JN 2001; Vol.14 N°4: 299-303Table of Contents Case Report JNEPHROL 2001; 14: 299-303 Kaposi's sarcoma in a patient with focal glomerulosclerosis Simona Zerbi 1, Massimo Saruggia 2, Lucia Brambilla 3, Daniela Lodeville 4, Gherardo Buccianti 2 - 1 Division of Nephrology and Dialysis, Desio Hospital, Milan - Italy 2 Division of Nephrology and Dialysis, Bassini Hospital, Cinisello Balsamo, Milan - Italy 3 Institute of Dermatology, IRCCS Maggiore Hospital, Milan - Italy 4 Division of Anatomy and Pathological Histology, Sesto San Giovanni Hospital, Milan - Italy ABSTRACT: We report the clinical features and outcome af a patient who presented Kaposi's sarcoma following immunosuppressive therapy for FGS; Cyclophosphamide and steroids were administered; the patient recovered after three months treatment with i.v. vinblastine. Key words: Cyclophosphamide, Cyclosporine, Focal glomerulosclerosis (FGS), Glomerulonephritis, Kaposi's sarcoma (KS), Vinblastine Introduction Focal glomerulosclerosis (FGS) is one of the most common causes of nephrotic syndrome in adults (1). It is a relatively non specific histologic finding. It can occur as a primary disease or associated with other causes such as healing of previous focal glomerular injury, marked nephron loss, renal vasodilatation (as in IDDM, sickle cell anemia, type I glycogen storage disease, obesity, severe preeclampsia), HIV infection, heroin abuse, malignancy, and chronic lithium therapy (2). Treatment with steroid and immunosuppressants can slow the progression toward end-stage renal failure (3-4). Kaposi's sarcoma (KS) is a vascular proliferative neoplastic process with many epidemiological forms; two of them are associated with immune impairment (organ transplants and human immunodeficiency virus type 1). Males are predominantly afflicted in all forms (5). We report on a patient with FGS who developed Kaposi's sarcoma after a treatment with cyclosporine, steroids and cyclophosphamide over a 2-year period (Fig. 1). Fig. 1 - Course of treatment. Case report A white 59-year-old male of Mediterranean origin was admitted to our hospital in October 1995 with complaints of shortness of breath under exertion, fatigue and weight gain. He had previous diagnoses of hypertension (1985) and gout (1988) with nephrolithiasis and acute arthritis. He was taking atenolol, nifedipine, enalapril (10 mg/day) and allopurinol. On admission his blood pressure was 180/110 mmHg, heart rate 60 beats/min, ventilatory rate 20 breaths/min, temperature 36.9 °C and body weight 88.7 kg. The clinical findings showed nephrotic syndrome (marked peripheral edema, urinary protein excretion 5.5 g/day, glomerular proteinuria without size-selectivity, serum creatinine 117 µmol/l, blood urea 32 mg/dL, creatinine clearance 72 mL/min, total protein 5.8 g/dL, serum albumin 2.8 g/dL). Hepatitis B surface antigene, anti-HCV, IgG, IgM, IgA, C3, C4, Le test, rheumatoid factor, TAS, antineutrophil cytoplasmic antibodies (ANCA) were in the normal range. Renal biopsy (Fig. 2) showed on light microscopy focal glomerulosclerosis with segmental capillary collapse, partial occlusion of afferent arterioles by hyaline deposits, absence of mesangial hypercellularity, slight tubulointerstitial sclerosis; immunofluorescence revealed nonspecific IgM deposits in sclerotic areas. The patient was managed with sodium restriction, furosemide (50 mg /day p.o.) and enalapril (20 mg/day). Four months later urinary protein excretion was 1.98 g/day and serum creatinine 140 µmol/l. One year later, a relapse of the nephrotic syndrome occurred (urinary protein excretion 7.04 g/day, plasma creatinine 184 µmol/l). Oral cyclosporine (3 mg/kg/day) and prednisone (25 mg on alternate days) were introduced: proteinuria came down. In November 1997 cyclosporine was discontinued because of nephrotoxicity (serum creatinine 270 µmol/l). In January 1998 the patient developed oliguria, anasarca and non-responsive hypertension (serum creatinine 272 µmol/l; urinary protein excretion 18.5 g/day). He was managed with an infusion of furosemide-albumin complex; a generalized skin rash and intractable pruritus occurred, associated with eosinophilia (white cell count 8.2 x 109/l; eosinophils 8.2 %) and rapid decrease of GFR (serum creatinine from 272 to 809 µmol/l); hemodialysis was performed. The concomitant non-responsive hypertension did not allow us to perform a second renal biopsy; the patient was suspected to have a drug-induced acute interstitial nephritis because of the time related administration of high dose i.v. furosemide to the decrease of GFR and skin rash. The suspected damaging drug was stopped and a trial of prednisone (1 mg/kg/day) was begun. Renal function improved within a week; at discharge serum creatinine and blood urea were 272 µmol/l and 231 ml/min respectively. In March 1998, gradual tapering of prednisone was started. The patient developed anasarca and a marked decrease of GFR (serum creatinine 1301 µmol/l). Steroid therapy (1 mg/kg/day) was restored and cyclophosphamide (100 mg/day) was started with success (serum creatinine 686 µmol/l; blood urea 272 mg/dL). In July 1998 serum creatinine was 117 µmol/l, urinary protein excretion 9 g/day. Over the following three months, slowly enlarging blue-purplish maculo-papular lesions appeared on the patient's legs (Fig. 3a), abdominal skin (Fig. 4a) and nose, causing some discomfort: he was hospitalized (October 1998). Laboratory tests found anemia (hematocrit 24 %; hemoglobin 7 g/dL), constant renal function (serum creatinine 131 µmol/l), proteinuria (4.5 g/day), presence of occult blood at stool examination. Blood transfusions were performed. Chest X-ray and ECG were normal. Endoscopic examination of the gastrointestinal tract revealed a great number of infiltrated red spots (some 40 mm wide) in the stomach (body and fundus), transverse and sigmoid colon, rectum. Gastroenteric mucosa and skin biopsies showed Kaposi's sarcoma (stage IV-B). Further laboratory tests revealed absence of HHV-8 and HIV-1 antibodies. Cyclophosphamide was stopped, the patient started methylprednisolone i.m. and intravenous vinblastine boli (3 mg/m2 weekly for 3 weeks and then 6 mg/m2 every 3 weeks). Chemotherapy was planned for the time necessary to reach the greatest degree of partial remission, plus 3 months of consolidation. The patient's response was assessed every 3 weeks by careful examination; before each course, leukocyte and platelet count were assessed. Neither myelotoxicity nor other potential side effects were observed. Skin lesions disappeared over a period of three months (Fig. 3b-4b). In July 1999 neither skin lesion nor spots on gastric endoscopic examination were observed; mild renal failure (serum creatinine 130 µmol/l) and urinary protein excretion of 10.8 g/day were detected in absence of signs of water overload. Fig 2 - light micrograph showing focal glomerulosclerosis with segmental capillary collapse (EE, x 120). Fig 3a - 3b - patient's leg before (a) and after (b) treatment with vinblastine. Fig. 4a - 4b - abdominal skin before (a) and after (b) treatment with vinblastine. Discussion Kaposi's sarcoma (KS) is a complex disease in its cellular composition, origin, epidemiology and pathogenesis. Many variants are known and a male predominance is found in all of them. The Mediterranean subtype (affecting people of Mediterranean, Eastern European or Jewish heritage) has a peak incidence after the sixth decade of life; it is usually chronic (average survival 10-15 years) and generally not life threatening. More aggressive forms of KS have been described in Africa (an endemic variant is observed in blacks) and in subjects with evidence of HIV infection. Immunosuppressive therapy is the major stimulus for microvascular inflammation and development as a clinical tumor in the iatrogenic subtype (5); most of patients are transplant recipients (7). Their risk of developing KS is some 400 to 1000 fold greater than in the general population (8). However, less is known about KS appearance in patients receiving immunosuppressive treatment for renal diseases. In an interesting Clinical Update, Camille Frances has discussed KS after renal trasplantation (7); the patients' age at onset of the post-transplantation subtype depends on the age at the time of immunosuppression therapy; organ transplantation confers a 224-fold magnitude of the increase of risk of KS in Italy (9) and the average interval between organ transplantation and KS is 20 months, becoming less than 12 months when cyclosporin A is used (10). KS in the allograft recipient is a life-threatening complication in about 21% of patients with visceral involvement (11). Reduction of immunosuppression is usually associated with disappearance of KS (7). In renal allograft recipients, the risk of organ loss from rejection and a resulting return to dialysis ranges from 21 to 58 % (10). The sequences of a new herpesvirus (HHV-8) have been detected in almost all epidemiological forms of KS (7); a small percentage of patients may present HHV-8 negative serologic results even in the acute phase of KS (12-13). Its proved ways of trasmission are sexual (14) and renal-transplant donors to recipients (15). It seems that HHV-8 encodes genes that stimulate angiogenesis (i.e. through interleukin 6, G-protein receptor) (16-17). KS presents a spectrum of lesions consisting of red-purple coalescents macules, papules and plaques. The earliest lesions may resemble a petechia or may be a red papulonodule; they may coalesce to form plaques. As the lesions enlarge, spongy nodular tumors arise measuring 70 mm or more in diameter. They are mainly localized on legs, but they could also appear on the trunk and arms; face involvement is less frequent. In disseminated disease (aggressive forms) mucosal surfaces, lymphonodes, salivary glands, and viscera (gastrointestinal tract, lungs, liver, spleen) may be involved. Bleeding from intestinal involvement is a common and serious complication. Intralesional chemotherapy, radiotherapy, cryotherapy, cryosurgery, laser, surgical removal, interferon-a, vinca alkaloids, antitumor antibiotics (bleomycin, doxorubicin, epirubicin) and etoposide have all proved to be helpful in the treatment of KS. Vinblastine is successfully used to treat the Mediterranean form in elderly patients with severe disease (6). HIV-related KS responds to combination chemotherapy including vincristine, bleomycin, doxorubicin. Other agents are under study, such as liposomal doxorubicin and paclitaxel (18-19). In the post-transplant form, immunosuppressive drugs must be tapered to the lowest level in order to allow allograft function; the regression of lesions is slow and can take several months (7). A very specific therapy is required when KS spreads and causes functional discomfort or life-threatening risk. Monotherapy consists of vinblastine or bleomycin, while - in case of a rapid multivisceral progress - a combination chemotherapy is advisable. KS may recur several months or years after remission (20). The different incidence of KS in transplant recipients compared to subjects with glomerulonephritis treated with immunosuppressive drugs is probably due to different dose and duration of therapy. Up to now, a few cases of KS developing in patients with glomerulonephritis have been described. In one case, a membranous glomerulonephritis was found and a month later KS appeared, without a background of steroid or immunosuppressive therapy (21). In another case, membranoproliferative glomerulonephritis and mild skin KS (violaceous nodule in a toe of the right foot) contemporaneously started in a 46-year-old white male of Italian origin; KS rapidly developed in the following months after the patient received prednisolone (22). To our knowledge, this is the first reported case of KS in a patient with FGS. We believe the most likely predisposing factor for the development of the neoplastic disease was the immunosuppressive drug therapy; our patient had been managed with cyclosporine, that increases the risk of developing KS (10), and cyclophosphamide made it worse. Immunosuppressive drugs were administered but, as KS was rapidly spreading, an intravenous therapy with vinblastine (6) was commenced reaching a partial remission. The same therapy is used in post-transplant KS. In conclusion, although uncommon, KS may be a serious complication of the use of immunosuppressive drugs for glomerulonephritis. We still know too little about prognosis and risk of recurrence. Reprint requests to: Simona Zerbi, M.D. - Divisione di Nefrologia e Dialisi Azienda Ospedaliera 'Ospedale Civile' di Vimercate Presidio 'Ospedale di Circolo' di Desio Via G. Mazzini, 1 20033 Desio (Milano), Italy simona.zerbi@tiscalinet.it References (when available, each reference has been linked to PubMed) 1. Haas M, Meehan SM, Karrison TG, Spargo BH. Changing etiologies of unexplained adult nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997. Am J Kidney Dis 1997; 30: 621-31. 2. D'Agati V. The many masks of focal segmental glomerulosclerosis. Kidney Int 1994; 46: 1223-41. 3. Korbet SM, Schwartz MM, Lewis EJ. Primary focal segmental glomerulosclerosis: clinical course and response to therapy. Am J Kidney Dis 1994; 23: 773-83. 4. Rydel JJ, Korbet SM, Borok RZ, Schwartz MM. Focal segmental glomerular sclerosis in adults: presentation, course and response to treatment. 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