To evaluate the role of calcium and the parathyroid gland in the pathophysiology of essential hypertension, creatinine clearance, urinary excretion of sodium, calcium and nephrogenous cyclic adenosine monophosphate (NcAMP) and serum parathyroid hormone (PTH) levels were measured in 25 newly diagnosed essentially hypertensive patients before institution of any treatment and in 25 age- and sex-matched normal volunteers. While no significant differences in creatinine clearance, serum total calcium levels or 24-hour sodium excretion existed between the two groups, hypertensives had a higher mean ( ± SD) 24-hour calcium excretion rate (199.0 ± 44.7 vs. 152.8 ± 33.6 mg, p < 0.001), a higher mean NcAMP excretion rate (2.54 ± 0.8 vs. 1.87 ± 0.5 nmol/l00 ml glomerular filtrate, p < 0.001) and a higher mean serum PTH concentration (1.87 ± 0.6 vs. 1.53 ± 0.4 ng/ml, p < 0.001) than the normotensives. A significant positive correlation existed between calcium and sodium excretion in both hypertensives (r=0.66, p < 0.001)) and normotensives (r = 0.67, p < 0.001), but given the same levels of creatinine clearance and sodium excretion, hypertensives excreted more calcium than normotensives (p < 0.001)). In both hypertensives and normotensives, serum PTH levels were positively correlated with NcAMP excretion (r = 0.42, p < 0.05, and r = 0.41, p < 0.05, respectively) and the ratio of urinary sodium to urinary calcium excretion (r = 0.59, p < 0.001, and r = 0.75, p < 0.001), respectively). The above results suggest that in essential hypertension, increased activity of parathyroid glands may occur as a consequence of increased urinary calcium losses which are presumably due to an intrinsic defect in renal calcium handling.
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.
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