Search

Metabolic acidosis, defined as a plasma or serum bicarbonate concentration, Graphical Abstract Graphical Abstract

Human kidney organoids possess early glomerular and tubular function. However, little is known about their hormone producing ability. In this report, we show that kidney organoids take up and metabolize inactive 25(OH) vitamin D (25(OH)D3). Uptake of 25(OH)D3 led to a significant upregulation of vitamin D metabolizing CYP24A1 mRNA levels, indicating that kidney organoids possess a feedback mechanism to control active vitamin D (1,25(OH)2D3) levels. They therefore resemble the kidney in its regulation of vitamin D and illustrate the presence of the kidney endocrine system in organoids. These findings underscore the value of kidney organoids for research into the hormonal function of the kidney.

Introduction: Kidney function declines with age, but its determinants in the general population remain incompletely understood. We investigated the rate and determinants of kidney function decline in the general population. Methods: Participants with information on kidney function were selected from a population-based cohort study. Joint models were used to investigate the evolution of the estimated glomerular filtration rate (eGFR, expressed in ml/min per 1.73 m2 per year) and the urine albumin-to-creatinine ratio (ACR, expressed in mg/g per year) with age. We stratified for 8 potential determinants of kidney function decline, including sex, cardiovascular risk factors, and cardiovascular disease. Results: We included 12,062 participants with 85,922 eGFR assessments (mean age 67.0 years, 58.7% women) and 3522 participants with 5995 ACR measurements. The annual eGFR decline was 0.82 and the ACR increase was 0.05. All determinants appeared detrimental for eGFR and ACR, except for prediabetes and higher body mass index which proved only detrimental for ACR. In participants without the determinants, eGFR decline was 0.75 and ACR increase was 0.002. Higher baseline eGFR but faster eGFR decline with age was detected in men (0.92 vs. 0.75), smokers (0.90 vs. 0.75), and participants with diabetes (1.07 vs. 0.78). Conclusion: We identify prediabetes, smoking, and blood pressure as modifiable risk factors for kidney function decline. As with diabetes, hyperfiltration seems important in accelerated kidney function decline in men and smokers. The interpretation of kidney function decline may require adjustment for age and sex to prevent overdiagnosis of chronic kidney disease in aging populations.

Background High mortality and rehospitalization rates demonstrate that improving risk assessment in heart failure patients remains challenging. Individual temporal evolution of kidney biomarkers is associated with poor clinical outcome in these patients and hence may carry the potential to move towards a personalized screening approach. Methods In 263 chronic heart failure patients included in the prospective Bio-SHiFT cohort study, glomerular and tubular biomarker measurements were serially obtained according to a pre-scheduled, fixed trimonthly scheme. The primary endpoint (PE) comprised cardiac death, cardiac transplantation, left ventricular assist device implantation or heart failure hospitalization. Personalized scheduling of glomerular and tubular biomarker measurements was compared to fixed scheduling in individual patients by means of a simulation study, based on clinical characteristics of the Bio-SHiFT study. For this purpose, repeated biomarker measurements and the PE were jointly modeled. For personalized scheduling, using this fitted joint model, we determined the optimal time point of the next measurement based on the patient’s individual risk profile as estimated by the joint model and the maximum information gain on the patient’s prognosis. We compared the schedule’s capability of enabling timely intervention before the occurrence of the PE and number of measurements needed. Results As compared to a pre-defined trimonthly scheduling approach, personalized scheduling of glomerular and tubular biomarker measurements showed similar performance with regard to prognostication, but required a median of 0.4–2.7 fewer measurements per year. Conclusion Personalized scheduling is expected to reduce the number of patient visits and healthcare costs. Thus, it may contribute to efficient monitoring of chronic heart failure patients and could provide novel opportunities for timely adaptation of treatment. Graphic abstract

Background Acidosis-induced kidney injury is mediated by the intrarenal renin-angiotensin system, for which urinary renin is a potential marker. Therefore, we hypothesized that sodium bicarbonate supplementation reduces urinary renin excretion in patients with chronic kidney disease (CKD) and metabolic acidosis. Methods Patients with CKD stage G4 and plasma bicarbonate 15–24 mmol/l were randomized to receive sodium bicarbonate (3 × 1000 mg/day, ~ 0.5 mEq/kg), sodium chloride (2 × 1,00 mg/day), or no treatment for 4 weeks (n = 15/arm). The effects on urinary renin excretion (primary outcome), other plasma and urine parameters of the renin-angiotensin system, endothelin-1, and proteinuria were analyzed. Results Forty-five patients were included (62 ± 15 years, eGFR 21 ± 5 ml/min/1.73m2, plasma bicarbonate 21.7 ± 3.3 mmol/l). Sodium bicarbonate supplementation increased plasma bicarbonate (20.8 to 23.8 mmol/l) and reduced urinary ammonium excretion (15 to 8 mmol/day, both P P = 0.07) and potassium (5.1 to 4.8 mmol/l, P = 0.06) was observed in patients receiving sodium bicarbonate. Sodium bicarbonate did not significantly change the urinary excretion of renin, angiotensinogen, aldosterone, endothelin-1, albumin, or α1-microglobulin. Sodium chloride supplementation reduced plasma renin (166 to 122 ng/L), and increased the urinary excretions of angiotensinogen, albumin, and α1-microglobulin (all P Conclusions Despite correction of acidosis and reduction in urinary ammonium excretion, sodium bicarbonate supplementation did not improve urinary markers of the renin-angiotensin system, endothelin-1, or proteinuria. Possible explanations include bicarbonate dose, short treatment time, or the inability of urinary renin to reflect intrarenal renin-angiotensin system activity. Graphic abstract

COVID-19 has changed the nature of medical consultations, emphasizing virtual patient counselling, with relevance for patients with diabetes insipidus (DI) or hyponatraemia. The main complication of desmopressin treatment in DI is dilutional hyponatraemia. Since plasma sodium monitoring is not always possible in times of COVID-19, we recommend to delay the desmopressin dose once a week until aquaresis occurs allowing excess retained water to be excreted. Patients should measure their body weight daily. Patients with DI admitted to the hospital with COVID-19 have a high risk for mortality due to volume depletion. Specialists must supervise fluid replacement and dosing of desmopressin. Patients after pituitary surgery should drink to thirst and measure their body weight daily to early recognize the development of postoperative SIAD. They should know hyponatraemia symptoms. Hyponatraemia in COVID-19 is common with a prevalence of 20–30% and is mostly due to SIAD or hypovolaemia. It mirrors disease severity and is an early predictor of mortality. Hypernatraemia may also develop in COVID-19 patients, with a prevalence of 3–5%, especially in ICU, and derives from different multifactorial reasons, for example, due to insensible water losses from pyrexia, increased respiration rate and use of diuretics. Hypernatraemic dehydration may contribute to the high risk of acute kidney injury in COVID-19. IV fluid replacement should be administered with caution in severe cases of COVID-19 because of the risk of pulmonary oedema.

Small interfering RNA (siRNA) targeting liver angiotensinogen (AGT) lowers blood pressure, but its effectiveness in hypertensive chronic kidney disease is unknown. Considering that the kidney may generate its own AGT, we assessed the effectiveness of liver-targeted AGT siRNA in the 5/6th Nx (5/6th nephrectomy) rat—a hypertensive chronic kidney disease model. Five weeks after 5/6th Nx (baseline), rats were subjected to vehicle, AGT siRNA, AGT siRNA+losartan, losartan, or losartan+captopril. Baseline mean arterial pressure was 160±6 mm Hg. Over the course of 4 weeks, mean arterial pressure increased further by ≈15 mm Hg during vehicle treatment. This rise was prevented by AGT siRNA. Losartan reduced mean arterial pressure by 37±6 mm Hg and increased plasma Ang (angiotensin) II. Both AGT siRNA and captopril suppressed these effects of losartan, suggesting that its blood pressure–lowering effect relied on stimulation of vasodilator Ang II type 2 receptors by high Ang II levels. Proteinuria and cardiac hypertrophy increased with vehicle, and these increases were comparably abrogated by all treatments. No intervention improved glomerular filtration rate, while siRNA and losartan equally diminished glomerulosclerosis. AGT siRNA±losartan reduced plasma AGT by >95%, and this was accompanied by almost complete elimination of Ang II in kidney and heart, without decreasing renal AGT mRNA. Multiple linear regression confirmed both mean arterial pressure and renal Ang II as independent determinants of proteinuria. In conclusion, AGT siRNA exerts renoprotection in the 5/6th Nx model in a blood pressure–independent manner. This relies on the suppression of renal Ang II formation from liver-derived AGT. Consequently, AGT siRNA may prove beneficial in human chronic kidney disease.

Chronic kidney disease (CKD) causes salt-sensitive hypertension that is often resistant to treatment and contributes to the progression of kidney injury and cardiovascular disease. A better understanding of the mechanisms contributing to salt-sensitive hypertension in CKD is essential to improve these outcomes. This review critically explores these mechanisms by focusing on how CKD affects distal nephron Na+reabsorption. CKD causes glomerulotubular imbalance with reduced proximal Na+reabsorption and increased distal Na+delivery and reabsorption. Aldosterone secretion further contributes to distal Na+reabsorption in CKD and is not only mediated by renin and K+but also by metabolic acidosis, endothelin-1, and vasopressin. CKD also activates the intrarenal renin-angiotensin system, generating intratubular angiotensin II to promote distal Na+reabsorption. High dietary Na+intake in CKD contributes to Na+retention by aldosterone-independent activation of the mineralocorticoid receptor mediated through Rac1. High dietary Na+also produces an inflammatory response mediated by T helper 17 cells and cytokines increasing distal Na+transport. CKD is often accompanied by proteinuria, which contains plasmin capable of activating the epithelial Na+channel. Thus, CKD causes both local and systemic changes that together promote distal nephron Na+reabsorption and salt-sensitive hypertension. Future studies should address remaining knowledge gaps, including the relative contribution of each mechanism, the influence of sex, differences between stages and etiologies of CKD, and the clinical relevance of experimentally identified mechanisms. Several pathways offer opportunities for intervention, including with dietary Na+reduction, distal diuretics, renin-angiotensin system inhibitors, mineralocorticoid receptor antagonists, and K+or H+binders.

Background It is uncertain that chronic heart failure (CHF) patients are susceptible to renal tubular damage with that of worsening renal function (WRF) preceding clinical outcomes.Hypothesis Changes in tubular damage biomarkers are stronger predictors of subsequent clinical events than changes in creatinine (Cr), and both have different clinical determinants.Methods During 2.2 years, we repeatedly simultaneously collected a median of 9 blood and 8 urine samples per patient in 263 CHF patients. We determined the slopes (rates of change) of the biomarker trajectories for plasma (Cr) and urinary tubular damage biomarkers N-acetyl-beta-d-glucosaminidase (NAG), and kidney-injury-molecule (KIM)-1. The degree of tubular injury was ranked according to NAG and KIM-1 slopes: increase in neither, increase in either, or increase in both; WRF was defined as increasing Cr slope. The composite endpoint comprised HF-hospitalization, cardiac death, left ventricular assist device placement, and heart transplantation.Results Higher baseline NT-proBNP and lower eGFR predicted more severe tubular damage (adjusted odds ratio, adj. OR [95%CI, 95% confidence interval] per doubling NT-proBNP: 1.26 [1.07-1.49]; per 10 mL/min/1.73 m(2) eGFR decrease 1.16 [1.03-1.31]). Higher loop diuretic doses, lower aldosterone antagonist doses, and higher eGFR predicted WRF (furosemide per 40 mg increase: 1.32 [1.08-1.62]; spironolactone per 25 mg decrease: 1.76 [1.07-2.89]; per 10 mL/min/1.73 m(2) eGFR increase: 1.40 [1.20-1.63]). WRF and higher rank of tubular injury individually entailed higher risk of the composite endpoint (adjusted hazard ratios, adj. HR [95%CI]: WRF 1.9 [1.1-3.4], tubular 8.4 [2.6-27.9]; when combined risk was highest 15.0 [2.0-111.0]).Conclusion Slopes of tubular damage and WRF biomarkers had different clinical determinants. Both predicted clinical outcome, but this association was stronger for tubular injury. Prognostic effects of both appeared independent and additive.

The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use "kidney" rather than "renal" or "nephro-" when referring to kidney disease and kidney function; (ii) to use "kidney failure" with appropriate descriptions of presence or absence of symptoms, signs, and treatment, rather than "end-stage kidney disease"; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI), rather than alternative descriptions, to define and classify severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate (GFR), rather than "abnormal" or "reduced" kidney function to describe alterations in kidney structure and function. A proposed 5-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary, but they considered standardization of scientific nomenclature to be essential for improving communication.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve hard renal outcomes in type 2 diabetes. This is possibly explained by the fact that SGLT2i normalize the measured glomerular filtration rate (mGFR) by increasing renal vascular resistance, as was shown in young people with type 1 diabetes and glomerular hyperfiltration. Therefore, we compared the renal hemodynamic effects of dapagliflozin with gliclazide in type 2 diabetes. The mGFR and effective renal plasma flow were assessed using inulin and para-aminohippurate clearances in the fasted state, during clamped euglycemia (5 mmol/L) and during clamped hyperglycemia (15 mmol/L). Filtration fraction and renal vascular resistance were calculated. Additionally, factors known to modulate renal hemodynamics were measured. In 44 people with type 2 diabetes on metformin monotherapy (Hemoglobin A1c 7.4%, mGFR 113 mL/min), dapagliflozin versus gliclazide reduced mGFR by 5, 10, and 12 mL/min in the consecutive phases while both agents similarly improved Hemoglobin A1c (-0.48% vs -0.65%). Dapagliflozin also reduced filtration fraction without increasing renal vascular resistance, and increased urinary adenosine and prostaglandin concentrations. Gliclazide did not consistently alter renal hemodynamic parameters. Thus, beyond glucose control, SGLT2i reduce mGFR and filtration fraction in type 2 diabetes. The fact that renal vascular resistance was not increased by dapagliflozin suggests that this is due to post-glomerular vasodilation rather than pre-glomerular vasoconstriction.

COVID-19 has changed the nature of medical consultations, emphasizing virtual patient counseling, with relevance for patients with diabetes insipidus (DI) or hyponatraemia. The main complication of desmopressin treatment in DI is dilutional hyponatraemia. Since plasma sodium monitoring is not always possible in times of COVID-19, we recommend to delay the desmopressin dose once a week until aquaresis occurs allowing excess retained water to be excreted. Patients should measure their body weight daily. Patients with DI admitted to the hospital with COVID-19 have a high risk for mortality due to volume depletion. Specialists must supervise fluid replacement and dosing of desmopressin. Patients after pituitary surgery should drink to thirst and measure their body weight daily to early recognize the development of the postoperative syndrome of inappropriate antidiuresis (SIAD). They should know hyponatraemia symptoms. The prevalence of hyponatraemia in patients with pneumonia due to COVID-19 is not yet known, but seems to be low. In contrast, hypernatraemia may develop in COVID-19 patients in ICU, from different multifactorial reasons, for example, due to insensible water losses from pyrexia, increased respiration rate and use of diuretics. Hypernatraemic dehydration may contribute to the high risk of acute kidney injury in COVID-19. IV fluid replacement should be administered with caution in severe cases of COVID-19 because of the risk of pulmonary oedema.

Background Retrospective studies suggest that tacrolimus-induced hypomagnesaemia is a risk factor for post-transplant diabetes mellitus (PTDM), but prospective studies are lacking. Methods This was a prospective study with measurements of serum magnesium and tacrolimus at pre-specified time points in the first year after living donor kidney transplantation (KT). The role of single nucleotide polymorphisms (SNPs) in hepatocyte nuclear factor 1β (HNF1β) was also explored because HNF1β regulates insulin secretion and renal magnesium handling. Repeated measurement and regression analyses were used to analyse associations with PTDM. Results In our cohort, 29 out of 167 kidney transplant recipients developed PTDM after 1 year (17%). Higher tacrolimus concentrations were significantly associated with lower serum magnesium and increased risk of hypomagnesaemia. Patients who developed PTDM had a significantly lower serum magnesium trajectory than patients who did not develop PTDM. In multivariate analysis, lower serum magnesium, age and body mass index were independent risk factors for PTDM. In recipients, the HNF1β SNP rs752010 G > A significantly increased the risk of PTDM [odds ratio (OR) = 2.56, 95% confidence interval (CI) 1.05–6.23] but not of hypomagnesaemia. This association lost significance after correction for age and sex (OR = 2.24, 95% CI 0.90–5.57). No association between HNF1β SNPs and PTDM was found in corresponding donors. Conclusions A lower serum magnesium in the first year after KT is an independent risk factor for PTDM. The HNF1β SNP rs752010 G > A may add to this risk through an effect on insulin secretion rather than hypomagnesaemia, but its role requires further confirmation.

Background: Impaired renal function predicts mortality in acute coronary syndrome (ACS), but its evolution immediately following index ACS and preceding next ACS has not been described in detail. We aimed to describe this evolution using serial measurements of creatinine, glomerular filtration rate [eGFRCr] and cystatin C [CysC]. Methods: From 844 ACS patients included in the BIOMArCS study, we analysed patient-specific longitudinal marker trajectories from the case-cohort of 187 patients to determine the risk of the endpoint (cardiovascular death or hospitalization for recurrent non-fatal ACS) during 1-year follow-up. Study included only patients with eGFRCr ≥ 30 ml/min/1.73 m2. Survival analyses were adjusted for GRACE risk score and based on data >30 days after the index ACS (mean of 8 sample per patient). Results: Mean age was 63 years, 79% were men, 43% had STEMI, and 67% were in eGFR stages 2–3. During hospitalization for index ACS (median [IQR] duration: 5 (3–7) days), CysC levels indicated deterioration of renal function earlier than creatinine did (CysC peaked on day 3, versus day 6 for creatinine), and both stabilized after two weeks. Higher CysC levels, but not creatinine, predicted the endpoint independently of the GRACE score within the first year after index ACS (adjusted HR [95% CI] per 1SD increase: 1.68 [1.03–2.74]). Conclusion: Immediately following index ACS, plasma CysC levels deteriorate earlier than creatinine-based indices do, but neither marker stabilizes during hospitalization but on average two weeks after ACS. Serially measured CysC levels predict mortality or recurrence of ACS during 1-year follow-up independently of patients' GRACE risk score.

Potassium disorders are common in patients with kidney disease, particularly in patients with tubular disorders and low glomerular filtration rate. A multidisciplinary group of researchers and clinicians met in October 2018 to identify evidence and address controversies in potassium management. The issues discussed encompassed our latest understanding of the regulation of tubular potassium excretion in health and disease; the relationship of potassium intake to cardiovascular and kidney outcomes, with increasing evidence showing beneficial associations with plant-based diet and data to suggest a paradigm shift from the idea of dietary restriction toward fostering patterns of eating that are associated with better outcomes; the paucity of data on the effect of dietary modification in restoring abnormal serum potassium to the normal range; a novel diagnostic algorithm for hypokalemia that takes into account the ascendency of the clinical context in determining cause, aligning the educational strategy with a practical approach to diagnosis; and therapeutic approaches in managing hyperkalemia when chronic and in the emergency or hospital ward. In sum, we provide here our conference deliberations on potassium homeostasis in health and disease, guidance for evaluation and management of dyskalemias in the context of kidney diseases, and research priorities in each of the above areas.

BACKGROUND: Distal diuretics are considered less effective than loop diuretics in CKD. However, data to support this perception are limited. METHODS: To investigate whether distal diuretics are noninferior to dietary sodium restriction in reducing BP in patients with CKD stage G3 or G4 and hypertension, we conducted a 6-week, randomized, open-label crossover trial comparing amiloride/hydrochlorothiazide (5 mg/50 mg daily) with dietary sodium restriction (60 mmol per day). Antihypertension medication was discontinued for a 2-week period before randomization. We analyzed effects on BP, kidney function, and fluid balance and related this to renal clearance of diuretics. RESULTS: A total of 26 patients (with a mean eGFR of 39 ml/min per 1.73 m(2)) completed both treatments. Dietary sodium restriction reduced sodium excretion from 160 to 64 mmol per day. Diuretics produced a greater reduction in 24-hour systolic BP (SBP; from 138 to 124 mm Hg) compared with sodium restriction (from 134 to 129 mm Hg), as well as a significantly greater effect on extracellular water, eGFR, plasma renin, and aldosterone. Both interventions resulted in a similar decrease in body weight and NT-proBNP. Neither approaches decreased albuminuria significantly, whereas diuretics did significantly reduce urinary angiotensinogen and β2-microglobulin excretion. Although lower eGFR and higher plasma indoxyl sulfate correlated with lower diuretic clearance, the diuretic effects on body weight and BP at lower eGFR were maintained. During diuretic treatment, higher PGE2 excretion correlated with lower free water clearance, and four patients developed mild hyponatremia. CONCLUSIONS: Distal diuretics are noninferior to dietary sodium restriction in reducing BP and extracellular volume in CKD. Diuretic sensitivity in CKD is maintained despite lower diuretic clearance. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: DD-study: Diet or Diuretics for Salt-sensitivity in Chronic Kidney Disease (DD), NCT02875886

Rationale & Objective Both hypo- and hyperkalemia can cause fatal cardiac arrhythmias. Although predialysis serum potassium level is a known modifiable risk factor for death in patients receiving hemodialysis, especially for hypokalemia, this risk may be underestimated. Therefore, we investigated the relationship between predialysis serum potassium level and death in incident hemodialysis patients and whether there is an optimum level. Study Design Prospective multicenter cohort study. Setting & Participants 1,117 incident hemodialysis patients (aged >18 years) from the Netherlands Cooperative Study on the Adequacy of Dialysis-2 study were included and followed from their first hemodialysis treatment until death, transplantation, switch to peritoneal dialysis, or a maximum of 10 years. Exposure Predialysis serum potassium levels were obtained every 6 months and divided into 6 categories: ≤4.0 mmol/L, >4.0 mmol/L to ≤4.5 mmol/L, >4.5 mmol/L to ≤5.0 mmol/L, >5.0 mmol/L to ≤5.5 mmol/L (reference), >5.5 mmol/L to ≤6.0 mmol/L, and >6.0 mmol/L. Outcomes 6-month all-cause mortality. Analytical Approach Cox proportional hazards and restricted cubic spline analyses with time-dependent predialysis serum potassium levels were used to calculate the adjusted HRs for death. Results At baseline, the mean age of the patients was 63 years (standard deviation, 14 years), 58% were men, 26% smoked, 24% had diabetes, 32% had cardiovascular disease, the mean serum potassium level was 5.0 mmol/L (standard deviation, 0.8 mmol/L), 7% had a low subjective global assessment score, and the median residual kidney function was 3.5 mL/min/1.73 m2 (IQR, 1.4-4.8 mL/min/1.73 m2). During the 10-year follow-up, 555 (50%) deaths were observed. Multivariable adjusted HRs for death according to the 6 potassium categories were as follows: 1.42 (95% CI, 1.01-1.99), 1.09 (95% CI, 0.82-1.45), 1.21 (95% CI, 0.94-1.56), 1 (reference), 0.95 (95% CI, 0.71-1.28), and 1.32 (95% CI, 0.97-1.81). Limitations Shorter intervals between potassium measurements would have allowed for more precise mortality risk estimations. Conclusions We found a U-shaped relationship between serum potassium level and death in incident hemodialysis patients. A low predialysis serum potassium level was associated with a 1.4-fold stronger risk of death than the optimal level of approximately 5.1 mmol/L. These results may imply the cautious use of potassium-lowering therapy and a potassium-restricted diet in patients receiving hemodialysis., Graphical abstract

Emerging cancer drugs introduce new forms of nephrotoxicity that may also present as electrolyte disorders. Here, we report a patient with non-Hodgkin lymphoma who developed severe hypokalaemia with concurrent hypophosphataemia, hypocalcaemia and hypomagnesaemia secondary to venetoclax. Although electrolyte disorders have been reported during treatment with venetoclax, these were ascribed to tumour lysis prophylaxis. Based on the temporal relationship and urinary studies, we show that venetoclax can cause these electrolyte disorders, likely through an effect on the proximal and distal convoluted tubule. In patients treated with venetoclax, we recommend close monitoring of electrolytes and avoiding co-medication that can contribute to electrolyte disorders.

Introduction Vascular endothelial growth factor (VEGF) inhibitors target the formation of new blood vessels required for growth and metastatic spread of a malignant tumor. Although this is an effective anticancer treatment, many patients develop cardiovascular side effects such as hypertension, requiring dose reduction or early termination of treatment. In animals, VEGF inhibitor-induced hypertension is salt-sensitive. Aim To prospectively study whether salt restriction can prevent or attenuate the rise in blood pressure in response to anti-cancer treatment with VEGF inhibitors. Method This is a single centre prospective open-label intervention study. Patients are eligible when treated with a VEGF inhibitor according to standard of care and developing hypertension or a blood pressure rises of 20 mmHg or more during the first treatment cycle. A salt restricted diet ( Results Between 28 November 2019 and 25 March 2021, 45 patients gave informed consent. Fourteen patients developed hypertension and/or a blood pressure rise of at least 20 mmHg after three- four weeks of treatment making them eligible for the intervention. In 10 patients, salt restriction was the only intervention to reduce the blood pressure rise during the following treatment cycle, leading to a reduction in blood pressure rise of 17 mmHg (10 vs 27 mmHg; p Conclusion Applying salt restriction might be an effective and well tolerated intervention to decrease blood pressure rise during treated with VEGF inhibitors. More importantly, this gives important information about the pathogenesis. Further studies of collected blood and 24h urine samples will allow conclusions on the role of endothelin-1, the renin aldosterone system and prostacyclins. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): De Merel (Charity aiming for research directly benefiting patients; yearly award, success rate ∼30% “Stichting De Merel”)

Background: Hyponatremia is the most common electrolyte disorder with a prevalence of up to 30% in hospitalized patients. In contrast to acute hyponatremia where the need for immediate treatment is well-recognized, chronic hyponatremia is often considered not clinically relevant. This is illustrated by reports showing that appropriate laboratory tests are ordered in Methods: This is a randomized (1:1 ratio) controlled, superiority, parallel-group international multi-center trial with blinded outcome assessment. In total 2,278 participants will be enrolled. Participants will be randomly assigned to undergo either targeted correction of plasma sodium levels or standard of care during hospitalization. The primary outcome is the combined risk of death or re-hospitalization within 30 days.Discussion: All data on hyponatremia and mortality are derived from observational studies and often lack methodologic robustness. Consequently, the direct impact of hyponatremia on mortality and rehospitalization risk is still debated, resulting in a clinical equipoise whether in-hospital chronic hyponatremia should be treated or not. Therefore, a randomized controlled trial is required to study whether targeted plasma sodium correction reduces the risk of mortality and rehospitalization associated with hyponatremia.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03557957.

Magnesium (Mg) is commonly addressed as the “forgotten ion” in medicine. Nonetheless, hypomagnesemia should be suspected in clinical practice in patients with relevant symptomatology and also be considered a predisposing factor for the development of other electrolyte disturbances. Furthermore, chronic hypomagnesemia has been associated with diabetes mellitus and cardiovascular disease. Hypomagnesemia as a consequence of drug therapy is relatively common, with the list of drugs inducing low serum Mg levels expanding. Culprit medications linked to hypomagnesemia include antibiotics (e.g. aminoglycosides, amphotericin B), diuretics, antineoplastic drugs (cisplatin and cetuximab), calcineurin inhibitors, and proton pump inhibitors. In recent years, the mechanisms of drug‐induced hypomagnesemia have been unraveled through the discovery of key Mg transporters in the gut and kidney. This narrative review of available literature focuses on the pathogenetic mechanisms underlying drug‐induced hypomagnesemia in order to increase the insight of clinicians toward early diagnosis and effective management.

BackgroundPrimary nephrogenic diabetes insipidus (NDI) is a rare disorder and little is known about treatment practices and long-term outcome.MethodsPaediatric and adult nephrologists contacted through European professional organizations entered data in an online form.ResultsData 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 ConclusionThis 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.

Urine is commonly used for clinical diagnosis and biomedical research. The discovery of extracellular vesicles (EV) in urine opened a new fast-growing scientific field. In the last decade urinary extracellular vesicles (uEVs) were shown to mirror molecular processes as well as physiological and pathological conditions in kidney, urothelial and prostate tissue. Therefore, several methods to isolate and characterize uEVs have been developed. However, methodological aspects of EV separation and analysis, including normalization of results, need further optimization and standardization to foster scientific advances in uEV research and a subsequent successful translation into clinical practice. This position paper is written by the Urine Task Force of the Rigor and Standardization Subcommittee of ISEV consisting of nephrologists, urologists, cardiologists and biologists with active experience in uEV research. Our aim is to present the state of the art and identify challenges and gaps in current uEV-based analyses for clinical applications. Finally, recommendations for improved rigor, reproducibility and interoperability in uEV research are provided in order to facilitate advances in the field. ESM-U, CG, GV, GJ, IVB, MvR, and VvS, are members of the “IMMPROVE” consortium (Innovative Measurements and Markers for Prostate Cancer Diagnosis and Prognosis using Extracellular Vesicles), which is sponsored by an Alpe d'HuZes grant of the Dutch Cancer Society (grant #EMCR2015-8022). AL is supported by Norges Forskningsråd, Kreftforeningen and Helse Sør-Øst RHF (NO). UE is supported by the NIH, National Heart, Lung, and Blood Institute, Award number K23-HL-126101. CJB and EJH are supported by the Dutch Kidney Foundation (Nierstichting), Award number: CP18.05.

Background and Aims A high potassium (K+) diet is part of a healthy lifestyle and reduces blood pressure. Indeed, salt substitution (replacing NaCl by KCl) reduces the incidence of hypertension. Furthermore, emerging data show that high urinary K+ excretion in patients with chronic kidney disease (CKD) is associated with better kidney outcomes. This suggests that higher dietary K+ intake is also beneficial for patients with CKD, but a potential concern is hyperkalemia. Thus, there is a need for data on the effects of KCl supplementation in patients with CKD. Methods The effect of KCl supplementation (40 mEq/day) was studied by analyzing the 2-week open-label run-in phase of an ongoing randomized clinical trial studying the renoprotective effects of 2-year K+ supplementation in patients with progressive CKD and hypertension. The aims were to (1) analyze the effects of KCl supplementation on whole-blood K+ (WBK+) and acid-base balance, (2) identify factors associated with a rise in WBK+, and (3) identify risk factors for hyperkalemia (WBK+ > 5.5 mEq/L) . Results In 200 patients (68 ± 11 years, 74% males, eGFR 32 ± 9 mL/min/1.73 m2, 84% on renin-angiotensin inhibitors, 39% with diabetes mellitus), KCl supplementation increased urinary K+ excretion from 73 ± 24 to 106 ± 29 mEq/day, urinary chloride excretion from 144 ± 63 to 174 ± 60 mEq/day, WBK+ from 4.3 ± 0.5 to 4.7 ± 0.6 mEq/L, and plasma aldosterone from 294 to 366 ng/L (P < 0.01 for all). Plasma chloride increased from 104 ± 4 to 106 ± 4 mEq/L, while plasma bicarbonate decreased from 24.4 ± 3.4 to 23.6 ± 3.5 mEq/L and venous pH from 7.36 ± 0.03 to 7.34 ± 0.04 (P < 0.001 for all); urinary ammonium excretion did not increase (stable at 17.2 mEq/day). KCl supplementation had no significant effect on plasma renin (33 to 39 pg/mL), urinary sodium excretion (156 ± 63 to 155 ± 65 mEq/day), systolic blood pressure (134 ± 16 to 133 ± 17 mm Hg), eGFR (32 ± 9 to 31 ± 8 mL/min/1.73 m2) or albuminuria (stable at 0.2 g/day). Multivariable linear regression identified that age, female sex, and renin-angiotensin inhibitor use were associated with an increase in WBK+, while diuretic use, baseline WBK+, and baseline bicarbonate were inversely associated with a change in WBK+ after KCl supplementation (Table 1). The majority of patients (n = 181, 91%) remained normokalemic (WBK+ 4.6 ± 0.4 mEq/L). The 19 patients who did develop hyperkalemia (WBK+ 5.9 ± 0.4 mEq/L) were older (75 ± 8 vs. 67 ± 11 years), had lower eGFR (24 ± 8 vs. 32 ± 8 mL/min/1.73 m2), lower baseline bicarbonate (22.3 ± 3.6 vs. 24.6 ± 3.3 mEq/L), higher baseline WBK+ (4.8 ± 0.4 vs. 4.2 ± 0.4 mEq/L), and lower baseline urinary K+ excretion (64 ± 16 vs. 73 ± 25 mEq/day, P < 0.05 for all). Conclusions The majority of patients with advanced CKD remains normokalemic upon KCl supplementation, despite low eGFR, diabetes mellitus, or the use of renin-angiotensin inhibitors. This short-term study illustrates the feasibility of investigating the renoprotective potential of increased K+ intake or KCl-enriched salt in patients with CKD and provides the characteristics of patients in whom this is safe. Our study also shows that KCl supplementation causes a tendency towards metabolic acidosis, possibly by preventing an increase in ammoniagenesis. Longer-term studies are required to study the anti-hypertensive and renoprotective potential of K+ supplementation.

Objective Our group recently showed that animal protein was independently associated with nonalcoholic fatty liver disease (NAFLD). We hypothesize that this may be explained by a high diet-dependent acid load [dietary acid load (DAL)]. Methods This cross-sectional study is embedded in a prospective population-based cohort. We estimated DAL proxies via food-frequency questionnaires using potential renal acid load (PRAL; using dietary protein, phosphorus, potassium, calcium, and magnesium intake), net endogenous acid production (NEAP; using protein and potassium intake), and the animal protein–to–potassium ratio (A:P). We defined NAFLD using ultrasound after excluding secondary steatogenic causes. We used logistic regression models—adjusted for sociodemographic, lifestyle, and metabolic traits—on categorized [quartile (Q)1 to 4] and continuous DAL proxies (allowing for nonlinearity) and NAFLD. Results We included 3882 participants, of which 1337 had NAFLD. All DAL proxies were higher, meaning more acidic, in individuals with NAFLD (PRAL, −2.9 vs −5.5 mEq/d; NEAP, 37.0 vs 35.1 mEq/d; and A:P, 13.3 vs 12.4; all P < 0.001). The highest Q of DAL proxies was associated with NAFLD independent of sociodemographic and lifestyle confounders, but significance dissipated after correction for metabolic confounders and multiple testing. However, the P value for nonlinearity was significant in all DAL proxies (P < 0.001). Natural cubic splines performed better with than without DAL proxies in the fully adjusted model (all P ≤ 0.038). The highest probability of NAFLD was found for an acidic diet. Conclusions This study showed an independent nonlinear association between an acidic diet and NAFLD. Further studies with acid-base biomarkers are needed, but our findings might provide a mechanistic explanation for the harmful association between an animal protein–rich diet and NAFLD.

PubMedID: 30773598 Background. Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-Termoutcome. Methods. We contacted paediatric and adult nephrologists through European professional organizations. Responding clinicians entered demographic, biochemical, genetic and clinical data in an online form. Results. Adequate data were collected on 340 patients (29 countries, female 52%). Mutation testing had been performed on 206 patients (61%); pathogenic mutations were identified in 170 patients (83%). The median (range) presentation age was 0.5 (0-54) years and age at last follow-up was 11.0 (0-70.0) years. Adult height was slightly below average with a mean (SD score) of -0.57 (61.16). There was an increased prevalence of chronic kidney disease (CKD) Stage -2 in children (35%) and adults (82%). Nephrocalcinosis was reported in 88%. Nephrolithiasis was more common with SLC4A1 mutations (42% versus 21%). Thirty-six percent had hearing loss, particularly in ATP6V1B1 (88%). The median (interquartile range) prescribed dose of alkali (mEq/kg/day) was 1.9 (1.2-3.3). Adequate metabolic control (normal plasma bicarbonate and normocalciuria) was achieved in 158 patients (51%), more commonly in countries with higher gross domestic product (67% versus 23%), and was associated with higher height and estimated glomerular filtration rate. Conclusion. Long-Term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD Stage 5. However, 82% of adult patients have CKD Stages 2-4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients. © The Author(s) 2018. Erciyes Üniversitesi Iran University of Medical Sciences Università degli Studi di Padova Chung Hua University American Ornithologists' Union University of Queensland 7Centre University College London Aristotle University of Thessaloniki Lunds Universitet Cairo University National Rosacea Society Heart of England NHS Foundation Trust Centre hospitalier universitaire Sainte-Justine Erasmus Universiteit Rotterdam Aristotle University of Thessaloniki 1Department of Paediatric Nephrology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK, 2Centre for Nephrology, University College London, London, UK, 3Division of Nephrology, Bambino Gesù Children’s Hospital—IRCCS, Rome, Italy, 4Pediatric Nephrology—CHU Arnaud de Villeneuve, Montpellier University Hospital, Montpellier, France, 5Ali-Asghar Clinical Research Development Center, Iran University of Medical Sciences, Tehran, Iran, 6Department of Pediatrics, University of Zielona Góra, Zielona Góra, Poland, 7Centre de référence Maladies rénales rares, Bron, France, 8ASST Niguarda, Milan, Italy, 9Department of Pediatrics, University Hospital of Cologne, Cologne, Germany, 10University Hospital Leuven, Leuven, Belgium, 11King Edward Memorial Hospital, Pune, India, 12Department of Pediatrics, Center of Pediatric Nephrology & Transplantation, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt, 13Hospital Universitario Vall d’Hebron, Barcelona, Spain, 14Division of Pediatric Nephrology, NRS Medical College, Kolkata, India, 15Pediatric Nephrology, Dialysis and Transplant Unit, Azienda Ospedaliera & University of Padova, Padova, Italy, 16University Children’s Hospital, Medical School, Skopje, Macedonia, 17National Medical and Research Centre for Children’s Health, Moscow, Russia, 18Centre Hospitalier Universitaire de Toulouse, Service de Nephrologie Pediatrique, Hopital des Enfants, Centre De Reference des Maladies Rénales Rares du Sud Ouest, Toulouse, France, 19Hospital Universitario Central de Asturias, Oviedo, Spain, 20Radboud University Medical Centre, Nijmegen, The Netherlands, 21Nephrology and Dialysis Unit, Department of Woman, Child and Urological Diseases, Azienda Ospedaliero—Universitaria Sant’Orsola-Malpighi, Bologna, Italy, 22Charité Universitätsmedizin Berlin, Berlin, Germany, 23University Children’s Hospital, Münster, Germany, 24Wilhelmina Children’s Hospital, University Medical Center, Utrecht, The Netherlands, 25Centro Hospitalar de Lisboa Central, Lisbon, Portugal, 26Fourth Pediatric Department, Aristotle University, Thessaloniki, Greece, 27Lady Cilento Children’s Hospital, Brisbane, Australia, 28School of Medicine, the University of Queensland, Brisbane, Australia, 29Department of Pediatric Nephrology, Pamukkale University School of Medicine, Denizli, Turkey, 30Nephrology Unit Azienda Ospedaliera, Papa Giovani XXIII, Bergamo, Italy, 31Karolinska Institutet, Lund University,Sweden,GroupFlorenceNightingaleHospitals,Ist32· anbul, Turkey,Fondazione Policlinico A. Gemelli, Universita` Cattolica del33 Sacro Cuore, Rome, Italy, 34Pediatric Nephrology Center of Excellence and Pediatric Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia, 35Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca’ Granda—Ospedale Maggiore Policlinico, Milan, Italy, 36Department of Translational Medical Sciences, University of Campania “L. Vanvitelli”, Naples, Italy, 37Pediatric Department, Lillebaelt Hospital Kolding, Kolding, Denmark, 38Division of Pediatric Nephrology, Center for Pediatrics and Adolescent Medicine, University Hospital of Heidelberg, Heidelberg, Germany, 39Haseki Education and Research Hospital, Istanbul, Turkey, 40Belarusian State Medical University, Minsk, Belarus, 41Department of Genetics, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France, 42Pediatric Nephrology Unit, AOU Policlinic G Martino, Messina, Italy, 43Necker Hospital, Paris, France, 44Faculty of Medicine, Department of Pediatric Nephrology, Erciyes University, Kayseri, Turkey, 45Cukurova University, Adana, Turkey, 46Nephrology Centre, Santaros Klinikos, Vilnius University, Vilnius, Lithuania, 47University Hospital of Lille, France, 48Department of Renal Medicine, Royal Brisbane and Women’s Hospital, Brisbane, Australia, 49University Hospital Centre Zagreb, Zagreb, Croatia, 50Department of Pediatrics, SMDZ in Zabrze, SUM in Katowice, Poland, 51Department of Pediatric Nephrology, Hannover Medical School, Hannover, Germany, The European dRTA Consortium consists of the authors, as well as: Amira Peco-Antic(Department of Nephrology, University Children’s Hospital, Belgrade, Serbia), Amrit Kaur (Department of Paediatric Nephrology, Royal Manchester Children’s Hospital, Manchester, UK), Antonino Paglialunga (ASP de Ragusa, Modica, Italy), Aude Servais (Department of Nephrology, Centre Hospitalier Universitaire Necker, APHP, Paris, France), Branko Lutovac (Clinical Centre of Montenegro, Institute for Children’s Disease, Podgorica, Montenegro), Ewout J. Hoorn (Erasmus Medical Center, Rotterdam, The Netherlands), Hadas Shasha-Lavsky (Galilee Medical Center, Nahariya, Israel), Jerome Harambat (Pediatric Nephrology Unit, Bordeaux University Hospital, Bordeaux, France), Astrid Godron-Dubrasquet (Pediatric Nephrology Unit, Bordeaux University Hospital, Bordeaux, France), Kathrin Buder (Pediatric Department, University Hospital, Carl Gustav Carus Dresden, Dresden, Germany), Lise Allard (Department of Pediatrics, Angers University Hospital, Angers, France), Ludwig Patzer (Children’s Hospital St Elisabeth and St Barbara, Halle, Germany), Marina Shumikhina (Filatov Children’s Clinical Hospital No. 13, Moscow, Russia), Matthias Hansen (KfH Centre of Paediatric Nephrology, Clementine Children’s Hospital, Frankfurt, Germany), Nikoleta Printza (First Pediatric Department, Aristotle University, Thessaloniki, Greece), Nuran Küc¸ük (Kartal Dr. Lütfi Kırdar Training and Research Hospital, İstanbul, Turkey), Ortraud Beringer (University Children’s Hospital, Ulm, Germany), Rajendra Bhimma (Inkosi Albert Luthuli, Central Hospital, Durban, South Africa), Rimante Cerkauskiene (Faculty of Medicine, Children’s Hospital, Vilnius University, Vilnius, Lithuania; Santaros Klinikos, Vilnius University Hospital, Vilnius, Lithuania), Thomas J. Neuhaus (Children’s Hospital of Lucerne, Cantonal Hospital of Lucerne, Lucerne, Switzerland), Valbona Stavileci (Pediatric Clinic, Prishtina, Kosovo), Tim Ulinski (Pediatric Nephrology Department, Armand Trousseau University Hospital, APHP, Paris, France), Nida Temizkan Dincel (Health Sciences University, Izmir Dr Behcet Uz Children’s Hospital, İzmir, Turkey) and Nilufar Mohebbi (Division of Nephrology, University Hospital Zurich, Zurich, Switzerland)

The worldwide increase in the number of patients with end-stage renal disease leads to a growing waiting list for kidney transplantation resulting from the scarcity of kidney donors. Therefore, alternative treatment options for patients with end-stage renal disease are being sought. In vitro differentiation of stem cells into renal tissue is a promising approach to repair nonfunctional kidney tissue. Impressive headway has been made in the use of stem cells with the use of adult renal progenitor cells, embryonic stem cells, and induced pluripotent stem cells for the development toward primitive kidney structures. Currently, efforts are directed at improving long-term maintenance and stability of the cells. This review aims to provide a comprehensive overview of the cell sources used for the generation of kidney cells and strategies used for transplantation in in vivo models. Furthermore, it provides a perspective on stability and safety during future clinical application of in vitro generated kidney cells.

The aim of the study is to review recent studies on the management of acute and chronic hyponatremia.In acute symptomatic hyponatremia, bolus infusion of hypertonic saline improves hyponatremia and neurological status more quickly than continuous infusion. In chronic hyponatremia, newly identified predictors of nonresponse to fluid restriction include a high urine osmolality (500 mOsm/kg) and high urine sodium (133 mmol/l). Vasopressin-receptor antagonists effectively raise the serum sodium concentration in patients with euvolemic or hypervolemic hyponatremia but have a risk of overcorrection, even at low doses. Several observational studies now support the use of urea for a more gradual correction of hyponatremia without a risk of overcorrection. Recently identified risk factors for overcorrection include lower serum sodium at presentation, polydipsia, hypovolemia, and early urine output during treatment. Specific treatments with potential efficacy are the use of intravenous albumin for hyponatremia because of liver cirrhosis, and fludrocortisone for hyponatremia in tuberculous meningitis.The recent data will help to further optimize and personalize the management of patients with acute and chronic hyponatremia. However, most data are still observational and retrospective. Therefore, the field is in need of prospective studies comparing interventions for chronic hyponatremia and focusing on patient-relevant outcomes.

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are well-established glucose-lowering drugs for type 2 diabetes mellitus (T2DM) management. Acute GLP-1RA administration increases urinary excretion of sodium and other electrolytes. However, the renal tubular effects of prolonged GLP-1RA treatment are largely unknown. In this secondary analysis of a randomized trial, we determined the renal tubular effects of 8-wk treatment with 20 μg lixisenatide, a short-acting (prandial) GLP-1RA, versus titrated once-daily insulin glulisine in 35 overweight T2DM-patients on stable insulin glargine background therapy (age: 62 ± 7 yr, glycated hemoglobin: 8.0 ± 0.9%, estimated glomerular filtration rate: >60 ml·min−1·1.73 m−2). After a standardized breakfast, lixisenatide increased absolute and fractional excretions of sodium, chloride, and potassium and increased urinary pH. In contrast, lixisenatide reduced absolute and fractional excretions of magnesium, calcium, and phosphate. At week 8, patients treated with lixisenatide had significantly more phosphorylated sodium-hydrogen exchanger isoform 3 (NHE3) in urinary extracellular vesicles than those on insulin glulisine treatment, which suggested decreased NHE3 activity in the proximal tubule. A rise in postprandial blood pressure with lixisenatide partly explained the changes in the urinary excretion of sodium, potassium, magnesium, and phosphate and the changes in urinary pH. In conclusion, lixisenatide affects postprandial urinary excretion of several electrolytes and increases urinary pH compared with insulin glulisine in T2DM patients after 8 wk of treatment. This is most likely explained by a drug-induced rise in blood pressure or direct inhibitory effects on NHE3 in the proximal tubule.

Background: Distal renal tubular acidosis (dRTA) can be inherited or acquired. Case Presentation: Here, we describe the case of a 45-year-old female patient with non-anion gap metabolic acidosis, hypokalemia, and alkaline urine. She had a history of rheumatoid arthritis and kidney stones and failed to acidify urine upon the fludrocortisone and furosemide test. Therefore, the diagnosis of dRTA secondary to an autoimmune disease was made. A kidney biopsy was examined for markers of acid-secretory intercalated cells. Surprisingly, no obvious difference in the relative number of acid-secretory intercalated cells or in the distribution of major proteins involved in acid secretion was found. Furthermore, increasing doses of potassium citrate failed to correct the hypokalemia and acidosis. Since these findings were rather atypical for autoimmune dRTA, alternative causes of her hypokalemia and metabolic acidosis were sought. The patient was found to chronically consume laxatives, which can also cause kidney stones and may result in a false-positive urinary acidification test. Conclusion: Chronic laxative abuse may mimic dRTA and should therefore be considered in unexplained hypokalemia with non-anion gap metabolic acidosis.

Chronic kidney disease contributes to hypertension, but the mechanisms are incompletely understood. To address this, we applied the 5/6th nephrectomy rat model to characterize hypertension and the response to dietary salt and renin-Angiotensin inhibition. 5/6th nephrectomy caused low-renin, salt-sensitive hypertension with hyperkalemia and unsuppressed aldosterone. Compared with sham rats, 5/6th nephrectomized rats had lower Na/H exchanger isoform 3, Na-K-2Cl cotransporter, Na-Cl cotransporter, a-epithelial Na channel (ENaC), and Kir4.1 levels but higher serum and glucocorticoid-regulated kinase 1, prostasin, c-ENaC, and Kir5.1 levels. These differences correlated with plasma renin, aldosterone, and/or K. On a normal-salt diet, adrenalectomy (0 ± 9 mmHg) and spironolactone (11 ± 10 mmHg) prevented a progressive rise in blood pressure (10 ± 8 mmHg), and this was enhanced in combination with losartan (41 ± 12 and 43 ± 9 mmHg). A high-salt diet caused skin Na and water accumulation and aggravated hypertension that could only be attenuated by spironolactone (16 ± 7 mmHg) and in which the additive effect of losartan was lost. Spironolactone also increased natriuresis, reduced skin water accumulation, and restored vasorelaxation. In summary, in the 5/6th nephrectomy rat chronic kidney disease model, salt-sensitive hypertension develops with a selective increase in c-ENaC and despite appropriate transporter adaptations to low renin and hyperkalemia. With a normal-salt diet, hypertension in 5/6th nephrectomy depends on angiotensin II and aldosterone, whereas a high-salt diet causes more severe hypertension mediated through the mineralocorticoid receptor. NEW and NOTEWORTHY Chronic kidney disease (CKD) causes salt-sensitive hypertension, but the interactions between dietary salt and the renin-Angiotensin system are incompletely understood. In rats with CKD on a normal-salt diet targeting aldosterone, the mineralocorticoid receptor (MR) and especially angiotensin II reduced blood pressure. On a high-salt diet, however, only MR blockade attenuated hypertension. These results reiterate the importance of dietary salt restriction to maintain renin-Angiotensin system inhibitor efficacy and specify the MR as a target in CKD.

Currently an evidence-based approach to nephrolithiasis is hampered by a lack of randomized controlled trials. Thus, there is a need for common platforms for data sharing and recruitment of patients to interventional studies. A first step in achieving this objective would be to share practice methods and protocols for subsequent standardization in what is still a heterogeneous clinical field. Here, we present the results of a pilot survey performed across 24 European clinical kidney stone centers. The survey was distributed by a voluntary online questionnaire circulated between June 2017 and January 2018. About 46% of centers reported seeing on average 20 or more patients per month. Only 21% adopted any formal referral criteria. Centers were relatively heterogeneous in respect of the definition of an incident stone event. The majority (71%) adopted a formal follow-up scheme; of these, 65% included a follow-up visit at 3 and 12 months, and 41% more than 12 months. In 79% of centers some kind of imaging was performed systematically. 75% of all centers performed laboratory analyses on blood samples at baseline and during follow-up. All centers performed laboratory analyses on 24-h urine samples, the majority (96%) at baseline and during follow-up. There was good correspondence across centers for analyses performed on 24-h urine samples, although the methods of 24-h urine collection and analysis were relatively heterogeneous. Our survey among 24 European stone centers highlights areas of homogeneity and heterogeneity that will be investigated further. Our aim is the creation of a European network of stone centers sharing practice patterns and hosting a common database for research and guidance in clinical care.

Purpose: Calcimimetics are currently indicated for severe secondary hyperparathyroidism (SHPT). However, the role of parathyroidectomy (PTX) for these patients is still under debate, and its impact on subsequent kidney transplantation (KTX) is unclear. In this study, we compare the outcomes of kidney transplantation after PTX or medical treatment. Methods: Patients who underwent KTX and had SHPT were analyzed retrospectively. Two groups were selected (patients who had either PTX or calcimimetics prior to KTX) using a propensity score for sex, age, donor type, and parathyroid hormone levels (PTH) during dialysis. The primary outcome was graft failure, and secondary outcomes were surgical KTX complications, survival, serum PTH, serum calcium, and serum phosphate levels post-KTX. Results: Matching succeeded for 92 patients. After PTX, PTH was significantly lower on the day of KTX as well as at 1 and 3 years post-KTX (14.00 pmol/L (3.80–34.00) vs. 71.30 pmol/L (30.70–108.30), p < 0.01, 10.10 pmol/L (2.00–21.00) vs. 32.35 pmol/L (21.58–51.76), p < 0.01 and 13.00 pmol/L (6.00–16.60) vs. 19.25 pmol/L (13.03–31.88), p = 0.027, respectively). No significant differences in post-KTX calcium and phosphate levels were noted between groups. Severe KTX complications were more common in the calcimimetics group (56.5% vs. 30.4%, p = 0.047). There were no differences in 10-year graft failure and overall survival. Conclusion: PTX resulted in lower PTH after KTX in comparison to patients who received calcimimetics. Severe complications were more common after calcimimetics, but graft failure and overall survival were similar.

With expanding kidney transplantation programs, remaining hemodialysis patients are more likely to have a high comorbidity burden and may therefore be more prone to lose muscle mass. Our aim was to analyze risk factors for muscle loss in hemodialysis patients with high comorbidity. Fifty-four chronic hemodialysis patients (Charlson Comorbidity Index 9.0 &plusmn, 3.4) were followed for 20 weeks using 4-weekly measurements of lean tissue mass, intracellular water, and body cell mass (proxies for muscle mass), handgrip strength (HGS), and biochemical parameters. Mixed models were used to analyze covariate effects on LTM. LTM (&minus, 6.4 kg, interquartile range [IQR] &minus, 8.1 to &minus, 4.8), HGS (&minus, 1.9 kg, IQR &minus, 3.1 to &minus, 0.7), intracellular water (&minus, 2.11 L, IQR &minus, 2.9 to &minus, 1.4) and body cell mass (&minus, 4.30 kg, IQR &minus, 5.9 to &minus, 2.9) decreased in all patients. Conversely, adipose tissue mass increased (4.5 kg, IQR 2.7 to 6.2), resulting in no significant change in body weight (&minus, 0.5 kg, IQR &minus, 1.0 to 0.1). Independent risk factors for LTM loss over time were male sex (&minus, 0.26 kg/week, 95% CI &minus, 0.33 to &minus, 0.19), C-reactive protein above median (&minus, 0.1 kg/week, 95% CI &minus, 0.2 to &minus, 0.001), and baseline lean tissue index &sup3, 10th percentile (&minus, 1.6 kg/week, 95% CI &minus, 2.1 to &minus, 1.0). Age, dialysis vintage, serum albumin, comorbidity index, and diabetes did not significantly affect LTM loss over time. In this cohort with high comorbidity, we found universal and prominent muscle loss, which was further accelerated by male sex and inflammation. Stable body weight may mask muscle loss because of concurrent fat gain. Our data emphasize the need to assess body composition in all hemodialysis patients and call for studies to analyze whether intervention with nutrition or exercise may curtail muscle loss in the most vulnerable hemodialysis patients.

BACKGROUND AND OBJECTIVES: Nephrolithiasis is a common health problem in autosomal dominant polycystic kidney disease (ADPKD) and significantly contributes to patient morbidity. Recently, Tolvaptan has been introduced for the treatment of ADPKD, but whether it is associated with alterations of the urinary lithogenic risk profile remains unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted an analysis of participants enrolled in the Bern ADPKD registry, a prospective observational cohort study. Twenty-four-hour urine analyses were performed at baseline and then at yearly follow-ups. Relative supersaturation ratios for calcium oxalate, brushite, and uric acid were calculated with the program EQUIL2. Unadjusted and multivariable mixed-effects linear regression models, adjusted for age, sex, body mass index, eGFR, net acid excretion, and height-adjusted total kidney volume, were used to assess the association of Tolvaptan with urinary parameters relevant for kidney stone formation. The maximum individual follow-up time was 3 years, median follow-up time 1.9 years, and cumulative follow-up time 169 years. RESULTS: In total, 125 participants (38 with and 87 without Tolvaptan treatment) were included in the analysis. In multivariable analysis, Tolvaptan treatment was associated [adjusted estimate of the difference between Tolvaptan and no Tolvaptan; 95% confidence interval (CI)] with lower urine relative supersaturation ratios for calcium oxalate (−0.56; 95% CI, −0.82 to −0.3; P

Background Live donor nephrectomy is a safe procedure. However, long-term donor prognosis is debated, necessitating high-quality studies. Methods A follow-up study of 761 living kidney donors was conducted, who visited the outpatient clinic and were propensity score matched and compared to 1522 non-donors from population-based cohort studies. Primary outcome was kidney function. Secondary outcomes were BMI (kg/m2), incidences of hypertension, diabetes, cardiovascular events, cardiovascular and overall mortality, and quality of life. Results Median follow-up after donation was 8.0 years. Donors had an increase in serum creatinine of 26 μmol/l (95% CI 24–28), a decrease in eGFR of 27 ml/min/1.73 m2 (95% CI − 29 to − 26), and an eGFR decline of 32% (95% CI 30–33) as compared to non-donors. There was no difference in outcomes between the groups for ESRD, microalbuminuria, BMI, incidence of diabetes or cardiovascular events, and mortality. A lower risk of new-onset hypertension (OR 0.45, 95% CI 0.33–0.62) was found among donors. The EQ-5D health-related scores were higher among donors, whereas the SF-12 physical and mental component scores were lower. Conclusion Loss of kidney mass after live donation does not translate into negative long-term outcomes in terms of morbidity and mortality compared to non-donors. Trial registration Dutch Trial Register NTR3795.

The decreased risk of osteoporotic fractures in thiazide diuretics (TD) users is possibly not only caused by an increase in bone mineral density (BMD), but by an increase in other determinants of bone strength as well, such as the trabecular bone score (TBS). To test this hypothesis, we studied the association between TD use and both lumbar spine BMD (LS-BMD) and lumbar spine TBS (LS-TBS) cross-sectionally in 6096 participants from the Rotterdam Study, as well as the association between TD use and bone turnover estimated by serum osteocalcin levels. We found that past and current use of TD were associated with an increase of LS-BMD (β = 0.021 g/cm 2 (95% CI: 0.006;0.036) and β = 0.016 g/cm 2 (95% CI: 0.002;0.031), respectively). Use of ≥1 defined daily dose (DDD) (β = 0.028, 95% CI: 0.010;0.046; p for trend within DDD of use 365 days (β = 0.033, 95% CI: 0.014;0.052; p for trend within duration of use

Aims: To determine the effects of glucagon-like peptide (GLP)-1 receptor agonists (RA) on uric acid (UA) levels and kidney UA clearance. Material and methods: This study involved post-hoc analyses of 4 controlled clinical trials, which assessed actions of GLP-1RA administration on kidney physiology. The immediate effects of GLP-1RA exenatide infusion vs placebo were determined in 9 healthy overweight men (Study-A) and in 52 overweight T2DM patients (Study-B). The effects of 12 weeks of long-acting GLP-1RA liraglutide vs placebo in 36 overweight T2DM patients (Study-C) and of 8 weeks of short-acting GLP-1RA lixisenatide vs once-daily titrated insulin glulisine in 35 overweight T2DM patients (Study-D) were also examined. Plasma UA, fractional (inulin-corrected) and absolute urinary excretion of UA (UEUA) and sodium (UENa), and urine pH were determined. Results: Median baseline plasma UA level was 5.39 to 6.33 mg/dL across all studies (17%-22% of subjects were hyperuricaemic). In Study-A, exenatide infusion slightly increased plasma UA (+0.07 ± 0.02 mg/dL, P =.04), and raised absolute-UEUA (+1.58 ± 0.65 mg/min/1.73 m2, P =.02), but did not affect fractional UEUA compared to placebo. Fractional UEUA and absolute UEUA correlated with increases in urine pH (r:0.86, P =.003 and r:0.92, P

Context Increased renal sodium reabsorption contributes to hypertension in Cushing syndrome (CS). Renal sodium transporters can be analyzed noninvasively in urinary extracellular vesicles (uEVs). Objective To analyze renal sodium transporters in uEVs of patients with CS and hypertension. Design Observational study. Setting University hospital. Participants The uEVs were isolated by ultracentrifugation and analyzed by immunoblotting in 10 patients with CS and 7 age-matched healthy participants. In 7 patients with CS, uEVs were analyzed before and after treatment. Main outcome measure Abundance of protein in uEVs. Results The 10 patients with CS were divided in those with suppressed and nonsuppressed renin-angiotensin-aldosterone system (RAAS; n = 5 per group). Patients with CS with suppressed RAAS had similar blood pressure but significantly lower serum potassium than patients with CS with nonsuppressed RAAS. Compared with healthy participants, only patients with suppressed RAAS had higher phosphorylated Na+-K+-Cl- cotransporter type 2 (pNKCC2) and higher total and phosphorylated Na+-Cl- cotransporter (pNCC) in uEVs. Serum potassium but not urinary free cortisol correlated with pNKCC2, pNCC, and Na+-Cl- cotransporter (NCC) in uEVs. Treatment of CS reversed the increases in pNKCC2, NCC, and pNCC. Conclusions CS increases renal sodium transporter abundance in uEVs in patients with hypertension and suppressed RAAS. Potassium has recently been identified as an important driver of NCC activity, and low serum potassium may also contribute to increased renal sodium reabsorption and hypertension in CS. These results may also be relevant for hypertension induced by exogenous glucocorticoids.

In nephrology, repeated measures are frequently available (glomerular filtration rate or proteinuria) and linked to adverse outcomes. However, several features of these longitudinal data should be considered before making such inferences. These considerations are discussed, and we describe how joint modeling of repeatedly measured and time-to-event data may help to assess disease dynamics and to derive personalized prognosis. Joint modeling combines linear mixed-effects models and Cox regression model to relate patient-specific trajectory to their prognosis. We describe several aspects of the relationship between time-varying markers and the endpoint of interest that are assessed with real examples to illustrate the aforementioned aspects of the longitudinal data provided. Thus, joint models are valuable statistical tools for study purposes but also may help health care providers in making well-informed dynamic medical decisions.

Background In autosomal dominant polycystic kidney disease (ADPKD), hypertension is prevalent and cardiovascular events are the main cause of death. Thiazide diuretics are often prescribed as second-line antihypertensives, on top of renin–angiotensin–aldosterone system (RAAS) blockade. There is a concern, however, that diuretics may increase vasopressin concentration and RAAS activity, thereby worsening disease progression in ADPKD. We aimed to investigate the validity of these suggestions. Methods We analysed an observational cohort of 533 ADPKD patients. Plasma copeptin (surrogate for vasopressin), aldosterone and renin were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. Linear mixed models were used to assess the association of thiazide use with estimated glomerular filtration rate (eGFR) decline and Cox proportional hazards models for the association with the composite kidney endpoint of incident end-stage kidney disease, 40% eGFR decline or death. Results A total of 23% of participants (n = 125) used thiazide diuretics at baseline. Compared with non-users, thiazide users were older, a larger proportion was male, they had lower eGFRs and similar blood pressure under more antihypertensives. Plasma copeptin was higher, but this difference disappeared after adjustment for age and sex. Both renin and aldosterone were higher in thiazide users. There was no difference between thiazide users and non-users in the rate of eGFR decline {difference −0.35 mL/min/1.73 m2 per year [95% confidence interval (CI) −0.83 to –0.14], P = 0.2} during 3.9 years of follow-up (interquartile range 2.5–4.9). This did not change after adjustment for potential confounders [difference final model: 0.08 mL/min/1.73 m2 per year [95% CI −0.46 to –0.62], P = 0.8). In the crude model, thiazide use was associated with a higher incidence of the composite kidney endpoint [hazard ratio (HR) 1.53 (95% CI 1.05–2.23), P = 0.03]. However, this association lost significance after adjustment for age and sex and remained unassociated after adjustment for additional confounders [final model: HR 0.80 (95% CI 0.50–1.29), P = 0.4]. Conclusions These data do not show that thiazide diuretics have a detrimental effect on the rate of disease progression in ADPKD and suggest that these drugs can be prescribed as second-line antihypertensives.

Acute kidney injury (AKI) is a common postoperative complication after liver transplantation (LT). The occurrence of postoperative AKI after LT (Post-LT AKI) is associated with inferior patient and graft outcomes. Post-LT AKI is multifactorial in origin and has been related to the severity of liver disease, pre-LT renal dysfunction, graft quality, perioperative events and toxicity of immunosuppressive therapy. Furthermore it is thought that hepatic ischaemia reperfusion injury might be a driving force in the aetiology of post-LT AKI. Novel biomarkers for AKI are emerging and can be useful for early identification and characterization of AKI. There is a clear need for strategies aimed at preventing or treating post-LT AKI. Several pharmacological and non-pharmacological interventions have been studied, but so far failed to show any benefit in the prevention of post-LT AKI. Further studies are needed to develop and evaluate new interventions aimed at preventing post-LT AKI and improve patient outcomes.

Hyponatremia is a common water balance disorder that often poses a diagnostic or therapeutic challenge. Therefore, guidelines were developed by professional organizations, one from within the United States (2013) and one from within Europe (2014). This review discusses the diagnosis and treatment of hyponatremia, comparing the two guidelines and highlighting recent developments. Diagnostically, the initial step is to differentiate hypotonic from nonhypotonic hyponatremia. Hypotonic hyponatremia is further differentiated on the basis of urine osmolality, urine sodium level, and volume status. Recently identified parameters, including fractional uric acid excretion and plasma copeptin concentration, may further improve the diagnostic approach. The treatment for hyponatremia is chosen on the basis of duration and symptoms. For acute or severely symptomatic hyponatremia, both guidelines adopted the approach of giving a bolus of hypertonic saline. Although fluid restriction remains the first-line treatment for most forms of chronic hyponatremia, therapy to increase renal free water excretion is often necessary. Vasopressin receptor antagonists, urea, and loop diuretics serve this purpose, but received different recommendations in the two guidelines. Such discrepancies may relate to different interpretations of the limited evidence or differences in guideline methodology. Nevertheless, the development of guidelines has been important in advancing this evolving field.

Background A significant proportion of patients with chronic kidney disease and secondary hyperparathyroidism (HPT) remain hyperparathyroid after kidney transplantation, a state known as tertiary HPT. Without treatment, tertiary HPT can lead to diminished kidney allograft and patient survival. Parathyroidectomy was commonly performed to treat tertiary HPT until the introduction of the calcimimetic drug, cinacalcet. It is not known whether surgery or medical treatment is superior for tertiary HPT. Methods A systematic review was performed and medical literature databases were searched for studies on the treatment of tertiary HPT that were published after the approval of cinacalcet. Results A total of 1669 articles were identified, of which 47 were included in the review. Following subtotal and total parathyroidectomy, initial cure rates were 98·7 and 100 per cent respectively, but in 7·6 and 4 per cent of patients tertiary HPT recurred. After treatment with cinacalcet, 80·8 per cent of the patients achieved normocalcaemia. Owing to side-effects, 6·4 per cent of patients discontinued cinacalcet treatment. The literature regarding graft function and survival is limited; however, renal graft survival after surgical treatment appears comparable to that obtained with cinacalcet therapy. Conclusion Side-effects and complications of both treatment modalities were mild and occurred in a minority of patients. Surgical treatment for tertiary HPT has higher cure rates than medical therapy.