Ali Lanewala

A spectrum of novel NPHS1 and NPHS2 gene mutations in pediatric nephrotic syndrome patients from Pakistan

BACKGROUND Mutations in the NPHS1 and NPHS2 genes are among the main causes of early-onset and familial steroid resistant nephrotic syndrome respectively. This study was carried out to assess the frequencies of mutations in these two genes in a cohort of Pakistani pediatric NS patients. METHODS Mutation analysis was carried out by direct sequencing of the NPHS1 and NPHS2 genes in 145 nephrotic syndrome (NS) patients. This cohort included 36 samples of congenital or infantile onset NS cases and 39 samples of familial cases obtained from 30 families. RESULTS A total of 7 homozygous (6 novel) mutations were found in the NPHS1 gene and 4 homozygous mutations in the NPHS2 gene. All mutations in the NPHS1 gene were found in the early onset cases. Of these, one patient has a family history of NS. Homozygous p.R229Q mutation in the NPHS2 gene was found in two children with childhood-onset NS. CONCLUSIONS Our results show a low prevalence of disease causing mutations in the NPHS1 (22% early onset, 5.5% overall) and NPHS2 (3.3% early onset and 3.4% overall) genes in the Pakistani NS children as compared to the European populations. In contrast to the high frequency of the NPHS2 gene mutations reported for familial SRNS in Europe, no mutation was found in the familial Pakistani cases. To our knowledge, this is the first comprehensive screening of the NPHS1 and NPHS2 gene mutations in sporadic and familial NS cases from South Asia.

Clinicopathologic characteristics and steroid response of IgM nephropathy in children presenting with idiopathic nephrotic syndrome.

Mubarak M, Kazi JI, Shakeel S, Lanewala A, Hashmi S, Akhter F. Clinicopathologic characteristics and steroid response of IgM nephropathy in children presenting with idiopathic nephrotic syndrome, APMIS 2011; 119: 180–186.

The Spectrum of Histopathological Lesions in Children Presenting with Steroid-Resistant Nephrotic Syndrome at a Single Center in Pakistan

Steroid-resistant nephrotic syndrome (SRNS) is a common problem in pediatric nephrology practice. There is currently little information in the literature on the spectrum of histopathologic lesions in children presenting with SRNS in Pakistan. This study was designed to determine the histopathologic lesions in children presenting with SRNS at our center. The study was conducted at the Histopathology Department, Sindh Institute of Urology and Transplantation (SIUT) from January 2009 to August 2011. All children (≤16 years) presenting with SRNS, in whom renal biopsies were performed, were included. Their demographic, clinical, laboratory, and histopathological data were retrieved from files and original renal biopsy forms. The results were analyzed by SPSS version 10.0. A total of 147 children were included. Of these, 91 (61.9%) were males and 56 (38.1%) females, with male-to-female ratio of 1.6 : 1. The mean age was 7.03 ± 4.0 years (range: 6 months–16 years). The histopathological lesions seen on renal biopsies comprised of focal segmental glomerulosclerosis (FSGS) (38.5%), followed by minimal change disease (MCD) (23.2%), IgM nephropathy (IgMN) (13.6%), idiopathic mesangial proliferative GN (10.2%), membranous GN (8.2%), and mesangiocapillary GN (4.8%). Our results indicate that FSGS is the predominant lesion in children with SRNS, followed by MCD and IgMN.

Pediatric Kidney Transplantation in the Developing World: Challenges and Solutions

The prevalence of pediatric RRT and transplantation are low in developing countries, 6–12 and <1 to 5 per million child population (pmcp), respectively. This is due to low GDP/capita of <

Pathology of idiopathic nephrotic syndrome in children: are the adolescents different from young children?

10 000, government expenditure on health of <2.6–9% of GDP and paucity of facilities. The reported incidence of pediatric CKD and ESRD is <1.0–8 and 3.4–35 pmcp, respectively. RRT and transplantation are offered mostly in private centers in cities where HD costs

Challenges in pediatric renal transplantation in developing countries.

20–100/session and transplants

Association of the ACE-II genotype with the risk of nephrotic syndrome in Pakistani children.

10 000–20 000. High costs and long distance to centers results in treatment refusal in up to 35% of the cases. In this backdrop 75–85% of children with ESRD are disfranchised from RRT and transplantation. Our center initiated an integrated dialysis–transplant program funded by a community‐government partnership where RRT and transplantation was provided “free of cost” with life long follow‐up and medication. Access to free RRT at doorsteps and transplantation lead to societal acceptance of transplantation as the therapy of choice for ESRD. This enabled us to perform 475 pediatric transplants in 25 years with 1‐ and 5‐year graft survival of 96% and 81%, respectively. Our model shows that pediatric transplantation is possible in developing countries when freely available and accessible to all who need it in the public sector.

Acute kidney injury in idiopathic nephrotic syndrome of childhood is a major risk factor for the development of chronic kidney disease.

BACKGROUND There is no specific data on the pathological lesions underlying idiopathic nephrotic syndrome (INS) in adolescents in Pakistan. Moreover, it is not known whether the pathological lesions in adolescents differ significantly from young children with INS in our setup. Materials and methods. A retrospective analysis was carried out on all patients with INS with onset ≤ 18 years of age. They were split into two groups: patients with onset of INS ≤ 12 years (young children group) and patients with onset ≥ 13 through 18 years of age (adolescent group). Renal biopsies were evaluated by light microscopy, immunoflourescence and electron microscopy. The histopathological lesions on renal biopsies were analyzed and compared between the two groups. RESULTS The adolescents comprised 173 (32.1%) patients, and there were 365 young children (67.8%). The mean age of adolescents at the time of onset of INS was 15.12 ± 1.5 years and there were 113 boys (65.3%) and 60 girls (34.6%). The mean age of young children was 7.26 ± 3.24 years and there were 231 boys (63.2%) and 134 girls (36.7%). Focal segmental glomerulosclerosis was the most common histopathological lesion in adolescents (36.4%) followed by minimal change disease (MCD) (28.9%). Adolescent-onset INS had a significantly higher frequency of membranous glomerulonephritis and membranoproliferative glomerulonephritis (MPGN) (P < 0.05) and significantly lower frequency of MCD (P < 0.05) than early childhood-onset INS. CONCLUSIONS Our data indicate that the pathological lesions in adolescent INS are different from younger children and resemble more closely those seen in adults. Our findings are concordant with the few previously published studies on this subject.

The prevalence and clinicopathological profile of IgM nephropathy in children with steroid-resistant nephrotic syndrome at a single centre in Pakistan

Purpose of studyThe present review summarizes the findings of most important reports on pediatric transplants from the developing world and highlights the challenges and results of the activity. Recent findingsIn the past 3 years, 10 reports appeared in the literature on pediatric renal transplantation and further six more in the past 5 years. The experience ranges from 1 to 28 years for 11–300 transplants. Recipients were older than 6 years and donors were living relatives in more than 94% of the series. Cyclosporine, azathioprin and steroids are the mainstay of immunosuppression and in many centres the high costs of drugs resulted in noncompliance and discontinuation of immunosuppression. Therefore, acute rejection rates were high, more than 40% in half of the series. One-year and 5-year survival rates for grafts were 89–98% and 67–84% and for patients 88–98% and 65–90%, respectively. Major causes of graft loss were chronic rejection, acute rejection and infection and for the patients, it was infection. Growth analysis is not generally reported but when reported the deficit remains or gets worse. SummaryPediatric transplantation activity in the developing world is limited to older children using mostly living related parental donors. High rejection and infection rates result in poor patient and graft survival.

Etiology, clinical profile and short-term outcome of acute kidney injury in children at a tertiary care pediatric nephrology center in Pakistan

Nephrotic syndrome is a common pediatric glomerular disease associated with heavy proteinuria. Since, the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism is a putative genetic risk factor for NS, in this study, ACE (I/D) polymorphism was analyzed in 268 NS and 223 control samples by a PCR-based method. The genotypic and allelic frequencies were determined and the association between ACE I/D polymorphism and NS was evaluated. The frequency distribution of the II, ID and DD genotypes was 82 (30.6%), 128 (47.8%) and 58 (21.6%) in the NS patients and 9 (4.0%), 171 (76.7%) and 43 (19.3%) in the control samples respectively. In the Pakistani pediatric NS population, the II genotypic and allelic frequencies were found to be significantly associated with the disease (OR=6.755; C.I=3-14.9). No significant association was found between this polymorphism and the response to standard steroid therapy. Thus, in contrast to reports from other parts of the world, the II genotype was found to be significantly associated with NS in the Indian and Malay populations and in the Pakistani population described here. To our knowledge, this is the first report from Pakistan describing the association of the ACE I/D polymorphism with pediatric NS. On the basis of these results, it is suggested that analysis of the ACE (I/D) polymorphism should be performed for the early diagnosis in the high risk NS patients in South Asia.