Resolving the classification rates and molecular architecture of early-onset chronic kidney disease with NephVar

The risk of nephrotic range proteinuria and kidney failure in primary laminopathies is genotype-specific.

BACKGROUND Primary laminopathies are a heterogeneous group of rare diseases caused by nuclear lamina dysfunction due to pathogenic LMNA variants. However, despite their ubiquitous expression, LMNA variants have rarely been linked to chronic kidney disease (CKD). Here, we systematically investigate clinical implications and functional underpinnings of a distinct LMNA missense variant (lamin A/C p.(Arg349Trp)) that has sporadically been found in patients with a complex phenotype including lipodystrophy, proteinuria, and focal segmental glomerulosclerosis (FSGS). METHODS In clinical and functional terms, we compare lamin A/C Arg349Trp with missense changes at Arg482, the most common hotspot residue for type 2 familial partial lipodystrophy (FPLD2). In particular, we assess renal endpoints in corresponding patient cohorts and investigate disease-associated alterations in vitro. RESULTS In contrast to FPLD2 patients, individuals with lamin A/C Arg349Trp experience high-grade proteinuria and a rapid decline of glomerular filtration rate with kidney failure at a median age of 43 years. Mechanistically, we demonstrate that Arg349Trp associates with an abrogation of the structural interaction between lamin A/C and nucleoporin 155, nuclear pore complex aggregation, and an alteration of TGF-β1-dependent signaling. CONCLUSIONS While patients with Lamin A/C Arg482 missense changes are at very low risk for progressive CKD, patients harboring Arg349Trp show nephrotic range proteinuria and kidney failure in midlife. Hence, high-grade proteinuric kidney disease is genotype-specific and patients with the Arg349Trp substitution require early renoprotective intervention to potentially halt progression and prevent kidney failure. FUNDING German Research Foundation, project IDs 502928386, 445703531, and grants HA 9779/2-1, HA 6908/4-1, HA 6908/7-1, HA 6908/8-1, HA 6908/12-1.

Diagnosing Mendelian Kidney Disease: Hidden Niches in the (Kidney) Genome.

The ease of use of MPS increasingly tempts non-specialized genetic laboratories to perform broad analyses of numerous diseases, which in specific cases may worsen the quality of investigations, i.e. for the relatively frequent ADPKD.

[Clinicopathological and molecular features of acquired cystic kidney disease and associated renal cell carcinoma].

Metabolomics in renal cystic disease: links to mechanisms and identification of pathways for potential pre-diagnosis.

Polycystic kidney disease (PKD) is a common hereditary kidney disorder with an insidious onset and complex mechanisms, making early diagnosis challenging. Current diagnostic methods, including imaging and genetic testing, have limitations. Imaging detects cysts only once formed, and genetic testing is costly, labour-intensive, and unable to guarantee complete diagnostic accuracy or predict onset and progression. Metabolomics may offer an approach to uncover PKD mechanisms by detecting metabolic alterations that precede clinical manifestations, enabling identification of disease-specific biomarkers and providing earlier and more practical detection than imaging or genetic testing. This review synthesizes existing metabolomics studies of human PKD and renal cystic disease with significant metabolites extracted, and pathway enrichment analyses conducted at the levels of overall cystic kidney disease and the ADPKD/Pkd1/non-Pkd1 subsets to identify significant pathways and their associated metabolic features. Overall, the top-ranked pathways were arginine biosynthesis; alanine, aspartate and glutamate metabolism; glycine, serine and threonine metabolism, and the citrate cycle, with glycine, serine and threonine metabolism only associated with ADPKD/Pkd1 mouse models. These pathways indicate marked activation of amino acid metabolism accompanied by relative suppression of carbohydrate-related energy metabolism, suggesting a shift in metabolic substrate utilization rather than a complete loss of energy supply. This study provides a foundation for applying metabolomics to early diagnosis and mechanistic investigation of cystic kidney disease.

Precision Medicine in Pediatric Nephrology: From Shared Clinical Phenotypes to Genotype-Guided Diagnosis and Management

Pediatric nephrology is shifting from broad phenotype-based labels toward molecularly defined, genotype-guided diagnosis and management. Childhood kidney disorders are enriched for monogenic causes, yet persistent microscopic hematuria, bilateral kidney cysts, steroid-resistant nephrotic syndrome, and thrombotic microangiopathy may represent shared endpoints of biologically distinct mechanisms. Using these four scenarios, this narrative review illustrates how structured phenotyping, pedigree analysis, biochemical evaluation, and appropriately selected genomic testing can establish etiology, revise diagnoses, and guide clinical decision-making. Molecular diagnosis may support early nephroprotection, prevent ineffective immunosuppression, reveal tumor or extrarenal risks, enable mechanism-based therapy, and optimize transplantation planning. It also enables cascade testing, reproductive counseling, presymptomatic evaluation of relatives, and safer assessment of living-related donors. Genomic findings, however, require clinical context. Variants must be evaluated against gene–disease validity, inheritance, segregation, molecular mechanism, and phenotype, while variants of uncertain significance should not independently determine treatment or donor eligibility. Negative or inconclusive findings should prompt phenotypic reassessment, evaluation of analytical limitations, targeted studies, and periodic genomic reanalysis. Emerging genome and long-read sequencing, multiomics, artificial intelligence, and RNA-based therapeutics may further expand precision care, but rigorous interpretation, equitable access, appropriate counseling, and multidisciplinary collaboration remain essential. Precision nephrology derives value not from identifying variants alone, but from converting molecular etiology into safer, anticipatory, and individualized care.

Modeling Complex Developmental Disease: The Case of Polycystic Kidney Disease

Underused Drosophila melanogaster offers high genomic and pathway conservation, a wealth of genetic tools, and rapid generation times, making it a reliable and sustainable model for mechanistic, genome-wide, and precision medicine studies.