Long-term outcome of focal segmental glomerulosclerosis after Japanese pediatric renal transplantation

Focal segmental glomerulosclerosis (FSGS) is known to recur in some patients after renal transplantation. Over a prolonged period, we followed 13 pediatric patients with FSGS who had undergone transplantation from living-related donors, analyzing risk factors for recurrent disease. Native nephrectomies were performed bilaterally in all patients at least 1 month prior to transplantation. Immunosuppressive therapy consisted of cyclosporine (CyA), mizoribine, prednisone, and antilymphocytic globulin or deoxyspergualin. We examined age at onset, time in months between diagnosis and end-stage disease (dialysis or transplantation), the duration of dialysis, age at transplantation, time since nephrectomy, doses of immunosuppressive agents, and HLA mismatch. Five patients (42.8%) developed recurrent disease in the graft; all showed proteinuria within 24 h of transplantation. However, all allografts have functioned well for 34–156 months following transplantation despite the recurrences, although 1 of these patients now shows proteinuria. The remaining 8 patients have had no recurrence for 104.6±30.4 months (mean±SD). The serum level of creatinine in patients with recurrence and without recurrence was 1.1±0.42 mg/dl and 0.98±0.29 mg/dl, respectively. The interval from diagnosis to initiation of dialysis was significantly shorter in patients with recurrence than those without recurrence (P<0.05), but no other variables differed between these two groups. No recurrence of FSGS was observed in the protocol biopsy at 100 days after transplantation. We believe that CyA and native nephrectomy may limit or reverse progression of recurrent FSGS in renal allografts of Japanese pediatric patients, although this is a limited study. Received: 22 December 2000 / Revised: 6 September 2001 / Accepted: 10 September 2001     

Recurrent focal glomerulosclerosis: natural course and treatment with plasma exchange.

BACKGROUND: Focal glomerulosclerosis (FGS) can recur after renal transplantation and prognosis is poor in untreated patients. A circulating plasma factor has been implicated in the pathogenesis of a recurrent FGS and treatment with plasma exchange has proven effective in decreasing proteinuria in some patients. METHODS: We retrospectively studied the course of disease in patients with recurrent FGS, transplanted in our centre. Seven patients transplanted between 1991 and 1997, received treatment with plasma exchange, whereas 10 patients, transplanted between 1973 and 1991, were left untreated and served as historical controls. RESULTS: The time of onset of proteinuria (>3.5 g/day) was comparable in the untreated and treated patients (9 and 10 days respectively), as was the average proteinuria at that time (5.5 and 5.8 g/day respectively). In the untreated patients, proteinuria persisted and eventually all grafts were lost, on average 43 months after the diagnosis of a recurrence. In five cases (50%) the recurrence was the single cause of graft loss. The clinical course was different in the seven patients who were treated with plasma exchange. In five of these patients, the recurrence occurred within 3 weeks after transplantation. Plasma exchange was started 1-14 days after onset of proteinuria in these patients. Two lost their grafts after 0.7 and 1.0 months because of untreatable rejection. In the remaining three patients the plasma exchange resulted in abrupt disappearance of the proteinuria, and the response has been lasting for 2-3.2 years. In these patients the only histological abnormality was foot effacement on electron-microscopy. In two patients the recurrence became manifest at 9 weeks and 5.8 years after transplantation respectively. These two patients relapsed after the initial course of plasma exchange, but responded to repeated session, and are currently being treated once a month. They have been followed for 1. 7 and 1.4 years after the onset of proteinuria and their urinary protein levels are 0.23 and 1.2 g/10 mmol creatinine. CONCLUSIONS: The prognosis of untreated recurrent FGS is poor. Treatment with plasma exchange can lead to complete remission of proteinuria and relapsing patients may respond to repeated sessions. Best results are obtained when plasma exchange is started early, when there are no visible lesions on light-microscopy.     

A case of homozygous familial hypercholesterolemia with focal segmental glomerulosclerosis

Familial hypercholesterolemia (FH) is a common autosomal dominant inherited disorder characterized by increased levels of circulating plasma low-density lipoprotein cholesterol (LDL-C), tendon xanthomas, and premature atherosclerotic cardiovascular disease. Homozygous FH occurs in only one in a million people. Focal segmental glomerulosclerosis (FSGS) is clinically characterized by proteinuria, which is marked in the majority of cases and accompanied by nephrotic syndrome, high incidence of hypertension, and progression to renal failure. To our knowledge, we herein report for the first time a case of homozygous FH associated with FSGS. A seven-and-a-half-year-old boy was referred to our hospital due to cutaneous xanthomata and growth retardation. He had multiple nodular yellowish cutaneous xanthomatous lesions each 1 cm in size over his knees and sacral region. Laboratory data included cholesterol level of 1,050 mg/dl, low density lipoprotein cholesterol (LDL-C) 951 mg/dl, high-density lipoprotein cholesterol (HDL-C) 29 mg/dl, triglycerides 168 mg/dl, total protein 6.3 g/dl, and albumin 3.2 g/dl. Urinary protein excretion was 78 mg/m² per hour. A percutaneous renal biopsy was performed, and histological findings showed FSGS. Treatment with cholestyramine and atorvastatin was unsuccessful in terms of lowering lipids, and he was placed on weekly sessions of plasmapheresis. Total cholesterol was reduced from 1,050 mg/dl to 223 mg/dl, LDL-C from 951 mg/dl to 171 mg/dl, and urinary protein excretion from 78 mg/m² per hour to 42 mg/m² per hour after eight sessions of plasmapheresis. It is our belief that plasmapheresis is a treatment of choice in patients with FSGS associated with FH.     

血浆置换预防和治疗肾移植后加速及超急性排斥反应的观察

目的　探讨血浆置换疗法（PE）对预防和治疗肾移植后排斥反应的疗效。方法　选择30例肾移植前群体反应抗体（PRA）增高≥30%及10例肾移植后出现加速性排斥反应的患者,在用免疫抑制剂的同时作膜分离法血浆置换。结果　PE能清除各种免疫球蛋白及循环抗体,PE前后对比差异有显著性（P＜0.01）,PE治疗后全部患者（30例）PRA≤10%,肾移植后经过6～9个月的观察,27例（占90%）未出现超急、加速或严重的急性排斥反应;10例肾移植后出现加速性排斥反应者,8例（占80%）逆转。结论　PE配合免疫抑制剂治疗,对预防和减轻肾移植后排斥反应疗效确切。     

Recurrence of nephrotic syndrome/focal segmental glomerulosclerosis following renal transplantation in children

The incidence of recurrence of nephrotic syndrome/focal segmental glomerulosclerosis (NS/FSGS) is variable (~30%). The incidence of recurrence is less in African-Americans than in whites and Hispanics. Graft survival rates are decreased in recipients with FSGS, especially if remission of the NS is not achieved in those with recurrence. Although controversial, the use of living donor (LD) transplants are not contraindicated; however, obligatory heterozygote parental grafts with a podocin mutation should be used with caution. Optimal treatment to induce a remission post-transplant has not been delineated. Pre-transplant and/or prophylactic post-transplant pre-operative plasmapheresis (PP) for high-risk patients--especially those with recurrence in a previous graft--may be promising. An international multicenter controlled study is required to delineate the optimal approach to prevent and/or treat the recurrence of NS/FSGS.     

Recurrent focal segmental glomerulosclerosis in grafts treated with plasma exchange and increased immunosuppression

We report on three children with severe, recurrent focal segmental glomeruloscerosis (FSGS) in their first allografts, treated with methylprednisolone, plasma exchange and cyclophosphamide. This protocol is based on a previous publication showing its successful use in three children. Our patients were 2 girls and 1 boy, aged 14.5, 14.6 and 13.2 years, respectively, at transplant. Concomitant immunosuppression included cyclosporin A and prednisolone. Recurrence occurred in all three patients within 24 h, and specific treatment was commenced within 48 h. All patients developed anuria and were dialysed. The boy stopped dialysis after 4 weeks, and has stable chronic renal failure (CRF) and no proteinuria 3 years later. One girl required dialysis for 4 months, and 3 years later has CRF with non-nephrotic range proteinuria. The other girl remained dialysis- dependent and died from septic complications. We conclude that even anuric patients treated with this protocol may have an improvement in renal function and reduction of proteinuria, which can last for over 3 years. However, treatment may need to be prolonged and carries the substantial risks of heavy immunosuppression. Received: 11 January 1999 / Revised: 20 July 1999 / Accepted: 21 July 1999     

肾移植术后局灶节段性肾小球硬化临床病理特征分析

目的  探讨肾移植术后复发及新发局灶节段性肾小球硬化(FSGS)的临床和病理特征。方法  选取经移植肾穿刺活组织检查(活检)病理确诊为FSGS的受者34例,根据自体肾原发病及循环渗透因子检测,将34例受者分为复发FSGS组(12例)和新发FSGS组(22例)。比较复发与新发两组间受者在临床指标及移植肾病理损伤程度的差异。结果  两组受者系膜增生评分、肾小球球性硬化率、肾小管萎缩评分、间质纤维化评分和足细胞增生发生率之间的差异均无统计学意义(均为P > 0.05); 复发FSGS组受者的节段性肾小球硬化率为0.10(0.08,0.27),低于新发FSGS组受者的0.19(0.13,0.33)(P < 0.05)。两组受者抗体介导的排斥反应、药物性肾小管损伤、BK病毒感染发生率之间的差异均无统计学意义(均为P > 0.05); 复发FSGS组受者T细胞介导的排斥反应发生率为17%,低于新发FSGS组受者的55%(P < 0.05)。免疫组织化学结果显示移植肾组织内浸润炎症细胞主要为T细胞; 复发FSGS组和新发FSGS组管周毛细血管C4d沉积阳性率分别为33%(4/12)和32%(7/22),差异无统计学意义(P > 0.05); 免疫荧光结果显示多数病例移植肾肾小球节段性硬化区IgM团块状沉积,电子显微镜显示移植肾肾小球均存在足突广泛融合或节段性分布。结论  复发FSGS组肾损伤程度和T细胞介导的排斥反应发生率低于新发FSGS组。综合分析肾移植受者术前和术后的临床表现、实验室检测和病理学检查等有助于复发和新发FSGS的早期诊断和治疗。     

Enhanced renal perfusion improves function in severe nephrosis with focal segmental glomerulosclerosis

Summary: Fourteen cases of severe steroid-resistant nephrosis with focal segmental glomerulosclerosis were identified by the moderate to severe impairment of glomerular function. Symptoms included low glomerular filtration rate, ultrafiltration coefficient and increased intraglomerular hydrostatic pressure, tubular dysfunction including a defect in transporting solute, which was reflected by increasing fractional excretion of filtered solutes, in concentrating and acidifying the urine, and vascular dysfunction including marked elevation of renal arteriolar resistances and inversely severe reduction of renal plasma flow and peritubular capillary blood flow.
Of these 14 nephrotics, eight patients were randomly treated with prednisolone, cyclophosphamide and antihypertensive agents, namely reserpine, hydralazine or prazosin, and the other six patients who had previously been resistant to prednisolone and cyclophosphamide were treated with an enhanced-renal-perfusion formula that consisted of a combination of antiplatelet agents, calcium channel blockers, angiotensin-converting-enzyme inhibitors, anticoagulant and prednisolone.
After follow-up of 62 months, all eight patients were refractory to the conventional treatment, showing persistent proteinuria with a progressive deterioration of renal function entering end-stage renal disease. In contrast, five of the six patients under the enhanced-renal-perfusion formula gradually improved their renal functions and survived after 82 months of follow-up. the remaining patient, who did not improve, died of sepsis.     

Recurrence of focal segmental glomerulosclerosis in transplanted kidneys: Analysis of incidence and risk factors in 59 allografts

Fifty-nine allografts were placed in 43 patients with renal failure from focal segmental glomerulosclerosis (FSGS): 27 allografts were put into 16 children aged less than 15 years, and 32 allografts into 27 adolescents and adults. Recurrence of FSGS was noted histologically in 13 allografts, 10 in 8 children and 3 in adults. None of the 9 children and 24 adults who never developed an allograft nephrotic syndrome showed FSGS in their allograft biopsies. The age of onset was a strong risk factor for recurrence: recurrent FSGS developed in 8 of 16 children (50%) but only in 11% of adolescents and adults (3 of 27 patients). Although the time from apparent onset to renal replacement treatment was shorter in those with recurrence than those without in the children, there was no difference in the time spent on dialysis prior to transplantation. Mesangial prominence was observed in the original biopsy in 12 of 13 patients with recurrence, and recurrence rate was similar in living and cadaver donor allografts; class I MHC matching was similar in those with and without recurrence. Three allografts treated with cyclosporin A as well as 9 with azathioprine showed recurrence. Of 9 second or subsequent allografts placed in those with recurrence in the first allograft, only 3 showed further recurence. rence. In 3 re-grafted after 13, 11 and 5 years, normal function was seen.     

Early recurrent nephrotic syndrome after renal transplantation in children with focal segmental glomerulosclerosis.

BACKGROUND: We analysed risk factors to predict the recurrence of nephrotic syndrome and the therapeutic efficacy of plasmapheresis combined with oral cyclophosphamide (PE+CPM) in early recurrent nephrotic syndrome after transplantation in children with focal segmental glomerulosclerosis (FSGS). METHODS: Medical records after 1990 of 16 children with biopsy-proven idiopathic FSGS and renal transplantation before the age of 18 years were reviewed. RESULTS: Early recurrence of nephrotic syndrome developed in six cases (37. 5%). While early kidney graft biopsies, performed within the first week after the onset of recurrence, revealed diffuse effacement of foot process only, late biopsies contained segmentally sclerosed glomeruli as well. Among several possible risk factors, the mean duration from onset of original nephrotic syndrome to development of end-stage renal disease was shorter in the recurrent group (P=0.045) and the percentage of globally sclerosed glomeruli was higher in the non-recurrent group (P=0.001). PE+CPM therapy resulted in complete remission of nephrotic syndrome if it was started early and if there was no evidence of accompanying acute rejection. CONCLUSION: These results support more liberal use of living-related donors for renal transplantation of children with FSGS and ESRD, considering the shortage of cadaveric donors in our society and relatively good efficacy of the early and intensive PE+CPM therapy for early recurrent nephrotic syndrome.     

Idiopathic collapsing focal segmental glomerulosclerosis in pediatric patients

The aim of this study was to evaluate the clinical outcome of our patients with idiopathic collapsing focal segmental glomerulosclerosis (FSGS) as compared to those with non-collapsing FSGS. The study included a total of 39 patients with idiopathic FSGS. Of these, 11 had collapsing FSGS and the remaining 28 were collectively grouped as non-collapsing FSGS. The mean ages, gender ratio (M:F), and percentage of African-American patients in collapsing versus non-collapsing FSGS groups were 12.7 ± 3.1 and 8.9 ± 5.1 years, 1.2:1 and 4.6:1, and 90.9 and 53.6%, respectively. After a mean followup period of 31.5 ± 22.3 months, 8 patients (73%) with collapsing FSGS had chronic renal impairment as compared to 8 (29%) patients with non-collapsing FSGS group after a mean follow-up period of 18.7 ± 12.9 months. However, the cumulated renal survival at 30 months did not reveal a significant difference. In comparison to non-collapsing FSGS, collapsing FSGS in our study was equally common in females as in males and occurred predominantly in African Americans. The outcome of our patients with collapsing FSGS at 30 months was better than in previous reports. Dr. El-Refaey’s fellowship at Children’s Hospital of Michigan was supported by a grant from the International Pediatric Nephrology Association.     

血浆置换治疗移植肾复发性FSGS合并大量蛋白尿的远期观察

目的 探讨血浆置换治疗移植肾复发性局灶性节段性肾小球硬化（FSGS）效果及其对远期预后的影响。方法 6例患者首次肾移植后出现大量蛋白尿或／和血肌酐（Cr）升高、并经移植肾活检确诊为FSGS，在不改变免疫抑制方案的情况下，采用血浆置换治疗，观察血浆置换后1年移植肾的病理改变情况，测定血肌酐和24h尿蛋白定量。结果 6例患者中，2例在血浆置换后1年接近完全缓解，4例部分缓解。患者血浆置换后1年，移植肾的肾小球、肾间质、血管及免疫球蛋白病变的等级与血浆置换前相比，差异均无统计学意义。血浆置换后1年及5年的Cr水平与血浆置换前相比，差异均无统计学意义；24h尿蛋白定量与血浆置换前相比，差异均有统计学意义（P〈0．01，P〈0．05）。结论 血浆置换能快速、有效地缓解移植肾复发性FSGS的病变程度和进程，其效果取决于FSGS诊断的及时性，如果已发展到肾小球硬化的程度，血浆置换亦无法将其逆转。     

Usefulness of Plasma Exchange in Recurrent Nephrotic Syndrome Following Renal Transplant

Abstract: Nephrotic syndrome due to focal segmental glomerulosclerosis (FSGS) frequently recurs even after transplantation and may cause failure of the renal al-lograft. We report a case in which plasma exchange (PE) was used to treat a 32-year-old patient with biopsy-proven recurrence of FSGS in a second renal transplant after the first allograft had failed. One year after the second renal graft, the patient presented with proteinuria of 5 g/day and a creatinine level of 1.46 mg/dl. A course of 9 PE was performed over a 15-day period. Proteinuria improved rapidly, and 20 days after the last PE, it was already down to 0.8 g/day. This level continued to decrease progressively (0.5 g/day after 3 months) and reached zero after approximately 6 months. Eleven months after PE treatment, the patient had no proteinuria and his plasma creatinine level was normal. In our opinion PE should be instituted early in recurrent nephrotic syndrome after renal transplantation. The optimum frequency of such treatment still has to be established, especially with regard to its use as long-term maintenance therapy.     

Successful treatment of recurrent focal segmental glomerulosclerosis after kidney transplantation by plasmapheresis and rituximab

A 22-year-old patient whose primary kidney disease was focal segmental glomerulosclerosis (FSGS) developed severe recurrence of proteinuria (up to 57 g/24 h) immediately after a haploidentic living donor kidney transplantation despite pre-operative plasmapheresis. The immunosuppressive treatment consisted of tacrolimus, mycophenolate mofetil, basiliximab and steroids. He underwent 10 plasmapheresis sessions in the first 3-week post-transplantation. In addition, he received 2 i.v. doses of rituximab (RTX) 600 mg (375 mg/m(2)) on days 7 and 15. Proteinuria decreased below nephrotic range at day 14 and serum creatinine returned progressively to normal values. A short course of oral ciclophosphamide (100 mg/j) was administrated between days 22 and 40 and three additional plasmapheresis sessions on days 34, 39 and 49. This strategy allowed obtaining sustained full remission of the nephrotic syndrome (NS) and excellent graft function, which persists over 2 years after transplantation. No notable adverse events related to RTX or plasmapheresis were observed. This case suggests that RTX associated with plasmapheresis may be an effective treatment of recurrent NS because of FSGS.     

Massive proteinuria and acute renal failure after oral bisphosphonate (alendronate) administration in a patient with focal segmental glomerulosclerosis

A 61-year-old Japanese man with nephrotic syndrome due to focal segmental glomerulosclerosis was initially responding well to steroid therapy. The amount of daily urinary protein decreased from 15.6 to 2.8 g. Within 14 days of the oral bisphosphonate (alendronate sodium) administration, the amount of daily urinary protein increased rapidly up to 12.8 g with acute renal failure. After discontinuing the oral alendronate, the patient underwent six cycles of hemodialysis and four cycles of LDL apheresis. Urinary volume and serum creatinine levels recovered to the normal range, with urinary protein disappearing completely within 40 days. This report demonstrates that not only intravenous, but also oral bisphosphonates can aggravate proteinuria and acute renal failure.     

Plasmapheresis treatment for recurrent focal sclerosis in pediatric renal allografts

Recurrence of focal segmental glomerulosclerosis (FSGS) in pediatric renal allografts is associated with a poor graft survival. This study reports on plasmapheresis for the treatment of recurrent FSGS in pediatric renal transplant recipients. The records of 100 consecutive pediatric (age <21 years) renal transplants were reviewed. Twenty patients had FSGS as the cause of renal failure. Eight of these (40%) had a recurrence (protein-uria >1 g/m² per day) within 1 month of transplantation. Five of six patients treated with plasmapheresis went into remission (<0.2 g/m² per day), receiving a total of 42±26 (12–73) sessions, with the mean number of sessions required to achieve a remission being 24±17 (8–51). One patient had a second recurrence 1 year following cessation of plasmapheresis and responded to another course of plasmapheresis. The 1 patient who did not respond to plasmapheresis had a delay in initiation of therapy of 42 days. Plasmapheresis initiated within 48 h of recurrence resulted in earlier remissions and improved graft survival among our patients. Plasmapheresis appears to be effective in treating recurrent FSGS following kidney transplantation and should be started as soon as possible. The number of plasmapheresis sessions used to achieve remission should be adjusted according to response rather than adhering to a fixed protocol. Received: 22 November 1999 / Revised: 2 March 2000 / Accepted: 6 March 2000     

Racial differences in the incidence and renal outcome of idiopathic focal segmental glomerulosclerosis in children

The North American Pediatric Registry reports that from 1987 to 1989 blacks and Hispanic children accounted for 23% of all renal transplants performed but 38% of those performed for focal segmental glomerulosclerosis (FSGS). From these data, we infer that blacks and Hispanics form a disproportionate number of FSGS patients who progress to end-stage renal disease (ESRD) compared with white children. To explore this hypothesis we assessed our single-center experience of FSGS comparing black and Hispanic with white children. Of 177 black and Hispanic children followed in our clinic for idiopathic nephrotic syndrome (NS) between 1974 and 1989, 57 were diagnosed as having FSGS (group I). The mean age at onset of NS of these group I patients was 7.3±4.6 years and the mean duration of follow-up was 8.25±4.3 years. During the same period, 13 of 65 white patients (group II) with idiopathic NS were found to have FSGS. Their mean age (7.8±4.8 years) and duration of follow-up (8.8±4.8 years) were similar. Therapeutic modalities in the two groups were also similar. Of group I patients, 78% (42/54) reached ESRD compared with 33% (4/12) of group II patients (P<0.01). Life table analysis showed that 50% of black and Hispanic children will reach ESRD within 3 years of FSGS. In a subset of patients, multiple regression analysis revealed that the higher the serum creatinine at the onset of NS (P<0.01,r=0.519), and the higher the serum cholesterol at the onset of NS (P<0.02,r=0.511), the more rapid the progression to ESRD. Based on our findings, a national survey to determine if FSGS is more virulent in black and Hispanic children is warranted.Presented in part at the 22nd Annual Meeting of the American Society of Nephrology, Washington, D. C., December 1989     

Impact of recurrent nephrotic syndrome after renal transplantation in young patients

Recurrent disease is a frequent complication of patients transplanted for steroid-resistant nephrotic syndrome associated with focal segmental glomerulosclerosis. Its long-term prognosis has rarely been studied. We examined 39 patients aged 4–25 (mean 13.5) years at the time of first transplantation (TX). Twelve of these (30%) developed nephrotic syndrome after the first TX and 2 of 8 after the second TX. The mean observation period from first TX to last observation with a functioning graft or graft loss was 5.4 (0.1–19.3) years. We confirmed that recurrent disease is associated with older age at onset of the primary disease, shorter time from onset to end-stage renal disease, and diffuse mesangial proliferation in the initial kidney biopsy. Remissions occurred in all 3 children undergoing early repeated plasma exchange and in 1 adolescent following introduction of cyclosporin A 7 years after TX. At last observation 42% of relapsing and 48% of non-relapsing patients with a similar follow-up period had a functioning first graft. Median first graft survival was almost identical in the relapsing and the non-relapsing patients (4.3 vs. 4.2 years). Histological lesions of focal glomerulosclerosis were detected in the posttranplant biopsies of only 3 patients. In conclusion, young patients with nephrotic syndrome associated with focal segmental sclerosis have a similar graft survival with and without recurrence of the nephrotic syndrome. Received October 29, 1997; received in revised form February 17, 1998; accepted February 18, 1998     

Rituximab therapy prevents focal and segmental glomerulosclerosis recurrence after a second renal transplantation

Preventive treatment of focal and segmental glomerulosclerosis (FSGS) allograft recurrence in high risk recipients having a prior history of graft loss caused by FSGS recurrence is still a challenging question. We retrospectively identified four patients who underwent a second renal transplantation because of recurrent FSGS and who received Rituximab therapy as a prophylactic treatment. Loss of their first allograft was directly related to an early (<3 months) recurrence of FSGS that was either resistant to plasmapheresis therapy in two cases or had escaped to this therapeutic management in the two others. After the second renal transplantation, all patients were free of FSGS recurrence during follow-ups that were between 12 and 54 months long. These preliminary results demonstrate for the first time that Rituximab therapy may constitute an attractive prophylactic option for patients being considered for a second renal transplantation because of recurrent FSGS in their first graft.