Renal transplantation in patients with Bardet-Biedl syndrome.

BACKGROUND: Bardet-Biedl syndrome is an autosomal recessive disorder characterized by obesity, polydactyly of hands and feet, retinitis pigmentosa, hypogenitalism, various degrees of intellectual impairment and renal anomalies. Other clinical features include speech disorder, brachydactyly, developmental delay, polyuria/polydipsia, ataxia, poor coordination/clumsiness, diabetes mellitus, left ventricular hypertrophy, hepatic fibrosis, and renal hypoplasia/dysplasia. If spasticity and mental retardation present, it fulfills the criteria for Laurence-Moon-Bardet-Biedl syndrome. METHODS: Between July 1985 and January 2005, 2,282 kidney transplantations were performed at Labbafinejad Medical Center, of whom 262 were children under 15 years of age (61% males). Among children, five (four females) had Bardet-Biedl syndrome who were transplanted preemptively. Kidneys were taken from living unrelated donors. RESULTS: All five patients had retinitis pigmentosa and obesity with body mass index up to 39.33 kg/m(2). The cause of end-stage renal failure was reflux nephropathy in one, neurogenic bladder in one, and renal hypoplasia/dysplasia in three patients. The mean age at transplantation was 11 years (range: 6-17 years). Immunosuppressives administered were prednisolone, cyclosporine, and mycophenolate mofetil. All of them suffered at least one episode of acute rejection shortly after transplantation but reversed with methylprednisolone pulses; in the last follow-up, the mean creatinine was 1.2 (range: 0.6 - 2.3 mg/dL). The mean glomerular filtration rate before transplantation was 10 mL/min/1.73 m(2); in the last follow-up it was 79 (range: 38-137). CONCLUSION: Renal transplantation is a safe and successful procedure and renal replacement therapy of choice in patients with Bardet-Biedl syndrome and end-stage renal failure, but special attention should be paid to body mass index and steroid-free immunosuppression if other suitable drugs, such as sirolimus and basiliximab are affordable.

CTNS molecular genetics profile in a Persian nephropathic cystinosis population.

PURPOSE: In this report, we document the CTNS gene mutations of 28 Iranian patients with nephropathic cystinosis age 1-17 years. All presented initially with severe failure to thrive, polyuria, and polydipsia. METHODS: Cystinosis was primarily diagnosed by a pediatric nephrologist and then referred to the Iran University of Medical Sciences genetics clinic for consultation and molecular analysis, which involved polymerase chain reaction (PCR) amplification to determine the presence or absence of the 57-kb founder deletion in CTNS, followed by direct sequencing of the coding exons of CTNS. RESULTS: The common 57-kb deletion was not observed in any of the 28 Iranian patients. In 14 of 28 patients (50%), mutations were observed in exons 6 and 7. No mutation was detected in exon 5, and only one (3.6%) patient with cystinosis showed a previously reported 4-bp deletion in exon 3 of CTNS. Four patients (14.3%) had a previously reported mutation (c.969C>A; p.N323K) in exon 11, and five (18%) had novel homozygous deletions in exon 6 leading to premature truncation of the protein. These deletions included c.323delA; p.Q108RfsX10 in three individuals and c.257-258delCT; p.S86FfsX37 in two cases. Other frame-shift mutations were all novel homozygous single base pair deletion/insertions including one in CTNS exon 9 (c.661insT; p.V221CfsX6), and four (14.3%) in exon 4, i.e., c.92insG; p.V31GfsX28 in two and c.120delC; p.T40TfsX10 in two. In total, we identified eight previously reported mutations and eight novel mutations in our patients. The only detected splice site mutation (IVS3-2A>C) was associated with the insertion mutation in the exon 9. CONCLUSION: This study, the first molecular genetic analysis of non-ethnic-specific Iranian nephropathic cystinosis patients, may provide guidance for molecular diagnostics of cystinosis in Iran.

A novel mutation pattern of kidney anion exchanger 1 gene in patients with distal renal tubular acidosis in Iran.

INTRODUCTION: Mutations of the anion exchanger 1 (AE1) gene encoding the kidney anion exchanger 1 can result in autosomal dominant or autosomal recessive form of distal renal tubular acidosis (DRTA). This study aimed to report deletion mutations of the AE1 and its impact on Iranian children with DRTA. MATERIALS AND METHODS: Twelve children with DRTA referred to Ali Asghar Children Hospital were investigated for all AE1 gene exons through polymerase chain reaction amplification, DNA sequencing, and bioinformatics analysis. RESULTS: Eleven of 12 patients (91.7%) showed an alteration in AE1 gene with a real hot spot in its exons 11 or 15. Homozygote and heterozygote deletions were confirmed in exon 15 in 5 (41.7%) and 3 (25.0%), respectively. Two patients (16.7%) showed homozygote deletions in exon 11 of AE1 gene, and 1 patient (8.3%) showed point mutation in exon 11. The 3-dimensional structures of the native and these mutant kidney AE1 proteins were determined by the multitemplate method using the Phyre and Hidden Markov Model algorithms. CONCLUSIONS: Parents' consanguinity of these patients reveals that cousins are at a high risk for DRTA. This study is considered as a pilot study showing the importance of AE1 mutations in Iranian children with DRTA and further studies is recommended in this geographic region of the world. These models suggest that alteration in the structures leads to alteration in function and change in the current role of AE1.

Effects of interleukin 2 receptor blockers on patient and graft survival in renal-transplanted children.

BACKGROUND: Monoclonal antibodies block interleukin-2 receptors on alloantigen-reactive T-Lymphocytes and induce selective immunosuppression. It is postulated that induction therapy with these agents in pediatric transplantation may decrease acute rejection and improve graft survival with no significant side effect or increase in the incidence of viral infections. OBJECTIVES: The aim of this study was to examine the effects of interleukin 2 receptor blockers on patient and graft survival in renal-transplanted children. PATIENTS AND METHODS: One hundred and eighty six children aged 7-13 years who received renal transplantation in university-affiliated hospital between 2003 and 2012 were enrolled in the study. All patients received prednisolone, cyclosporine and mycophenolate mofetil or azathioprine as basic immunosuppressive therapy. Patients were divided into two groups according to receiving induction therapy with IL2-receptor blockers. We investigated for acute rejection episodes, Cytomegalovirus (CMV) and BK virus infection and one and three year's survival of the patients and the grafts. RESULTS: From 186 renal-transplanted children included in this study, 36 patients were in treated group (group 1) and 150 patients in control group (group 2). The mean age of the patients was 10.4 ± 2 years and 55.6% were males. In first six months of transplantation, eight patients in group one had one episode of acute rejection and no one had two episodes. Early acute rejection rate was 8.36 (22%). In the control group, 37 patients had one episode and three patients had two episodes of acute rejection (rejection rate 28.6%). Therefore, early acute rejection rates were lower in group one. Late acute rejection rates did not show any difference in group 1 and group 2 (27.7% vs. 27.3% respectively). There was lower prevalence of steroid-resistance rejection in group 1 patients (5.5%) compared with 6.6% in group 2, but it did not reach statistical significance. None of the patients in IL2-R blocker group died at one year follow-up (patient survival 100%). However, in control group, four (2.6%) patients died toward the end of first year (patient survival 97.4%). When patients in group 1 and group 2 were age and sex matched with equal number the difference was significant (P < 0.05). CONCLUSIONS: Induction therapy with IL2-R blockers reduced the rate of early acute rejection, but had no effect on late acute rejections. Patient and graft survival were better in treated group, but did not reach statistical significance. A longer period of follow-up may be required to discern a clear advantage for induction therapy with these agents.

CTNS molecular genetics profile in a Persian nephropathic cystinosis population / Perfil genético molecular del gen CTNS en una población persa con cistinosis nefropática

Purpose: In this report, we document the CTNS gene mutations of 28 Iranian patients with nephropathic cystinosis age 1-17 years. All presented initially with severe failure to thrive, polyuria, and polydipsia. Methods: Cystinosis was primarily diagnosed by a pediatric nephrologist and then referred to the Iran University of Medical Sciences genetics clinic for consultation and molecular analysis, which involved polymerase chain reaction (PCR) amplification to determine the presence or absence of the 57-kb founder deletion in CTNS, followed by direct sequencing of the coding exons of CTNS. Results: The common 57-kb deletion was not observed in any of the 28 Iranian patients. In 14 of 28 patients (50%), mutations were observed in exons 6 and 7. No mutation was detected in exon 5, and only one (3.6%) patient with cystinosis showed a previously reported 4-bp deletion in exon 3 of CTNS. Four patients (14.3%) had a previously reported mutation (c.969C>A; p.N323K) in exon 11, and five (18%) had novel homozygous deletions in exon 6 leading to premature truncation of the protein. These deletions included c.323delA; p.Q108RfsX10 in three individuals and c.257-258delCT; p.S86FfsX37 in two cases. Other frame-shift mutations were all novel homozygous single base pair deletion/insertions including one in CTNSexon 9 (c.661insT; p.V221CfsX6), and four (14.3%) in exon 4, i.e., c.92insG; p.V31GfsX28 in two and c.120delC; p.T40TfsX10 in two. In total, we identified eight previously reported mutations and eight novel mutations in our patients. The only detected splice site mutation (IVS3-2A>C) was associated with the insertion mutation in the exon 9. Conclusion: This study, the first molecular genetic analysis of non-ethnic-specific Iranian nephropathic cystinosis patients, may provide guidance for molecular diagnostics of cystinosis in Iran (AU)

Objetivo: En este informe, documentamos las mutaciones del gen CTNS de 28 pacientes iraníes con cistinosis nefropática y una edad de 1-17 años. En un principio, todos presentaron retraso del desarrollo, poliuria y polidipsia. Métodos: En primer lugar, un nefrólogo pediátrico diagnosticó la cistinosis y luego los pacientes fueron trasladados a la clínica genética de la Universidad de Ciencias Médicas de Irán para consulta y análisis molecular, que incluía la multiplicación por reacción en cadena de la polimerasa (PCR), para determinar la existencia o ausencia de la deleción del fundador del 57kb en el CTNS, seguida por la secuenciación directa de los exones de codificación del CTNS. Resultados: La deleción frecuente del 57kb no se observó en ninguno de los 28 pacientes iraníes. En 14 de los 28 pacientes (50%) se observaron mutaciones en los exones 6 y 7. No se detectó ninguna mutación en el exón 5 y solo un paciente (3,6%) con cistinosis mostró una deleción del 4pb, anteriormente comunicada, en el exón 3 del CTNS. De ellos, 4 pacientes (14,3%) tenían una mutación anteriormente comunicada (c.969C > A; p.N323K) en el exón 11 y 5 (18%) tenían nuevas deleciones homocigóticas en el exón 6 que produjeron el vaciamiento prematuro de la proteína. Entre estas deleciones se puede citar c.323delA; p.Q108RfsX10 en 3 personas y c.257-258delCT; p.S86FfsX37 en 2 casos. Otras mutaciones con desplazamiento del marco de lectura fueron todas nuevas deleciones/inserciones de un par de bases únicas homocigóticas, incluyendo una en el exón 9 del CTNS(c.661insT; p.V221CfsX6) y 4 (14,3%) en el exón 4, es decir, c.92insG; p.V31GfsX28 en 2 y c.120delC; p.T40TfsX10 en 2. En total, en nuestros pacientes se identificaron 8 mutaciones anteriormente comunicadas y 8 mutaciones nuevas. La única mutación del sitio de empalme detectada (IVS3-2A>C) estaba asociada con la mutación de inserción en el exón 9. Conclusión: Este estudio, el primer análisis genético molecular de pacientes iraníes con cistinosis nefropática de carácter no específicamente étnico, puede servir como guía para el diagnóstico molecular de la cistinosis en Irán (AU)

Management and outcome of steroid-resistant nephrotic syndrome in children.

INTRODUCTION: Steroid-resistant nephrotic syndrome (SRNS) is uncommon in children, but often leads to ESRD. We report our experience with SRNS and its treatments and outcomes. MATERIALS AND METHODS: We assessed 73 children with SRNS admitted to Ali Asghar Children Hospital in Tehran, Iran. Their clinical presentations, treatment, and disease courses were reviewed. The mean follow-up duration was 6.0 +/- 4.2 years. Moreover, survival times were calculated and the Cox regression method was used to determine variables able to predict survival of the kidneys. RESULTS: Age at the onset of the disease, sex, and hematuria were not predictive of the response to treatment with immunosuppressive drugs in the children with SRNS. The type of resistance (early or late) was associated with the responsiveness to immunosuppressives. Response to any of the immunosuppressive drugs determined the responsiveness to other immunosuppressive drugs. Cyclosporine was more effective than cyclophosphamide as initial therapy. The mean kidney survival time was 11.62 years. Kidney survival rates were 94.6%, 70.0%, 56.0%, and 34.0% at 1, 5, 10, and 15 years, respectively, in patients with initial resistance to steroid, while these were 100%, 100%, 83.0%, and 83.0% in those with late resistance, respectively (P = .03). CONCLUSIONS: We showed that patients with late steroid resistance had better response to immunosuppressive drugs than patients with early resistance. We also showed that resistance to immunosuppressive therapies increased the risk of resistance to other immunosuppressive drugs. Achievement of complete or partial remission with any therapy reduced the risk of ESRD.

Fungal peritonitis in Iranian children on continuous ambulatory peritoneal dialysis: a national experience.

INTRODUCTION: Fungal peritonitis (FP), causing catheter obstruction, dialysis failure, and peritoneal dysfunction, is a rare but serious complication of peritoneal dialysis. In this study, the frequency and risk factors of FP are evaluated in children who underwent peritoneal dialysis. MATERIALS AND METHODS: A retrospective multicenter study was performed at the 5 pediatric peritoneal dialysis centers in Iran from 1971 to 2006, and FP episodes among 93 children were reviewed. Risk ratios were calculated for the clinical and demographic variables to determine the risk factors of FP. RESULTS: Ninety-three children aged 39 months on average were included in study. Sixteen out of 155 episodes of peritonitis were fungi infections, all by Candida albicans. The risk of FP was higher in those with relapsing bacterial peritonitis (P = .009). Also, all of the patients had received antibiotics within the 1 month prior to the development of FP. Catheters were removed in all patients after 1 to 7 days of developing FP. Six out of 12 patients had catheter obstruction and peritoneal loss after the treatment and 5 died due to infection. CONCLUSIONS: Fungal peritonitis, accompanied by high morbidity and mortality in children should be reduced by prevention of bacterial peritonitis. Early removal of catheter after recognition of FP should be considered.