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SIOD is a multisystem disorder caused by a mutant chromatin remodelling protein. The main clinical findings are spondyloepiphyseal dysplasia with disproportionate growth restriction, defective cellular immunity, and steroid-resistant nephrotic syndrome secondary to biopsy proven FSGS leading to ESRF. Concerning ESRF, kidney transplantation is the therapy of choice since FSGS does not recur in the graft. However, with respect to the underlying immune disorder and the increased susceptibility to life threatening infections, the question of the optimal immunosuppressive therapy after renal transplantation remains unresolved. Under conventional immunosuppressive regimens some SIOD patients have developed severe disseminated cutaneous papilloma virus infections or EBV associated lymphoproliferative disease. We present several cases of children with SIOD (four of five had SMARCAL1 mutations) and monotherapy maintenance immunosuppression after renal transplantation and compare them with 13 patients from the SIOD registry. We have found that post-renal transplantation immunosuppressive monotherapy results in a good outcome with a reduced number of severe infections. Due to the underlying immunodeficiency in SIOD, limited immunosuppression may be possible without increasing the risk of acute or chronic rejection.

It has been shown in adult kidney transplant recipients that a conversion from MMF to EC-MPS significantly reduced the GI related symptom burden. No such study exists on children with GI problems while receiving MMF therapy. Ten paediatric kidney transplant recipients (mean age 14.5 yr, s.d. 4.5) receiving triple immunosuppression (Cyclosporin A or Tacrolimus + MMF + Prednisolone) with severe GI symptoms were converted to an equimolar dose of EC-MPS. The GSRS was completed before and at four wk after the switch, and GFR was determined for a mean period of six months. Values were compared by the paired t-test. Mean GSRS improved significantly after the switch to EC-MPS in all but one patient, from 2.1 (s.d. 0.9) to 1.1 (s.d. 0.6). The differences could be found in all four subscales. Graft function did not change after conversion to EC-MPS. In children with moderate or severe GI symptoms while receiving MMF, conversion to EC-MPS led to significantly reduced GI symptoms.

Until now there have been no good therapeutic options in children with biopsy-proven transplant nephropathy (TN) and loss of glomerular filtration rate (GFR) while receiving cyclosporine A (CsA), mycophenolate mofetil (MMF) and prednisolone (Pred). In 13 kidney transplanted children (mean age 13 yr, SD 4) with CsA/MMF/Pred immunosuppression, renal biopsy revealed significant TN. MMF was discontinued, CsA dose was reduced to 50% and Everolimus was started (1.6 mg/m(2)/day). Pred was stopped in 10 of 13 patients. The mean GFR was 55 mL/min/1.73 m(2) (SD 24) one yr before switch, 45 mL/min/1.73 m(2) (SD 16, p < 0.05) at the time of switch and 47 mL/min/1.73 m(2) (SD 18, p < 0.05) 12 months later. There were no severe side-effects or acute rejections. Lactate dehydrogenase, cholesterol, creatine kinase, and U-albumin/creatinine ratio did not increase significantly. After six months, the mean certican-C0 level was 4.0 microg/L (SD 1.5) and mean CsA-C0 level was 52 ng/mL (SD 23). The GFR of transplanted kidneys in children with TN improved by changing immunosuppression from CsA/MMF/Pred to everolimus and low-dose CsA.

Many children with a late steroid-resistant nephrotic syndrome (SRNS) and focal glomerulosclerosis have a poor prognosis and enter end-stage renal failure (ESRF) within five years. Reports are scarce on the long-term follow-up of patients entering remission while receiving immunosuppressive therapy after steroids have failed. A two-year-old boy with focal and segmental glomerulosclerosis having both late steroid and cyclophosphamide resistance entered complete remission of the SRNS almost two years after starting induction therapy with cyclosporine A (CSA). During the 15-year follow-up, the patient experienced five relapses during CSA maintenance therapy. All relapses were successfully treated within 10 days by intravenous methylprednisolone pulses in addition to CSA. The relapses were accompanied by a drop in the glomerular filtration rate (GFR). At the age of 18 years, the patient had grade II chronic kidney disease (GFR=61 ml/min/1.73 m2). At the age of 14 years, mycophenolate mofetil (MMF) was added to the maintenance therapy and the CSA dosage was reduced. Two renal biopsies at the ages of 10 and 18 years failed to detect CSA nephrotoxicity. We conclude that children with SRNS may have long-term benefit from a combination therapy using intravenous methylprednisolone pulses and CSA.

Background: Antigen-specific immunoadsorption combined with rituximab offers the possibility for ABO-incompatible kidney transplantation without splenectomy., Patient and Method: An 8-year-old mentally retarded girl with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis due to mitochondriopathy poorly tolerated hemodialysis. Paternal blood group A1B was incompatible with blood group B of the child. Therefore, we decided to perform the first ABO-incompatible renal transplantation in a child in Germany using antigen-specific immunoadsorption. Rituximab (1 x 375 mg/m2) was administered 2 weeks before the first immunoadsorption (Glycosorb) ABO A-column). Triple-drug immunosuppression (tacrolimus, mycophenolate mofetil and prednisolone) was simultaneously started with immunoadsorption. Initial tacrolimus levels were targeted between 15 and 20 ng/ml. Before transplantation, six immunoadsorptions were applied on days -9, -7, -4, -3, -2 and -1. Intravenous immunoglobulin (0.5 g/kg) was administered preoperatively. After transplantation, three immunoadsorptions were performed on days +4, +6 and +8., Results: Before transplantation, antibody (Ab) titers against paternal erythrocytes (20 degrees C) were reduced from 1 : 64 to 1 : 4 by six antigen-specific immunoadsorptions. After transplantation, we performed three more immunoadsorptions and the Ab titers were stable between 1 : 1 and 1 : 8. One, 2 and 8 months later we observed increases in the Ab titer up to 1 : 32 requiring no change in immunosuppressive therapy. No side effects of immunoadsorption were observed. The girl had excellent initial graft function with a serum creatinine of 55 to 70 micromol/l. Two weeks after transplantation, graft biopsy showed no signs of rejection; there was focal positivity for C4d only. Twelve months after transplantation, renal function was stable, with a serum creatinine of 117 micromol/l. Episodes of rejection or severe infections were absent., Conclusion: ABO-incompatible transplantation using antigen-specific immunoadsorption and rituximab may serve as a suitable alternative for children urgently needing renal transplantation and missing a blood group-compatible donor.

Clinical trials in adult liver and heart recipients have shown that management of cyclosporine (CsA) dose with 2-h levels (C2) leads to lower rejection rates and serum creatinine levels compared with C0 monitoring. Therefore, we investigated whether C2 monitoring might also improve late graft survival after kidney transplantation in children. To date, no results in adult renal transplantation and in pediatric transplantation have been published. Forty-nine stable pediatric kidney recipients with a minimum time of 1 year after transplantation (mean=7+/-5 years) entered the study. None of the patients had experienced an acute rejection up to 6 months before entering the study. CsA dosing was based on C0 monitoring for the first 6 months and then based on C2 monitoring for the following 6 months. C0 and C2 levels were measured at 4-weekly intervals. Percentage decline in glomerular filtration rate (GFR) and mean coefficients of variation of CsA levels (C(var)) were calculated and compared during the 6-months periods. At the beginning of the study, the mean calculated GFR was 53+/-15 ml/min per 1.73 m(2). During the 6 months of C0 monitoring, the mean GFR decreased to 49+/-12 m/min per 1.73 m(2 )( P=0.001, paired t-test). Six months after switching to C2 monitoring, the mean GFR remained stable, at 49+/-15 ml/min per 1.73 m(2 )( P=0.3 paired t-test). The largest increase in GFR (3.9+/-7.9%) was found in patients with a decrease of their CsA dose of more than 5% under C2 monitoring. C(var) was significantly lower under C2 than under C0 monitoring (0.24+/-0.10 vs. 0.30+/-0.15, P=0.02, unpaired t-test). We conclude that the switch to C2 monitoring helped to identify patients with CsA overdosing as well as to reduce variation in CsA level, which resulted in a halt in GFR decline.

Background: Mycophenolate mofetil (MMF) has been used for the treatment of chronic allograft nephropathy (CAN) in adults with inconsistent results, but data in children are rare. To evaluate its impact on advanced CAN, we studied changes in glomerular filtration rate (GFR) and the correlation of GFR changes to histology., Methods: Thirty-six children (13.1+/-3.6 years) with a progressive decline in GFR of 16.9+/-12.4 mL/min per 1.73 m2/year and biopsy confirmed CAN 4.3+/-2.9 years after transplantation were studied. MMF was added to conventional immunosuppression (IS) consisting of cyclosporine (CsA) and prednisolone (n=26) or tacrolimus (n=1) or replaced azathioprine in triple IS (n=9). Alterations of GFR were correlated to histologic guidelines according to the Banff chronic score (BCS)., Results: One year after conversion, 22 (61%) children showed a rise in GFR (7.5+/-6 mL/min per 1.73 m2), 8 (22%) remained stable, and 6 (17%) showed a further decline of GFR (7.4+/-2 mL/min per 1.73 m2). Mean CsA trough levels were 114 ng/mL before and 98 ng/mL 1 year after conversion. MMF side effects required dose reduction in 14 children. Children responding to MMF with increasing GFR showed a trend toward less fibrosis, less incidence of vasculopathy, and transplant glomerulopathy in the initial biopsy but had a similar incidence of borderline tubulitis compared with the other groups., Conclusions: Cotreatment with MMF reversed the progressive loss of GFR in approximately two thirds of children with CAN for at least 1 year. Less chronicity signs in histology seem to indicate a more favorable response to treatment.

Unexpectedly lower CsA 2-h levels were found in patients who received additional immunosuppression by MMF in our center. The aim of this study is to prove whether there are differences in CsA metabolization when MMF is added to treatment. In 33 children who received an immunosuppression of prednisolone and CsA as well as in 15 children who were treated with additional MMF, C2 and C0 were taken. In 11 children, full AUC of CsA were obtained. C2 levels differed significantly (p < 0.05) between patients treated with (617 +/- 230 ng/mL) and without MMF (750 +/- 271 ng/mL) but with similar CsA dosages. C2 correlated better with the AUC than CsA levels at other time points with r = 0.95. The equation AUC = 139 + 6.17 x C2 was calculated to match best in a C2-limited sampling strategy. This formula proved to be safer than equations that had been published before. According to our findings, we suspect that MMF alters the CsA metabolism. When MMF is used in pediatric transplant recipients, either target values of CsA have to be changed or patients may require higher doses of CsA.

This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with the microemulsion formulation of cyclosporin (CyA) in children undergoing renal transplantation. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 years) were randomly assigned (1:1) to receive either Tac ( n=103) or CyA microemulsion ( n=93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection. Baseline characteristics were comparable between treatment groups. Tac therapy resulted in a significantly lower incidence of acute rejection (36.9%) compared with CyA therapy (59.1%) ( P=0.003). The incidence of corticosteroid-resistant rejection was also significantly lower in the Tac group compared with the CyA group (7.8% vs. 25.8%, P=0.001). The differences were also significant for biopsy-confirmed acute rejection (16.5% vs. 39.8%, P<0.001). At 1 year, patient survival was similar (96.1% vs. 96.6%), while 10 grafts were lost in the Tac group compared with 17 graft losses in the CyA group ( P=0.06). At 1 year, mean glomerular filtration rate (Schwartz estimate) was significantly higher in the Tac group (62+/-20 ml/min per 1.73 m(2), n=84) than in the CyA group (56+/-21 ml/min per 1.73 m(2), n=74, P=0.03). The most frequent adverse events during the first 6 months were hypertension (68.9% vs. 61.3%), hypomagnesemia (34.0% vs. 12.9%, P=0.001), and urinary tract infection (29.1% vs. 33.3%). Statistically significant differences ( P<0.05) were observed for diarrhea (13.6% vs. 3.2%), hypertrichosis (0.0% vs. 7.5%), flu syndrome (0.0% vs. 5.4%), and gum hyperplasia (0.0% vs. 5.4%). In previously non-diabetic children, the incidence of long-term (>30 days) insulin use was 3.0% (Tac) and 2.2% (CyA). Post-transplant lymphoproliferative disease was observed in 1 patient in the Tac group and 2 patients in the CyA group. In conclusion, Tac was significantly more effective than CyA microemulsion in preventing acute rejection after renal transplantation in a pediatric population. The overall safety profiles of the two regimens were comparable.

Background: Introduction of IL-2-receptor antagonists has led to significantly decreasing numbers of acute rejection episodes in renal transplantation in adults. No data are available in paediatric recipients., Methods: Between 1997 and 2000, 78 renal transplantations were performed in 77 children aged 0.5-16 years. Basiliximab, cyclosporin A (CsA) and prednisolone were administered in 48 children (age 7.8 +/- 5.3 years) and compared with 29 children (age 7.3 +/- 5.2 years) receiving CsA and prednisolone only. The number of acute rejections, survival, glomerular filtration rate (GFR) and side effects were determined for 3 years after transplantation., Results: All 77 patients survived the observation period. One year graft survival in the basiliximab group was 95%, which is similar to the comparison group (93%). Children receiving basiliximab showed a lower incidence of acute rejection than the comparison group (14% vs 34%). The calculated GFR was lower in the basiliximab group when discharging from hospital, with 51 compared with 66 ml/min/1.73 m(2) in the non-basiliximab group. This was associated with higher CsA trough levels (214 vs 174 ng/ml) in the basiliximab patients. After 1 year the GFR was comparable in both groups (58 vs 52 ml/min/1.73 m(2))., Conclusions: Basiliximab offers excellent allograft survival, a lower incidence of acute rejections and almost no side effects. Therefore it can be recommended for routine immunosuppressive therapy in paediatric renal transplantation.

Corticosteroid-resistant nephrotic syndrome (CRNS) with focal and segmental glomerulosclerosis (FSGS) is a heterogeneous disorder and the most severe and frequent type of all glomerulopathies in children leading to end-stage renal failure. The podocyte is at the center of development and progress of FSGS; this unique cell type plays a major role in the integrity of glomerular structure and permeability.The rate of complete remission of CRNS after induction therapy using different immunosuppressant agents is reported to range between 30% and 84%, depending on the treatment schedule and on the underlying defects of FSGS. Children with genetic types of FSGS barely respond to immunosuppressant therapies and over-treatment prior to transplantation should be avoided. The response of children with an idiopathic type of FSGS to immunosuppressants is superior to those with genetic FSGS. However, many children with idiopathic FSGS do not enter complete remission if they are under-treated, for example, with short-term immunosuppressant monotherapies. If immunosuppressant treatment fails, these patients will have to undergo renal transplantation. However, as unknown pathogenetic mechanisms may persist, more than one-third of these patients with idiopathic FSGS develop a rapid recurrence of CRNS that responds poorly to further long-term therapeutic attempts.In contrast with previously published data, this review takes into account recently identified genetic etiologies of CRNS, and superior results with long-term combination therapy in idiopathic forms to avoid over- and under-treatment. [ABSTRACT FROM AUTHOR]