Nineteen novel NPHS1 mutations in a worldwide cohort of patients with congenital nephrotic syndrome (CNS)

Background. Recessive mutations in the NPHS1 gene encoding nephrin account for ∼40% of infants with congenital nephrotic syndrome (CNS). CNS is defined as steroid-resistant nephrotic syndrome (SRNS) within the first 90 days of life. Currently, more than 119 different mutations of NPHS1 have been published affecting most exons. Methods. We here performed mutational analysis of NPHS1 in a worldwide cohort of 67 children from 62 different families with CNS. Results. We found bi-allelic mutations in 36 of the 62 families (58%) confirming in a worldwide cohort that about one-half of CNS is caused by NPHS1 mutations. In 26 families, mutations were homozygous, and in 10, they were compound heterozygous. In an additional nine patients from eight families, only one heterozygous mutation was detected. We detected 37 different mutations. Nineteen of the 37 were novel mutations (∼51.4%), including 11 missense mutations, 4 splice-site mutations, 3 nonsense mutations and 1 small deletion. In an additional patient with later manifestation, we discovered two further novel mutations, including the first one affecting a glycosylation site of nephrin. Conclusions. Our data hereby expand the spectrum of known mutations by 17.6%. Surprisingly, out of the two siblings with the homozygous novel mutation L587R in NPHS1, only one developed nephrotic syndrome before the age of 90 days, while the other one did not manifest until the age of 2 years. Both siblings also unexpectedly experienced an episode of partial remission upon steroid treatmen

A systematic approach to mapping recessive disease genes in individuals from outbred populations

The identification of recessive disease-causing genes by homozygosity mapping is often restricted by lack of suitable consanguineous families. To overcome these limitations, we apply homozygosity mapping to single affected individuals from outbred populations. In 72 individuals of 54 kindred ascertained worldwide with known homozygous mutations in 13 different recessive disease genes, we performed total genome homozygosity mapping using 250,000 SNP arrays. Likelihood ratio Z-scores (ZLR) were plotted across the genome to detect ZLR peaks that reflect segments of homozygosity by descent, which may harbor the mutated gene. In 93% of cases, the causative gene was positioned within a consistent ZLR peak of homozygosity. The number of peaks reflected the degree of inbreeding. We demonstrate that disease-causing homozygous mutations can be detected in single cases from outbred populations within a single ZLR peak of homozygosity as short as 2 Mb, containing an average of only 16 candidate genes. As many specialty clinics have access to cohorts of individuals from outbred populations, and as our approach will result in smaller genetic candidate regions, the new strategy of homozygosity mapping in single outbred individuals will strongly accelerate the discovery of novel recessive disease genes

ARHGDIA mutations cause nephrotic syndrome via defective RHO GTPase signaling

Nephrotic syndrome (NS) is divided into steroid-sensitive (SSNS) and -resistant (SRNS) variants. SRNS causes end-stage kidney disease, which cannot be cured. While the disease mechanisms of NS are not well understood, genetic mapping studies suggest a multitude of unknown single-gene causes. We combined homozygosity mapping with whole-exome resequencing and identified an ARHGDIA mutation that causes SRNS. We demonstrated that ARHGDIA is in a complex with RHO GTPases and is prominently expressed in podocytes of rat glomeruli. ARHGDIA mutations (R120X and G173V) from individuals with SRNS abrogated interaction with RHO GTPases and increased active GTP-bound RAC1 and CDC42, but not RHOA, indicating that RAC1 and CDC42 are more relevant to the pathogenesis of this SRNS variant than RHOA. Moreover, the mutations enhanced migration of cultured human podocytes; however, enhanced migration was reversed by treatment with RAC1 inhibitors. The nephrotic phenotype was recapitulated in arhgdia-deficient zebrafish. RAC1 inhibitors were partially effective in ameliorating arhgdia-associated defects. These findings identify a single-gene cause of NS and reveal that RHO GTPase signaling is a pathogenic mediator of SRNS.ope

Reasons for new MIS. Let's be fair: iTIND, Urolift and Rezūm

Purpose!#!To review and discuss the literature regarding iTIND, Urolift and Rezūm and investigate the precise clinical indications of all three different approaches for their application in benign prostatic hyperplasia (BPH) treatment.!##!Materials and methods!#!The PubMed-Medline and Cochrane Library databases were screened to identify recent English literature relevant to iTIND, Urolift and Rezūm therapies. The surgical technique and clinical results for each approach were summarized narratively.!##!Results!#!iTIND, Urolift and Rezūm are safe and effective minimally invasive procedures for the symptomatic relief of lower urinary tract symptoms (LUTS) due to BPH. iTIND requires the results of ongoing prospective studies, a long-term follow-up and a comparison against a reference technique to confirm the generalizability of the first pivotal study. Urolift provides symptomatic relief but the improvements are inferior to TURP at 24 months and long-term retreatments have not been evaluated. Rezūm requires randomized controlled trials against a reference technique to confirm the first promising clinical results. However, clinical evidence from prospective clinical trials demonstrates the efficacy and safety of these procedures in patients with small- and medium-sized prostates.!##!Conclusions!#!Although iTIND, Urolift, and Rezūm cannot be applied to all bladder outlet obstruction (BOO) cases resulting from BPH, they provide a safe alternative for carefully selected patients who desire symptom relief and preservation of erectile and ejaculatory function without the potential morbidity of more invasive procedures

Robotic stone surgery - Current state and future prospects: A systematic review

Objective: To provide a comprehensive review of robot-assisted surgery in urolithiasis and to consider the future prospects of robotic approaches in stone surgery. Materials and methods: We performed a systematic PubMed© literature search using predefined Medical Subject Headings search terms to identify PubMed-listed clinical research studies on robotic stone surgery. All authors screened the results for eligibility and two independent reviewers performed the data extraction. Results: The most common approach in robotic stone surgery is a robot-assisted pyelolithotomy using the da Vinci™ system (Intuitive Surgical Inc., Sunnyvale, CA, USA). Several studies show this technique to be comparable to classic laparoscopic and open surgical interventions. One study that focused on ureteric stones showed a similar result. In recent years, promising data on robotic intrarenal surgery have been reported (Roboflex Avicenna™; Elmed Medical Systems, Ankara, Turkey). Initial studies have shown its feasibility and high stone-free rates and prove that this novel endoscopic approach is safe for the patient and comfortable for the surgeon. Conclusions: The benefits of robotic devices in stone surgery in existing endourological, laparoscopic, and open treatment strategies still need elucidation. Although recent data are promising, more prospective randomised controlled studies are necessary to clarify the impact of this technique on patient safety and stone-free rates. Keywords: Robotic stone surgery, Urolithiasis, Nephrolithiasis, Stone disease, Endourolog

Robotic waterjet wound debridement - Workflow adaption for clinical application and systematic evaluation of a novel technology.

OBJECTIVE:We evaluated the clinical potential of a novel robotic system for autonomous performance of waterjet wound debridement. SUMMARY BACKGROUND DATA:Within the last decade, waterjet wound debridement has proven to be a valid alternative to the conventional approach using sharp spoons and scalpel. METHODS:The DLR MIRO robot using the DLR MICA instrument for robotic surgery was adapted for actuation of an ERBEJET 2 flexible endoscopic waterjet probe. Waterjet debridement of various wound shapes and sizes using a porcine skin model was compared between this novel robotic system and a control group of human medical professionals with regard to wound area cleaned by the waterjet, off-target area, and procedural time. RESULTS:After the wound area was registered in the robotic system, it automatically generated a cleaning path and performed debridement based on generated surface model. While the robotic system demonstrated a significant advantage for the covered wound area (p = 0.031), the average off-target area was not significantly different from human controls. Human participants had high variability in cleaning quality across users and trials, while the robotic system provided stable results. Overall procedural time was significantly lower in trials performed by humans. CONCLUSIONS:Robotic waterjet wound debridement is a promising new technological approach compared to the current clinical standard of interventional wound therapy, providing higher efficiency and quality of wound cleaning compared to human performance. Additional trials on more complicated wound shapes and in vivo tissue are necessary to more thoroughly evaluate the clinical potential of this technology

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