Alteration of the maximal renal water excretion capacity with kidney function and age in human.

PURPOSE: The kidney's capability to concentrate and dilute urine is crucial to maintaining body fluid compartments and plasma osmolality. Advanced age and chronic kidney disease (CKD) result in decreased maximal urine concentration. Less is known regarding urine dilution ability. The primary purpose of this study was to determine the relationship between maximal renal water excretion and renal function, age, and gender in humans. METHODS: This monocentric retrospective study includes patients referred to the Department of Clinical Physiology in Toulouse University Hospital to measure the glomerular filtration rate (mGFR) between April 2013 and February 2018. mGFR was assessed using inulin renal clearance and required ample hydration. We quantified the effects of age, gender and mGFR have on water excretion ability, which was assessed by minimal urinary osmolality (minUosm) and maximal free water clearance (maxCH2O). RESULTS: 666 patients were included (mean age 51 ± 14 years, 53% female). Mean mGFR was 82 ± 25 mL/min/1.73m2. MinUosm after hydration was higher in patients with renal insufficiency while maxCH2O was markedly lower. Age was also, with a weaker effect, associated with decreased in water excretion, independently of mGFR. MaxCH2O clearance was similar in both genders, whereas minUosm was lower in women, possibly resulting from a lower osmotic load. DISCUSSION: This study shows a decrease in maximal urinary dilution capacity and free water clearance with CKD and age, without gender difference. These alterations are mild but must be considered when a significant water intake is required or in the case of hyponatremia.

[Kidney failure after liver transplantation]. / Insuffisance rénale après transplantation hépatique.

One third of cirrhotic patients present impaired kidney function. It has multifactorial causes and has a harmful effect on patients' morbi-mortality before and after liver transplant. Kidney function does not improve in all patients after liver transplantation and liver-transplant recipients are at high risk of developing chronic kidney disease. Causes for renal dysfunction can be divided in three groups: preoperative, peroperative and postoperative factors. To date, there is no consensus for the modality of evaluation the risk for chronic kidney disease after liver transplantation, and for its prevention. In the present review, we describe the outcome of kidney function after liver transplantation, and the prognostic factors of chronic kidney disease to determine a risk stratification for each patient. Furthermore, we discuss therapeutic options to prevent kidney dysfunction in this setting, and highlight the indications of combined liver-kidney transplantation.

Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA.

BACKGROUND: Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown. METHODS: We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport. RESULTS: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF), and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. CONCLUSION: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.

Impact of menopausal status on kidney adaptation after unilateral nephrectomy for kidney donation in women.

INTRODUCTION: Although living kidney donation is not a high-risk surgery, there is still a need to identify situations at risk of kidney disease after uninephrectomy. Estrogens exhibit a protective role against various nephropathies. The aim of this study was to assess renal adaptation following nephrectomy according to menopausal status in women. METHODS: A prospective bicentric study including living women donors measured glomerular filtration rate (GFR) (inulin or 51-Cr-EDTA clearances) and kidney volume (using CT-scan and 3-dimensional reconstruction), before and after 1-year post-uninephrectomy. Renal adaptation was compared according to menopausal status. RESULTS: Sixteen non-menopausal women and 18 menopausal women were included. One year following uninephrectomy, the mean decrease in GFR (global population) was - 32 ± 12 ml/min/1.73 m2, and the mean increase in remnant kidney volume was + 32 ± 13 cm3/1.73 m2. No significant difference was observed between the two groups for both the decrease in GFR (-32.9 ± 13.3 in non-menopausal vs - 31.5 ± 9.9 in menopausal, ml/min/1.73 m2, p = 0.84), and the increase in kidney volume (+ 36.1 ± 13.4 in non-menopausal vs + 28.1 ± 12.5 in menopausal, cm3/1.73 m2, p = 0.09). DISCUSSION: Menopausal status did not influence kidney adaptation following uninephrectomy, and in this respect is not a potential limiting factor for living kidney donation.

Urine osmolality predicts calcium-oxalate crystallization risk in patients with recurrent urolithiasis.

Our aim was to investigate the validity of osmolality from 24-h urine collection in examining the risk for calcium-oxalate (CaOx) kidney stone formation in patients with recurrent urolithiasis. Three hundred and twelve subjects (males/females: 184/128) from France with a history of recurrent kidney stones from confirmed or putative CaOx origin were retrospectively included in the study (46 ± 14 years, BMI: 25.3 ± 5.0 kg·m-2). Tiselius' crystallization risk index (CRI) was calculated based on urinary calcium, oxalate, citrate, magnesium, and volume from 24-h samples. The diagnostic ability of 24-h urine osmolality to classify patients as high risk for kidney stone crystallization was examined through the receivers operating characteristics analysis. High risk for CaOx crystallization was defined as CRI > 1.61 and > 1.18, for males and females, respectively. The accuracy of urine osmolality to diagnose risk of CaOx stone formation (AUC, area under the curve) for females was 84.6%, with cut-off point of 501 mmol·kg-1 (sensitivity: 83.3%, specificity: 76.0%). Males had AUC of 85.8% with threshold of 577 mmo·kg-1 (sensitivity: 85.5%, specificity: 77.6%). A negative association was found between 24-h urine volume and osmolality (r = - 0.63, P < 0.001). Also, a positive association was found between 24-h urine osmolality and CRI (r = 0.65, P < 0.001), as well as urea excretion with CRI (r = 0.37, P < 0.001). In conclusion, urine osmolality > 501 and > 577 mmol·kg-1, in female and in male, respectively, was associated with a risk for CaOx kidney stone formation in patients with a history of recurrent urolithiasis. Thus, when CaOx origin is confirmed or suspected, 24-h urine osmolality provides a simple way to define individualized target of urine dilution to prevent urine crystallization and stone formation.

Monitoring acid base status in CKD patients: can urinary citrate help?

Metabolic acidosis is an early and deleterious complication of chronic kidney disease. Because it is frequently eubicarbonatemic, diagnosis may be difficult. In this issue, Gianella et al. suggest that lower urinary citrate excretion, considered as an homeostatic response to metabolic acidosis, may be helpful for early diagnosis and monitoring of alkali treatment. This study should be an incentive for further assessment of the tubular handling of urinary citrate in CKD patients and determination of the performance of urinary citrate for the diagnosis of eubicarbonatemic metabolic acidosis and monitoring of alkali therapy.

Resistance to Insulin in Patients with Gitelman Syndrome and a Subtle Intermediate Phenotype in Heterozygous Carriers: A Cross-Sectional Study.

BACKGROUND: Gitelman syndrome is a salt-losing tubulopathy caused by mutations in the SLC12A3 gene, which encodes the thiazide-sensitive sodium-chloride cotransporter. Previous studies suggested an intermediate phenotype for heterozygous carriers. METHODS: To evaluate the phenotype of heterozygous carriers of pathogenic SLC12A3 mutations, we performed a cross-sectional study of patients with Gitelman syndrome, heterozygous carriers, and healthy noncarriers. Participants measured their BP at home for three consecutive days before hospital admission for blood and urine sampling and an oral glucose tolerance test. RESULTS: We enrolled 242 participants, aged 18-75 years, including 81 heterozygous carriers, 82 healthy noncarriers, and 79 patients with Gitelman syndrome. The three groups had similar age, sex ratio, and body mass index. Compared with healthy noncarriers, heterozygous carriers showed significantly higher serum calcium concentration (P=0.01) and a trend for higher plasma aldosterone (P=0.06), but measures of home BP, plasma and urine electrolytes, renin, parathyroid hormone, vitamin D, and response to oral glucose tolerance testing were similar. Patients with Gitelman syndrome had lower systolic BP and higher heart rate than noncarriers and heterozygote carriers; they also had significantly higher fasting serum glucose concentration, higher levels of markers of insulin resistance, and a three-fold higher sensitivity to overweight. According to oral glucose tolerance testing, approximately 14% of patients with Gitelman syndrome were prediabetic, compared with 5% of heterozygous carriers and 4% of healthy noncarriers. CONCLUSIONS: Heterozygous carriers had a weak intermediate phenotype, between that of healthy noncarriers and patients with Gitelman syndrome. Moreover, the latter are at risk for development of type 2 diabetes, indicating the heightened importance of body weight control in these patients.

Urinary citrate: helpful to predict acid retention in CKD patients?

Acid retention occurs early during the course of chronic kidney disease (CKD). Studies conducted in patients with CKD suggest that alkali supplementation may slow CKD progression. However, the diagnosis of acid retention is challenging when plasma bicarbonate concentration is still normal. In this issue, Goraya et al. suggest that urinary citrate may predict acid retention in eubicarbonatemic patients with stages 1 and 2 CKD . Although interesting, this claim yet requires confirmation by further studies.

[Which biological parameters for volemic status estimation?] / Quels paramètres biologiques pour estimer le statut volémique ?

INTRODUCTION: Estimation of volemic status can be useful in the diagnosis of some hydro-electrolytic disorders such as hyponatremia and dyskalemia. As a matter of fact, clinical examination and classical biological parameters are not discriminant enough. The aim of this study was to determine the biological parameters that are better correlated to volemic status. METHOD: Volemic status was established using extracellular fluid volume, measured by apparent distribution of inuline, in non-edematous patients and without cardiac or hepatic insufficiency. Patients were split in three groups according to their extracellular fluid volume: hypovolemic, normovolemic, and hypervolemic. Clinical and biological parameters were compared between the three groups and were correlated to extracellular fluid volume. RESULTS: Data of 91 explorations were collected. There were no difference between groups regarding clinical parameters, plasma proteins, and urinary sodium excretion. Parameters better correlated to extracellular fluid volume were fasting calcium/creatinine ratio (r=0.51; P<0.0001), fasting urinary pH (r=0.43; P<0.0001), and plasma uric acid (r=-0.39; P=0.002). CONCLUSION: In addition to uric acid, already proposed as a biological marker to estimate volemic status, fasting calciuria and fasting urinary pH could also be useful.

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.

[Vitamin D deficiency prediction by patient questionnaire and secondary hyperparathyroidism in a cohort of 526 healthy subjects in their fifties]. / Le déficit en vitamine D, très fréquent, n'entraîne qu'exceptionnellement une hyperparathyroïdie secondaire chez des sujets sains de la cinquantaine: cohorte de 526 sujets.

INTRODUCTION: Can vitamin D deficiency be predicted by patient questionnaire? Does it lead to secondary hyperparathyroidism that may cause excessive bone resorption? We studied non-osteoporotic subjects in their fifties, in whom vitamin D levels are often tested. PATIENTS AND METHODS: Patients hospitalised for degenerative osteoarthritis or consulting for assessment of menopause, without renal failure and not treated with vitamin D, completed a questionnaire on sun exposure and underwent measurement of serum calcium, creatinine, 25OH vitamin D, PTH and CTX. RESULTS: Five hundred and twenty-six subjects, mean age 54.6 years (71% women), were investigated throughout the year. 25OH vitamin D levels were correlated with sun exposure and varied according to the month of the year, unlike PTH and CTX levels. From November to May, over 90% of subjects had 25OH vitamin D levels<30ng/mL. Of the subjects who did not expose their face, arms and legs to the sun for at least 20min/day, 94% had 25OH vitamin D levels<30ng/mL. PTH levels were negatively correlated with those of 25OH vitamin D. Serum CTX levels were not correlated with PTH or 25OH vitamin D. Only 13% of subjects presented with secondary hyperparathyroidism, characterised by serum calcium<2.55mmol/L and PTH>65pg/mL, associated with increased CTX levels. CONCLUSION: Vitamin D deficiency can be predicted by patient questionnaire. It very rarely leads to secondary hyperparathyroidism.

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.

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.

Renal ß-intercalated cells maintain body fluid and electrolyte balance.

Inactivation of the B1 proton pump subunit (ATP6V1B1) in intercalated cells (ICs) leads to type I distal renal tubular acidosis (dRTA), a disease associated with salt- and potassium-losing nephropathy. Here we show that mice deficient in ATP6V1B1 (Atp6v1b1-/- mice) displayed renal loss of NaCl, K+, and water, causing hypovolemia, hypokalemia, and polyuria. We demonstrated that NaCl loss originated from the cortical collecting duct, where activity of both the epithelial sodium channel (ENaC) and the pendrin/Na(+)-driven chloride/bicarbonate exchanger (pendrin/NDCBE) transport system was impaired. ENaC was appropriately increased in the medullary collecting duct, suggesting a localized inhibition in the cortex. We detected high urinary prostaglandin E2 (PGE2) and ATP levels in Atp6v1b1-/- mice. Inhibition of PGE2 synthesis in vivo restored ENaC protein levels specifically in the cortex. It also normalized protein levels of the large conductance calcium-activated potassium channel and the water channel aquaporin 2, and improved polyuria and hypokalemia in mutant mice. Furthermore, pharmacological inactivation of the proton pump in ß-ICs induced release of PGE2 through activation of calcium-coupled purinergic receptors. In the present study, we identified ATP-triggered PGE2 paracrine signaling originating from ß-ICs as a mechanism in the development of the hydroelectrolytic imbalance associated with dRTA. Our data indicate that in addition to principal cells, ICs are also critical in maintaining sodium balance and, hence, normal vascular volume and blood pressure.

Renal functional decline and glomerulotubular injury are arrested but not restored by release of unilateral ureteral obstruction (UUO).

Murine unilateral ureteral obstruction (UUO), a major model of progressive kidney disease, causes loss of proximal tubular mass and formation of atubular glomeruli. Adult C57BL/6 mice underwent a sham operation or reversible UUO under anesthesia. In group 1, kidneys were harvested after 7 days. In group 2, the obstruction was released after 7 days, and a physiological study of both kidneys was performed 30 days later. Renal blood flow (RBF), glomerular filtration rate (GFR), urine protein, and albumin excretion were measured after ligation of either the left or right ureter. Glomerular volume (periodic acid-Schiff), glomerulotubular integrity and proximal tubular mass (Lotus tetragonolobus lectin), and interstitial collagen (Sirius red) were measured by histomorphometry. Obstructed kidney weight was reduced by 15% at 7 days but was not different from sham after a 30-day recovery. Glomerular volume and proximal tubular area of the obstructed kidney were reduced by 55% at 7 days, but normalized after 30 days. Interstitial collagen deposition increased 2.4-fold after 7 days of UUO and normalized after release. However, GFR and RBF were reduced by 40% and urine albumin/protein ratio was increased 2.8-fold 30 days after release of UUO. This was associated with a 50% reduction in glomerulotubular integrity despite a 30-day recovery (P < 0.05 for all data). We conclude that release of 7-day UUO can arrest progression but does not restore normal function of the postobstructed kidney. Although the remaining intact nephrons have hypertrophied, glomerular injury is revealed by albuminuria. These results suggest that glomerulotubular injury should become the primary target of slowing progressive kidney disease.

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.

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.