Clinical and histopathological characteristics of COL4A3 c.2881+1G>A variant causing Alport spectrum disorders in Croatian population

Abstract

Alport syndrome (AS) and thin basement membrane nephropathy (TBMN) are part of the spectrum of kidney disorders caused by pathogenic variants in α3, α4, or α5 chains of the collagen type IV, the major structural component of the glomerular basement membrane (GBM). Using targeted next-generation sequencing (NGS), 34 AS/TBMN patients (58.8% male) from 12 unrelated families were found positive for heterozygous c.2881+1G>A variant of the COL4A3gene, that is considered disease-causing. All patients were from the continental or island part of Croatia. Clinical, laboratory, and histopathological data collected from the medical records were analyzed and compared to understand the clinical course and prognosis of the affected patients. At the time of biopsy or first clinical evaluation, the mean age was 31 years (median: 35 years; range: 1 - 72 years). Hematuria was present in 33 patients (97.1%) and 19 (55.9%) patients had proteinuria. There were 6 (17.6%) patients with hearing loss, 4 (11.8%) with ocular lesions, and 11 (32.4%) with hypertension. Twenty-three (67.6%) patients had proteinuria at follow-up, and 5 (14.7%) patients with the median age of 48 years (range: 27-55) progressed to kidney failure, started dialysis, or underwent kidney transplantation. Of the 13 patients who underwent kidney biopsy, 4 (30.8%) developed focal segmental glomerulosclerosis (FSGS), and 8 (66.7%) showed lamellation of the GBM, including all patients with FSGS. It is essential to conduct a detailed analysis of each collagen type IV genetic variant to optimize the prognosis and therapeutic approach for affected patients.

Figure 1.

Proteinuria and changes of the CKD stage between the time of diagnosis and an adverse outcome or the last follow-up. All patients with a deterioration of the CKD stage had proteinuria (P = 0.012 between patients with proteinuria and without proteinuria, Fisher’s exact test). CKD: chronic kidney disease

Figure 2.

Renal survival time in relation to proteinuria at diagnosis or follow-up. The Kaplan–Meier method and the log-rank statistic for time to an adverse event (onset of KF, dialysis, or kidney transplantation) showed no statistically significant association with proteinuria at the time of diagnosis (A) or the last follow-up (B). KF: kidney failure.

Figure 3.

Kidney biopsy specimen of patient D04 on light microscopy. Perihilar focal segmental glomerulosclerosis (black arrow) in one glomerulus. Other 18 glomeruli were enlarged and without other morphological changes. There was no interstitial fibrosis or tubular atrophy. Arteries and arterioles had normal morphology. PAS stain, original magnification ×400.

Figure 4.

Kidney biopsy specimen of patient J03 on electron microscopy. Thinning of glomerular basement membrane (arrowhead) with focal lamellation (arrow). Transmission electron microscopy, original magnification ×15.000.

Figure 5.

Family pedigree of family D. The affected heterozygous members are marked with black half and probands are marked with an arrow. We had no data for the eldest family members. All patients had hematuria (D02 had macrohematuria) and all except D02 had proteinuria. D04 had maintained renal function (CKD stage 1), D02 had CKD stage 2, D06 and D07 had CKD stage 3b, and D11 had kidney failure (CKD stage 5). Patients D04, D06, D07, and D11 had hearing loss, whereas D06 and D11 had ocular abnormalities and hypertension. Patient D04 was diagnosed with Alport syndrome with lamellation on electron microscopy and focal segmental glomerulosclerosis on light microscopy. Patient D07 was diagnosed with thin basement membrane nephropathy and focal segmental glomerulosclerosis with only discrete focal lamellation found on electron microscopy.

Figure 6.

Family pedigree of family K. The affected heterozygous members are marked with black half and probands are marked with an arrow. We had no data for the eldest family members. All patients had hematuria (K05 had macrohematuria) whereas K02, K05, K06, and K07 had proteinuria. Patient K02 had CKD stage 2 whereas others had maintained renal function (CKD stage 1). None had hearing or ocular abnormalities. Patients K02, K05, and K06 had hypertension. Patient K01 was diagnosed with thin basement membrane nephropathy with only discrete focal lamellation on electron microscopy.