Ozlem Erdogan

The effect of triple therapy on rapidly progressive type of Henoch-Schönlein nephritis

Twelve patients with Henoch-Schönlein purpura, aged 6–14 years (mean 10.3 years), presenting with rapidly progressive glomerulonephritis (RPGN) were investigated prospectively. Analysis of the initial clinical features revealed: oedema (8 patients), hypertension (7 patients), gross haematuria (11 patients), oliguria (5 patients) and a decreased glomerular filtration rate (GFR) (<40 ml/min per 1.73 m2, 8 patients). Renal biopsies were available in 9 patients and revealed focal necrotising and a fibroepithelial type of crescentic glomerulonephritis (with 60%–90% crescent formation). The remaining 3 patients fulfilled the clinical criteria of RPGN. Two patients who were in the acute stage required peritoneal dialysis for a period of 2 weeks. The treatment protocol in all patients consisted of intravenous pulse methylprednisolone (3 days), oral cyclophosphamide (2 months), oral dipyridamole (6 months) and oral prednisolone (3 months). At the end of triple therapy, GFR returned to normal in all but 1 patient. During a follow-up period of 9–39 months, 7 patients achieved complete remission, while 4 patients showed partial remission, 3 of whom had persistent proteinuria and haematuria and 1 microscopic haematuria only. One patient had persistent nephropathy with decreased GFR and macroscopic haematuria and nephrotic-range proteinuria. His renal biopsy, performed 30 months after the onset of the disease, showed chronic diffuse sclerosing glomerulonephritis and intratubular severe IgA deposition. Although our patient group was small, this type of intensive treatment appears to be effective; further studies are needed.

Spectrum of Steroid-Resistant and Congenital Nephrotic Syndrome in Children: The PodoNet Registry Cohort

BACKGROUND AND OBJECTIVES Steroid-resistant nephrotic syndrome is a rare kidney disease involving either immune-mediated or genetic alterations of podocyte structure and function. The rare nature, heterogeneity, and slow evolution of the disorder are major obstacles to systematic genotype-phenotype, intervention, and outcome studies, hampering the development of evidence-based diagnostic and therapeutic concepts. To overcome these limitations, the PodoNet Consortium has created an international registry for congenital nephrotic syndrome and childhood-onset steroid-resistant nephrotic syndrome. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Since August of 2009, clinical, biochemical, genetic, and histopathologic information was collected both retrospectively and prospectively from 1655 patients with childhood-onset steroid-resistant nephrotic syndrome, congenital nephrotic syndrome, or persistent subnephrotic proteinuria of likely genetic origin at 67 centers in 21 countries through an online portal. RESULTS Steroid-resistant nephrotic syndrome manifested in the first 5 years of life in 64% of the patients. Congenital nephrotic syndrome accounted for 6% of all patients. Extrarenal abnormalities were reported in 17% of patients. The most common histopathologic diagnoses were FSGS (56%), minimal change nephropathy (21%), and mesangioproliferative GN (12%). Mutation screening was performed in 1174 patients, and a genetic disease cause was identified in 23.6% of the screened patients. Among 14 genes with reported mutations, abnormalities in NPHS2 (n=138), WT1 (n=48), and NPHS1 (n=41) were most commonly identified. The proportion of patients with a genetic disease cause decreased with increasing manifestation age: from 66% in congenital nephrotic syndrome to 15%-16% in schoolchildren and adolescents. Among various intensified immunosuppressive therapy protocols, calcineurin inhibitors and rituximab yielded consistently high response rates, with 40%-45% of patients achieving complete remission. Confirmation of a genetic diagnosis but not the histopathologic disease type was strongly predictive of intensified immunosuppressive therapy responsiveness. Post-transplant disease recurrence was noted in 25.8% of patients without compared with 4.5% (n=4) of patients with a genetic diagnosis. CONCLUSIONS The PodoNet cohort may serve as a source of reference for future clinical and genetic research in this rare but significant kidney disease.

Genetic screening in adolescents with steroid-resistant nephrotic syndrome

Genetic screening paradigms for congenital and infantile nephrotic syndrome are well established; however, screening in adolescents has received only minor attention. To help rectify this, we analyzed an unselected adolescent cohort of the international PodoNet registry to develop a rational screening approach based on 227 patients with nonsyndromic steroid-resistant nephrotic syndrome aged 10-20 years. Of these, 21% had a positive family history. Autosomal dominant cases were screened for WT1, TRPC6, ACTN4, and INF2 mutations. All other patients had the NPHS2 gene screened, and WT1 was tested in sporadic cases. In addition, 40 sporadic cases had the entire coding region of INF2 tested. Of the autosomal recessive and the sporadic cases, 13 and 6%, respectively, were found to have podocin-associated nephrotic syndrome, and 56% of them were compound heterozygous for the nonneutral p.R229Q polymorphism. Four percent of the sporadic and 10% of the autosomal dominant cases had a mutation in WT1. Pathogenic INF2 mutations were found in 20% of the dominant but none of the sporadic cases. In a large cohort of adolescents including both familial and sporadic disease, NPHS2 mutations explained about 7% and WT1 4% of cases, whereas INF2 proved relevant only in autosomal dominant familial disease. Thus, screening of the entire coding sequence of NPHS2 and exons 8-9 of WT1 appears to be the most rational and cost-effective screening approach in sporadic juvenile steroid-resistant nephrotic syndrome.

Genotype-phenotype associations in WT1 glomerulopathy.

WT1 mutations cause a wide spectrum of renal and extrarenal manifestations. Here we evaluated disease prevalence, phenotype spectrum, and genotype-phenotype correlations of 61 patients with WT1-related steroid-resistant nephrotic syndrome relative to 700 WT1-negative patients, all with steroid-resistant nephrotic syndrome. WT1 patients more frequently presented with chronic kidney disease and hypertension at diagnosis and exhibited more rapid disease progression. Focal segmental glomerulosclerosis was equally prevalent in both cohorts, but diffuse mesangial sclerosis was largely specific for WT1 disease and was present in 34% of cases. Sex reversal and/or urogenital abnormalities (52%), Wilms tumor (38%), and gonadoblastoma (5%) were almost exclusive to WT1 disease. Missense substitutions affecting DNA-binding residues were associated with diffuse mesangial sclerosis (74%), early steroid-resistant nephrotic syndrome onset, and rapid progression to ESRD. Truncating mutations conferred the highest Wilms tumor risk (78%) but typically late-onset steroid-resistant nephrotic syndrome. Intronic (KTS) mutations were most likely to present as isolated steroid-resistant nephrotic syndrome (37%) with a median onset at an age of 4.5 years, focal segmental glomerulosclerosis on biopsy, and slow progression (median ESRD age 13.6 years). Thus, there is a wide range of expressivity, solid genotype-phenotype associations, and a high risk and significance of extrarenal complications in WT1-associated nephropathy. We suggest that all children with steroid-resistant nephrotic syndrome undergo WT1 gene screening.

Prevalence of MEFV gene mutations and their clinical correlations in Turkish children with Henoch–Schönlein purpura

Aim:  To investigate the frequency of MEFV mutations and their associations with the clinical and laboratory findings in children with Henoch–Schönlein purpura (HSP).

Genetic risk factors of amyloidogenesis in familial mediterranean fever

Background/Aims: Evaluation of the risk factors, and phenotype-genotype correlation of familial Mediterranean fever (FMF) gene (MEFV) and serum amyloid A1 (SAA1) gene polymorphisms in renal amyloidosis. Methods: We investigated MEFV and SAA1 genotypes (α, β, and γ isoforms) in 50 FMF patients and 50 healthy children. Tel-Hashomer criteria were used for the diagnosis and severity scoring of FMF. Results: The most common MEFV mutation and SAA1 genotype were M694V/M694V (n = 26/50) and SAA1 α/α (n = 26/50), respectively. Positive family history for amyloidosis was significantly higher (p < 0.001) with more severe clinical course (p = 0.006) in the amyloidosis group than the non-amyloid group. In M694V/M694V mutation, erysipelas-like skin erythema (p = 0.029), arthritis (p = 0.004), arthralgia (p < 0.001) were significantly more frequent with higher severity scores (p = 0.008) than the patients with other mutations. Comparison of the SAA1 α/α genotype with other genotypes revealed more frequent arthritis (p = 0.003) in the SAA1 α/α genotype. In amyloidosis group patients having both M694V/M694V and SAA1 α/α genotypes were the largest subgroup (n = 14, p < 0.001). Logistic regression analysis for amyloidosis corrected risk revealed a 1.2 times increase in M694V/M694V, a 2.4 times increase in SAA1 α/α genotypes and a 2.5 times increase when both are together. Conclusion: Positive family history for amyloidosis and presence of SAA1 α/α genotype in M694V/M694V mutation may predispose to amyloidosis by increasing the clinical severity. Therefore, in such children early colchicine treatment might be recommended even if they are asymptomatic.

FMF50: a score for assessing outcome in familial Mediterranean fever

Background Colchicine is the main treatment for familial Mediterranean fever (FMF). However, biological agents and other treatments are available for patients who are unable to receive optimal treatment. Objective To develop outcome criteria that define response to treatment. Methods Two rounds of Delphi exercise were followed by a consensus conference enabling the definition of the criteria to be employed. Data for patients with FMF responding and resistant to their treatment were obtained from the FMF Arthritis Vasculitis and Orphan disease Research in paediatric rheumatology (FAVOR) website. The suggested criteria were analysed and validated in this patient cohort. Sensitivity/specificity measures and the ability of the score to discriminate between patients with active and inactive disease via the best cut-off score were calculated by a receiver operating characteristic analysis. Results Compliance with the maximum dose of the drug was considered essential for evaluation of the patients. Seven criteria were suggested in the consensus conference. The performance of each criterion, in differentiating between resistant and responsive patients, was tested. The final set of criteria was defined as at least 50% improvement in five of six criteria, without worsening in any one defined response to treatment with a very high sensitivity and specificity. The items of this FMF50 included: 1. Percentage change in the frequency of attacks with the treatment. 2. Percentage change in the duration of attacks with the treatment. 3. Patients/parents’ global assessment of disease severity (10 cm visual analogue scale (VAS)). 4. Physicians’ global assessment of disease severity (10 cm VAS). 5. Percentage change in arthritis attacks with the treatment. 6. Percentage change in C-reactive protein, erythrocyte sedimentation rate or serum amyloid A level with the treatment. Conclusions The FMF50 produced is a user-friendly measurement tool to guide physicians and can be used in clinical trials.

Hemolytic uremic syndrome triggered with a new pandemic virus: influenza A (H1N1)

Sirs, In April 2009, a new strain of human influenza A (H1N1) virus causing human disease was identified. Based on evidence of community transmission of this new strain from person to person in more than one of its regions, the World Health Organization (WHO) declared a pandemic in June 2009. We present a case of recurrent hemolytic uremic syndrome (HUS) in a patient who was admitted with a new attack triggered by influenza A (H1N1) virus infection. We also discuss the progression of the disease. A 15-year-old girl was admitted to our hospital in December 2009 with complaints of throat pain, fever, and nasal drip, followed by weakness, vomiting, and nonbloody diarrhea lasting for a few days. There were people with similar complaints in her vicinity. The patient had first been admitted to our hospital with HUS at the age of 4 years; at this time, her admittance was followed by 2 days of non-bloody diarrhea. She had completely recovered without dialysis treatment but had recurrences at 12, 13, and 14 years of age. However, during the attacks her serum creatinine levels did not exceed 2.65 mg/dl (Fig. 1). On physical examination she was pale and showed signs of dehydration, pharyngeal hyperemia, and postnasal discharge. Her arterial tension was 150/100 mmHg. Laboratory tests indicated severe anemia with findings of intravascular hemolysis and thrombocytopenia. She had 2+ proteinuria and microscopic hematuria on urinalysis. Serum creatinine was 5.1 mg/dl; blood urea nitrogen, 97 mg/dl; uric acid, 9.7 mg/dl; total protein, 6.6 g/dl; albumin, 3.3 g/dl; total bilirubin, 2.1 mg/dl; indirect bilirubin, 1.9 mg/dl; serum aspartate transaminase, 129 U/l; alanine transaminase, 27 U/l; lactate dehydrogenase, 847 U/l. Serum haptoglobin was <5 mg/dl (range 36–195 mg/dl). Prothrombin and activated partial thromboplastin times were normal. Throat, stool, urine, and blood cultures were negative. Serum complement 3 (C3) level was 0.979 g/l (normal range 0.83–1.77 g/l), C4 level were 0.256 g/l (normal range 0.12– 0.4 g/l). Serum antinuclear antibodies (ANA), anti-doublestranded (ds)DNA, and pand c-antinuclear cytoplasmic antibody titers were negative. She was diagnosed with HUS. Viral PCR analysis of the nasopharynx swab for the detection of influenza A (H1N1) was positive and believed to be the triggering factor of the HUS. She was started on oseltamivir therapy with an adjusted dose according to the degree of renal failure. Dialysis treatment was not initiated on the first day due to her history of improving without dialysis treatment in previous HUS attacks. She was given daily fresh frozen plasma infusions together with erythrocyte and platelet transfusions when necessary. Her serum creatinine value decreased the following day. Six days later, her serum creatinine level had decreased to 3.2 mg/dl, her uric acid level was 8.8 mg/dl, and her hemoglobin had increased to 9.3 g/dl and platelets to 48,000/mm. Daily fresh frozen plasma therapies were sustained until her renal function was normal. Oseltamivir treatment was completed at 7 days. On the 14th day following treatment initiation, her serum creatinine was 0.8 mg/dl, and all of her laboratory test results were normal. Atypical HUS (aHUS) has a poor prognosis, with approximately 50% of patients progressing to end-stage renal disease (ESRD). Several studies have confirmed a genetic predisposition to this disease that involves factors A. Çaltik (*) : S. G. Akyüz :Ö. Erdogan :G. Demircin Pediatric Nephrology Department, Dr Sami Ulus Children Hospital, Ankara, Turkey e-mail: acaltik@hotmail.com

Central Pontine and Extrapontine Myelinolysis Owing to Disequilibrium Syndrome

Neurologic disorders can be seen in patients with end-stage renal failure owing to complications of hemodialysis or peritoneal dialysis. The disequilibrium syndrome can be seen, usually soon after or toward the end of dialysis. We report a patient with central pontine and extrapontine myelinolysis owing to disequilibrium syndrome. The patient had depressed consciousness, agitation, tremor, stupor and hyperactive deep tendon reflexes toward the end of the second peritoneal dialysis. A brain computed tomographic (CT) scan showed hypodense lesions in pontine and extrapontine locations without radiocontrast medium enhancement After 2 days, the patient had only minimal memory deficits. A control brain CT scan 1 week later showed a decrease of the lesions in central pontine and extrapontine locations. Central pontine and extrapontine myelinolysis should be suspected and investigated in the acute neurologic disorders of dialysis patients.Neurologic disorders can be seen in patients with end-stage renal failure owing to complications of hemodialysis or peritoneal dialysis. The disequilibrium syndrome can be seen, usually soon after or toward the end of dialysis. We report a patient with central pontine and extrapontine myelinolysis owing to disequilibrium syndrome. The patient had depressed consciousness, agitation, tremor, stupor, and hyperactive deep tendon reflexes toward the end of the second peritoneal dialysis. A brain computed tomographic (CT) scan showed hypodense lesions in pontine and extrapontine locations without radiocontrast medium enhancement. After 2 days, the patient had only minimal memory deficits. A control brain CT scan 1 week later showed a decrease of the lesions in central pontine and extrapontine locations. Central pontine and extrapontine myelinolysis should be suspected and investigated in the acute neurologic disorders of dialysis patients. (J Child Neurol 2003;18:292—296).

Long-Term Efficacy and Safety of Quadruple Therapy in Childhood Diffuse Proliferative Lupus Nephritis

In this study, we evaluated the frequency, clinical presentation, treatment protocols, prognostic factors, and outcome in children with diffuse proliferative lupus nephritis (DPLN). Between June 1990 and December 2004, 46 patients were diagnosed to have systemic lupus erythematosus (SLE), and 26 of them (56.5%) were found to have DPLN. Renal manifestations were present in 25 patients, and the majority of them presented with severe renal findings, such as nephrotic syndrome and renal failure. All patients were given a quadruple therapy protocol including 6–12 monthly courses of methyl prednisolone pulse therapy combined with oral prednisolone, oral cyclophosphamide, azathioprine, and dipyridamole. Nineteen of these patients were regularly followed up with a mean follow-up period of 5.9 years. Complete remission was achieved in 15 of 19 patients, and chronic renal failure developed in four patients. Renal survival rate was calculated to be 78.9% at the end of 5, 10, and 14 years. Although nephrotic range proteinuria, hypoalbuminemia, renal failure, and activity index above 12/24 at presentation seemed to be associated with poor prognosis, no significant difference could be found. Hypertension and chronicity index greater than 6/12 were found to be bad prognostic predictors. We concluded that satisfactory results were achieved with our quadruple therapy protocol; thus, more aggressive and expensive therapies can be avoided and preserved for more serious and persistent diseases.