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Alport syndrome (AS) is the most frequent monogenic inherited glomerulopathy and is also genetically and clinically heterogeneous. It is caused by semi-dominant pathogenic variants in the X-linked COL4A5 (NM_000495.5) gene or recessive variants in the COL4A3/COL4A4 (NM_000091.4/NM_000092.4) genes. The disease manifests in early childhood with persistent microhematuria and can progress to proteinuria and kidney failure in adolescence or early adulthood if left untreated. On biopsy, pathognomonic features include alternate thinning, thickening and lamellation of the glomerular basement membrane (GBM), in the presence of podocyte foot process effacement. Although previous studies indicate a prevalence of AS of about 1/50,000, a recent publication reported a predicted rate of pathogenic COL4A5 variants of 1/2320. We herewith present 98 patients (40 M/58 F) from 26 Greek families. We are selectively presenting the families segregating the X-linked form of AS with pathogenic variants in the COL4A5 gene. We found 21 different pathogenic variants, 12 novel: eight glycine and one proline substitutions in the collagenous domain, one cysteine substitution in the NC1 domain, two premature termination of translation codons, three splicing variants, one 5-bp insertion/frameshift variant, one indel-frameshift variant and four gross deletions. Notably, patients in six families we describe here and three families we reported previously, carried the COL4A5-p.G624D substitution, a founder defect encountered all over Europe which is hypomorphic with mostly milder symptomatology. Importantly, on several occasions, the correct genetic diagnosis reclassified patients as patients with AS, leading to termination of previous immunosuppressive/cyclosporine A therapy and a switch to angiotensin converting enzyme inhibitors (ACEi). With the understanding that all 98 patients span a wide range of ages from infancy to late adulthood, 15 patients (11 M/4 F) reached kidney failure and 11 (10 M/1 F) received a transplant. The prospects of avoiding lengthy diagnostic investigations and erroneous medications, and the advantage of delaying kidney failure with very early administration of renin-angiotensin-aldosterone system (RAAS) blockade, highlights the importance of timely documentation of AS by genetic diagnosis.

Familial microscopic hematuria (FMH) is associated with a genetically heterogeneous group of conditions including the collagen-IV nephropathies, the heritable C3/CFHR5 nephropathy and the glomerulopathy with fibronectin deposits. The clinical course varies widely, ranging from isolated benign familial hematuria to end-stage renal disease (ESRD) later in life. We investigated 24 families using next generation sequencing (NGS) for 5 genes: COL4A3, COL4A4, COL4A5, CFHR5 and FN1. In 17 families (71%), we found 15 pathogenic mutations in COL4A3/A4/A5, 9 of them novel. In 5 families patients inherited classical AS with hemizygous X-linked COL4A5 mutations. Even more patients developed later-onset Alport-related nephropathy having inherited heterozygous COL4A3/A4 mutations that cause thin basement membranes. Amongst 62 heterozygous or hemizygous patients, 8 (13%) reached ESRD, while 25% of patients with heterozygous COL4A3/A4 mutations, aged >50-years, reached ESRD. In conclusion, COL4A mutations comprise a frequent cause of FMH. Heterozygous COL4A3/A4 mutations predispose to renal function impairment, supporting that thin basement membrane nephropathy is not always benign. The molecular diagnosis is essential for differentiating the X-linked from the autosomal recessive and dominant inheritance. Finally, NGS technology is established as the gold standard for the diagnosis of FMH and associated collagen-IV glomerulopathies, frequently averting the need for invasive renal biopsies.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II (AT II) receptor blockers (ARBs) are widely used antihypertensives with well-recognized renoprotective and cardioprotective effects. Although treatment with these agents generally does not result in adverse metabolic consequences, their use during human pregnancy has been associated with negative reactions. Here we report a premature baby with a history of oligohydramnios and maternal exposure to the ARB olmesartan medoxomil who was transferred to our institution with acute renal failure. Conservative treatment with diuretics and meticulous management of fluids and electrolytes resulted in an improvement in renal function in the patient. We conclude that olmesartan medoxomil may cause reversible renal failure in premature neonates.

Henoch-Schonlein purpura glomerulonephritis (HSP-GN) is a common form of systemic small vessel vasculitis in children. Although prognosis is usually favourable, the disease is occasionally associated with a risk of renal insufficiency. Various immunosuppressive agents have been used in patients with severe HSP-GN, but none have shown convincing favourable effects. We report a case of biopsy-proven HSP-related GN in a 4-year-old girl that responded remarkably well to cyclosporine A (CsA), following failure to respond to other immunosuppressive agents. At 8 months post-CsA treatment, repeat renal biopsy findings were consistent with histological improvement. We conclude that CsA treatment not only exerts beneficial effects on resistant HSP-related GN but may also arrest progression of the disease.

To investigate clinically and genetically all the distal renal tubular acidosis (dRTA) cases in Cyprus, to study one more family from Greece and to perform the first dRTA prenatal diagnosis. We also tried to find any association with sensorineural hearing loss (SNHL) onset and particular mutations.Nine dRTA families from Cyprus and one from Greece were analyzed for mutations in ATP6V1B1 gene by DNA resequencing and PCR-RFLPs. Clinical diagnosis was performed by standard criteria. Prenatal diagnosis was performed for one Cypriot family.Results show that 7/9 dRTA cases in Cyprus are caused by 229+1GT and R157C founder mutations in ATP6V1B1 gene. 229+1GT mutation was estimated to be older than 400 years. No genotype- phenotype correlation was found with SNHL. A known (L81P) and a novel mutation (912delT) were found in the Greek family. Prenatal diagnosis was performed for one Cypriot family, after parents' demand, showing that the embryo was a heterozygous carrier.Existence of only two ATP6V1B1 mutations in the Cypriot population is a diagnostic advantage. The age of onset of SNHL varies in our patients and probably is not related to ATP6V1B1 genotypes. Effective therapy for most of the syndrome symptoms is not satisfactory for some parents who choose prenatal diagnosis to ensure their child's health.