Is there a dominant-negative effect in individuals with heterozygous disease-causing variants in COL4A3/COL4A4?

Alport syndrome (AS) shows a broad phenotypic spectrum ranging from isolated microscopic hematuria (MH) to end-stage kidney disease (ESKD). Monoallelic disease-causing variants in COL4A3/COL4A4 have been associated with autosomal dominant AS (ADAS) and biallelic variants with autosomal recessive AS (ARAS). The aim of this study was to analyze clinical and genetic data regarding a possible genotype-phenotype correlation in individuals with disease-causing variants in COL4A3/COL4A4. Eighty-nine individuals carrying at least one COL4A3/COL4A4 variant classified as (likely) pathogenic according to the American College of Medical Genetics guidelines and current amendments were recruited. Clinical data concerning the prevalence and age of first reported manifestation of MH, proteinuria, ESKD, and extrarenal manifestations were collected. Individuals with monoallelic non-truncating variants reported a significantly higher prevalence and earlier diagnosis of MH and proteinuria than individuals with monoallelic truncating variants. Individuals with biallelic variants were more severely affected than those with monoallelic variants. Those with biallelic truncating variants were more severely affected than those with compound heterozygous non-truncating/truncating variants or individuals with biallelic non-truncating variants. In this study an association of heterozygous non-truncating COL4A3/COL4A4 variants with a more severe phenotype in comparison to truncating variants could be shown indicating a potential dominant-negative effect as an explanation for this observation. The results for individuals with ARAS support the, still scarce, data in the literature.

Structures, Organization, and Delivery of Kidney Care to Children Living in Low-Resource Settings.

Introduction: There is a disparity in the availability of health care for children in resource-constrained countries. The International Pediatric Nephrology Association (IPNA) commissioned an initiative exploring the challenges in the care of children with kidney disease in low- or middle-income countries (LMICs) with a focus on human, diagnostic, and therapeutic resources. Methods: A survey was sent by e-mail to all members of IPNA and its affiliated regional or national societies residing in LMICs. Data were extracted from individual responses after merging duplicate data. Descriptive analysis was done using Microsoft Excel. Results: Responses were obtained from 245 centers across 62 countries representing 88% of the LMIC pediatric population. Regional disparity in the availability of basic diagnostic and therapeutic resources was noted. Even when resources were available, they were not accessible or affordable in 15% to 20% of centers. Acute and chronic dialysis were available in 85% and 75% of centers respectively. Lack of trained nurses, pediatric-specific supplies, and high costs were barriers to providing dialysis in these regions. Kidney transplantation was available in 32% of centers, with the cost of transplantation and lack of surgical expertise reported as barriers. About 65% of centers reported that families with chronic disease opted to discontinue care, with financial burden as the most common reason cited. Conclusion: The survey highlights the existing gaps in workforce, diagnostic, and therapeutic resources for pediatric kidney care in resource-constrained regions. We need to strengthen the health care workforce, address disparities in health care resources and funding, and advocate for equitable access to medications, and kidney replacement therapy (KRT).

Diversity of kidney care referral pathways in national child health systems of 48 European countries.

Background: Primary, secondary and tertiary healthcare services in Europe create complex networks covering pediatric subspecialties, sociology, economics and politics. Two surveys of the European Society for Paediatric Nephrology (ESPN) in 1998 and 2017 revealed substantial disparities of kidney care among European countries. The purpose of the third ESPN survey is to further identify national differences in the conceptualization and organization of European pediatric kidney health care pathways during and outside normal working hours. Methods: In 2020, a questionnaire was sent to one leading pediatric nephrologist from 48 of 53 European countries as defined by the World Health Organization. In order to exemplify care pathways in pediatric primary care nephrology, urinary tract infection (UTI) was chosen. Steroid sensitive nephrotic syndrome (SSNS) was chosen for pediatric rare disease nephrology and acute kidney injury (AKI) was analyzed for pediatric emergency nephrology. Results: The care pathways for European children and young people with urinary tract infections were variable and differed during standard working hours and also during night-time and weekends. During daytime, UTI care pathways included six different types of care givers. There was a shift from primary care services outside standard working hours to general outpatient polyclinic and hospital services. Children with SNSS were followed up by pediatric nephrologists in hospitals in 69% of countries. Patients presenting with community acquired AKI were admitted during regular working hours to secondary or tertiary care hospitals. During nights and weekends, an immediate shift to University Children's Hospitals was observed where treatment was started by intensive care pediatricians and pediatric nephrologists. Conclusion: Gaps and fragmentation of pediatric health services may lead to the risk of delayed or inadequate referral of European children with kidney disease to pediatric nephrologists. The diversity of patient pathways outside of normal working hours was identified as one of the major weaknesses in the service chain.