Clinical phenotype of familial hypertensive nephropathy

Technical Summary: Clinical Phenotype of Familial Hypertensive Nephropathy in Turkish Cypriot Families

Problem Statement
Chronic kidney disease (CKD) and end-stage kidney disease (ESKD) are significantly more prevalent in Cyprus and the Eastern Mediterranean compared to Northern Europe. While familial kidney disease in this region is often associated with autosomal dominant (AD) variants in the COL4A3 and COL4A4 genes (causing Alport spectrum nephropathy characterized by microscopic hematuria and thin glomerular basement membranes), a substantial proportion of affected families lack identifiable pathogenic variants in these or other known Mendelian glomerulopathy genes. Previous investigations suggested that some of these "genetic-negative" families present with a phenotype resembling "hypertensive nephropathy" or tubular disease rather than classic glomerular pathology, but the clinical characteristics and natural history of this specific cohort remained undefined.

Methodology
This retrospective study analyzed the natural history of progressive kidney disease in Turkish Cypriot families. The study population consisted of 20 families (10 with the COL4A4 variant p.G545A and 10 with the p.G999E variant) selected from a larger cohort of 118 investigated families. These 20 families were chosen because they exhibited an AD inheritance pattern, contained at least six clinically affected members, and lacked pathogenic variants in COL4A3, COL4A4, or other Mendelian glomerulopathy genes (e.g., INF2, PAX2).

• Data Collection: Hospital records were reviewed (January 2024–May 2026), and family trees were constructed based on data accumulated since 2009. A total of 581 family members were recorded, with 215 showing evidence of CKD (Stages 1–5).
• Genetic Analysis: DNA was extracted and analyzed via Whole Exome Sequencing (WES) or Next Generation Sequencing (NGS) using a 5-gene panel (COL4A3, COL4A4, COL4A5, CFHR5, FN1). Specific real-time PCR was used to screen for the p.G545A and p.G999E variants.
• Clinical Assessment: Patients underwent urinalysis (microscopic hematuria, proteinuria via 24-hour collection or creatinine ratios), renal function evaluation (eGFR via MDRD formula), and blood pressure monitoring.
• Histology: Eleven kidney biopsies were performed across 10 families, examined via light microscopy and immunofluorescence; electron microscopy was available for only one case.
• Statistical Analysis: Age of onset for CKD Stage 3 and ESKD, and the percentage of patients reaching ESKD after age 50, were compared using t-tests.

Key Results
The study found that families with the p.G545A and p.G999E variants presented with an identical clinical phenotype, which the authors characterize as familial hypertensive nephropathy.

• Clinical Presentation: The earliest feature was microscopic hematuria, detected at least once in 76% of affected members. Proteinuria was notably absent or mild (<1 g/day) until the glomerular filtration rate (GFR) dropped below 30 ml/min. Mildly raised blood pressure was universal by CKD Stage 3 but was easily controlled.
• Disease Progression: Among affected members over 50 years of age, 24.1% progressed to ESKD. The median age of reaching ESKD was 62.8 years (range 36–86).
• Histological Findings: Biopsies (n=11) predominantly showed secondary focal and segmental glomerulosclerosis (2o FSGS) or hypertensive nephropathy. Key features included a high degree of global glomerulosclerosis (median 49%) relative to interstitial fibrosis and tubular atrophy, with vascular pathology affecting arterioles. Segmental sclerosis was less conspicuous.
• Genetic Context: Despite the presence of COL4A4 variants (p.G545A and p.G999E) in the studied groups, these variants are common in the general population (gnomAD frequencies of 0.0817 and 0.012, respectively) and are currently classified as benign by ACMG guidelines, though in silico tools predict deleterious effects. Families without these specific variants exhibited identical clinical phenotypes.

Significance and Claims
The paper claims that this specific cohort of Turkish Cypriot families presents with a clinical phenotype best characterized as familial hypertensive nephropathy, distinct from the classic glomerular presentation of Alport syndrome.

• Phenotypic Expansion: The authors propose that "hematuric nephropathy" in this population extends beyond the glomerular basement membrane (GBM) to include a tubular phenotype. They suggest that the pathology involves the distal renal tubule, where collagen IV chains are also expressed, leading to widespread tubular atrophy and interstitial fibrosis before significant proteinuria or glomerular sclerosis occurs.
• Epidemiological Impact: The study posits that this condition accounts for the disproportionately high incidence of ESKD in the Eastern Mediterranean, particularly in individuals over 65 years of age. Data indicates that the excess renal failure in Cyprus compared to the UK is driven almost entirely by the higher incidence in the >60 and >75 age groups.
• Genetic Mystery: The authors acknowledge that the precise monogenetic cause remains unknown. While they hypothesize a link to COL4A3/4/5 variants (potentially involving non-coding regions, copy number variations, or regulatory factors like LMX1B or PXDN), they note that current genetic testing has not identified a definitive pathogenic variant in the majority of these families.

In conclusion, the paper argues that what is clinically diagnosed as "hypertensive nephropathy" in this demographic may actually be a genetic disorder with a tubular-predominant presentation, contributing significantly to the regional burden of kidney failure.