Sawsan M Jalalah

Inactive matrix metalloproteinase 2 is a normal constituent of human glomerular basement membrane. An immuno‐electron microscopic study

Remodelling of the extracellular matrix requires tight control not only of matrix synthesis, but also of matrix degradation. Control of matrix degradation is achieved mainly through the matrix metalloproteinase (MMP) enzymes. In the glomerulus, MMP‐2 and MMP‐9 are believed to be particularly important, as they have activity against type IV collagen. This study has demonstrated by immuno‐electron microscopy that most of the immunoreactivity for MMP‐2 in the normal glomerulus is located within the glomerular basement membranes and mesangial matrix. mRNA for MMP‐2 is also detectable in normal glomeruli, but the other main gelatinase, MMP‐9, could not be localized by immuno‐electron microscopy. In the normal glomerulus, it seemed likely that MMP‐2 is present in an inactive form. To confirm this, in situ zymography was carried out using frozen sections of normal kidney. Baseline activity of normal kidney was relatively weak, but this was dramatically increased by chemical activation of metalloproteinases. The results imply that MMP‐2, in an inactive form, is a normal constituent of the extracellular matrix and glomerular basement membranes. Activation would presumably render the matrix ‘self‐degrading’; membrane‐bound MMPs (MT‐MMPs) seem particularly likely to be involved in leukocyte penetration of basement membranes in inflammation. Copyright

Histopathology of steroid-resistant nephrotic syndrome in children living in the Kingdom of Saudi Arabia

Sirs, Steroid-resistant nephrotic syndrome (SRNS) is believed to be associated with a high risk of developing chronic renal failure (CRF). The underlying histopathology usually affects the course of the disease and the response to treatment [1]. Focal segmental glomerulosclerosis (FSGS) was reported as the main cause of SRNS in Western countries [2] as well as in many other parts of the world [3]. However, in black South Africans, membranous nephropathy associated with hepatitis B infection was reported as a main cause of SRNS [4], and minimal change nephrotic syndrome [minimal change disease (MCD)] was reported as the main cause in Kuwaiti children [5]. In this study we report on the pattern of the histopathology of SRNS in children coming to King Abdul-Aziz University Hospital (KAUH). We reviewed the notes of all children with primary nephrotic syndrome that was steroid resistant who had come to the pediatric renal unit at KAUH between 2002 and 2007. Only patients who had undergone renal biopsy were included in the study. The histopathology slides were reviewed by two renal pathologists independently. Patients with congenital nephrotic syndrome, lupus or sickle cell disease, were excluded from the study. Thirty-six children fulfilled the inclusion criteria: 25 girls and 11 boys, with a female (F) to male (M) ratio of 2.3:1. Fifty percent (18 children) were Saudi and the other 50% were from various racial backgrounds (nine Asians, four Arabs, two Africans and three from the Far East). Their mean age at presentation ± standard deviation (SD) was 4.3±3.0 (range 1–12) years. Their mean serum albumin level at presentation was 15.6±7.1 g/l, and all had 4+ proteinuria. Five children had high creatinine concentrations at presentation, while the mean serum creatinine level was 50.4±45.6 μmol/l. Three children had low levels of complements at presentation, and none had positive test results for hepatitis surface antigen or antinuclear antibody (ANA). Renal histopathology was compatible with focal segmental glomerulosclerosis (FSGS) in 39% (14 children), immunoglobulin (Ig)M nephropathy in 28% (ten children), mesangio-proliferative glomerulonephritis (MesPGN) in 17% (six children), MCD in 8% (three children), complement C1q nephropathy (C1qNP) in 8% (three children) and IgA nephropathy in one patient (3%). The incidence and frequency of various histological subtypes of steroid-resistant nephrotic syndrome in children in the Kingdom of Saudi Arabia (KSA) do not seem to differ from those observed in Western and other countries. Therefore, similar diagnostic and therapeutic strategies for SRNS can be applied to our patients in KSA. Genetics studies have to be done in the future. Pediatr Nephrol (2009) 24:1429–1430 DOI 10.1007/s00467-008-1106-5

Mutations in six nephrosis genes delineate a pathogenic pathway amenable to treatment

No efficient treatment exists for nephrotic syndrome (NS), a frequent cause of chronic kidney disease. Here we show mutations in six different genes (MAGI2, TNS2, DLC1, CDK20, ITSN1, ITSN2) as causing NS in 17 families with partially treatment-sensitive NS (pTSNS). These proteins interact and we delineate their roles in Rho-like small GTPase (RLSG) activity, and demonstrate deficiency for mutants of pTSNS patients. We find that CDK20 regulates DLC1. Knockdown of MAGI2, DLC1, or CDK20 in cultured podocytes reduces migration rate. Treatment with dexamethasone abolishes RhoA activation by knockdown of DLC1 or CDK20 indicating that steroid treatment in patients with pTSNS and mutations in these genes is mediated by this RLSG module. Furthermore, we discover ITSN1 and ITSN2 as podocytic guanine nucleotide exchange factors for Cdc42. We generate Itsn2-L knockout mice that recapitulate the mild NS phenotype. We, thus, define a functional network of RhoA regulation, thereby revealing potential therapeutic targets.Nephrotic syndrome is the second most common chronic kidney disease but there are no targeted treatment strategies available. Here the authors identify mutations of six genes codifying for proteins involved in cytoskeleton remodelling and modulation of small GTPases in 17 families with nephrotic syndrome.

Severe acute post-streptococcal glomerulonephritis in an infant

Acute post-streptococcal glomerulonephritis (APSGN) is very rare below the age of two years. We report a 14-month-old girl who presented with frank hematuria and nephrotic syndrome following group A streptococcal pharyngitis (GAS), which was confirmed by laboratory investigations. The patient underwent a renal biopsy to confirm the diagnosis and was treated with prednisolone. The proteinuria and hematuria resolved completely in eight weeks. Our case demonstrates that APSGN should be considered in evaluating hematuria and nephrotic syndrome in infants and children below two years of age.

GAPVD1 and ANKFY1 Mutations Implicate RAB5 Regulation in Nephrotic Syndrome

BACKGROUND Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of CKD. The discovery of monogenic causes of SRNS has revealed specific pathogenetic pathways, but these monogenic causes do not explain all cases of SRNS. METHODS To identify novel monogenic causes of SRNS, we screened 665 patients by whole-exome sequencing. We then evaluated the in vitro functional significance of two genes and the mutations therein that we discovered through this sequencing and conducted complementary studies in podocyte-like Drosophila nephrocytes. RESULTS We identified conserved, homozygous missense mutations of GAPVD1 in two families with early-onset NS and a homozygous missense mutation of ANKFY1 in two siblings with SRNS. GAPVD1 and ANKFY1 interact with the endosomal regulator RAB5. Coimmunoprecipitation assays indicated interaction between GAPVD1 and ANKFY1 proteins, which also colocalized when expressed in HEK293T cells. Silencing either protein diminished the podocyte migration rate. Compared with wild-type GAPVD1 and ANKFY1, the mutated proteins produced upon ectopic expression of GAPVD1 or ANKFY1 bearing the patient-derived mutations exhibited altered binding affinity for active RAB5 and reduced ability to rescue the knockout-induced defect in podocyte migration. Coimmunoprecipitation assays further demonstrated a physical interaction between nephrin and GAPVD1, and immunofluorescence revealed partial colocalization of these proteins in rat glomeruli. The patient-derived GAPVD1 mutations reduced nephrin-GAPVD1 binding affinity. In Drosophila, silencing Gapvd1 impaired endocytosis and caused mistrafficking of the nephrin ortholog. CONCLUSIONS Mutations in GAPVD1 and probably in ANKFY1 are novel monogenic causes of NS. The discovery of these genes implicates RAB5 regulation in the pathogenesis of human NS.

Simultaneous onset of steroid resistant nephrotic syndrome and IDDM in two young children

The cases are reported of two young children who developed insulin-dependent diabetes mellitus (IDDM) within 2 weeks of receiving a diagnosis of nephrotic syndrome. Neither patient responded to 8 weeks of daily prednisolone. The first patient presented at 2 years and 9 months of age. Her renal biopsy showed mesangial proliferation. The second child presented with steroid resistant nephrotic syndrome at 18 months of age and developed IDDM 2 weeks later. He achieved partial remission with cyclosporine therapy. His initial renal biopsy at 3 years of age showed minimal change disease and follow-up renal biopsy at 5 years of age showed early diabetic glomerulosclerosis. Tests for NPHS2 and WT1 genetic mutations were negative in both patients. To our knowledge this is the first report of steroid resistant nephrotic syndrome with almost simultaneous onset of IDDM in young children.