Cystatin C-Based Equation to Estimate GFR without the Inclusion of Race and Sex.

BACKGROUND: The accuracy of estimation of kidney function with the use of routine metabolic tests, such as measurement of the serum creatinine level, has been controversial. The European Kidney Function Consortium (EKFC) developed a creatinine-based equation (EKFC eGFRcr) to estimate the glomerular filtration rate (GFR) with a rescaled serum creatinine level (i.e., the serum creatinine level is divided by the median serum creatinine level among healthy persons to control for variation related to differences in age, sex, or race). Whether a cystatin C-based EKFC equation would increase the accuracy of estimated GFR is unknown. METHODS: We used data from patients in Sweden to estimate the rescaling factor for the cystatin C level in adults. We then replaced rescaled serum creatinine in the EKFC eGFRcr equation with rescaled cystatin C, and we validated the resulting EKFC eGFRcys equation in cohorts of White patients and Black patients in Europe, the United States, and Africa, according to measured GFR, levels of serum creatinine and cystatin C, age, and sex. RESULTS: On the basis of data from 227,643 patients in Sweden, the rescaling factor for cystatin C was estimated at 0.83 for men and women younger than 50 years of age and 0.83 + 0.005 × (age - 50) for those 50 years of age or older. The EKFC eGFRcys equation was unbiased, had accuracy that was similar to that of the EKFC eGFRcr equation in both White patients and Black patients (11,231 patients from Europe, 1093 from the United States, and 508 from Africa), and was more accurate than the Chronic Kidney Disease Epidemiology Collaboration eGFRcys equation recommended by Kidney Disease: Improving Global Outcomes. The arithmetic mean of EKFC eGFRcr and EKFC eGFRcys further improved the accuracy of estimated GFR over estimates from either biomarker equation alone. CONCLUSIONS: The EKFC eGFRcys equation had the same mathematical form as the EKFC eGFRcr equation, but it had a scaling factor for cystatin C that did not differ according to race or sex. In cohorts from Europe, the United States, and Africa, this equation improved the accuracy of GFR assessment over that of commonly used equations. (Funded by the Swedish Research Council.).

Rescaling creatinine makes GFR estimation equations generally applicable across populations - validation results for the Lund-Malmö equation in a French cohort of sub-Saharan ancestry.

OBJECTIVES: To make glomerular filtration rate (GFR) estimating equations applicable across populations with different creatinine generation by using rescaled serum creatinine (sCr/Q) where sCr represents the individual creatinine level and Q the average creatinine value in healthy persons of the same population. METHODS: GFR measurements (mGFR, plasma clearance of 51Cr-EDTA) were conducted in 964 adult Black Europeans. We established the re-expressed Lund-Malmö revised equation (r-LMR) by replacing serum creatinine (sCr) with rescaled creatinine sCr/Q. We evaluated the r-LMR equation based on Q-values of White Europeans (r-LMRQ-white; Q-values females: 62 µmol/L, males: 80 µmol/L) and Black Europeans (r-LMRQ-Black; Q-values females: 65 µmol/L, males: 90 µmol/L), and the European Kidney Function Consortium equation (EKFCQ-White and EKFCQ-Black) regarding bias, precision (interquartile range, IQR) and accuracy (percentage of estimates within ±10 % [P10] and ±30 % [P30] of mGFR). RESULTS: Median bias of r-LMRQ-White/r-LMRQ-Black/EKFCQ-White/EKFCQ-Black were -9.1/-4.5/-6.3/-0.9 mL/min/1.73 m2, IQR 14.7/14.5/14.5/15.6 mL/min/1.73 m2, P10 25.1 %/34.8 %/30.3 %/37.2 % and P30 74.2 %/84.1 %/80.6 %/83.6 %. The improvement of bias and accuracy when using proper Q-values was most pronounced in men. Similar improvements were obtained above and below mGFR 60 mL/min/1.73 m2 and at various age and BMI intervals, except for BMI<20 kg/m2 where bias increased, and accuracy decreased. CONCLUSIONS: GFR estimating equations may be re-expressed to include rescaled creatinine (sCr/Q) and used across populations with different creatinine generation if population-specific average creatinine concentrations (Q-values) for healthy persons are established.

Performance of creatinine-based equations to estimate glomerular filtration rate in White and Black populations in Europe, Brazil and Africa.

BACKGROUND: A new Chronic Kidney Disease Epidemiology Collaboration equation without the race variable has been recently proposed (CKD-EPIAS). This equation has neither been validated outside USA nor compared with the new European Kidney Function Consortium (EKFC) and Lund-Malmö Revised (LMREV) equations, developed in European cohorts. METHODS: Standardized creatinine and measured glomerular filtration rate (GFR) from the European EKFC cohorts (n = 13 856 including 6031 individuals in the external validation cohort), from France (n = 4429, including 964 Black Europeans), from Brazil (n = 100) and from Africa (n = 508) were used to test the performances of the equations. A matched analysis between White Europeans and Black Africans or Black Europeans was performed. RESULTS: In White Europeans (n = 9496), both the EKFC and LMREV equations outperformed CKD-EPIAS (bias of -0.6 and -3.2, respectively versus 5.0 mL/min/1.73 m², and accuracy within 30% of 86.9 and 87.4, respectively, versus 80.9%). In Black Europeans and Black Africans, the best performance was observed with the EKFC equation using a specific Q-value (= concentration of serum creatinine in healthy males and females). These results were confirmed in matched analyses, which showed that serum creatinine concentrations were different in White Europeans, Black Europeans and Black Africans for the same measured GFR, age, sex and body mass index. Creatinine differences were more relevant in males. CONCLUSION: In a European and African cohort, the performances of CKD-EPIAS remain suboptimal. The EKFC equation, using usual or dedicated population-specific Q-values, presents the best performance in the whole age range in the European and African populations included in this study.

MRI-based kidney radiomic analysis during chronic lithium treatment.

BACKGROUND: Lithium therapy during bipolar disorder is associated with an increased risk of chronic kidney disease (CKD) that is slowly progressive and undetectable at early stages. We aimed at identifying kidney image texture features as possible imaging biomarkers of decreased measured glomerular filtration rate (mGFR) using radiomics of T2-weighted magnetic resonance imaging (MRI). METHODS: One hundred and eight patients treated with lithium were evaluated including mGFR and kidney MRI, with T2-weighted sequence single-shot fast spin-echo. Computed radiomic analysis was performed after kidney segmentation. Significant features were selected to build a radiomic signature using multivariable Cox analysis to detect an mGFR <60 ml/min/1.73 m². The texture index was validated using a training and a validation cohort. RESULTS: Texture analysis index was able to detect an mGFR decrease, with an AUC of 0.85 in the training cohort and 0.71 in the validation cohort. Patients with a texture index below the median were older (59 [42-66] vs. 46 [34-54] years, p = .001), with longer treatment duration (10 [3-22] vs. 6 [2-10] years, p = .02) and a lower mGFR (66 [46-84] vs. 83 [71-94] ml/min/1.73m², p < .001). Texture analysis index was independently and negatively associated with age (ß = -.004 ± 0.001, p < .001), serum vasopressin (-0.005 ± 0.002, p = .02) and lithium treatment duration (-0.01 ± 0.003, p = .001), with a significant interaction between lithium treatment duration and mGFR (p = .02). CONCLUSIONS: A renal texture index was developed among patients treated with lithium associated with a decreased mGFR. This index might be relevant in the diagnosis of lithium-induced renal toxicity.

Long-term outcomes of chronic coronary syndrome worldwide: insights from the international CLARIFY registry.

AIMS: Over the last decades, the profile of chronic coronary syndrome has changed substantially. We aimed to determine characteristics and management of patients with chronic coronary syndrome in the contemporary era, as well as outcomes and their determinants. METHODS AND RESULTS: Data from 32 703 patients (45 countries) with chronic coronary syndrome enrolled in the prospective observational CLARIFY registry (November 2009 to June 2010) with a 5-year follow-up, were analysed. The primary outcome [cardiovascular death or non-fatal myocardial infarction (MI)] 5-year rate was 8.0% [95% confidence interval (CI) 7.7-8.3] overall [male 8.1% (7.8-8.5); female 7.6% (7.0-8.3)]. A cox proportional hazards model showed that the main independent predictors of the primary outcome were prior hospitalization for heart failure, current smoking, atrial fibrillation, living in Central/South America, prior MI, prior stroke, diabetes, current angina, and peripheral artery disease. There was an interaction between angina and prior MI (P = 0.0016); among patients with prior MI, angina was associated with a higher primary event rate [11.8% (95% CI 10.9-12.9) vs. 8.2% (95% CI 7.8-8.7) in patients with no angina, P < 0.001], whereas among patients without prior MI, event rates were similar for patients with [6.3% (95% CI 5.4-7.3)] or without angina [6.4% (95% CI 5.9-7.0)], P > 0.99. Prescription rates of evidence-based secondary prevention therapies were high. CONCLUSION: This description of the spectrum of chronic coronary syndrome patients shows that, despite high rates of prescription of evidence-based therapies, patients with both angina and prior MI are an easily identifiable high-risk group who may deserve intensive treatment. CLINICAL REGISTRY: ISRCTN43070564.

Knowledge self-monitoring, efficiency, and determinants of self-confidence statement in multiple choice questions in medical students.

BACKGROUND: Multiple-choice question (MCQ) tests are commonly used to evaluate medical students, but they do not assess self-confidence nor penalize lucky guess or harmful behaviors. Based on a scoring method according to the appropriateness of confidence in answers, the study aimed at assessing knowledge self-monitoring and efficiency, and the determinants of self-confidence. METHODS: A cross-sectional study of 842 s- and third-year medical students who were asked to state their level of confidence (A: very confident, B: moderately confident and C: not confident) during 12 tests (106,806 events). A bonus was applied if the level of confidence matched with the correctness of the answer, and a penalty was applied in the case of inappropriate confidence. RESULTS: Level A was selected more appropriately by the top 20% students whereas level C was selected more appropriately by the lower 20% students. Efficiency of higher-performing students was higher when correct (among correct answers, rate of A statement), but worse when incorrect compared to the bottom 20% students (among incorrect answers, rate of C statement). B and C statements were independently associated with female and male gender, respectively (OR for male vs female = 0.89 [0.82-0.96], p = 0.004, for level B and 1.15 [1.01-1.32], p = 0.047, for level C). CONCLUSION: While both addressing the gender confidence gap, knowledge self-monitoring might improve awareness of students' knowledge whereas efficiency might evaluate appropriate behavior in clinical practice. These results suggest differential feedback during training in higher versus lower-performing students, and potentially harmful behavior in decision-making during clinical practice in higher-performing students.

Extracellular fluid volume is associated with incident end-stage kidney disease and mortality in patients with chronic kidney disease.

Volume overload has been shown to be an independent risk factor for mortality in patients receiving chronic dialysis, but data in non-dialysis patients are scarce. Therefore we evaluated the prognostic value of extracellular fluid (ECF) volume for chronic kidney disease (CKD) progression and mortality in a prospective hospital-based cohort with CKD stage 1-4 (NephroTest Study). ECF (scaled to body surface area) and the measured glomerular filtration rate (mGFR) were determined using the distribution volume and clearance of 51Cr-EDTA, respectively. Cause-specific Cox and linear mixed-effect regression models were used to analyze the association of ECF with end-stage kidney disease (ESKD) and mortality, and with mGFR decline, respectively. The 1593 patients were mean age 58.8 years, 67% were men, mean mGFR of 43.6 mL/min/1.73m2 and mean ECF 15.1 L/1.73m2. After a median follow-up of 5.3 years, ESKD occurred in 324 patients and 185 patients died before ESKD. In multivariable analysis, ECF was significantly associated with the risk of ESKD (hazard ratio per 1L/1.73m2 increase: 1.14; 95% confidence interval [1.07; 1.21]) and with a faster GFR decline (adjusted mean difference in mGFR slope per 1L/1.73m2 increase -0.14 [-0.23; -0.05] mL/min/year). The relationship of ECF with mortality was non-linear and not significant (per 1L/1.73m2 increase 0.92, [0.73; 1.16]), below 15L/1.73m2, but significant (1.28; [1.14-1.45]) above 15L/1.73m2. Thus, in this large cohort of carefully phenotyped patients with CKD, ECF was an independent risk factor of CKD progression and mortality. Hence, close monitoring and treatment of fluid overload are important for the clinical management of patients with non-dialysis CKD.

Usefulness of Magnetic Resonance Imaging in the Diagnosis of Juxtaglomerular Cell Tumors: A Report of 10 Cases and Review of the Literature.

Juxtaglomerular cell tumors (JCTs), a rare but potentially curable cause of hypertension, are difficult to diagnose because they may be missed or misidentified as a cyst by computed tomography (CT). Their magnetic resonance imaging (MRI) pattern has not been well described. We report the clinical, biological, and radiologic features of 10 patients with JCTs. Eight were women, and median age was 24.5 years. All had severe hypokalemic hypertension related to marked secondary hyperaldosteronism. Median plasma renin and aldosterone concentrations were 392 (minimum-maximum [min-max], 70.5-4,800) mIU/L and 1,490 (min-max, 671-2,492) pmol/L, respectively. Plasma prorenin concentration was 835.5 (min-max, 133-6,546) mIU/L. Median tumor size was 17.5mm. On CT, JCTs were spontaneously isodense, with little enhancement after contrast media injection. On MRI, JCTs were iso- (7/10) or hypointense (3/10) on T1-weighted images (WIs). On T2-WIs, JCTs were hypointense (2/10), isointense (4/10), or heterogeneously hyperintense (4/10). A thin peripheral "pseudo-capsule" (hypointense on T2-WIs) was observed in 6 of 10 cases. Contrast enhancement was low, slightly heterogeneous, and delayed. On diffusion-WIs, tumors were hyperintense with a restricted apparent diffusion coefficient. When hypertension with secondary hyperaldosteronism remains unexplained after CT, MRI of the kidney should be considered, especially for young women.

Potential impact of the 2017 ACC/AHA guideline on high blood pressure in normotensive patients with stable coronary artery disease: insights from the CLARIFY registry.

Aims: The 2017 American College of Cardiology/American Heart Association (ACC/AHA) guideline on high blood pressure (BP) lowered the threshold defining hypertension and BP target in high-risk patients to 130/80 mmHg. Patients with coronary artery disease and systolic BP 130-139 mmHg or diastolic BP 80-89 mmHg should now receive medication to achieve this target. We aimed to investigate the relationship between BP and cardiovascular events in 'real-life' patients with coronary artery disease considered as having normal BP until the recent guideline. Methods and results: Data from 5956 patients with stable coronary artery disease, no history of hypertension or heart failure, and average BP <140/90 mmHg, enrolled in the CLARIFY registry (November 2009 to June 2010), were analysed. In a multivariable-adjusted Cox proportional hazards model, after a median follow-up of 5.0 years, diastolic BP 80-89 mmHg, but not systolic BP 130-139 mmHg, was associated with increased risk of the primary endpoint, a composite of cardiovascular death, myocardial infarction, or stroke (hazard ratio 2.15, 95% confidence interval 1.22-3.81 vs. 70-79 mmHg and 1.12, 0.64-1.97 vs. 120-129 mmHg). No significant increase in risk for the primary endpoint was observed for systolic BP <120 mmHg or diastolic BP <70 mmHg. Conclusion: In patients with stable coronary artery disease defined as having normal BP according to the 140/90 mmHg threshold, diastolic BP 80-89 mmHg was associated with increased cardiovascular risk, whereas systolic BP 130-139 mmHg was not, supporting the lower diastolic but not the lower systolic BP hypertension-defining threshold and treatment target in coronary artery disease. ClinicalTrials identifier: ISRCTN43070564.

The age-calibrated measured glomerular filtration rate improves living kidney donation selection process.

Recommendations on the glomerular filtration rate (GFR) threshold compatible with living kidney donation are not agreed upon. The recent KDIGO guidelines suggested a reset of the conventional cutoff value of 80 to 90 mL/min/1.73 m2. While GFR physiologically declines with age, it is unclear whether and how age should be taken into account for selecting acceptable pre-donation GFR. In this multicenter retrospective study encompassing 2007 kidney donors in France, we evaluated the impact of age using two threshold measured GFR (mGFR)s (80 and 90 mL/min/1.73 m2). Three groups of donors were defined according to baseline mGFR: below 80, 80-89.9 and 90 mL/min/1.73 m2 or more. Thirty-two percent of donors were selected despite an mGFR below 90 mL/min/1.73 m2. Donors with the lowest mGFR were significantly older (60 ± 9 vs. 47 ± 11 years) and this applied to both male and female donors. The lifetime-standardized renal reserve, defined as the pre-donation mGFR value divided by the expected number of remaining years of life, was similar irrespective of baseline mGFR groups. Similar results were obtained when eGFR was used instead of mGFR. Finally, in a subgroup of 132 donors with repeated mGFR five years after donation, the magnitude of mGFR decrease was similar in all groups (-34.3%, -33.9%, and -34.9% respectively). Thus, the decision to accept individuals with mGFR lower than 90 mL/min/1.73 m2 for kidney donation is highly dependent on the age of the candidate. Hence, threshold values lower than 90 mL/min/1.73 m2 are reasonable for older donors. Age-calibrated mGFR may improve efficiency of the selection process.

Single- versus multiple-sample method to measure glomerular filtration rate.

Background: There are many different ways to measure glomerular filtration rate (GFR) using various exogenous filtration markers, each having their own strengths and limitations. However, not only the marker, but also the methodology may vary in many ways, including the use of urinary or plasma clearance, and, in the case of plasma clearance, the number of time points used to calculate the area under the concentration-time curve, ranging from only one (Jacobsson method) to eight (or more) blood samples. Methods: We collected the results obtained from 5106 plasma clearances (iohexol or 51Cr-ethylenediaminetetraacetic acid (EDTA)) using three to four time points, allowing GFR calculation using the slope-intercept method and the Bröchner-Mortensen correction. For each time point, the Jacobsson formula was applied to obtain the single-sample GFR. We used Bland-Altman plots to determine the accuracy of the Jacobsson method at each time point. Results: The single-sample method showed within 10% concordances with the multiple-sample method of 66.4%, 83.6%, 91.4% and 96.0% at the time points 120, 180, 240 and ≥300 min, respectively. Concordance was poorer at lower GFR levels, and this trend is in parallel with increasing age. Results were similar in males and females. Some discordance was found in the obese subjects. Conclusion: Single-sample GFR is highly concordant with a multiple-sample strategy, except in the low GFR range (<30 mL/min).

Visit-to-visit variability of blood pressure and cardiovascular outcomes in patients with stable coronary heart disease. Insights from the STABILITY trial.

AIMS: To study the relation between visit-to-visit variability of blood pressure (BP) and cardiovascular risk in patients with stable coronary heart disease. METHODS AND RESULTS: In 15 828 patients from the STABILITY trial (darapladib vs. placebo in patients with established coronary heart disease), BP variability was assessed by the standard deviation (SD) of systolic BP, the SD of diastolic BP, maximum BP, and minimum BP, from 5 measurements (baseline and months 1, 3, 6, and 12) during the first year after randomisation. Mean (SD) average BP during the first year of study was 131.0 (13.7) mmHg over 78.3 (8.3) mmHg. Mean (SD) of the visit-to-visit SD was 9.8 (4.8) mmHg for systolic and 6.3 (3.0) mmHg for diastolic BP. During the subsequent median follow-up of 2.6 years, 1010 patients met the primary endpoint, a composite of time to cardiovascular death, myocardial infarction, or stroke. In Cox regression models adjusted for average BP during first year of study, baseline vascular disease, treatment, renal function and cardiovascular risk factors, the primary endpoint was associated with SD of systolic BP (hazard ratio for highest vs. lowest tertile, 1.30, 95% CI 1.10-1.53, P = 0.007), and with SD of diastolic BP (hazard ratio for highest vs. lowest tertile, 1.38, 95% CI 1.18-1.62, P < 0.001). Peaks and troughs in BP were also independently associated with adverse events. CONCLUSION: In patients with stable coronary heart disease, higher visit-to-visit variabilities of both systolic and diastolic BP are strong predictors of increased risk of cardiovascular events, independently of mean BP.

Cardiovascular event rates and mortality according to achieved systolic and diastolic blood pressure in patients with stable coronary artery disease: an international cohort study.

BACKGROUND: The optimum blood pressure target in hypertension remains debated, especially in coronary artery disease, given concerns for reduced myocardial perfusion if diastolic blood pressure is too low. We aimed to study the association between achieved blood pressure and cardiovascular outcomes in patients with coronary artery disease and hypertension. METHODS: We analysed data from 22 672 patients with stable coronary artery disease enrolled (from Nov 26, 2009, to June 30, 2010) in the CLARIFY registry (including patients from 45 countries) and treated for hypertension. Systolic and diastolic blood pressures before each event were averaged and categorised into 10 mm Hg increments. The primary outcome was the composite of cardiovascular death, myocardial infarction, or stroke. Hazard ratios (HRs) were estimated with multivariable adjusted Cox proportional hazards models, using the 120-129 mm Hg systolic blood pressure and 70-79 mm Hg diastolic blood pressure subgroups as reference. FINDINGS: After a median follow-up of 5·0 years, increased systolic blood pressure of 140 mm Hg or more and diastolic blood pressure of 80 mm Hg or more were each associated with increased risk of cardiovascular events. Systolic blood pressure of less than 120 mm Hg was also associated with increased risk for the primary outcome (adjusted HR 1·56, 95% CI 1·36-1·81). Likewise, diastolic blood pressure of less than 70 mm Hg was associated with an increase in the primary outcome (adjusted HR 1·41 [1·24-1·61] for diastolic blood pressure of 60-69 mm Hg and 2·01 [1·50-2·70] for diastolic blood pressure of less than 60 mm Hg). INTERPRETATION: In patients with hypertension and coronary artery disease from routine clinical practice, systolic blood pressure of less than 120 mm Hg and diastolic blood pressure of less than 70 mm Hg were each associated with adverse cardiovascular outcomes, including mortality, supporting the existence of a J-curve phenomenon. This finding suggests that caution should be taken in the use of blood pressure-lowering treatment in patients with coronary artery disease. FUNDING: Servier.

Creatinine-based equations for the adjustment of drug dosage in an obese population.

AIM: For drug dosing adaptation, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend using estimated glomerular filtration rate (eGFR) by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, after 'de-indexation' by body surface area (BSA). In pharmacology, the Cockcroft-Gault (CG) equation is still recommended to adapt drug dosage. In the context of obesity, adjusted ideal body weight (AIBW) is sometimes preferred to actual body weight (ABW) for the CG equation. The aim of the present study was to compare the performance of the different GFR-estimating equations, non-indexed or de-indexed by BSA for the purpose of drug-dosage adaptation in obese patients. METHODS: We analysed data from patients with a body mass index (BMI) higher than 30 kg m(-2) who underwent a GFR measurement. eGFR was calculated using the CKD-EPI and Modification of Diet in Renal Disease (MDRD) equations, de-indexed by BSA, and the CG equation, using either ABW, AIBW or lean body weight (LBW) for the weight variable and compared with measured GFR, expressed in ml min(-1). RESULTS: In our population of obese patients, use of the AIBW instead of the ABW in the CG equation, markedly improved the overall accuracy of this equation [57% for CGABW and 79% for CGAIBW (P < 0.05)]. For high BMI (over 40 kg m(-2)), the accuracy of the CG equations is no different when using LBW than when using AIBW. The MDRD and CKD-EPI equations de-indexed by the BSA also performed well, with an overall higher accuracy for the MDRD de-indexed equation [(80% and 76%, respectively (P < 0.05)]. CONCLUSIONS: The de-indexed MDRD equation appeared to be the most suitable for estimating the non-indexed GFR for the purpose of drug dosage adaptation in obese patients.

WNK1-related Familial Hyperkalemic Hypertension results from an increased expression of L-WNK1 specifically in the distal nephron.

Large deletions in the first intron of the With No lysine (K) 1 (WNK1) gene are responsible for Familial Hyperkalemic Hypertension (FHHt), a rare form of human hypertension associated with hyperkalemia and hyperchloremic metabolic acidosis. We generated a mouse model of WNK1-associated FHHt to explore the consequences of this intronic deletion. WNK1(+/FHHt) mice display all clinical and biological signs of FHHt. This phenotype results from increased expression of long WNK1 (L-WNK1), the ubiquitous kinase isoform of WNK1, in the distal convoluted tubule, which in turn, stimulates the activity of the Na-Cl cotransporter. We also show that the activity of the epithelial sodium channel is not altered in FHHt mice, suggesting that other mechanisms are responsible for the hyperkalemia and acidosis in this model. Finally, we observe a decreased expression of the renal outer medullary potassium channel in the late distal convoluted tubule of WNK1(+/FHHt) mice, which could contribute to the hyperkalemia. In summary, our study provides insights into the in vivo mechanisms underlying the pathogenesis of WNK1-mediated FHHt and further corroborates the importance of WNK1 in ion homeostasis and blood pressure.