Marion Vallet

Urinary ammonia and long-term outcomes in chronic kidney disease

Recent studies suggest that alkalinizing treatments improve the course of chronic kidney disease (CKD), even in patients without overt metabolic acidosis. Here, we tested whether a decreased ability in excreting urinary acid rather than overt metabolic acidosis may be deleterious to the course of CKD. We studied the associations between baseline venous total CO2 concentration or urinary ammonia excretion and long-term CKD outcomes in 1065 patients of the NephroTest cohort with CKD stages 1-4. All patients had measured glomerular filtration rate (mGFR) by (51)Cr-EDTA renal clearance. Median mGFR at baseline was 37.6 ml/min per 1.73 m(2). Urinary ammonia excretion decreased with GFR, whereas net endogenous acid production did not. After a median follow-up of 4.3 years, 201 patients reached end-stage renal disease (ESRD) and 114 died before ESRD. Twenty-six percent of the patients had mGFR decline rate greater than 10% per year. Compared with patients in the highest tertile of urinary ammonia excretion, those in the lowest tertile had a significantly increased hazard ratio for ESRD, 1.82 (95% CI, 1.06-3.13), and a higher odds ratio of fast mGFR decline, 1.84 (0.98-3.48), independent of mGFR and other confounders. Patients in the lowest tertile of venous total CO2 had significantly increased risk of fast mGFR decline but not of ESRD. None of these biomarkers was associated with mortality. Thus, these results suggest that the inability to excrete the daily acid load is deleterious to renal outcomes.

Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis: Phenotype–Genotype Correlation and Outcome in 32 Patients with CLDN16 or CLDN19 Mutations

BACKGROUND AND OBJECTIVES Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is a rare autosomal recessive renal tubular disease. It is caused by mutations in CLDN16 and CLDN19, encoding claudin-16 and -19, respectively. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is usually complicated by progressive CKD. The objectives of this study were to describe the clinical and genetic features of familial hypomagnesemia with hypercalciuria and nephrocalcinosis and analyze phenotype-genotype associations in patients with CLDN16 or CLDN19 mutations. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Data from 32 genetically confirmed patients (9 patients with CLDN16 and 23 patients with CLDN19 mutations) from 26 unrelated families were retrospectively reviewed. RESULTS Diagnosis was based on clinical criteria at a median age of 9.5 years and confirmed by genetic testing at a median age of 15.5 years. In total, 13 CLDN16 or CLDN19 mutations were identified, including 8 novel mutations. A founder effect was detected for the recurrent CLDN16 p.Ala139Val mutation in North African families and the CLDN19 p.Gly20Asp mutation in Spanish and French families. CKD was more frequently observed in patients with CLDN19 mutations: survival without CKD or ESRD was 56% at 20 years of age in CLDN19 versus 100% in CLDN16 mutations (log rank P<0.01). Ocular abnormalities were observed in 91% of patients with CLDN19 mutations and none of the patients with CLDN16 mutations (P<0.01). Treatments seem to have no effect on hypercalciuria and CKD progression. CONCLUSIONS Patients with CLDN19 mutations may display more severe renal impairment than patients with CLDN16 mutations. Ocular abnormalities were observed only in patients with CLDN19 mutations.

Indomethacin, Amiloride, or Eplerenone for Treating Hypokalemia in Gitelman Syndrome

Patients with Gitelman syndrome (GS), an inherited salt-losing tubulopathy, are usually treated with potassium-sparing diuretics or nonsteroidal anti-inflammatory drugs and oral potassium and magnesium supplementations. However, evidence supporting these treatment options is limited to case series studies. We designed an open-label, randomized, crossover study with blind end point evaluation to compare the efficacy and safety of 6-week treatments with one time daily 75 mg slow-release indomethacin, 150 mg eplerenone, or 20 mg amiloride added to constant potassium and magnesium supplementation in 30 patients with GS (individual participation: 48 weeks). Baseline plasma potassium concentration was 2.8±0.4 mmol/L and increased by 0.38 mmol/L (95% confidence interval [95% CI], 0.23 to 0.53; P<0.001) with indomethacin, 0.15 mmol/L (95% CI, 0.02 to 0.29; P=0.03) with eplerenone, and 0.19 mmol/L (95% CI, 0.05 to 0.33; P<0.01) with amiloride. Fifteen patients became normokalemic: six with indomethacin, three with eplerenone, and six with amiloride. Indomethacin significantly reduced eGFR and plasma renin concentration. Eplerenone and amiloride each increased plasma aldosterone by 3-fold and renin concentration slightly but did not significantly change eGFR. BP did not significantly change. Eight patients discontinued treatment early because of gastrointestinal intolerance to indomethacin (six patients) and hypotension with eplerenone (two patients). In conclusion, each drug increases plasma potassium concentration in patients with GS. Indomethacin was the most effective but can cause gastrointestinal intolerance and decreased eGFR. Amiloride and eplerenone have similar but lower efficacies and increase sodium depletion. The benefit/risk ratio of each drug should be carefully evaluated for each patient.

Four Cases of Hypovolemic Renin-Aldosterone Axis Deficiency Without Hyperkalemia Following Unilateral Adrenalectomy for Primary Aldosteronism

ABSTRACT Objective: Hyperkalemia can occur following unilateral adrenalectomy for primary aldosteronism due to hypoaldosteronism. We hereby report the cases of 4 male patients exhibiting prolonged failure of the renin-aldosterone (RA) axis in association with normal-to-high kalemia or labile blood pressure and, most significantly, a decrease in extracellular fluid volume (ECFV). Methods: Prior to surgery, all patients exhibited hypokalemic hypertension, with documented primary aldosteronism. Within a few weeks of undergoing unilateral adrenalectomy, the patients developed either mild hyperkalemia or labile blood pressure. Complementary investigations revealed a decrease in measured ECFV with inappropriate normal renal sodium excretion, low supine plasma renin activity, and insufficient orthostatic-related aldosterone production. The adrenocorticotropic hormone (ACTH) stimulation test demonstrated no glucocorticoid deficiency, along with responsive aldosterone secretion. Results: The discrepancy between th...

A pseudo-dominant form of Gitelman’s syndrome

Gitelman’s syndrome is an autosomal recessive salt losing nephropathy caused by inactivated mutations of the SLC12A3 gene, encoding the NaCl cotransporter of the distal convoluted tubule. We report a French family with five affected members over two generations suggesting a dominant transmission. After SLC12A3 sequencing of seven individuals, four mutations were detected. Pseudo-dominant transmission was explained by the union of a compound heterozygous woman (two mutations on one allele and one mutation on the other) with a heterozygous healthy man. This study shows the importance of complete genetic analysis of families with unusual presentation.

Diminished bone resorption in overweight/obese women despite vitamin D insufficiency

Joint Bone Spine - In Press.Proof corrected by the author Available online since lundi 25 avril 2016

24 hours calciuria: normal values, regulations: about a cohort of 317 control subjects

In a control population, we filed the 24-hour urinary calcium to set normal values, based on weight, BMI and menopause. By assessing calcium intake, 25OHD, PTH, CTX, GFR, we wanted to study how these could influence calcium excretion. A total of 317 subjects of 55.82 ± 12.6 years were studied: 249 women (210 were postmenopausal) and 66 men. Mean urinary calcium 24h was 4.07 ± 2.53 mmol: 3.99 ± 2.89 in men, 3.54 ± 2.44 in premenopausal women, 4.18 ± 2.42 in postmenopausal women. 24-hour urine calcium was lower in overweight subjects whether they are men or women. It was positively correlated to 25OHD, CTX, GFR, serum calcium and negatively to PTH, BMI and weight. In conclusion, urinary calcium was lower in overweight subjects, it increases after menopause. Dietary calcium intake seems little involved in explaining variations in urinary calcium which depends essentially on bone remodeling (CTX), GFR, levels of vitamin D and PTH.