Amir Tejani1 and Donald H. Stablein

Transcription

1 Recurrence of Focal Segmental Glomerulosclerosis Posttransplantation: A Special Report of the North American Pediatric Renal Transplant Cooperative Study Amir Tejani1 and Donald H. Stablein A. Tejani, D.H. Stablein, SUNY Health Science Center at Brooklyn, Brooklyn, NY, and the EMMES Corp., MD (J. Am. Soc. Nephrol. 1992; 2: ) ABSTRACT Among various forms of glomerulonephritis, focal segmental glomerulosclerosis (FSGS) is the most common cause of end-stage renal disease leading to transplantation in children. Previous reports of the recurrence of FSGS vary widely. The North American Pediatric Renal Transplant Cooperative Study carried out a special study to determine the rate of recurrence and risk factors leading to recurrence in 132 transplants. Fifty-five percent of the patients were white children, and the remaining were black and Hispanic children. Fifty percent of the patients were under 5 yr of age at the time of the diagnosis of FSGS. Twenty-seven (20.5%) of I 32 patients (95% confidence interval, 14 to 27) had a biopsy-proven recurrence of FSGS. The median time to recurrence was 14 days. The recurrence rate was similar in white children (23%) when compared with that in Hispanic children (20%) but was lower than that in black children (9%) (3 of 32 children). Recurrence rates did not vary between various age groups. Mesangial proliferation in patients with recurrence (25%) was similar to mesangial proliferation in patients without recurrence (20%). The mean serum albumin level of patients with recurrence was 1.7 versus 2.0 g/dl for those without recurrence. The mean serum cholesterol level of patients with recurrence was 525 versus 476 mg/dl for those without recurrence. The duration of dialysis was similar in the two groups. The mean time from diagnosis to end-stage renal disease status was 33 months for patients with recurrence and 52 months for those without recurrence (P < 0.05). Recurrence was noted in 18% of cadaveric kidneys, Correspondence to Dr. A. Tejani, SUNY Health Science Center at Brooklyn. 450 Clarkson Avenue, Box 49, Brooklyn, NY I /02 12-S258$03.00/0 Journal of the American Society of Nephrology Copyright 1992 by the American Society of Nephrology compared with 24% in live related donor (LRD) kidneys. Two-year graft survival for live related kidneys was 74% compared with 64% for cadaveric kidneys (P< 0.05). In summary, a 20% rate of recurrence of FSGS was noted in this heterogeneous population (95% confidence interval of 14 to 27%). A shortened time from diagnosis to end-stage renal disease was the only significant risk factor. We conclude that FSGS is not a contraindication for LRD transplantation, because graft survival for LRD kidneys is still significantly better. Key Words: Recurrence, transplant, focal. sclerosis S ince the original description of the recurrence of focal segmental glomerulosclerosis (FSGS) in a transplant patient by Hoyer et at. (1), a large body of literature reporting on recurrent FSGS has developed (2-7). These rates vary from a low of 5.6% (4) to a high of 1 00% (7). In recent years. two large studies, both based on American children, have been published with differing rates. Striegel and associates (8) reported a 50% rate in 24 children, whereas a more recent study of 42 transplants had a rate of 14% (9). Additionally, the immunosuppressive regimen used in these two studies was also different. All but two patients in the study of Striegel et at. (8) were maintamed on azathioprine, whereas in the study of Ingulli and Tejani, (9) half of the patients were maintamed on cyclosporine. Cyclosporine has been shown to have an effect on proteinuria in a variety of histobogical lesions (10-14). The North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) therefore undertook a special study to determine the rate of recurrence in its national registry and to clarify whether the use of cyclosporine posttransplantation reduced the rate of the recurrence of FSGS. MATERIALS AND METHODS The NAPRTCS is a voluntary cooperative group that collects data on all transplants carried out in children from 0 to 1 7 yr in the United States and Canada since The study group is organized with a Clinical Coordinating Center, a Data Coordinating Center, and 83 volunteer participating renal centers. Since 1 987, each allograft received by a S258 Volume 2 Supplement

2 :.. Tejani and Stablein pediatric recipient at the participating center is reported with information on the original disease leading to transplantation, graft function, and therapy. Data are submitted at 1 -month posttransplant, and thereafter, a status report is submitted on each patient every 6 months. A detailed questionnaire was developed by the Scientific Advisory Committee of NAPRTCS and mailed to the participating clinics reporting transplants carned out on patients with the diagnosis of focal segmental sclerosis leading to end-stage renal disease status (see Appendix). The questionnaire requested the participating clinics to identify patients in whom recurrence was noted posttransplantation. The recurrence of FSGS after transplantation was defined as the development of a nephrotic range of proteinuria that did not respond to antirejection therapy and that was confirmed histologically by a transplant kidney biopsy. Risk factors analyzed for recurrence included race, age at FSGS, clinical severity as assessed by serum albumin and cholesterol levels at onset, and histological severity as assessed by the presence of mesangial proliferation on biopsy. Additional risk factors analyzed were the duration of disease, the time spent on dialysis, HLA matching, previous therapy, and posttransplant immunosuppression. Graft survival was calculated by the use of Kaplan Myer estimates. Statistical analysis was carried out by t test, and a P value <0.05 was considered significant. RESULTS From January 1987 through December 1990, the NAPRTCS registry recorded 1 68 transplants performed on children 0 to 1 7 yr with the diagnosis for end-stage renal disease being focal segmental scherosis. Of 1 68 questionnaires sent out to the participating clinics, 1 32 were adequately answered for a detailed analysis. The data presented here deal with 127 children who received 132 transplants. Demographic characteristics of the 1 27 patients are presented in Table 1. Background characteristics of the 1 27 patients are depicted in Table 2. Steroids have been used in 74% and cyclosporine in only 9% as therapy for the original disease, whereas 10% of patients had no treatment given for proteinuria. Of 1 32 transplants, 27 had a biopsy-proven recurrence of their original disease, producing a recurrence rate of 20.5% (95% confidence interval, 14 to 27). When the recurrence rate was examined by pretransplant therapy. cyclosporine recipients had a rate of 27% recurrence compared with 32% for those who did not receive pretransplant cycbosporine; the differences, however, were not significant. Recurrence rates by age and donor source are depicted in Table 3. The recurrence rate for living re- TABLE 1. Demographic characteristics of the 127 patients N % Race White Black Hispanic Other 4 3 Sex Male Female Age at diagnosis (yr) TABLE 2. Background characteristics of the 127 patients Prior FSGS Therapy Cyclosporine I I 9 Alkylating Agents Methylprednisolone Prednisone No therapy attempted I 3 10 Response Complete clearing of protein- I I 9 uria Partial clearing, resolution of edema None TABLE 3. Recurrence rate by age and donor source Recurrence N Rate 27/ Donor Source Live 12/49 24 Cadaver 15/83 18 Age at Transplant (yr) 2-5 5/ / / / /83 19 hated donor (LRD) transplants was higher, but there was no significant difference, compared with cadaver donor transplants. Similarly, no significant differences were noted as regards to age at transplantation. Recurrence rates analyzed by race and sex are shown ( /0) Journal of the American Society of Nephrology 5259

3 Recurrence of FSGS Posttransplantation TABLE 4. Recurrence rate by race and gender-all transplants TABLE 5. Recurrence rate by antigen-matching status-all transplants Recurrence Rate (%) Recurrence Rate ( /o) Race White 17/73 23 Black 3/32 9 Hispanic 6/23 26 Other 1/4 25 Sex Male 21/82 26 Female 6/50 12 in Table 4. The rate was similar for Hispanic and white children, but the recurrence rate for black children (3 of 32) was much lower. Clinical severity was assessed by serum albumin and cholesterol levels at the time of the diagnosis of FSGS. The mean serum albumin level of 1.7 g/dl for 25 children with recurrence was lower than the mean serum albumin level of 2.0 g/dl for 88 patients without recurrence; however, the difference did not reach significance. Similarly, the mean serum cholesterol level of 525 mg/dl for 1 7 recurrent patients was higher than the 476 mg/dl for 64 nonrecurrent cases but the difference was not significant. Histological severity was assessed by the evidence of mesangial proliferation. Fifty-three patients had evidence of mesangial proliferation on native kidney biopsy. Recurrence was noted in 1 3 of these patients with a rate of 25%. Among 64 patients with no mesangial proliferation, 1 3 developed recurrence with a rate of 20%. Table 5 shows the rate of recurrence with HLA mismatches. No differences were noted between the various groups. The mean duration of dialysis of 24 months in 96 patients without recurrence was not different from the mean duration of dialysis of 20 months in patients with recurrence. The single significant risk factor to emerge from this study was the time from the diagnosis of FSGS to end-stage renal disease status. Both the mean (52 months) and median (38 months) for 94 patients without recurrence was significantly longer than the mean (38 months) and median (28 months) for 26 patients with recurrence (P < 0.05). The recurrence of FSGS was delineated as the cause of graft failure in 5 of the 10 failing LRD graphs and in 5 of the 20 cadaveric source grafts. Two-year graft survival for LRD grafts was 74% compared with 64% for cadaver source grafts (P < 0.05) (Figure 1). DISCUSSION The recurrence of original disease after a renal transplant has been described in a variety of disor- HLA-A 2 Mismatch 8/35 23 I Mismatch 14/ Mismatch 5/12 42 HLA-B 2 Mismatch 11/52 21 I Mismatch 12/67 18 OMismatch 4/13 31 HLA-Dr 2 Mismatch 13/44 30 I Mismatch 10/ Mismatch 4/ J 90 > C,) 4 (9 I- 50, C) 100 4o, a- 30 I, : Live Donor adover MONTHS Figure 1. Graft survival of LRD kidneys and cadaveric kidneys. ders; however, unlike other diseases, such as membranoprohiferative gbomerubonephritis where recurrence does not necessarily lead to graft loss (15), steroid-resistant FSGS when seen in a transplant kidney will eventually lead to graft loss (1 6). Studies on the recurrence of FSGS posttransphantation tend to vary tremendously. The small sample size in most studies, together with the different patient population, is the primary factor that results in the wide variation. When a large patient population of adults and chitdren is studied, it becomes obvious that the recurrence of FSGS is primarily a pediatric problem. Thus, Senguttuvan et at. ( 1 7) noted that age at onset was a strong risk factor for recurrence. The recurrence of FSGS in their study was noted in 50% of children but only in 1 1 % of adolescents and adults. Because rates of recurrence in children also vary widely, the NAPRTCS decided to carry out this special study. This is the largest study of a heterogeneous population, and our observation that the 95% confidence 5260 Volume 2. Supplement

4 Tejani and Stablein interval limits of recurrence rates in children are 14 to 27% gives national recurrence rates for the first time. The rate observed in this study is much lower than the rate of 50% observed in the study of Striegel et at. (8). Their study was carried out in Minnesota where most of the transplanted children are white. When our results are analyzed by racial background, our rate of 25% for the white children is still much lower than the Minnesota figure. The higher rate in the study of Striegel et at. may be related to a subset of patients with a shortened time from diagnosis to end-stage renal disease, because that appears to be the only significant factor in our study. Our study would also help to explain the tow rate of 14% reported by Ingulli and Tejani (9). Most of the patients in that study were black, and our study does record a lower rate of recurrence in the black population (9%). FSGS as a disease tends to be more severe in black patients (1 8), and the decreased rate of recurrence seen in the black population in our study is surprising. Because the pathogenesis of the disease is unknown, a variety of suggestions have been made to account for recurrence. Thus, it has been suggested that a circulating factor is responsible (1,19); hence, prolonged dialysis would eliminate the risk of recurrence. On the basis of our study and on data from previous large studies (17,20), no useful purpose is served in keeping the patient on dialysis for a prolonged period. Histological severity has also been implicated (20). Similarly, a younger age at the onset of the disease has been thought to be a risk factor (9, 1 7). Our large study did not implicate any of these as risk factors. Because the only significant risk factor noted in our study was time from diagnosis to end-stage renal disease, the observation of St. Hillier et at. (2 1) that a malignant form of FSGS has an increased risk of recurrence seems to be borne out. Others doing a large study also seemed to have noted a subset of patients in whom deterioration to endstage renal disease is rapid (20,22-24), and such patients may be at a higher risk for recurrence. The recurrence of original disease leads to graft loss unless plasmapheresis (25) or high-dose cyclosporine therapy (26) is able to control the proteinuria. On the basis of the increased risk of graft loss, Senguttuvan et at. (1 7) suggest that LRD grafts should not be used for the initial transplant for patients with FSGS as the original disease. Our study shows that, despite recurrence, the 2-yr graft survival of LRD transplant was 1 0% better than the 2-yr graft survival of cadaver kidney transplants. Among 1,667 transplants in the NAPRTCS registry, the graft survival of LRD kidneys is 1 5% better than that of cadaver kidneys at 2 yr posttransplant (27). However, 5 1 % of all kidneys transplanted in white children in our study are derived from a LRD source and the overall figure for all races is 43% (27). These figures are very different from the data in adults in the United States as well as in the European Dialysis and Transplant Association (EDTA) data regarding European children. The overall rate for LRD transplants in the United States is 2 1 % (28) and the rate from the EDTA data for children is 20% (29). Having demonstrated a national rate of recurrence that is lower than that for previous studies and having also demonstrated that in patients with FSGS the graft survival of kidneys derived from a living related source is still superior to that of cadaveric source kidneys, we feel that the recommendation of not using LRD kidneys in children is not justified. We suggest that if a cadaveric kidney is not available, a living donor transplant should be considered for patients with FSGS. REFERENCES 1. Hoyer JR, Raij L, Vernier RI, Simmons RL, Najarian JS, Michael AF: Recurrence of idiopathic nephrotic syndrome after renal transplantation. Lancet 1972;2: Cameron JS, Turner DR: Recurrent glomerubonephritis in allografted kidneys. Clin Nephrol 1 977;7: Noel LH, Berger J, DeCamps B, et at.: Recurrence of glomerubonephritis after renal transplantation [Abstract No. 1026J. VIth International Congress in Nephrology, Florence, Italy, June Malekzadeh MH, Houser ET, Ettenger RB, et at. : Focal glomerulosclerosis and renal transplantation. J Pediatr 1 979;95: Leumann EP, Briner J, Donckerwolcke RAM, Kuijten R, Largiader F: Recurrence of focal segmental glomerulosclerosis in the transplanted kidney. Nephron 1980:25: Tejani A, Nicastri AD, Sen D, et al.: Long-term evaluation of children with nephrotic syndrome and focal segmental glomerular sclerosis. Nephron 1983:35: Alexsen RA, Seymour AE, Mathew TH, Fisher G, Canny A, Pascoe V: Recurrent focal glomeruboscherosis in renal transplants. Clin Nephrol 1984:21: Striegel JE, Sibley RK, Fryd DS, Mauer SM: Recurrence of focal segmental sclerosis in chitdren following renal transplantation. Kidney Int 1986:30:S44-S Ingulli E, Tejani A: Incidence, treatment, and outcome of recurrent focal segmental gbomerulosclerosis posttransphantation in 42 allografts in children-a single-center experience. Transplantation 1991 ;51 : Tejani A, Butt K, Trachtman H, Suthanthiran M, Rosenthal CJ, Khawar MR: Cycbosporineinduced remission of relapsing nephrotic syndrome in children. J Pediatr 1 987; 111: Meyrier A, Simon P, Perret G, Condamin MC: Remission of idiopathic nephrotic syndrome after treatment with cyclosporine A. Br Med J 1 986;292: Capodicasa G, DeSanto NG, Nuzzi F, Giordano C: Cyclosporin A in nephrotic syndrome in childhood: A 1 4 month experience. Int J Pediatr Nephrol 1986:7: Journal of the American Society of Nephrology 261

5 Recurrence of FSGS Posttransplantation 1 3. Brandis M, Burghard R, Leititis J, Zimmerhacki B, Hildebrandt F, Helmchen U: Cycbosporin A for treatment in nephrotic syndromes [Abstracti. Pediatr Nephrol 1987; 1 :C Niaudet P, Tete MJ, Habib R, Broyer M: Cyclosporin A in the treatment of idiopathic nephrosis in children [Abstract]. Pediatr Nephrol 1987; 1:C Cameron JS: Glomeruhonephritis in renal transplants-overview. Transplantation 1982; 34: Alexander SR, Arbus GS, Butt KM, et at.: The Report of the N.A.P.R.T.C.S. Pediatr Nephrol 1990:4: Senguttuvan P. Cameron JS, Hartley B, et at.: Recurrence of focal segmental glomerulosclerosis (FSGS) in 58 renal ahhografts from a single centre: Analysis of risk factors for recurrence. Pediatr Nephrol 1990:4: Ingulli E, Tejani A: Racial differences in the incidence and renal outcome of idiopathic focal segmental glomeruloscherosis in children. Pediatr Nephrol 1991:5: Zimmerman SW: Increased urinary protein excretion in the rat produced by serum from a patient with recurrent focal ghomerularsclerosis after renal transplantation. Chin Nephrol 1 984;22: Donckerwolcke RA, Broyer M, Brunner FP, et at.: Combined report on regular dialysis and transplantation of children in Europe, XL, Proc Eur Dial Transplant Assoc 1982; 19: St. Hillier Y, Morel-Maroger L, Woodrow D, et at.: Focal segmental hyalinosis. Adv Nephrol 1975:5: Pinto J, Lacerda G, Cameron JS, Turner DR. Bewick M, ogg CS: Recurrence of focal segmentat fbomerulosclerosis in renal albografts. Transplantation 1981:32: Habib R, Bois E. Congenital and infantile nephrotic syndrome. In: Strauss J, ed. Pediatric Nephrology. Vol. 2. New York: Stratton Intercontinental; 1975: Munoz J, Sanchez R, Perez Garcia R, Anaya F, Valderrabano F: Recurrent focal segmental fbomerulosclerosis in renal transplants. Proteinuria relapsing following plasma exchange. Clin Nephrol 1985;24: Laufer J, Ettenger RB, Ho WG, Cohen AH, Mrik JL, Fine RN: Plasma exchange for recurrent nephrotic syndrome following renal transplantation. Transplantation ; 46: Ingulli E, Tejani A, Butt KMH, et at.: High-dose cychosporine therapy in recurrent nephrotic syndrome following renal transplantation. Transplantation 1 990;49: McEnery P. Stablein D, Arbus G, Tejani A: Renal transplantation in children. A report of the North American Pediatric Renal Transplant Cooperative Study. N Engl J Med 1 992;326: U.S. Renal Data System 1990 Report. Bethesda, MD: The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease: Broyer M: Kidney transplantation in children- Data from the EDTA registry. Transplant Proc 1989:21: APPENDIX. Participating centers/principal investigators in the FSGS study. Center Principal Investigator Children s Hospital-Boston Children s Hosp Med Ctr-Cincinnati Phoenix Children s Hospital Eastern Virginia Sch of Medicine Medical College of Virginia University of California at LA Children s Renal Center-San Francisco Children s Memorial Hosp-Chicago Egleston Hospital for Children Tulane Medical Center The Children s Mercy Hospital-KC University of Wisconsin Hospital Children s Medical Center-Dallas SUNY-Brooklyn St. Francis Renal Inst-Honolulu Univ of Texas HSC at Houston U of Tenn/Le Bonheur Children s BC Children s Hospital Columbia Presbyterian Medical Ctr U of Neb/Bishop Clarkson Hospital University of Minnesota Hospital University of Iowa Hospitals University of Michigan University of Alabama Medical Ctr St Christopher s Hosp for Children Children s Hospital of Pittsburgh William E. Harmon, M.D. Paul T. McEnery, M.D. Mel Cohen, M.D. Michael J. Solhaug, M.D. John Foreman, M.D. Robert Ettinger, M.D. Donald E. Potter, M.D. Richard A. Cohn, M.D. Barry L. Warshaw, M.D. Frank G. Boineau, M.D. Bradley A. Warady, M.D. Aaron Friedman, M.D. Steven R. Alexander, M.D. Amir Tejani, M.D. James E. Musgrave, M.D. Ronald Portman, M.D. Shone Roy Ill, M.D. David S. Lirenman, M.D. Martin A. Nash, M.D. Mark T. Houser, M.D. Thomas E. Nevins, M.D. Jean Robillard, M.D. Aileen Sedman, M.D. Edward Kohaut, M.D. H. Jorge Baluarte, M.D. Demetrius Ellis, M.D. $262 Volume 2 Supplement

6 Tejani and Stablein APPENDIX. Participating centers/principal investigators in the FSGS study. Center Principal Investigator Akron Children s Hospital Children s Hospital of Wisconsin Children s Hospital-Columbus Children s Renal Center-Galveston Wyler Children s Hospital Mayo Clinic Massachusetts General Hospital Children s Hospital of LA St. Louis Children s Hospital The Bowman Gray School of Medicine East Carolina University Children s Hosp National Med Ctr Arkansas Children s Hospital University of Utah Oregon Health Sciences University Loma Linda University Medical Ctr Ian Dresner, M.D. Heinz E. Leichter, M.D. Mark I. Mentser, M.D. Luther B. Travis, M.D. Andrew Aronson, M.D. Dawn S. Milliner, M.D. John T. Herrin, M.D. Paul S. Kurtin, M.D. Barbara R. Cole, M.D. William B. Lorentz, M.D. Roberta Gray, M.D. Edward J. Ruley, M.D. Eileen Ellis, M.D. Miriam Turner, M.D. Cindy Bliseld, M.D. Shobha Sahney-Long, M.D. Journal of the American Society of Nephrology S263