Roxana Cleper

Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible

Nephrotic syndrome, a malfunction of the kidney glomerular filter, leads to proteinuria, edema and, in steroid-resistant nephrotic syndrome, end-stage kidney disease. Using positional cloning, we identified mutations in the phospholipase C epsilon gene (PLCE1) as causing early-onset nephrotic syndrome with end-stage kidney disease. Kidney histology of affected individuals showed diffuse mesangial sclerosis (DMS). Using immunofluorescence, we found PLCε1 expression in developing and mature glomerular podocytes and showed that DMS represents an arrest of normal glomerular development. We identified IQ motif–containing GTPase-activating protein 1 as a new interaction partner of PLCε1. Two siblings with a missense mutation in an exon encoding the PLCε1 catalytic domain showed histology characteristic of focal segmental glomerulosclerosis. Notably, two other affected individuals responded to therapy, making this the first report of a molecular cause of nephrotic syndrome that may resolve after therapy. These findings, together with the zebrafish model of human nephrotic syndrome generated by plce1 knockdown, open new inroads into pathophysiology and treatment mechanisms of nephrotic syndrome.

Genotype/Phenotype Correlation in Nephrotic Syndrome Caused by WT1 Mutations

BACKGROUND AND OBJECTIVES The risk of developing Wilms tumor (WT) can be present or absent in patients with nephrotic syndrome (NS) caused by WT1 mutations. Here, the genotype/phenotype correlation regarding the outcome and risk for WT in 52 patients from 51 families with NS due to WT1 mutations is described. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS This study followed 19 patients with mutations in intron 9 splice donor site (KTS mutations), 27 patients with missense mutations, 4 patients with nonsense mutations, 1 patient with a splice site mutation in intron 8, and 1 patient with a deletion. RESULTS Twenty-four different WT1 mutations were detected. Sixteen of the 19 patients with KTS mutations were females. These patients had isolated NS if karyotype was 46,XX and Frasier syndrome if karyotype was 46,XY. Patients with KTS mutations presented at a significantly older age and with a slower progression toward chronic kidney disease (CKD) stage 5, compared with missense mutations. Patients with nonsense mutations presented initially with WT. Six patients with missense mutations developed WT after the diagnosis of NS (interval-range from NS onset to WT of 0.1 to 1.4 years). CONCLUSIONS (1) KTS mutations cause isolated NS with absence of WT in 46,XX females. (2) KTS mutations cause Frasier syndrome with gonadoblastoma risk in 46,XY phenotypic females. (3) KTS mutations cause NS with a slower progression when compared with missense mutations. (4) Missense mutations can occur with and without WT. (5) WT1 analysis is important in young patients with NS for early detection and tumor prophylaxis.

Prevalence of Vesicoureteral Reflux in Neonatal Urinary Tract Infection

Vesicoureteral reflux (VUR) after a first episode of urinary tract infection (UTI) is apparently diagnosed much more frequently (25%-40%) in children than in neonates. The aims of the study were to determine the actual rate of VUR in neonates with UTI and to define the clinical clues to its diagnosis. The study sample included term infants with a diagnosis of UTI during their first month of life who were seen in this hospital between January 1997 and May 1999. All infants underwent complete diagnostic work-up (renal ultrasound and voiding cystourethrography [VCUG]). The medical files were reviewed for patient sex, age at UTI diagnosis, laboratory findings (including causative pathogen), and ultrasonographic findings. These parameters were correlated with the finding of VUR on VCUG. Sixty-four neonates (55 males, 9 females) with UTI were included in this study. UTI was 6 times more common in males than females, although the incidence of VUR was equal between the sexes (about 20%). The presence of VUR was associated with a significantly younger age at presentation of UTI (11.4±4 vs 16.9±6.6 days, p<0.01). VUR was diagnosed at a fourfold higher rate in neonates with Klebsiella-induced UTI compared to those with E. Coli-UTI. In 80% of those with significantly abnormal ultrasonographic findings VUR was found on VCUG. Jaundice was noted at UTI diagnosis 3 times more often in infants with VUR, and elevated creatinine level, 2.5 times more often.

New-onset post-transplantation food allergy in children--is it attributable only to the immunosuppressive protocol?

Abstract:  New‐onset post‐transplantation food allergy has been described mainly after liver transplantation, and its pathogenesis was attributed to the immunomodulatory effects of tacrolimus therapy. The aim of the present study was to evaluate the association of food allergy with solid organ transplantation in our center. The medical records of children who underwent kidney transplantation and children who underwent liver or liver and kidney transplantation from 1986 to 2005 were reviewed. A total of 189 children (124 after kidney transplantation, 65 after liver or liver and kidney transplantation) received tacrolimus as part of the immunosuppressive regimen. New‐onset post‐transplantation food allergy was documented in four of them: two with liver transplants and two with combined kidney and liver transplants. The absence of new‐onset food allergy in the children with isolated kidney transplants is compatible with other reports in the literature. This study supports the concept that the functioning liver itself, and not only tacrolimus immunosuppression, is a main contributor to food allergy in this patient population.

Renal Hypodysplasia Associates with a Wnt4 Variant that Causes Aberrant Canonical Wnt Signaling

Abnormal differentiation of the renal stem/progenitor pool into kidney tissue can lead to renal hypodysplasia (RHD), but the underlying causes of RHD are not well understood. In this multicenter study, we identified 20 Israeli pedigrees with isolated familial, nonsyndromic RHD and screened for mutations in candidate genes involved in kidney development, including PAX2, HNF1B, EYA1, SIX1, SIX2, SALL1, GDNF, WNT4, and WT1. In addition to previously reported RHD-causing genes, we found that two affected brothers were heterozygous for a missense variant in the WNT4 gene. Functional analysis of this variant revealed both antagonistic and agonistic canonical WNT stimuli, dependent on cell type. In HEK293 cells, WNT4 inhibited WNT3A induced canonical activation, and the WNT4 variant significantly enhanced this inhibition of the canonical WNT pathway. In contrast, in primary cultures of human fetal kidney cells, which maintain WNT activation and more closely represent WNT signaling in renal progenitors during nephrogenesis, this mutation caused significant loss of function, resulting in diminished canonical WNT/β-catenin signaling. In conclusion, heterozygous WNT4 variants are likely to play a causative role in renal hypodysplasia.

Maxillomandibular brown tumor – a rare complication of chronic renal failure

Abstract We report a 17-year-old hemodialysis patient with a rapidly growing maxillary mass diagnosed as a brown tumor. Although successful control of the parathyroid hormone (PTH) levels was achieved by treatment with vitamin D pulse therapy, the lesion progressed, invaded the maxillary sinus, and caused severe eating and speech disabilities. No recurrence was observed following surgical excision. The differential diagnosis and considerations regarding the causes of the disease in a child, therapy options, and review of the literature are presented.

Renal functional reserve after acute poststreptococcal glomerulonephritis

Abstract. We evaluated renal functional reserve (RFR) in 36 patients aged 5 – 21 years, who had recovered from an acute episode of poststreptococcal glomerulonephritis (PSGN) 1 – 16 years previously, without apparent sequelae, as evidenced by normal serum creatinine, blood pressure, and urinary sediment. The control group consisted of 12 children aged 2 – 12 years with recurrent urinary tract infections or nocturnal enuresis, without active infection or anatomical anomalies. The basal creatinine clearance was similar in the PSGN and control groups: 140.0±27.4 ml/min per 1.73 m2 and 142.9±15.5 ml/min per 1.73 m2, respectively. The RFR in the PSGN group was significantly reduced compared with that of the control group: 18.6±12.9 ml/min per 1.73 m2 and 41.1±25.3 ml/min per 1.73 m2, respectively (P <0.02). In 7 PSGN patients (19.4%), no RFR was found. In 69% of patients who had recovered from PSGN more than 10 years before the protein loading tests, a significantly reduced RFR (less than 10% of baseline) was found. The same degree of reduction in RFR was found in only 26% of patients who had suffered from PSGN less than 10 years ago.

Cryptosporidiosis in children following solid organ transplantation.

Background: Cryptosporidium parvum is a common cause of diarrhea. In immunocompetent individuals, spontaneous recovery is the rule. In immunocompromised patients, it may cause a serious disease. Data on cryptosporidiosis in children after solid organ transplantation are few. We report on 6 pediatric solid organ recipients with gastroenteritis caused by Cryptosporidium. Patients and Methods: All episodes of gastroenteritis in solid organ transplant recipients hospitalized in Schneider Children’s Medical Center from January 2008 to August 2011 were identified. Data on the episodes with positive staining for Cryptosporidium antigen in stool were reviewed. Results: Fifty-seven episodes of gastroenteritis were recorded. In 6 (11%) patients (4 kidney recipient, 1 liver and kidney recipient and 1 heart transplant recipient) Cryptosporidium antigen was detected in stool. Mean age at transplantation was 3.7 ± 2 years, mean time between transplantation and cryptosporidial disease was 39 ± 53.9 months. Symptoms included prolonged diarrhea, fever, abdominal pain and weight loss. Mean duration of symptoms before diagnosis was 10.5 ± 8.7 days. In 5 children, kidney function deteriorated, blood concentrations of tacrolimus increased in 5 patients and abnormal values of liver enzymes were detected in 4 patients. All patients were hospitalized and received intravenous fluid replacement and were treated with nitazoxanide for 5–21 days. Two patients had recurrence of symptoms after short course (5 days) therapy. All patients recovered eventually from the disease. Conclusion: Cryptosporidium should be routinely tested in solid organ transplant recipients with diarrhea. Delay in initiation of treatment can result in serious complications including acute renal failure. Long-term therapy with nitazoxanide (at least 14 days) may facilitate recovery.

Hypothyroidism in children with steroid-resistant nephrotic syndrome

BACKGROUND Non-autoimmune hypothyroidism has been reported in children with congenital nephrotic syndrome. The hypothyroid state was attributed to massive prolonged thyroid hormone loss. However, this endocrine abnormality has not been reported in steroid-resistant nephrotic syndrome (SRNS) despite similar long-standing proteinuria. METHOD We describe all the patients with SRNS in our clinics follow-up who developed non-autoimmune hypothyroidism. RESULTS Five children aged 3-11 years at diagnosis of SRNS and followed for 5-42 months developed hypothyroidism (depressed free thyroxin and elevated thyrotropin levels) without evidence of autoimmune thyroiditis. The diagnosis of hypothyroidism was not temporarily related to disease duration or renal function. The disease was resistant to all therapies, renal function deteriorated in all the patients within 1.5-14.5 years from diagnosis. Despite thyroxine treatment and a decline in renal function, thyroid hormone level normalized only after reaching end stage renal disease (ESRD) and hemodialysis start. Nephrotic syndrome recurrence after kidney transplantation (in three patients with focal segmental glomerulosclerosis) was not accompanied by recurrent hypothyroidism. CONCLUSION It is our impression that non-autoimmune hypothyroidism is a potential significant complication of SRNS, and should be actively sought for especially in cases with renal function deterioration. Hypothyroidism usually resolved when these patients reach ESRD. The incidence and pathogenesis of this condition require further study.

Low serum C3, leukopenia, and thrombocytopenia: unusual features of henoch-schonlein purpura.

Abstract Henoch-Schonlein purpura (HSP) affects predominantly the skin, joints, gastrointestinal tract and kidney. Although the pathogenesis is probably of immune origin and complement activation is thought to play a role, laboratory findings including the serum level of the complement components are usually normal. We present a patient with a severe form of HSP nephritis who had unusual laboratory findings of a low level of C3, mild leukopenia and thrombocytopenia. These findings may further support the importance of complement activation in the pathogenesis of HSP.