounts for 3-14% of cases of acute renal failure and may account for up to 40% of cases of drug-induced renal failure (12-15). The clinical diagnosis of ATIN may be difficult to make as the classical triad of rash, fever, and eosinophilia occurs in less than one-third of these patients (16). Urinalysis may reveal eosinophiluria (17). Microscopic hematuria and pyuria are also common but nonspecific findings (18). However, a renal biopsy is the definitive diagnostic test in such cases (19). The characteristic pathological findings are of a diffuse or patchy infiltrate, consisting mainly of plasma cells and lymphocytes. Eosinophils may be present. The glomeruli and vessels are normal, and immunofluorescence is usually negative but may show linear IgG and C3 staining.

Immunologically mediated damage is thought to play a major role in the pathogenesis of ATIN. Most drugs are small molecules and, therefore, are incapable of inducing a direct immunologic response. As a result they appear to need to first bind to a macromolecule such as the tubulointerstitium. This complex is then recognized by the body as foreign, inducing helper T cells to bring about the differentiation of nephritogenic T and B cells. Subsequent recruitment of macrophages, lymphocytes, plasma cells, and eosinophils with release of cytolytic and proinflammatory compounds results in tubulointerstitial damage (17,20-23). It has been suggested that the activation of the immune system may be under genetic control, and this probably plays a role in the susceptibility of people to drug nephrotoxicity (22). We believe that in our first patient, hypericum or ledum in homeo- pathic doses was probably responsible for inducing such an immune response, resulting in the cellular and immunofluorescence finding seen on biopsy. Both the histological lesion and the time frame of the ATIN are consistent with a drug-induced lesion. This patient took no other medications except for the homeopathy. We believe that this patient represents the first ever described case of alternative hypericumlledum induced ATIN.

The second case describes a female who, following mesotherapy, developed a rapidly progressive interstitial fibrosis. The histological lesion found in this patient differs from that typically found in chronic drug nephropathy in that there was a marked absence of an inflammatory infiltrate. Fungal and plant nephrotoxins have previously been implicated as causes of isolated interstitial fibrosis as seen in Balkan nephropathy (24, 25). Vanher- weghem et al. have described nine cases of progressive interstitial fibrosis in patients on mesotherapy (10). Jadoul et al. reported a case of bilateral hydronephrosis secondary to periureteral fibrosis in a patient on this therapy (11).

Chinese herbal medicine has been practiced for centuries with few reported side effects. However, cardiotoxicity and hepatotoxicity have recently been described (7, 8). Stephania tetranda and Magnolia oflcinalis in China are considered safe herbs. However, the former is also known in China as Fangji, which has been confused in Western cultures with a herb called Fangchi, a known nephrotoxin. Samples of the herbs taken by the patients described by Vanherweghem did indeed identify Fangchi as one of the substances used (26). It is possible that since the second patient we described also received mesotherapy from the

Ren

Fai

l Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

UB

Kie

l on

11/0

7/14

For

pers

onal

use

onl

y.

Renal Failure in Alternative Therapies 763

same source. that she too was mistakenly given Fangchi. In our patient's slimming cocktail, acetazolamide was also used, which by causing urinary alkinization may also have led to delayed excretion of any nephrotoxic agent (27).

Our third case describes the development of acute tubular necrosis after chelation therapy. Although apparently rare, this outcome has previously been reported by Sarles (28). The mechanism by which chelation therapy causes nephrotoxicity is unknown but has been ascribed to the release of heavy metals, with their subsequent deposition in the tubulointerstitium of the kidney. It also appears that patients most at risk of developing nephrotoxicity from EDTA are those with preexisting renal disease. In this regard, it is noteworthy that our patient did have mild renal impairment prior to the onset of her chela- tion therapy.

Although little is known about their mode of action. alternative medical therapies continue to flourish in Europe ( 3 ) . In a recent review, 2.5% of the population in Belgium and 16% in France were noted to have used these therapies (3). Unfortunately, efforts to evaluate the usefulness have been hampered by the poor methodological quality of alterna- tive medicines trials and by the unknown role of publication bias (29).

The patients we described developed three different types of renal histological lesions that have been previously described in association with currently available pharmacologi- cal agents. However, it is now apparent that such lesions can also be caused by alternative medical therapies. In these circumstances, is it now time to consider: (a) stricter regulation of such therapies, bringing them in line with the government regulations imposed on the pharmaceutical industry; and (b ) the possibility that such therapies could be responsible for many cases of unexplained renal tubulointerstitial disease.

REFERENCES

1.

2. 3. 4.

5 .

6.

7.

8. 9.

10.

I I . 12. 13. 14.

15.

16.

Bennet WM. Plamp C. Poner GA: Drug-related syndromes in clinical nephrology. Ann Intern Med 87582- 590, 1977. Jorkasky D. Singer I: Drug-induced tubulo-interstitial nephritis: special cases. Semin Nt~phro/8:62-71.1988. Aldridge D: Europe looks at complementary medicine. Br Med J 299:1121-1122, 1989. Knipschild P, Kleijnen J. Roetter G: Belief in the efticacy of alternati\e medicine among general practi- tioners in the Netherlands. So<. Sci Med 31:625--626. 1990. Reilly DT. Taylor MA. Campbell J. et al: Is homeopathy ;i placebo response'? A controlled trial of homeopathic immunotherapy (HIT) in atopic asthma (ahstract). Proceedings of the 45th Congress of the Liga Medicorum Homeopathica Internationalis. 1990. Swayne JM: Survey of the use of homeopathic medicine in the U.K. health system. J Ro! C ~ f l Gerz Pruct 39(329):503-506, 1989. Chu-Pak Lau et al: Cardiotoxicity after accidental herb-induced aconite poisoning. Luncrt 40:1254-1256, 1992. Murray V. Perharic-Walton L: Toxicity of Chinese herbal remedie\. Lnncrr 340574. 1992. De Ridder A. et al: Mesotherapy in articular rheumatism. Actu B~lqrcn-Med P h p 12(3):91-93. 1989. Vanherweghem JL. et al: Rapidlj progres\ive interstitial renal fibrosis in young women: Association with slimming regimen including Chinese hcrbs. h i c c r 341:387-391. 1993 Jadoul M. et al: Adverse effects from traditicinal Chinese medicine. LLIrrcet 341:892-893, 1993. Heptinstall RH: Interstitial nephritis Am J Pnrhoi 83:214, 1976. Wilson DM. Turner D, KourilskS 0. et al: Value of renal biopsy in acute renal failure. Br Med J 2:459, 1976. Kleinknicht D, Landais P. Goldfarb B: Drug a s~ ic i a t ed acute renal lailure: a prospective multicentre report. Proc EDTA-ERA 22:1002. 1988. Pesey CD. Saltissi D, Blodworth L.. et al: Drug associated acute intentitial nephritis: clinical and pathologic features and the response to high dose steroid therapy. Q J Med 52:194. 1983. Appel GB, Kunis CL: Acute tubulointerstitial nephritis. Crvztemp fsr Nephruf 10:151-185, 1983.

Ren

Fai

l Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

UB

Kie

l on

11/0

7/14

For

pers

onal

use

onl

y.

764 Farrell, Campbell, and Walshe

17. 18. 19.

20. 21.

22.

23.

24. 25.

26. 27. 28.

29.

Neilsen E: Pathogenesis and therapy of interstitial nephritis. Kid Inr 35:1257-1270, 1989. Toto R: Acute interstitial nephritis. Am J Med Sci 299(6):392-410, 1990. Ooi BS, Wellington I, First MR, et al: Acute interstitial nephritis: a clinical and pathologic study based on renal biopsies. Am J Med 59:614, 1975. Zollinger HU, Mihatsch MJ: Morphology of acute S interstitial nephropathies. Conrrib Nephrol 16: 118,1979. Neilsen EG, McCafferty E, Feldman A, Clayman MD, Zakheim B, Komgold R: Spontaneous interstitial nephritis in Kd mice: a new model of autoimmune renal disease. J Immunol 133:2560-2562, 1984. Zakheim B, Neilson EG: T Cell regulation, anti-idiotypic immunity and the nephritogenic immune response. Kid Int 24:289-302, 1983. Neilson EG, Clayman MD, Haverty T, Kelly CJ, Mann R: Experimental strategies for the study of cellular immunity in renal disease. Kid Int 30:264-297, 1986. Austwick PKC, Carter RL, Greig JB, et al: Balkan nephropathy. Contrib Nephrol 16:154, 1979. Stefanovic V, Pollenakovic MH: Balkan nephropathy: kidney disease beyond the Balkans? Am J Nephrol 11:1-11. 1991. Atherton DJ, et al: Lancet 341:637-638, 1993. Chu-Pak Lau et al: Adverse effects from traditional Chinese medicine. Lancet 341:892, 1993. Oliver LD, Mehata R, Sarles HE: Acute renal failure following administration of ethylenediaminetetraacetic acid (EDTA). Tex Med 40:126, 1952. Kleijnen J, Knipschild P, Ter Riet G: Clinical trials of homeopathy. Br Med J 302:316-323, 1991.

Ren

Fai

l Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

UB

Kie

l on

11/0

7/14

For

pers

onal

use

onl

y.