C1q nephropathy in association with Gitelman syndrome: a case report

Abstract

There have been rare reports of glomerulopathies developing in patients with Bartter syndrome (BS) and its milder variant, Gitelman syndrome (GS). We present the first case of C1q nephropathy (C1qN) in an African American child with GS. This child was diagnosed with GS at 9 years of age and subsequently developed nephrotic range proteinuria 3 years later. Renal biopsy revealed mesangial hypercellularity and focal segmental glomerulosclerosis (FSGS). The segmental lesions were generally located at the vascular pole. Dominant C1q (2+) staining along with IgG (1-2+) was demonstrated in the mesangium, which correlated with scattered electron dense mesangial deposits demonstrated by electron microscopy. Treatment with an angiotensin-converting enzyme inhibitor led to an improvement in proteinuria to near-normal values (urine protein/creatinine ratio down to 0.5), but the creatinine clearance declined to approximately 58 ml/min/1.73 m(2). This case highlights the possible association between the milder hypokalemic tubulopathy, GS, and glomerular disease, including C1qN. Prompt evaluation of proteinuria with renal biopsy in these patients is recommended to detect significant glomerular pathology. Further research is needed to define risk factors for this complication.

Clinical and Genetic Spectrum of Bartter Syndrome Type 3

“…Three out of other five, classified as VOUS, were expressed in X. 15 laevis oocytes (p.Arg395Trp, p.Ala469Pro, and p.Gly345Ser) as were two previously 16 described mutations (p.Gly424Arg and p.Gly433Glu) detected as the only heterozygous 17 mutation in two patients. All these mutations significantly decreased chloride conductance.…”

“…Among these changes, only the p.Arg395Trp has been described in databases 19 (rs34255952) with an allelic frequency of 2% in African Americans and has not been detected 20 in European Americans. Of the 33 missense mutations detected in our population, 13 were 21 previously shown to result in loss of function 16 . In silico predictions are presented in Table 2 summarizes clinical and biochemical characteristics at birth and at diagnosis.…”

“…Defective basolateral Cl -exit in the DCT decreases NaCl reabsorption via 15 the Na-Cl cotransporter (NCC), accounting for the GLS phenotype in other patients. Two 16 recent studies in which the mouse Clcnk2 gene (corresponding to CLCNKB in humans) was 17 disrupted confirmed that ClC-K2 is the principal chloride channel in all three nephron 18 segments and that TAL impairment is not compensated by ClC-K1 (corresponding to the 19 human ClC-Ka channel, which is also expressed in the TAL) 27,28 . Nevertheless, it cannot be 20 excluded that allelic variants of genes encoding KCl cotransporters or other chloride channels 21 may also compensate for renal sodium loss accounting for phenotypic variability 27, 29 .…”

“…15 Nine of the 10 mutations expressed in vitro decreased or abolished chloride conductance. 16 Severe (large deletions, frameshift, nonsense, and essential splicing) and missense mutations 17 resulting in poor residual conductance were associated with younger age at diagnosis. 18 Electrolyte supplements and indomethacin were frequently used to induce catch-up growth 19 with few adverse effects.…”

“…Median follow-up was eight years and was similar in the three groups. The main 15 treatments administered to these patients were NaCl and KCl supplementation and non- 16 steroidal anti-inflammatory drugs (NSAIDs, mainly indomethacin). The main adverse effects 17 were abdominal pain (n=5), weight gain (n=1), esophagitis (n=1), and diarrhea (n=1).…”