Effect of the DASH diet on the sodium-chloride cotransporter and aquaporin-2 in urinary extracellular vesicles.

The Dietary Approach to Stop Hypertension (DASH) diet, with its low sodium and high potassium content, acts like a diuretic by reducing sodium reabsorption in the kidney's distal convoluted tubule but without the side effects. Previous studies based on animal models didn't explore changes in human ion channel proteins. Recent insights into urinary extracellular vesicles (uEVs) suggest they reflect kidney tissue and physiological modifications. In our inpatient study, we shifted hypertensive volunteers from an American diet to the DASH diet, examining changes in those with stage 1 untreated hypertension. We analyzed a large range of pure uEVs, from small to large, in urine samples from nine volunteers over three time points. Mass spectrometry of these uEVs identified 1,800 proteins, revealing an increase in SCL12A3 (NCC) and a decrease in aquaporin 2 (AQP2). Immunoblotting showed an increase in activated (phosphorylated) NCC ratio to total NCC and a decrease in AQP2 from day 5 to 11, indicating the DASH diet induces measurable kidney responses via uEV protein abundance changes. This non-invasive method offers new insights into the diet's renal mechanism. Future studies should confirm these findings in a larger cohort, clarify the drivers behind NCC and AQP2 changes, their impact on hypertension, and investigate if uEVs also act as a waste pathway for inactive proteins, expanding our understanding of dietary effects on kidney physiology.

Animal models to study cognitive impairment of chronic kidney disease.

Mild cognitive impairment (MCI) is common in people with chronic kidney disease (CKD) and its prevalence increases with progressive loss of kidney function. MCI is characterized by a decline in cognitive performance greater than expected for an individual age and education level but with minimal impairment of instrumental activities of daily living. Deterioration can affect one or several cognitive domains (attention, memory, executive functions, language, and perceptual motor or social cognition). Given the increasing prevalence of kidney disease, more and more people with CKD will also develop MCI causing an enormous disease burden for these individuals, their relatives and society. However, the underlying pathomechanisms are poorly understood and current therapies mostly aim at supporting patients in their daily life. This illustrates the urgent need to elucidate the pathogenesis, and potential therapeutic targets and test novel therapies in appropriate preclinical models. Here, we will outline the necessary criteria for experimental modelling of cognitive disorders in CKD. We discuss the use of mice, rats and zebrafish as model systems and present valuable techniques through which kidney function and cognitive impairment can be assessed in this setting. Our objective is to enable researchers to overcome hurdles and accelerate preclinical research aimed at improving therapy of people with CKD and MCI.

Discrepancies between transcutaneous and estimated glomerular filtration rates in rats with chronic kidney disease.

Accurate assessment of the glomerular filtration rate (GFR) is crucial for researching kidney disease in rats. Although validation of methods that assess GFR is crucial, large-scale comparisons between different methods are lacking. Both transcutaneous GFR (tGFR) and a newly developed estimated GFR (eGFR) equation by our group provide a low-invasive approach enabling repeated measurements. The tGFR is a single bolus method using FITC-labeled sinistrin to measure GFR based on half-life of the transcutaneous signal, whilst the eGFR is based on urinary sinistrin clearance. Here, we retrospectively compared tGFR, using both 1- and 3- compartment models (tGFR_1c and tGFR_3c, respectively) to the eGFR in a historic cohort of 43 healthy male rats and 84 male rats with various models of chronic kidney disease. The eGFR was on average considerably lower than tGFR-1c and tGFR-3c (mean differences 855 and 216 µL/min, respectively) and only 20 and 47% of measurements were within 30% of each other, respectively. The relative difference between eGFR and tGFR was highest in rats with the lowest GFR. Possible explanations for the divergence are problems inherent to tGFR, such as technical issues with signal measurement, description of the signal kinetics, and translation of half-life to tGFR, which depends on distribution volume. The unknown impact of isoflurane anesthesia used in determining mGFR remains a limiting factor. Thus, our study shows that there is a severe disagreement between GFR measured by tGFR and eGFR, stressing the need for more rigorous validation of the tGFR and possible adjustments to the underlying technique.

Urinary Prostaglandin E2 Excretion and the Risk of Cardiovascular and Kidney Disease.

BACKGROUND: Inhibition of prostaglandin synthesis by nonsteroidal anti-inflammatory drugs is associated with cardiovascular mortality and kidney disease. This study hypothesizes that urinary prostaglandin E2 (PGE2) and PGE2 metabolite (PGEM) excretions are markers of cardiovascular and kidney health, because they reflect both systemic and kidney-derived PGE2 production. METHODS AND RESULTS: PGE2 and PGEM were measured in spot urine samples from 2291 participants (≥55 years old) of the population-based Rotterdam Study. Urinary PGE2 and PGEM excretions were analyzed using linear regression analyses to identify cross-sectional associations with cardiovascular risk factors and baseline estimated glomerular filtration rate (eGFR). Longitudinal associations with cardiovascular mortality and kidney outcomes (eGFR <60 or <45 mL/min per 1.73 m2 and the composite outcome 40% eGFR loss or kidney failure) were assessed with Cox regression. Urinary PGE2 and PGEM excretions were higher with increasing age, lower eGFR, smoking, diabetes, and albuminuria. A 2-fold higher urinary PGE2 and PGEM excretion was associated with a higher risk of cardiovascular mortality (28 825 patient-years; 160 events; PGE2 hazard ratio [HR], 1.27, [95% CI, 1.06-1.54]; PGEM HR, 1.36 [95% CI, 1.10-1.67]). Higher PGE2 excretions were also associated with a higher risk of incident eGFR <60 mL/min per 1.73 m2 (31 530 person-years; 691 events; HR, 1.13 [95% CI, 1.02-1.25]) with similar HRs for the other kidney outcomes. CONCLUSIONS: Urinary PGE2 and PGEM excretions are novel markers for the presence and progression of cardiovascular and kidney disease. Future studies should address whether these associations are causal and can be targeted to improve cardiovascular and kidney outcomes.

Hyponatremia is associated with unfavorable outcomes after reperfusion treatment in acute ischemic stroke.

BACKGROUND AND PURPOSE: In patients with acute ischemic stroke, hyponatremia (plasma sodium < 136 mmol/L) is common and associated with unfavorable outcomes. However, data are limited for patients who underwent intravenous thrombolysis (IVT) and/or endovascular thrombectomy (EVT). Therefore, our aim was to assess the impact of hyponatremia on postreperfusion outcomes. METHODS: We analyzed data of consecutive patients who presented with acute ischemic stroke and were treated with IVT and/or EVT at Isala Hospital, the Netherlands, in 2019 and 2020. The primary outcome measure was the adjusted common odds ratio (acOR) for a worse modified Rankin Scale (mRS) score at 3-month follow-up. Secondary outcomes included symptomatic intracranial hemorrhage, in-hospital mortality, infarct core, and penumbra volumes. RESULTS: Of the 680 patients (median age = 73 years, 49% female, median National Institutes of Health Stroke Scale = 5), 430 patients (63%) were treated with IVT, 120 patients (18%) with EVT, and 130 patients (19%) with both. Ninety-two patients (14%) were hyponatremic on admission. Hyponatremia was associated with a worse mRS score at 3 months (acOR = 1.76, 95% confidence interval [CI] = 1.12-2.76) and in-hospital mortality (aOR = 2.39, 95% CI = 1.23-4.67), but not with symptomatic intracranial hemorrhage (OR = 1.17, 95% CI = 0.39-3.47). Hyponatremia was also associated with a larger core (17.2 mL, 95% CI = 2.9-31.5) and core to penumbra ratio (55.0%, 95% CI = 7.1-102.9). CONCLUSIONS: Admission hyponatremia in patients with acute ischemic stroke treated with IVT and/or EVT was independently associated with unfavorable postreperfusion outcomes, a larger infarct core, and a larger core to penumbra ratio. Future studies should address whether correction of hyponatremia improves the prognosis.

Matrix Metalloproteinase-7 in Urinary Extracellular Vesicles Identifies Rapid Disease Progression in Autosomal Dominant Polycystic Kidney Disease.

SIGNIFICANCE STATEMENT: There is an unmet need for biomarkers of disease progression in autosomal dominant polycystic kidney disease (ADPKD). This study investigated urinary extracellular vesicles (uEVs) as a source of such biomarkers. Proteomic analysis of uEVs identified matrix metalloproteinase 7 (MMP-7) as a biomarker predictive of rapid disease progression. In validation studies, MMP-7 was predictive in uEVs but not in whole urine, possibly because uEVs are primarily secreted by tubular epithelial cells. Indeed, single-nucleus RNA sequencing showed that MMP-7 was especially increased in proximal tubule and thick ascending limb cells, which were further characterized by a profibrotic phenotype. Together, these data suggest that MMP-7 is a biologically plausible and promising uEV biomarker for rapid disease progression in ADPKD. BACKGROUND: In ADPKD, there is an unmet need for early markers of rapid disease progression to facilitate counseling and selection for kidney-protective therapy. Our aim was to identify markers for rapid disease progression in uEVs. METHODS: Six paired case-control groups ( n =10-59/group) of cases with rapid disease progression and controls with stable disease were formed from two independent ADPKD cohorts, with matching by age, sex, total kidney volume, and genetic variant. Candidate uEV biomarkers were identified by mass spectrometry and further analyzed using immunoblotting and an ELISA. Single-nucleus RNA sequencing of healthy and ADPKD tissue was used to identify the cellular origin of the uEV biomarker. RESULTS: In the discovery proteomics experiments, the protein abundance of MMP-7 was significantly higher in uEVs of patients with rapid disease progression compared with stable disease. In the validation groups, a significant >2-fold increase in uEV-MMP-7 in patients with rapid disease progression was confirmed using immunoblotting. By contrast, no significant difference in MMP-7 was found in whole urine using ELISA. Compared with healthy kidney tissue, ADPKD tissue had significantly higher MMP-7 expression in proximal tubule and thick ascending limb cells with a profibrotic phenotype. CONCLUSIONS: Among patients with ADPKD, rapid disease progressors have higher uEV-associated MMP-7. Our findings also suggest that MMP-7 is a biologically plausible biomarker for more rapid disease progression.

Kidney phosphate wasting predicts poor outcome in polycystic kidney disease.

BACKGROUND AND HYPOTHESIS: Patients with ADPKD have disproportionately high levels of fibroblast growth factor-23 (FGF-23) for their CKD-stage with only a subgroup that develops kidney phosphate wasting. We assessed factors associated with phosphate wasting and hypothesize that it identifies patients with more severe disease and predicts disease progression. METHODS: We included 604 patients with ADPKD from a multi-center prospective observational (DIPAK) cohort in 4 university medical centers in the Netherlands. We measured parathyroid hormone (PTH), total plasma FGF-23 levels and calculated the ratio of tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) with < 0.8 mmol/L defined as kidney phosphate wasting. We analysed the association of TmP/GFR with eGFR decline over time and the risk for a composite kidney outcome (≥ 30% eGFR decline, kidney failure or kidney replacement therapy). RESULTS: In our cohort (age 48 ± 12 years, 39% male, eGFR 63 ± 28 mL/min/1.73m2), 59% of patients had phosphate wasting. Male sex (coefficient -0.2, 95% confidence interval [CI] -0.2; -0.1), eGFR (0.002, 0.001-0.004), FGF-23 (0.1, 0.03-0.2), PTH(-0.2, -0.3; -0.06) and Copeptin(-0.08, -0.1; -0.08) were associated with TmP/GFR. Corrected for PTH, FGF-23 and eGFR, every 0.1 mmol/L decrease in TmP/GFR was associated with a greater eGFR decline of 0.2 ml/min/1.73m2/year (95% CI 0.01-0.3) and an increased hazard ratio of 1.09 (95% CI 1.01-1.18) of the composite kidney outcome. CONCLUSION: Our study shows that in patients with ADPKD phosphate wasting is prevalent and associated with more rapid disease progression. Phosphate wasting may be a consequence of early proximal tubular dysfunction and insufficient suppression of PTH.

Chronic kidney disease increases the susceptibility to negative effects of low and high potassium intake.

BACKGROUND AND HYPOTHESIS: Dietary potassium (K+) has emerged as a modifiable factor for cardiovascular and kidney health in the general population, but its role in people with chronic kidney disease (CKD) is unclear. Here, we hypothesize that CKD increases the susceptibility to negative effects of low and high K+ diets. METHODS: We compared the effects of low, normal, or high KChloride (KCl) diets and a high KCitrate diet for four weeks in male rats with normal kidney function and in male rats with CKD using the 5/6th nephrectomy model (5/6Nx). RESULTS: Compared to rats with normal kidney function, 5/6Nx rats on the low KCl diet developed more severe extracellular and intracellular hypokalemia and more severe kidney injury, characterized by nephromegaly, infiltration of T-cells and macrophages, decreased eGFR and increased albuminuria. The high KCl diet caused hyperkalemia, hyperaldosteronism, hyperchloremic metabolic acidosis and severe hypertension in 5/6Nx but not in sham rats. The high KCitrate diet caused hypochloremic metabolic alkalosis but attenuated hypertension despite higher abundance of the phosphorylated sodium chloride cotransporter (pNCC) and similar levels of plasma aldosterone and epithelial sodium channel (ENaC) abundance. All 5/6Nx groups had more collagen deposition than the sham groups and this effect was most pronounced in the high KCitrate group. Plasma aldosterone correlated strongly with kidney collagen deposition. CONCLUSIONS: CKD increases the susceptibility to negative effects of low and high K+ diets in male rats, although the injury patterns are different. The low K+ diet caused inflammation, nephromegaly and kidney function decline, whereas the high K+ diet caused hypertension, hyperaldosteronism and kidney fibrosis. High KCitrate attenuated the hypertensive but not the pro-fibrotic effect of high KCl, which may be attributable to K+-induced aldosterone secretion. Our data suggest that especially in people with CKD it is important to identify the optimal threshold of dietary K+ intake.

Effects of correcting metabolic acidosis on muscle mass and functionality in chronic kidney disease: a systematic review and meta-analysis.

Metabolic acidosis unfavourably influences the nutritional status of patients with non-dialysis dependent chronic kidney disease (CKD) including the loss of muscle mass and functionality, but the benefits of correction are uncertain. We investigated the effects of correcting metabolic acidosis on nutritional status in patients with CKD in a systematic review and meta-analysis. A search was conducted in MEDLINE and the Cochrane Library from inception to June 2023. Study selection, bias assessment, and data extraction were independently performed by two reviewers. The Cochrane risk of bias tool was used to assess the quality of individual studies. We applied random effects meta-analysis to obtain pooled standardized mean difference (SMD) and 95% confidence intervals (CIs). We retrieved data from 12 intervention studies including 1995 patients, with a mean age of 63.7 ± 11.7 years, a mean estimated glomerular filtration rate of 29.8 ± 8.8 mL/min per 1.73 m2 , and 58% were male. Eleven studies performed an intervention with oral sodium bicarbonate compared with either placebo or with standard care and one study compared veverimer, an oral HCl-binding polymer, with placebo. The mean change in serum bicarbonate was +3.6 mEq/L in the intervention group and +0.4 mEq/L in the control group. Correcting metabolic acidosis significantly improved muscle mass assessed by mid-arm muscle circumference (SMD 0.35 [95% CI 0.16 to 0.54], P < 0.001) and functionality assessed with the sit-to-stand test (SMD -0.31 [95% CI -0.52 to 0.11], P = 0.003). We found no statistically significant effects on dietary protein intake, handgrip strength, serum albumin and prealbumin concentrations, and blood urea nitrogen. Correcting metabolic acidosis in patients with CKD improves muscle mass and physical function. Correction of metabolic acidosis should be considered as part of the nutritional care for patients with CKD.

Prostaglandin E2, Osmoregulation, and Disease Progression in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Prostaglandin E2 (PGE2) plays a physiological role in osmoregulation, a process that is affected early in autosomal dominant polycystic kidney disease (ADPKD). PGE2 has also been implicated in the pathogenesis of ADPKD in preclinical models, but human data are limited. Here, we hypothesized that urinary PGE2 excretion is associated with impaired osmoregulation, disease severity, and disease progression in human ADPKD. METHODS: Urinary excretions of PGE2 and its metabolite (PGEM) were measured in a prospective cohort of patients with ADPKD. The associations between urinary PGE2 and PGEM excretions, markers of osmoregulation, eGFR and height-adjusted total kidney volume were assessed using linear regression models. Cox regression and linear mixed models were used for the longitudinal analysis of the associations between urinary PGE2 and PGEM excretions and disease progression defined as 40% eGFR loss or kidney failure, and change in eGFR over time. In two intervention studies, we quantified the effect of starting tolvaptan and adding hydrochlorothiazide to tolvaptan on urinary PGE2 and PGEM excretions. RESULTS: In 562 patients with ADPKD (61% female, eGFR 63±28 ml/min per 1.73 m 2 ), higher urinary PGE2 or PGEM excretions were independently associated with higher plasma copeptin, lower urine osmolality, lower eGFR, and greater total kidney volume. Participants with higher baseline urinary PGE2 and PGEM excretions had a higher risk of 40% eGFR loss or kidney failure (hazard ratio, 1.28; 95% confidence interval [CI], 1.13 to 1.46 and hazard ratio, 1.50; 95% CI, 1.26 to 1.80 per two-fold higher urinary PGE2 or PGEM excretions) and a faster change in eGFR over time (-0.39 [95% CI, -0.59 to -0.20] and -0.53 [95% CI, -0.75 to -0.31] ml/min per 1.73 m 2 per year). In the intervention studies, urinary PGEM excretion was higher after starting tolvaptan, while urinary PGE2 excretion was higher after adding hydrochlorothiazide to tolvaptan. CONCLUSIONS: Higher urinary PGE2 and PGEM excretions in patients with ADPKD are associated with impaired osmoregulation, disease severity, and progression.

Trajectories of kidney function and risk of mortality.

BACKGROUND: We aimed to identify patterns within the rate of kidney function decline, determinants of these patterns and their association with all-cause mortality risk in the general population. METHODS: Participants aged ≥ 45 years with at least one assessment of creatinine-based estimated glomerular filtration rate (eGFR) taken between 1997 and 2018 were selected from a population-based cohort study. Analyses were performed using several distinct latent class trajectory modelling methods. Cumulative incidences were calculated with 45 years of age as the starting point. RESULTS: In 12 062 participants (85 922 eGFR assessments, mean age 67.0 years, 58.7% women, median follow-up 9.6 years), four trajectories of eGFR change with age were identified: slow eGFR decline [rate of change in mL/min/1.73 m2 per year (RC), -0.9; 95% CI, -0.9 to -0.9; reference group], intermediate eGFR decline (RC, -2.5; 95% CI, -2.7 to -2.5) and fast eGFR decline (RC, -4.3; 95% CI, -4.4 to -4.1), and an increase/stable eGFR (RC, 0.3; 95% CI, 0.3 to 0.4). Women were more likely to have an increase/stable eGFR [odds ratio (OR), 1.94; 95% CI, 1.53 to 2.46] whereas men were more likely to have a fast eGFR decline (OR, 1.86; 95% CI, 1.33 to 2.60). Participants with diabetes, cardiovascular disease (CVD) or hypertension were more likely to have an intermediate or fast eGFR decline. All-cause mortality risks (cumulative incidence at age of 70 years) were 32.3% (95% CI, 21.4 to 47.9, slow eGFR decline), 6.7% (95% CI, 3.5 to 12.4, intermediate eGFR decline), 68.8% (95% CI, 44.4 to 87.8, fast eGFR decline) and 9.5% (95% CI, 5.5 to 15.7, increase/stable eGFR). CONCLUSION: Sex, hypertension, diabetes and CVD were identified as trajectory membership determinants. Having fast eGFR decline was associated with the highest risk of all-cause mortality, highlighting the need for extensive monitoring and prevention of kidney function decline in individuals at risk of having fast eGFR decline.

Sex Differences in the Association Between Serum Testosterone and Kidney Function in the General Population.

Introduction: Testosterone might prevent kidney function decline, although evidence is limited in men and lacking in women from the general population. We investigated the association between serum testosterone and kidney function in men and women from a large population-based cohort study. Methods: Participants aged ≥45 years with available measurements of serum testosterone, sex hormone-binding globulin (SHBG), creatinine, and cystatine C were included. Assessments of kidney function included baseline assessments of the estimated glomerular filtration rate (eGFR) based on serum creatinine (eGFRcreat) or serum cystatin C (eGFRcys), and the urine albumin-to-creatinine ratio (ACR), and repeated assessments of eGFRcreat. Linear regression and linear mixed models were used to assess the associations of serum free and total testosterone with kidney function, stratified for sex. Results: A total of 4095 men and 5389 women (mean age 65.2 years) were included. In men, higher free testosterone was associated with lower eGFRcreat (beta -0.63, 95% confidence interval [CI]: -1.05; -0.21), higher eGFRcys (beta 0.56, 95% CI: 0.07; 1.05), and lower ACR (beta -0.25, 95% CI: -0.35; -0.16) at baseline. Higher total testosterone was associated with higher baseline and follow-up eGFRcreat, and with lower eGFRcreat when additionally adjusted for SHBG. In women, higher free testosterone was associated with lower baseline eGFRcreat and eGFRcys (beta -1.03, 95% CI: -1.36; -0.71; beta -1.07, 95% CI: -1.44; -0.70; respectively) and lower eGFRcreat over time (beta -0.78, 95% CI: -1.10; -0.46), but not with ACR. Conclusions: eGFRcys might be a better parameter than eGFRcreat for the association of testosterone with kidney function, although further studies investigating this are needed. Furthermore, we identified sex differences in the association between testosterone and kidney function, with a positive association in men and a negative association in women.

Novel mechanisms of salt-sensitive hypertension.

A high dietary sodium-consumption level is considered the most important lifestyle factor that can be modified to help prevent an increase in blood pressure and the development of hypertension. Despite numerous studies over the past decades, the pathophysiology explaining why some people show a salt-sensitive blood pressure response and others do not is incompletely understood. Here, a brief overview of the latest mechanistic insights is provided, focusing on the mononuclear phagocytic system and inflammation, the gut-kidney axis, and epigenetics. The article also discusses the effects of 3 types of novel drugs on salt-sensitive hypertension-sodium-glucose cotransporter 2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists, and aldosterone synthase inhibitors. The conclusion is that besides kidney-centered mechanisms, vasoconstrictor mechanisms are also relevant for both the understanding and treatment of this blood pressure phenotype.

Kaliuresis and Intracellular Uptake of Potassium with Potassium Citrate and Potassium Chloride Supplements: A Randomized Controlled Trial.

BACKGROUND: A potassium replete diet is associated with lower cardiovascular risk but may increase the risk of hyperkalemia, particularly in people using renin-angiotensin-aldosterone system inhibitors. We investigated whether intracellular uptake and potassium excretion after an acute oral potassium load depend on the accompanying anion and/or aldosterone and whether this results in altered plasma potassium change. METHODS: In this placebo-controlled interventional cross-over trial including 18 healthy individuals, we studied the acute effects of one oral load of potassium citrate (40 mmol), potassium chloride (40 mmol), and placebo in random order after overnight fasting. Supplements were administered after a 6-week period with and without lisinopril pretreatment. Linear mixed effect models were used to compare blood and urine values before and after supplementation and between the interventions. Univariable linear regression was used to determine the association between baseline variables and change in blood and urine values after supplementation. RESULTS: During the 4-hour follow-up, the rise in plasma potassium was similar for all interventions. After potassium citrate, both red blood cell potassium-as measure of the intracellular potassium-and transtubular potassium gradient (TTKG)-reflecting potassium secretory capacity-were higher than after potassium chloride or potassium citrate with lisinopril pretreatment. Baseline aldosterone was significantly associated with TTKG after potassium citrate, but not after potassium chloride or potassium citrate with lisinopril pretreatment. The observed TTKG change after potassium citrate was significantly associated with urine pH change during this intervention ( R =0.60, P < 0.001). CONCLUSIONS: With similar plasma potassium increase, red blood cell potassium uptake and kaliuresis were higher after an acute load of potassium citrate as compared with potassium chloride alone or pretreatment with lisinopril. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Potassium supplementation in patients with chronic kidney disease and healthy subjects: effects on potassium and sodium balance, NL7618.

Treatment Guidelines for Hyponatremia: Stay the Course.

International guidelines designed to minimize the risk of complications that can occur when correcting severe hyponatremia have been widely accepted for a decade. On the basis of the results of a recent large retrospective study of patients hospitalized with hyponatremia, it has been suggested that hyponatremia guidelines have gone too far in limiting the rate of rise of the serum sodium concentration; the need for therapeutic caution and frequent monitoring of the serum sodium concentration has been questioned. These assertions are reminiscent of a controversy that began many years ago. After reviewing the history of that controversy, the evidence supporting the guidelines, and the validity of data challenging them, we conclude that current safeguards should not be abandoned. To do so would be akin to discarding your umbrella because you remained dry in a rainstorm. The authors of this review, who represent 20 medical centers in nine countries, have all contributed significantly to the literature on the subject. We urge clinicians to continue to treat severe hyponatremia cautiously and to wait for better evidence before adopting less stringent therapeutic limits.

Serum Potassium and Risk of Death or Kidney Replacement Therapy in Older People With CKD Stages 4-5: Eight-Year Follow-up.

RATIONALE & OBJECTIVE: Hypokalemia may accelerate kidney function decline. Both hypo- and hyperkalemia can cause sudden cardiac death. However, little is known about the relationship between serum potassium and death or the occurrence of kidney failure requiring replacement therapy (KRT). We investigated this relationship in older people with chronic kidney disease (CKD) stage 4-5. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: We followed 1,714 patients (≥65 years old) from the European Quality (EQUAL) study for 8 years from their first estimated glomerular filtration rate (eGFR)<20mL/min/1.73m2 measurement. EXPOSURE: Serum potassium was measured every 3 to 6 months and categorized as≤3.5,>3.5-≤4.0,>4.0-≤4.5,>4.5-≤5.0 (reference),>5.0-≤5.5, >5.5-≤6.0, and>6.0mmol/L. OUTCOME: The combined outcome death before KRT or start of KRT. ANALYTICAL APPROACH: The association between categorical and continuous time-varying potassium and death or KRT start was examined using Cox proportional hazards and restricted cubic spline analyses, adjusted for age, sex, diabetes, cardiovascular disease, renin-angiotensin-aldosterone system (RAAS) inhibition, eGFR, and subjective global assessment (SGA). RESULTS: At baseline, 66% of participants were men, 42% had diabetes, 47% cardiovascular disease, and 54% used RAAS inhibitors. Their mean age was 76±7 (SD) years, mean eGFR was 17±5 (SD) mL/min/1.73m2, and mean SGA was 6.0±1.0 (SD). Over 8 years, 414 (24%) died before starting KRT, and 595 (35%) started KRT. Adjusted hazard ratios for death or KRT according to the potassium categories were 1.6 (95% CI, 1.1-2.3), 1.4 (95% CI, 1.1-1.7), 1.1 (95% CI, 1.0-1.4), 1 (reference), 1.1 (95% CI, 0.9-1.4), 1.8 (95% CI, 1.4-2.3), and 2.2 (95% CI, 1.5-3.3). Hazard ratios were lowest at a potassium of about 4.9mmol/L. LIMITATIONS: Shorter intervals between potassium measurements would have allowed for more precise estimations. CONCLUSIONS: We observed a U-shaped relationship between serum potassium and death or KRT start among patients with incident CKD 4-5, with a nadir risk at a potassium level of 4.9mmol/L. These findings underscore the potential importance of preventing both high and low potassium in patients with CKD 4-5. PLAIN-LANGUAGE SUMMARY: Abnormal potassium blood levels may increase the risk of death or kidney function decline, especially in older people with chronic kidney disease (CKD). We studied 1,714 patients aged≥65 years with advanced CKD from the European Quality (EQUAL) study and followed them for 8 years. We found that both low and high levels of potassium were associated with an increased risk of death or start of kidney replacement therapy, with the lowest risk observed at a potassium level of 4.9 mmol/L. In patients with CKD, the focus is often on preventing high blood potassium. However, this relatively high optimum potassium level stresses the potential importance of also preventing low potassium levels in older patients with advanced CKD.

Expanding the Phenotypic Spectrum of Kenny-Caffey Syndrome.

CONTEXT: Kenny-Caffey syndrome (KCS) is a rare hereditary disorder characterized by short stature, hypoparathyroidism, and electrolyte disturbances. KCS1 and KCS2 are caused by pathogenic variants in TBCE and FAM111A, respectively. Clinically the phenotypes are difficult to distinguish. OBJECTIVE: The objective was to determine and expand the phenotypic spectrum of KCS1 and KCS2 in order to anticipate complications that may arise in these disorders. METHODS: We clinically and genetically analyzed 10 KCS2 patients from 7 families. Because we found unusual phenotypes in our cohort, we performed a systematic review of genetically confirmed KCS cases using PubMed and Scopus. Evaluation by 3 researchers led to the inclusion of 26 papers for KCS1 and 16 for KCS2, totaling 205 patients. Data were extracted following the Cochrane guidelines and assessed by 2 independent researchers. RESULTS: Several patients in our KCS2 cohort presented with intellectual disability (3/10) and chronic kidney disease (6/10), which are not considered common findings in KCS2. Systematic review of all reported KCS cases showed that the phenotypes of KCS1 and KCS2 overlap for postnatal growth retardation (KCS1: 52/52, KCS2: 23/23), low parathyroid hormone levels (121/121, 16/20), electrolyte disturbances (139/139, 24/27), dental abnormalities (47/50, 15/16), ocular abnormalities (57/60, 22/23), and seizures/spasms (103/115, 13/16). Symptoms more prevalent in KCS1 included intellectual disability (74/80, 5/24), whereas in KCS2 bone cortical thickening (1/18, 16/20) and medullary stenosis (7/46, 27/28) were more common. CONCLUSION: Our case series established chronic kidney disease as a new feature of KCS2. In the literature, we found substantial overlap in the phenotypic spectra of KCS1 and KCS2, but identified intellectual disability and the abnormal bone phenotype as the most distinguishing features.

Withdrawn as duplicate: Expanding the phenotypic spectrum of Kenny-Caffey syndrome: a case series and systematic literature review.

This article has been withdrawn due to a publisher error that caused it to be duplicated. The definitive version of this article is published under https://doi.org/10.1210/clinem/dgad147.

Novel Concepts in Nephron Sodium Transport: A Physiological and Clinical Perspective.

The kidneys play a critical role in maintaining total body sodium (Na+) balance across a wide range of dietary intake, accomplished by a concerted effort involving multiple Na+ transporters along the nephron. Furthermore, nephron Na+ reabsorption and urinary Na+ excretion are closely linked to renal blood flow and glomerular filtration such that perturbations in either of them can modify Na+ transport along the nephron, ultimately resulting in hypertension and other Na+-retentive states. In this article, we provide a brief physiological overview of nephron Na+ transport and illustrate clinical syndromes and therapeutic agents that affect Na+ transporter function. We highlight recent advances in kidney Na+ transport, particularly the role of immune cells, lymphatics, and interstitial Na+ in regulating Na+ reabsorption, the emergence of potassium (K+) as a regulator of Na+ transport, and the evolution of the nephron to modulate Na+ transport.