Morphometric insights into nephrotic syndrome in children: Are we any wiser?

Summary: The present study was undertaken in the hope that conflicting opinions concerning interrelationships among minimal change disease (MCD), mesangial proliferative glomerulonephritis (MPG) and focal segmental glomeruloscierosis (FSGS) might be elucidated by morphometric methods performed by image analysis, as well as to study whether serum creatinine and changes in quantitatively analysed glomeruli could correlate with the interstitial fibrosis in these glomerulopathies. Fifteen renal biopsy specimens from children with MCD, 10 with primary MPG and 12 with FSGS for whom both light and electron microscopy as well as immunofluorescence microscopy and full clinical data were available, were examined quantitatively. As a control five biopsy and 10 autopsy specimens of the normal kidneys were used. Our quantitative study showed that in MCD, MPG and FSGS glomerular and interstitial values differed from normal. Morphometric differences between MPG and both MCD and FSGS groups were also shown. Although the mean values of total glomerular area and relative interstitial volume were increased in FSGS patients, in total glomerular cells per unit of glomerular area and mesangium (% of total glomerular area) were similar in both MCD and FSGS groups. In MPG strong positive correlations existed between interstitial volume and serum creatinine, interstitial volume and total glomerular cells per unit of glomerular area as well as between interstitial volume and glomerular mesangium (% of total glomerular area). In FSGS there was significant positive correlation between interstitial volume and serum creatinine. In the MCD group all correlations were weak and not significant. In conclusion, our morphometric studies suggest a close relationship between MCD and FSGS, and indicate that MPG is a separate morphologic entity in children.     

Tacrolimus: a new therapy for steroid-resistant nephrotic syndrome in children.

This study was conducted to evaluate the safety and efficacy of tacrolimus (TAC) in children with SRNS. The study group comprised of 22 consecutive children with steroid-resistant nephrotic syndrome (SRNS) who were studied prospectively. TAC was initiated with a dose of 0.10 mg/kg/day, and the dose was increased to attain a trough level of 5.0-10.0 g/l. These patients were treated with concomitant prednisone, which was subsequently tapered off and stopped. The primary outcome variable was the number of patients who attained a complete remission (CR) or partial remission (PR). The mean age of onset was 7.33 +/- 5.9 years, and there were 20 boys and 2 girls. Of the 22 children, 9 had minimal change disease, 11 had focal segmental glomerulosclerosis and the other 2 had diffuse mesangial hypercellularity on histopathology. TAC had to be withdrawn in 3 children because of its side effects. Of the remaining 19 children who received adequate therapy and were able to achieve target levels, CR was seen in 16 (84%) children, 2 (10.5%) attained PR and 1 was nonresponsive. The mean time to achieve remission was 63.2 +/- 44 days and the mean dose of TAC was 0.18 +/- 0.07 mg/kg. The mean urine spot protein/creatinine ratios were significantly lower (0.33 +/- 0.58 vs. 13.5 +/- 21.9 mg/mg, p = 0.002) and the mean serum albumin levels were significantly higher (3.92 +/- 0.35 g/dl vs. 2.39 +/- 0.56 g/dl, p = 0.00005), as compared to those prior to starting TAC. The mean glomerular filtration rate values at the end of the study were similar to those prior to starting TAC (97.9 +/- 21.2 ml/min/1.73 m(2) vs. 96.4 +/- 18.4 ml/min/1.73 m(2), p = 0.30). The mean duration of follow-up was 290 +/- 126 days. This is the largest study so far on the safety and efficacy of TAC therapy in SRNS. Our results suggest that TAC is an effective therapeutic modality for SRNS, including the subgroup of children who are nonresponsive to the current therapeutic modalities like cyclophosphamide and cyclosporine.     

Angiotensin converting enzyme gene polymorphisms do not predict the course of idiopathic nephrotic syndrome in Swiss children

AIM: Contradictory reports exist about a correlation of angiotensin I converting enzyme (ACE) gene polymorphisms to the outcome of idiopathic nephrotic syndrome (INS) in children. We investigated the frequency of ACE polymorphisms and their impact on the clinical course of INS in children in a Swiss hospital. METHODS: The ACE gene polymorphism (I, insertion; D, deletion) was assessed in 32 children - 22 with steroid-sensitive INS and 10 with steroid-resistant INS - with a median age at onset of INS of 2.9 years (range 1.1-15.0). Polymerase chain reaction amplification was performed on genomic DNA isolated from blood leucocytes. Results were correlated to clinical course and renal morphology. RESULTS: The ACE genotype was I/I, I/D and D/D in two, 12 and eight patients, respectively, with steroid-sensitive INS, and in one, eight and one patient, respectively, with steroid resistance. Renal morphology, available in 25 patients showed minimal change glomerulopathy in 17 patients (14 steroid-sensitive; three steroid-resistant) and focal segmental glomerulosclerosis in eight (one steroid-sensitive; seven steroid-resistant). There was no significant correlation between ACE genotype and steroid responsiveness, histology or outcome. ACE genotype was I/I, I/D and D/D in none, 12 and five patients, respectively, with minimal change glomerulopathy, and in one, five and two patients, respectively, with focal segmental glomerulosclerosis. Six patients with steroid-resistant nephrotic syndrome went into end stage renal disease; ACE genotype was I/I in one and I/D in five, but none were D/D. CONCLUSION: In contrast to previous reports, ACE gene polymorphism is irrelevant for clinical outcome, steroid responsiveness or morphology in Swiss children with INS.     

Late onset of familial nephrotic syndrome associated with a compound heterozygous mutation of the podocin-encoding gene

A case of two young adult brothers with nephrotic syndrome secondary to focal segmental glomerulosclerosis is reported. Steroid resistance prompted us to perform genetic studies. These showed a compound heterozygous mutation of NPHS2, the gene encoding podocin. It was composed of a missense mutation in exon 7 (A284V) and the non-neutral polymorphism R229Q in exon 5. We review literature supporting the genetic basis of the disease.