Javed Iqbal Kazi

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.

Pattern of renal diseases observed in native renal biopsies in adults in a single centre in Pakistan

Aim:  In the absence of a national renal biopsy registry, there is a paucity of information on the pattern of renal disease observed in native renal biopsies in adults in Pakistan.

Detection of immunoglobulins and complement components in formalin fixed and paraffin embedded renal biopsy material by immunoflourescence technique

BACKGROUND The technique of direct immunoflourescence (IF) is essential in the accurate diagnosis of renal glomerular diseases. The optimal results are obtained when the procedure is done on fresh frozen tissue (IF-F). However, techniques are available for IF study on formalin fixed and paraffin embedded (FFPE) renal biopsy specimens with variable reported success rates. OBJECTIVES We evaluated three such techniques on FFPE tissue and compared the results with those obtained by IF-F from the same patients. MATERIALS AND METHODS Heat treatment with Tris buffer and citrate buffer, and pronase treatment of the FFPE material was carried out. Direct IF was done for renal panel immunoglobulins and complement components on all biopsies and the results were compared with the historical IF-F study. RESULTS When compared to the IF-F, the immunoflourescence staining on the paraffin sections was less sensitive and less intense in all immune complex-mediated renal diseases, but the diagnostic findings were detected in majority of the cases. CONCLUSIONS In conclusion, it is possible to establish the diagnosis in most cases of immune complex-mediated glomerular diseases with IF on paraffin embedded tissue specimens.

Role of immunofluorescence and electron microscopy in the evaluation of renal biopsies in nephrotic syndrome in a developing country.

ABSTRACT To determine the role of immunofluorescence (IF) and electron microscopy (EM) in the evaluation of renal biopsies in a developing country, the authors carried out a study in 200 patients with nephrotic syndrome. Renal biopsies were studied by light microscopy, IF, and EM. IF study was useful in all, being essential in 23.5% and helpful in remaining cases. EM was useful in 94.5% cases, being essential in 43% and helpful in 51.5% cases. The results demonstrate that IF and EM are essential in the evaluation of renal biopsies in nephrotic syndrome and these should be employed in the pathologic evaluation of renal biopsies.

IgM nephropathy revisited

IgM nephropathy (IgMN) is an idiopathic immune complex-mediated glomerulopathy that was first described as a distinct disease in a nephropathology literature in 1978. Here, a historical review and the current status of IgMN in the light of world literature and the current experience will be presented. The Pubmed (www.pubmed.gov) search was made for articles on IgMN as the sole subject of the study or where it constituted a significant number of cases in a biopsy series in the world literature written in English. A total of 41 articles were found. A critical review of the literature was made. Soon after 1978, a series of reports were published mostly from the western world, but the interest in the entity did not withstand the test of time. No substantial basic medical research was carried out and the disease was largely ignored by the western researchers. More recently, a flurry of articles have appeared in the literature on the topic, mostly from tropical countries, and have renewed the interest in the entity. However, most of the current literature on IgMN is based on clinical observations, and experimental models and mechanistic studies of IgMN are lacking. There is an urgent need to develop consensus based criteria for the diagnosis of the condition, as well as, to focus the research on mechanistic studies to understand the pathogenesis of the disease better.

Biopsy Findings in Renal Allograft Dysfunction in a Live Related Renal Transplant Program

Background: There is little information in literature on renal allograft biopsy findings in renal allograft dysfunction in live related renal transplant recipients. Material and Methods: A retrospective review of 1210 renal allograft biopsies from 575 renal transplant patients was carried out over a period of seven years from June 1997 till December 2004. The demographic, clinical, laboratory and biopsy findings were collected and analyzed. Results: A total of 1210 graft biopsies were performed on 575 patients. The mean age of recipients and donors was 29.2±9.7 years, and 35.7±10.5 years, respectively. The males were predominant among recipients (76.7 vs. 23.3%), while among donors they only slightly outnumbered females (51.8 vs. 48.2%). Regarding pathological lesions, acute rejection was seen in 292 (24%) cases, followed by acute tubular injury and cyclosporine A (CsA) toxicity, found in 281 (23.2%) and 134 (11%) cases respectively. Chronic allograft nephropathy (CAN) with variable degree of tubular atrophy was seen in 361 (29.8%) cases. Seventy nine cases (6.5%) of acute pyelonephritis were detected on graft biopsies. A number of rare lesions were also found, including 13 (1.07%) cases of recurrent/de novo renal disease, and 13 (1.07%) of polyoma virus infection. Five cases of CsA induced hemolytic uremic syndrome (HUS) were also noted. Conclusion: In conclusion, the incidence of acute rejection is low in our patients as compared to cadaveric renal transplant recipients as reported in Western studies and CsA toxicity is more common. Recurrent/de novo renal disease is uncommon in our patients.

Cyclosporine withdrawal in post-renal transplant thrombotic microangiopathy.

Abstract:  Introduction:  Thrombotic microangiopathy (TMA) is a well known complication of cyclosporine (CsA)‐treated renal transplantation but optimum treatment strategies are not clearly defined.

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

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.