Hydrochlorothiazide and Prevention of Kidney-Stone Recurrence.

BACKGROUND: Nephrolithiasis is one of the most common conditions affecting the kidney and is characterized by a high risk of recurrence. Thiazide diuretic agents are widely used for prevention of the recurrence of kidney stones, but data regarding the efficacy of such agents as compared with placebo are limited. Furthermore, dose-response data are also limited. METHODS: In this double-blind trial, we randomly assigned patients with recurrent calcium-containing kidney stones to receive hydrochlorothiazide at a dose of 12.5 mg, 25 mg, or 50 mg once daily or placebo once daily. The main objective was to investigate the dose-response effect for the primary end point, a composite of symptomatic or radiologic recurrence of kidney stones. Radiologic recurrence was defined as the appearance of new stones on imaging or the enlargement of preexisting stones that had been observed on the baseline image. Safety was also assessed. RESULTS: In all, 416 patients underwent randomization and were followed for a median of 2.9 years. A primary end-point event occurred in 60 of 102 patients (59%) in the placebo group, in 62 of 105 patients (59%) in the 12.5-mg hydrochlorothiazide group (rate ratio vs. placebo, 1.33; 95% confidence interval [CI], 0.92 to 1.93), in 61 of 108 patients (56%) in the 25-mg group (rate ratio, 1.24; 95% CI, 0.86 to 1.79), and in 49 of 101 patients (49%) in the 50-mg group (rate ratio, 0.92; 95% CI, 0.63 to 1.36). There was no relation between the hydrochlorothiazide dose and the occurrence of a primary end-point event (P = 0.66). Hypokalemia, gout, new-onset diabetes mellitus, skin allergy, and a plasma creatinine level exceeding 150% of the baseline level were more common among patients who received hydrochlorothiazide than among those who received placebo. CONCLUSIONS: Among patients with recurrent kidney stones, the incidence of recurrence did not appear to differ substantially among patients receiving hydrochlorothiazide once daily at a dose of 12.5 mg, 25 mg, or 50 mg or placebo once daily. (Funded by the Swiss National Science Foundation and Inselspital; NOSTONE ClinicalTrials.gov number, NCT03057431.).

Thiazides for kidney stone recurrence prevention.

PURPOSE OF REVIEW: Kidney stones are the most common condition affecting the kidney, and characterized by a high rate of recurrence. Thiazide and thiazide-like diuretics (thiazides) are commonly prescribed to prevent the recurrence of kidney stones. This review offers a comprehensive up-to-date assessment of the evidence supporting the use of thiazides for kidney stone recurrence prevention, highlights potential harms associated with treatment, and identifies areas of knowledge that require further investigation. RECENT FINDINGS: The clinical routine to prescribe thiazides for kidney stone prevention has recently been challenged by the findings of the large NOSTONE trial that failed to show superiority of hydrochlorothiazide at doses up to 50 mg daily over placebo in preventing a composite of clinical or radiological recurrence in patients at high risk of recurrence. Yet, adverse events such as new onset diabetes mellitus and gout were more common in patients receiving hydrochlorothiazide compared to placebo. As demonstrated by a novel meta-analysis presented in this review encompassing all randomized placebo-controlled trials with thiazide monotherapy, current trial evidence does not indicate that thiazide monotherapy is significantly better than placebo in preventing kidney stone recurrence. SUMMARY: Given the limited efficacy and possible adverse effects, we advocate for a restrictive use of thiazides for kidney stone recurrence prevention. Clearly, there remains a high unmet medical need for effective, targeted therapies to prevent recurrence of kidney stones.

[Change in the prevention of kidney stones]. / Lithiase rénale, un changement de paradigme?

Kidney stone is one of the most frequent disorders of the urinary tract. Once the stone has passed, the management should be oriented on prevention. If changes in lifestyle and diet should be implemented in a true therapeutic education of the patient, prescription of drugs has been recently challenged by the NOSTONE trial. This randomized controlled trial did not show any benefit of hydrochlorothiazide in the prevention of recurrence of kidney stone event in patients with calcium-containing stone. Therefore, prescription of thiazide in the sole purpose of decreasing kidney stone recurrence should be limited and the risk/benefit of this treatment should be carefully balanced for each case.

La maladie rénale lithiasique est une des affections les plus fréquentes de l'axe urinaire. Une fois l'expulsion du calcul obtenue, la prise en charge est orientée sur la prévention. Si les modifications diététiques et comportementales doivent être implémentées dans le cadre d'une véritable éducation thérapeutique, la prescription de traitements médicamenteux préventifs est remise en question par l'étude NOSTONE. Cette étude randomisée contrôlée n'a pas montré de bénéfice de l'hydrochlorothiazide dans la prévention de la récidive des calculs à contenu calcique. Dès lors, la prescription de thiazide en monothérapie dans le but de diminuer les récidives de calculs doit être limitée et le risque/bénéfice soigneusement évalué dans chaque cas.

The Swiss Kidney Stone Cohort: A Longitudinal, Multicentric, Observational Cohort to Study Course and Causes of Kidney Stone Disease in Switzerland.

BACKGROUND: Kidney stone disease has a high prevalence worldwide of approximately 10% of the population and is characterized by a high recurrence rate. Kidney stone disease results from a combination of genetic, environmental, and lifestyle risk factors, and the dissection of these factors is complex. METHODS: The Swiss Kidney Stone Cohort (SKSC) is an investigator-initiated prospective, multicentric longitudinal, observational study in patients with kidney stones followed with regular visits over a period of 3 years after inclusion. Ongoing follow-ups by biannual telephone interviews will provide long-term outcome data. SKSC comprises 782 adult patients (age >18 years) with either recurrent stones or a single stone event with at least one risk factor for recurrence. In addition, a control cohort of 207 individuals without kidney stone history and absence of kidney stones on a low-dose CT scan at enrolment has also been recruited. SKSC includes extensive collections of clinical data, biochemical data in blood and 24-h urine samples, and genetic data. Biosamples are stored at a dedicated biobank. Information on diet and dietary habits was collected through food frequency questionnaires and standardized recall interviews by trained dieticians with the Globodiet software. CONCLUSION: SKSC provides a unique opportunity and resource to further study cause and course of kidney disease in a large population with data and samples collected of a homogeneous collective of patients throughout the whole Swiss population.

Differences in the Food Consumption Between Kidney Stone Formers and Nonformers in the Swiss Kidney Stone Cohort.

OBJECTIVE: Diet has a major influence on the formation and management of kidney stones. However, kidney stone formers' diet is difficult to capture in a large population. Our objective was to describe the dietary intake of kidney stone formers in Switzerland and to compare it to nonstone formers. METHODS: We used data from the Swiss Kidney Stone Cohort (n = 261), a multicentric cohort of recurrent or incident kidney stone formers with additional risk factors, and a control group of computed tomography-scan proven nonstone formers (n = 197). Dieticians conducted two consecutive 24-h dietary recalls, using structured interviews and validated software (GloboDiet). We took the mean consumption per participant of the two 24-h dietary recalls to describe the dietary intake and used two-part models to compare the two groups. RESULTS: The dietary intake was overall similar between stone and nonstone formers. However, we identified that kidney stone formers had a higher probability of consuming cakes and biscuits (odds ratio (OR) [95% CI] = 1.56[1.03; 2.37]) and soft drinks (OR = 1.66[1.08; 2.55]). Kidney stone formers had a lower probability of consuming nuts and seeds (OR = 0.53[0.35; 0.82]), fresh cheese (OR = 0.54[0.30; 0.96]), teas (OR = 0.50[0.3; 0.84]), and alcoholic beverages (OR = 0.35[0.23; 0.54]), especially wine (OR = 0.42[0.27; 0.65]). Furthermore, among consumers, stone formers reported smaller quantities of vegetables (ß coeff[95% CI] = - 0.23[- 0.41; - 0.06]), coffee (ß coeff = - 0.21[- 0.37; - 0.05]), teas (ß coeff = - 0.52[- 0.92; - 0.11]) and alcoholic beverages (ß coeff = - 0.34[- 0.63; - 0.06]). CONCLUSION: Stone formers reported lower intakes of vegetables, tea, coffee, and alcoholic beverages, more specifically wine, but reported drinking more frequently soft drinks than nonstone formers. For the other food groups, stone formers and nonformers reported similar dietary intakes. Further research is needed to better understand the links between diet and kidney stone formation and develop dietary recommendations adapted to the local settings and cultural habits.

Empagliflozin Changes Urine Supersaturation by Decreasing pH and Increasing Citrate.

Clinical Trial registry name and registration number: Empagliflozin and Renal Oxygenation in Healthy Volunteers (EMPA-REIN), NCT03093103.

[Management of genetic renal disorders: local experience and importance of the network]. / Prise en charge des maladies rénales génétiques : expérience locale et importance du réseau.

In nephrology, rare disorders are frequently encountered. In children, about 60% of the renal disorders are rare, with congenital abnormalities of the kidney and urinary tract disorders (CAKUT), being highly prevalent. In adults, about 22% of the disorders leading to renal replacement therapies are rare and include glomerulonephritis and genetic disorders. Rarity may preclude the rapid and extensive access to care for patients suffering of renal disorders, especially in Switzerland, which is small and fragmented. Only collaborative network and access to databases, shared resources and to specific competence may help patient management. Lausanne and Geneva University Hospitals have started specialized outpatient clinics for rare renal disorders several years ago and are part of national and international networks.

Dans le domaine des maladies rénales, la rareté est fréquente. Chez l'enfant, 60 % des maladies touchant les reins sont rares et les malformations de l'axe urinaire sont prépondérantes. Chez l'adulte, près de 22 % des pathologies qui mènent à la maladie rénale terminale sont rares et incluent les glomérulonéphrites et les maladies génétiques. La rareté de ces pathologies fait que les compétences médicales peuvent être difficiles à trouver et l'expérience locale insuffisante. Ainsi, seule la mise en réseau des données, des ressources et des compétences peut permettre d'améliorer la prise en charge de ces patients. Le CHUV et les HUG ont mis en place des consultations spécialisées pour les maladies rénales rares. Elles s'inscrivent dans un réseau national et international.

Acute decrease of urine calcium by amiloride in healthy volunteers under high-sodium diet.

BACKGROUND: Amiloride is a competitive blocker of the epithelial sodium (Na) channel in the renal collecting duct. It is a less potent diuretic than thiazides or loop diuretics, but is often used in association with its potassium (K)-sparing profile. Whether amiloride has a hypocalciuric effect similar to thiazides remains unclear. Animal studies and experiments on cell lines suggested that amiloride increases calcium (Ca) reabsorption in the distal nephron, but human studies are scarce. METHODS: We performed a post hoc analysis of a study with 48 healthy males (mean ± standard deviation age, 23.2 ± 3.9 years) who were assigned to a high-Na/low-K diet for 7 days before receiving 20 mg of amiloride orally. Urinary excretions of electrolytes were measured at 3 and 6 h afterwards; we calculated the relative changes in urinary excretion rates after amiloride administration. RESULTS: The high-Na/low-K diet led to an expected suppression of plasma renin and aldosterone. Amiloride showed a mild natriuretic effect associated with a decreased kaliuresis. Urinary Ca excretion dropped substantially (by 80%) 3 h after amiloride administration and remained low at the sixth hour. At the same time, fractional excretion of lithium decreased by a third, reflecting an increased proximal tubular reabsorption. CONCLUSIONS: During a high-Na/low-K diet, amiloride had a strong acute hypocalciuric effect, most probably mediated by increased proximal Ca reabsorption, even though a distal effect cannot be excluded. Further studies should establish if chronic amiloride or combined amiloride/thiazide treatment may decrease calciuria more efficiently and be useful in preventing kidney stones.

[Management of hyperuricemia in chronic kidney disease]. / Hyperuricémie et maladie rénale : prise en charge.

Hyperuricemia is often encountered as glomerular filtration rate decreased. It is associated with a more rapid decline of the renal function, but causality has not been demonstrated. Recent studies showed that treatment of hyperuricemia did not affect the progression in chronic kidney disease (CKD) patients. Thus, treatment with hypouricemic drugs of patients suffering of CKD and displaying asymptomatic hyperuricemia is not recommended. However, patients with CKD present often with acute flairs of gout, which might be difficult to treat. Therapeutic options are discussed in this article.

Une hyperuricémie apparaît précocement en cas de diminution de la filtration glomérulaire et de maladie rénale chronique. Elle est associée à un déclin plus rapide de la fonction rénale, mais un lien de causalité n'a pas été démontré. Plusieurs études récentes n'ont pas montré d'effet bénéfique d'un traitement hypo-uricémiant sur l'évolution de la fonction rénale. Ainsi, en cas d'hyper uricémie asymptomatique chez un patient souffrant de maladie rénale chronique, un traitement hypo-uricémiant n'est pas indiqué. Cependant, les patients souffrant de maladie rénale chronique font plus fréquemment des crises de goutte, et leur prise en charge est complexe car la maladie est à la fois plus résistante au traitement et les options thérapeutiques sont limitées. Celles-ci sont revues dans cet article.

[Metabolic investigation of stone formers]. / Metabolische Abklärung von Nierensteinen.

Metabolic investigation of stone formers Abstract. Once a kidney stone has passed, patients must be carefully evaluated in order to identify the underlying cause of the disease and to guide preventive measures and treatment. General recommendations can be offered to all kidney stone formers, but personalized counseling and follow-up adaptations need to be guided by in-depth assessment. Metabolic evaluation for recurrent stone formers is based on 24 h urine collection. This allows a comprehensive understanding of the dietary habits of the patient and helps identifying treatable metabolic diseases and renal tubulopathies. Additional specific assessments may include urine acidification test (in case of suspected partial renal distal tubular acidosis), characterization of hypercalciuria or osteodensitometry. Metabolic evaluation often needs to be repeated over time to guide therapeutic interventions, both dietetic and drug-related.

[Clinical use of tolvaptan: a 2021 review]. / Histoire d'eau : le tolvaptan dans tous ses états.

Along with the arrival of the first vasopressin-receptor V2R inhibitor, the indications for its use have increased. We review here and focus on polycystic kidney disease (PKD) and hyponatremia. Tolvaptan is the first drug available to slow down the progression of PKD in patients with rapid progressing disease. However, the benefits are moderate and the side effects are important, making important to share the decision of treatment together with the patient. Hyponatremia with preserved extra-cellular volume or associated with edema may be reversed by tolvaptan. Patients with SIADH or hyponatremia and edema might benefit from this treatment under strict monitoring. Overall, vaptans are helpful in several conditions, but remain tools that must be used under close control.

Depuis l'arrivée des inhibiteurs des récepteurs rénaux à la vasopressine V2, les indications à leur utilisation ont explosé. Nous revoyons ici certaines d'entre elles, en particulier la polykystose rénale et l'hyponatrémie. Première molécule à ralentir la progression de la polykystose rénale, le tolvaptan est réservé à des patients très motivés, dont la maladie progresse rapidement. En effet, les bénéfices sont modérés et les effets secondaires importants. La décision de traiter doit donc être partagée avec le patient. L'hyponatrémie à volume conservé ou liée à des œdèmes peut être corrigée par le tolvaptan. Les patients avec syndrome de sécrétion inappropriée d'hormone antidiurétique ou avec œdèmes peuvent en bénéficier sous certaines conditions et sous stricte surveillance. Le tolvaptan permet d'améliorer plusieurs pathologies, mais exige une étroite surveillance.

The proton-activated ovarian cancer G protein-coupled receptor 1 (OGR1) is responsible for renal calcium loss during acidosis.

Hypercalciuria is a common feature during metabolic acidosis and associates to nephrolithiasis and nephrocalcinosis. The mechanisms sensing acidosis and inducing increased urinary calcium excretion are still unknown. Here we tested whether mice deficient for proton-activated Ovarian cancer G-protein coupled receptor 1 (OGR1 or Gpr68) have reduced urinary excretion of calcium during chronic metabolic acidosis. In the kidney, OGR1 mRNA was found in cells of the glomerulus, proximal tubule, and interstitium including endothelial cells. Wild type (OGR1+/+) and OGR1 knockout (OGR1-/-) mice were given standard chow without (control) or loaded with ammonium chloride for one or seven days to induce acute or chronic metabolic acidosis, respectively. No differences in responding to the acid load were observed in the knockout mice, except for higher plasma bicarbonate after one day. Bone mineral density, resorption activity of osteoclasts, and urinary deoxypyridinoline were similar between genotypes. During metabolic acidosis the expression levels of key proteins involved in calcium reabsorption, i.e. the sodium/proton exchanger (NHE3), the epithelial calcium-selective channel TRPV5, and the vitamin D-dependent calcium binding protein calbindin-D28k were all higher in the knockout mice compared to wild type mice. This is consistent with the previous demonstration that OGR1 reduces NHE3 activity in proximal tubules of mice. Wild-type mice displayed a non-linear positive association between urinary proton and calcium excretion which was lost in the knockout mice. Thus, OGR1 is a pH sensor involved in the hypercalciuria of metabolic acidosis by controlling NHE3 activity in the proximal tubule. Hence, novel drugs modulating OGR1 activity may improve renal calcium handling.

Clinical and genetic spectra of autosomal dominant tubulointerstitial kidney disease due to mutations in UMOD and MUC1.

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is an increasingly recognized cause of end-stage kidney disease, primarily due to mutations in UMOD and MUC1. The lack of clinical recognition and the small size of cohorts have slowed the understanding of disease ontology and development of diagnostic algorithms. We analyzed two registries from Europe and the United States to define genetic and clinical characteristics of ADTKD-UMOD and ADTKD-MUC1 and develop a practical score to guide genetic testing. Our study encompassed 726 patients from 585 families with a presumptive diagnosis of ADTKD along with clinical, biochemical, genetic and radiologic data. Collectively, 106 different UMOD mutations were detected in 216/562 (38.4%) of families with ADTKD (303 patients), and 4 different MUC1 mutations in 72/205 (35.1%) of the families that are UMOD-negative (83 patients). The median kidney survival was significantly shorter in patients with ADTKD-MUC1 compared to ADTKD-UMOD (46 vs. 54 years, respectively), whereas the median gout-free survival was dramatically reduced in patients with ADTKD-UMOD compared to ADTKD-MUC1 (30 vs. 67 years, respectively). In contrast to patients with ADTKD-UMOD, patients with ADTKD-MUC1 had normal urinary excretion of uromodulin and distribution of uromodulin in tubular cells. A diagnostic algorithm based on a simple score coupled with urinary uromodulin measurements separated patients with ADTKD-UMOD from those with ADTKD-MUC1 with a sensitivity of 94.1%, a specificity of 74.3% and a positive predictive value of 84.2% for a UMOD mutation. Thus, ADTKD-UMOD is more frequently diagnosed than ADTKD-MUC1, ADTKD subtypes present with distinct clinical features, and a simple score coupled with urine uromodulin measurements may help prioritizing genetic testing.

Treatment and long-term outcome in primary nephrogenic diabetes insipidus.

BACKGROUND: Primary nephrogenic diabetes insipidus (NDI) is a rare disorder and little is known about treatment practices and long-term outcome. METHODS: Paediatric and adult nephrologists contacted through European professional organizations entered data in an online form. RESULTS: Data were collected on 315 patients (22 countries, male 84%, adults 35%). Mutation testing had been performed in 270 (86%); pathogenic variants were identified in 258 (96%). The median (range) age at diagnosis was 0.6 (0.0-60) years and at last follow-up 14.0 (0.1-70) years. In adults, height was normal with a mean (standard deviation) score of -0.39 (±1.0), yet there was increased prevalence of obesity (body mass index >30 kg/m2; 41% versus 16% European average; P < 0.001). There was also increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (32%) and adults (48%). Evidence of flow uropathy was present in 38%. A higher proportion of children than adults (85% versus 54%; P < 0.001) received medications to reduce urine output. Patients ≥25 years were less likely to have a university degree than the European average (21% versus 35%; P = 0.003) but full-time employment was similar. Mental health problems, predominantly attention-deficit hyperactivity disorder (16%), were reported in 36% of patients. CONCLUSION: This large NDI cohort shows an overall favourable outcome with normal adult height and only mild to moderate CKD in most. Yet, while full-time employment was similar to the European average, educational achievement was lower, and more than half had urological and/or mental health problems.

[Hypophosphatemia after iron infusion†: can we still ignore it†?] / Hypophosphatémie après perfusion de fer†: pouvons-nous encore l'ignorer†?

The occurrence of hypophosphatemia after iron infusion has been known for a long time but has only recently led to clinical concerns. It was considered to be of low clinical importance. The elucidation of the physiological mechanisms responsible for this effect, involving FGF23 and the ever-increasing number of cases with regard to the potentially very serious consequences on bone metabolism have recently raised probably justified concerns. In this article, we summarize the mechanisms of phosphate homeostasis, how intravenous iron can induce a phosphate deficiency and what precautions and treatments needs to be undertaken to prevent it.

La survenue d'une hypophosphatémie après une perfusion de fer est connue de longue date mais n'a que depuis peu suscité des inquiétudes cliniques. L'élucidation des mécanismes physiologiques à l'origine de cet effet indésirable, impliquant le facteur de croissance des fibroblastes 23 (FGF23), et les rapports de cas toujours plus nombreux quant aux conséquences potentiellement graves sur le métabolisme osseux ont récemment soulevé des préoccupations probablement justifiées. Dans cet article, nous résumons les mécanismes de régulation du phosphate et la manière dont le fer par voie intraveineuse peut induire un déficit en phosphate, ainsi que les précautions et traitements à mettre en œuvre pour le prévenir.

[Prevention of nephrolithiasis - Preliminary results of the Swiss Kidney Stone Cohort (SKSC) and the NOSTONE trial]. / Prévention de la lithiase urinaire ­ Résultats préliminaires de la Cohorte suisse des patients souffrant de calculs rénaux et de l'étude NOSTONE.

Nephrolithiasis is a major health care problem with increasing incidence and prevalence worldwide. Prevention consists mainly of conservative therapeutic measures, including dietary measures and drug treatments. However, the understanding of the pathophysiology and molecular genetic basis of nephrolithiasis is incomplete and complicates the development of new treatments. In this context, the Swiss Kidney Stone Cohort (SKSC) aims to improve the understanding of nephrolithiasis and the NOSTONE trial aims to confirm the efficacy of hydrochlorothiazide in the recurrence prevention of calcium containing kidney stones.

La maladie lithiasique est un problème de santé majeur avec une incidence et une prévalence en augmentation au niveau mondial. Sa prévention est constituée essentiellement de mesures thérapeutiques conservatrices, incluant mesures diététiques et traitements médicamenteux. La compréhension de la physiopathologie et des bases génétiques moléculaires de la maladie lithiasique est cependant incomplète et entrave le développement de nouveau traitement. Dans ce contexte, la Cohorte suisse des patients souffrant de calculs rénaux cherche à améliorer la compréhension de la maladie lithiasique et l'étude interventionnelle NOSTONE à confirmer l'efficacité de l'hydrochlorothiazide dans la prévention de la récurrence de lithiases urinaires calciques.

A model of uric acid transport in the rat proximal tubule.

The objective of the present study was to theoretically investigate the mechanisms underlying uric acid transport in the proximal tubule (PT) of rat kidneys, and their modulation by factors, including Na+, parathyroid hormone, ANG II, and Na+-glucose cotransporter-2 inhibitors. To that end, we incorporated the transport of uric acid and its conjugate anion urate in our mathematical model of water and solute transport in the rat PT. The model accounts for parallel urate reabsorption and secretion pathways on apical and basolateral membranes and their coupling to lactate and α-ketoglutarate transport. Model results agree with experimental findings at the segment level. Net reabsorption of urate by the rat PT is predicted to be ~70% of the filtered load, with a rate of urate removal from the lumen that is 50% higher than the rate of urate secretion. The model suggests that apical URAT1 deletion significantly reduces net urate reabsorption across the PT, whereas ATP-binding cassette subfamily G member 2 dysfunction affects it only slightly. Inactivation of basolateral glucose transporter-9 raises fractional urate excretion above 100%, as observed in patients with renal familial hypouricemia. Furthermore, our results suggest that reducing Na+ reabsorption across Na+/H+ exchangers or Na+-glucose cotransporters augments net urate reabsorption. The model predicts that parathyroid hormone reduces urate excretion, whereas ANG II increases it. In conclusion, we have developed the first model of uric acid transport in the rat PT; this model provides a framework to gain greater insight into the numerous solutes and coupling mechanisms that affect the renal handing of uric acid.

SLC2A9 (GLUT9) mediates urate reabsorption in the mouse kidney.

Uric acid (UA) is a metabolite of purine degradation and is involved in gout flairs and kidney stones formation. GLUT9 (SLC2A9) was previously shown to be a urate transporter in vitro. In vivo, humans carrying GLUT9 loss-of-function mutations have familial renal hypouricemia type 2, a condition characterized by hypouricemia, UA renal wasting associated with kidney stones, and an increased propensity to acute renal failure during strenuous exercise. Mice carrying a deletion of GLUT9 in the whole body are hyperuricemic and display a severe nephropathy due to intratubular uric acid precipitation. However, the precise role of GLUT9 in the kidney remains poorly characterized. We developed a mouse model in which GLUT9 was deleted specifically along the whole nephron in a tetracycline-inducible manner (subsequently called kidney-inducible KO or kiKO). The urate/creatinine ratio was increased as early as 4 days after induction of the KO and no GLUT9 protein was visible on kidney extracts. kiKO mice are morphologically identical to their wild-type littermates and had no spontaneous kidney stones. Twenty-four-hour urine collection revealed a major increase of urate urinary excretion rate and of the fractional excretion of urate, with no difference in urate concentration in the plasma. Polyuria was observed, but kiKO mice were still able to concentrate urine after water restriction. KiKO mice displayed lower blood pressure accompanied by an increased heart rate. Overall, these results indicate that GLUT9 is a crucial player in renal handling of urate in vivo and a putative target for uricosuric drugs.