Renal Disease and Syphilis: A Report of Nephrotic Syndrome With Minimal Change Disease

Renal Disease and Syphilis: A Report of Nephrotic Syndrome With Minimal Change Disease N. Kevin Krane, MD, Pierre Espenan, MD, Patrick D. Walker, MD, Suzanne M. Bergman, MD, and J.D. Wallin, MD • A case of nephrotic syndrome and acute renal failure in a 74-year-old man with latent syphilis is described. A renal biopsy demonstrated focal global sclerosis in three of nine glomeruli, however, the remaining glomeruli revealed typical lesions of minimal change disease. Previous reports of renal involvement in syphilis have described membranous glomerulonephritis, mesangial and endothelial cell proliferative glomerulonephritis, and, recently, rapidly progressive glomerulonephritis. The proteinuria and renal failure resolved after penicillin therapy alone. This response strongly suggested that there was a causal relationship between the syphilis and the nephrotic syndrome. This is the first report of such a relationship. © 1987 by the National Kidney Foundation, Inc. INDEX WORDS: Nephrotic syndrome; syphilis; minimal change disease; treponemal antigens and antibodies; proteinuria.

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ENAL DISEASE is a well-documented complication of syphilis. A review of several series of reports suggests that the prevalence of renal disease in conjunction with syphilis is approximately 0.3 %. 1 The most common pathologic lesion described is membranous glomerulopathy,24 however, mesangial proliferation, endothelial proliferative glomerulonephritis, 5 and, more recently, rapidly progressive renal failure with crescentic glomerulonephritis in a patient with latent syphilis 6 have been reported. The present report is that of a 74-year-old man who presented with nephrotic syndrome (NS) and acute renal failure (ARF). After a complete evaluation, renal biopsy showed the patient to have minimal change disease. In addition, he had a positive serologic test for syphilis and a strongly positive fluorescent treponemal antibody test. He was treated with the recommended course of penicillin for latent syphilis and was not treated with corticosteroids. With penicillin therapy alone, rapid resolution of renal failure occurred and the NS resolved 2 weeks after the first injection. This represents the first reported case of minimal change disease associated with syphilis. A causative association of the two entities is suggested From the Section of Nephrology, Tulane University School of Medicine, and li>terans Administration Hospital, New Orleans. Address reprint requests to J.D. Wallin, MD, Section of Nephrology, Tulane University School of Medicine, 1430 Tulane Ave, New Orleans, LA 70112. © 1987 by the National Kidney Foundation, Inc. 0272-6386/87/0902-0012/$03.00/0

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because of the response of the proteinuria to the treatment of the treponemal infection. CASE REPORT A 74-year-old black man was transferred to Tulane Medical Center on December 30, 1983, with a history of sudden onset of generalized swelling and shortness of breath on exertion beginning 3 weeks previously. The patient had a history of mild hypertension treated successfully with Dyazide (Smith, Kline and French, Philadelphia) once daily for the previous 10 years. He denied exposure to any medications. A left ureteroplasty was performed in 1954, but there was no other history of genitourinary or renal disease. The patient specifically denied skin rash, penile lesions, fever, or previous treatment for syphilis. He had documented normal renal function 1 year previously (BUN 17 mg/dL, serum creatinine 1.1 mg/dL). A VDRL performed at the referring hospital was weakly positive. Physical examination revealed an elderly black male: weight 75.9 kg, BP 170/95, pulse 80, temperature 37°C. Fundoscopic examination revealed arteriolar narrowing. Facial edema and marked edema ofthe lower extremities to the level of the upper thighs were present, as well as scrotal and penile edema. Chest examination revealed a few left basilar inspiratory crackles. There was no evidence of adenopathy or splenomegaly. The remainder of the physical examination was normal. Laboratory studies on admission showed the following: glucose 93 mg/dL, BUN 61 mg/dL, serum creatinine 3.4 mg/dL, electrolytes normal, protein 5.6 g/dL, albumin 2.4 g/dL, hemoglobin 10.6 g/dL, hematocrit 31 %, WBC count 6,200. Urinalysis revealed sp gr 1.019, pH 6; protein 4 + , WBC 10 to 15/ HPF, RBC I to 3/hpf, 8 to 10 granular casts/LPF. Urine and serum protein electrophoresis demonstrated selective proteinuria, consistent with NS. ANA was negative, fluorescent treponema! antibody 3 + , C3 123 mg/dL (normal range 83 to 177 mg/dL), spinal fluid VDRL negative. The chest x-ray demonstrated small right and left pleural effusions. A percutaneous renal biopsy was performed for light, immunofluorescence, and electron microscopic examination. Tissue for light microscopy was fixed in buffered formalin, dehy-

American Journal of Kidney Diseases, Vol IX, No 2 (February), 1987: pp 176-179

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Fig 1. A Glomerulus showing no light microscopic changes. There is mild patchy tubular basement membrane thickening. (Periodic acid-Schiff stain, original magnification x 200.)

drated , and embedded in glycol methacrylate. Serial sections were cut at 1.5 Jl and stained with either hematoxylin and eosin, periodic acid-Schiff, toluidine blue, or Jones silver. Light microscopy revealed nine glomeruli, three of which were globally sclerotic. The remaining six glomeruli had thin and delicate capillary loops with no evidence of loop collapse, foamy epithelial cell change, sclerosis, hyalinosis, proliferation, or crescent formation (Fig 1). There were patchy areas of tubular dropout and tubular basement membrane thickening adjacent to the globally sclerotic glomeruli. In these same areas, the interstitium showed a mild increase in fibrous connective tissue and a mild chronic inflammatory cell infiltrate . The remaining tubules had intact-lining epithelia with preservation of the brush border and unremarkable nuclei. The blood vessels showed moderate intimal thickening with focal hyalinosis. Tissue for immunofluorescence was quenched in liquid nitrogen and 5-Jl sections cut in a cryostat. The sections were stained with fluorescein-conjugated antiserum to IgG, IgA, IgM, complement components 3 and 4, albumin , and fibrinogen (Meloy Laboratories, Springfield, VA). The glomeruli were negative for immunoglobulins, complement, and fibrinogen. Tissue for electron microscopy was fixed in glutaraldehyde. dehydrated, and embedded in maraglas. Silver and gold sections were obtained on an LKB Ultratome V ultramicrotome (LKB Instruments, Inc, Gaithersburg, MD) , stained with uranyl acetate and examined in a Phillips 200 electron microscope (Phillips Co, The Netherlands). The glomerular basement membranes were of the usual thickness and contained no electron dense deposits. The foot processes were extensively effaced and there was associated microvillous proliferation (Fig 2). The mesangium showed no evidence of proliferation or electron dense deposits . The mesangial matrix was not increased. The tubules showed an intact brush border, maintenance of the cytoplasmic organelles , and unremarkable nuclei. The patient was treated only with injections of penicillin, 2.4 million units intramuscularly (on January 10, 16, and 24, 1984)

while steroid and diuretic therapy were withheld . One week after the first treatment, the serum creatinine had returned nearly to normal (1.3 mg/dL). Two weeks after the first injection, the patient lost 12 kg of weight and his edema had completely disappeared. In order to quantitate protein excretion in urine on a continuing basis , the ratio of protein to creatinine (mg protein/mg creatinine) was measured. This has been shown to correlate with 24-hour urinary protein excretion in a reasonable fashion. 7 This value is plotted as a function of time along with body weight and serum creatinine in Fig 3. Five and a half months after treatment, the patient was well, continued to have mild proteinuria (546 mg/24 h-protein/creatinine 0.4 g/ mg) and has maintained constant renal function (serum creatinine 1.3 mg/dL).

Fig 2. A capillary loop showing foot process effacement and no electron dense depOSits. (Lead citrate and uranyl acetate, original magnifIcation x 31,350.)

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KRANE ET AL

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DISCUSSION

Renal disease due to syphilis is a relatively infrequent complication of this disorder; estimates of prevalence average less than 1%. I When the kidney is involved, the most frequently observed pathologic lesion is membranous glomerulopathy. The identification of this lesion as a direct consequence of systemic treponemal infection has been confirmed through the elution of immune complexes from basement membrane and identification oftreponemal antigens and antibodies. 2.3 Both mesangial and endothelial cell proliferative glomerulonephritis have been reported in association with syphilis, but without clear-cut evidence of the presence of specific antigens or antibodies. In 1984, extracapillary proliferative glomerulonephritis was reported by our group,6 and in this case, identification of both treponemal antigens and antibodies was possible. The absence of elutable antigens or antibodies makes the establishment of cause and effect difficult in minimal change disease. The association of minimal change disease in Hodgkin's disease, lymphocytic lymphoma, and with nonsteroidal antiinflammatory drugs has previously been inferred by the resolution of NS with treatment of the underlying disease or withdrawal of the offending agent. 815 The rapid resolution of NS following institution of penicillin therapy in this patient suggests a causal relationship. Minimal change disease may remit spontaneously, as has been reported in children in the

pre-steroid era. 16 However, this usually occurs after a protracted period with NS and seems unlikely in this patient. This is in contrast to the patient illustrated in our case report in whom there was prompt resolution of his NS by instituting therapy with penicillin. This patient's clinical presentation was also remarkable for the degree of renal failure. The development of renal failure in patients with minimal change disease is an unusual, though welldocumented, complication of this disorderY22 The majority of the previously reported cases have been adults in whom recovery of renal function occurred following either diuretic or steroid therapy; however, spontaneous remission has also been reported. 18 It is possible that the ARF is a consequence of altered glomerular hemodynamics due to renal interstitial edema. 20 Preexisting arteriosclerosis and/or hypertension has also been suggested as playing a role in the development of ARF in the elderly patient with minimal change disease. 21 It seems most likely, therefore, that the ARF described in our case report was actually due to minimal change disease, especially without evidence of the typical histopathologic changes of acute tubular necrosis. The case illustrated in this article demonstrates an association between minimal change disease and syphilis that has not previously been reported. Though cause and effect cannot be absolutely established, the prompt response to treatment and exclusion of other explanations for the resolution of NS strongly support the theory that renal involvement in syphilis may manifest as minimal change disease. REFERENCES 1. Thomas EW, Schur M: Clinical nephropathies in early syphilis. Arch Intern Med 78:679-686. 1946 2. Gamble CN, Reardon JB: Immunopathogenesis of syphilitic glomerulonephritis: Elution of anti-treponemal antibody from glomerular immune complex deposits. N Engl J Med 292:449-454, 1975 3. O'Regan S, Fong JSC, deChadarevcan Jp, et al: Treponemal antigens in congenital and acquired syphilitic nephritis. Ann Intern Med 85:325-327, 1976 4. Losito A, Bucciarelli E, Massi-Benedetti F, et al: Membranous glomerulonephritis in congenital syphilis. Clin Nephrol 12:32-37, 1979 5. Braunstein GO, Lewis El, Galvanek EG, et al: The nephrotic syndrome associated with secondary syphilis: An immune deposit disease. Am J Med 48:643-648, 1970 6. Walker PO, Oeeves EC, Sahba G, et al: Rapidly progressive glomerulonephritis in a patient with syphilis. Identification

MINIMAL CHANGE DISEASE AND SYPHILIS

of anti-treponemal antibody and treponemal antigen in renal tissue. Am 1 Med 76: lI06-1112 , 1984 7. Ginsberg 1M, Chang BS, Matarese RA, et a1: Use of single voided urine samples to estimate quantitative proteinuria. N Engl 1 Med 309:1543-1546, 1983 8. Kiely 1M, Wagoner RD, Holley KE: Renal complications of lymphoma. Ann Intern Med 71 :1159-1175, 1969 9. Ghos (Banerji) L, Muehrke RL: The nephrotic syndrome. A p rodrome to lymphoma. Ann Intern Med 72:379-382, 1970 10. Plager 1, Stutzman L: Acute nephrotic syndrome as a manifestation of active Hodgkin 's disease . Am 1 Med 50:5666, 1971 II. Couser WG, Badger A, Cooperband S, et aI: Hodgkin 's disease and nephrotic syndrome. Lancet 1:912-913, 1977 12. Sherman RL, Susin M, Weksler ME, et al: Lipoid nephrosis in Hodgkin's disease. Am 1 Med 52:699-700, 1972 13. Gagliano RG, Costanzi 11 , Beathard GA, et al: The nephrotic syndrome associated with neoplasia: An unusual paraneoplastic syndrome. Report of a case and review of the literature. Am 1 Med 60:1026-1029, 1976 14 . Garella SG, Matarese RA: Renal effects of prostaglandins and clinical adverse effects of non-steroidal antiinflammatory agents . Medicine 63 : 165-181, 1984 15. Feinfeld DA , Olesnicky L, Pirani CL, et al: Nephrotic

179 syndrome associated with use of the non-steroidal antiinflammatory drugs. Case report and review of the literature. Nephron 37:174-179, 1984 16. Arneil GC: Children with nephrosis. Lancet 2: 11031110,1961 17 . Conolly ME, Wrong OM, 10nes NP: Reversible renal failure in idiopathic nephrotic syndrome with minimal glomerular changes . Lancet 1:665-668, 1968 18. Holdsworth DR, Stephenson P, Dowling Ip, et al: Reversible acute renal failure in the nephrotic syndrome with minimal glomerular pathology. Med 1 Aust 2:532-533, 1977 19. Huller HN, Bonner EL lr: Lipoid nephrosis appearing as acute oliguric renal failure . Arch Intern Med 140:403-405 , 1980 20. Lowenstein 1, Schacht RG, Baldwin DS: Renal failure in minimal change nephrotic syndrome. Am 1 Med 70:227-233, 1981 21. Esparza AR, Kahn SI, Garella S, et aI: Spectrum of acute renal failure in nephrotic syndrome with minimal (or minor) glomerular lesions . Role of hemodynamic factors. Lab Invest 45 :510-521 , 1981 22. Sjoberg Rl , McMillan VM , Bartram LS , et al : Renal failure with minimal change nephrotic syndrome: Reversal with hemodialysis. Clin Nephrol 20:98-100, 1983