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Abstract 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

Kidney organoids are an innovative tool in transplantation research. The aim of the present study was to investigate whether kidney organoids are susceptible for allo-immune attack and whether they can be used as a model to study allo-immunity in kidney transplantation. Human induced pluripotent stem cell-derived kidney organoids were co-cultured with human peripheral blood mononuclear cells (PBMC), which resulted in invasion of allogeneic T-cells around nephron structures and macrophages in the stromal cell compartment of the organoids. This process was associated with the induction of fibrosis. Subcutaneous implantation of kidney organoids in immune-deficient mice followed by adoptive transfer of human PBMC led to the invasion of diverse T-cell subsets. Single cell transcriptomic analysis revealed that stromal cells in the organoids upregulated expression of immune response genes upon immune cell invasion. Moreover, immune regulatory PD-L1 protein was elevated in epithelial cells while genes related to nephron differentiation and function were downregulated. This study characterized the interaction between immune cells and kidney organoids, which will advance the use of kidney organoids for transplantation research.

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

Author(s): Michiel L. A. J. Wieërs [sup.1] , Jaap Mulder [sup.2] [sup.3] , Joris I. Rotmans [sup.4] , Ewout J. Hoorn [sup.1] Author Affiliations: (1) grid.5645.2, 000000040459992X, Department of Internal [...], By controlling urinary potassium excretion, the kidneys play a key role in maintaining whole-body potassium homeostasis. Conversely, low urinary potassium excretion (as a proxy for insufficient dietary intake) is increasingly recognized as a risk factor for the progression of kidney disease. Thus, there is a reciprocal relationship between potassium and the kidney: the kidney regulates potassium balance but potassium also affects kidney function. This review explores this relationship by discussing new insights into kidney potassium handling derived from recently characterized tubulopathies and studies on sexual dimorphism. These insights reveal a central but non-exclusive role for the distal convoluted tubule in sensing potassium and subsequently modifying the activity of the sodium-chloride cotransporter. This is another example of reciprocity: activation of the sodium-chloride cotransporter not only reduces distal sodium delivery and therefore potassium secretion but also increases salt sensitivity. This mechanism helps explain the well-known relationship between dietary potassium and blood pressure. Remarkably, in children, blood pressure is related to dietary potassium but not sodium intake. To explore how potassium deficiency can cause kidney injury, we review the mechanisms of hypokalemic nephropathy and discuss if these mechanisms may explain the association between low dietary potassium intake and adverse kidney outcomes. We discuss if potassium should be repleted in patients with kidney disease and what role dietary potassium plays in the risk of hyperkalemia. Supported by data and physiology, we reach the conclusion that we should view potassium not only as a potentially dangerous cation but also as a companion in the battle against kidney disease.

Objective/design: Testosterone might mediate sex differences in kidney function and chronic kidney disease (CKD). However, few studies analyzing the association between testosterone and kidney function showed conflicting results. Therefore, we performed a systematic review and meta-analysis. Methods: Six electronic databases were searched from inception to March 4, 2020, for studies that investigated the association of (i) testosterone status with kidney function in the general population or (ii) testosterone status with clinical outcomes (kidney function decline, kidney failure, cardiovascular (CV) events, and cardiovascular and all-cause mortality) in CKD patients. We used random and fixed-effect models to obtain pooled effect estimates with 95% confidence intervals (CIs). Results: No randomized–controlled trials that met the inclusion criteria were identified. One study was conducted in the general population and reported an increased risk of incident CKD with low vs normal testosterone (hazard ratio (HR): 1.38, 95% CI: 1.05;1.80). Seven studies were conducted in men with CKD and included testosterone as determinant, of which six could be meta-analyzed. Low testosterone was associated with an increased risk of all-cause mortality and CV events (pooled HR: 1.98, 95% CI: 1.36;2.89; pooled HR of 2.40, 95% CI: 1.22;4.71, respectively). Two studies showed an increased risk of all-cause mortality with decreased dehydroepiandrosterone sulfate (DHEAS) in men with CKD; results regarding CV events were conflicting. Conclusions: Although literature is scarce, evidence suggests that lower testosterone may increase CKD risk in the general population and risk of all-cause mortality and CV events in men with CKD. Whether testosterone supplementation could prevent these potential detrimental outcomes should be determined in future intervention studies.

Background Calcineurin inhibitors (CNIs) affect kidney electrolyte handling and blood pressure (BP) through an effect on the distal tubule. The second-generation CNI voclosporin causes hypomagnesaemia and hypercalciuria less often than tacrolimus. This suggests different effects on the distal tubule, but this has not yet been investigated experimentally. Methods Rats were treated with voclosporin, tacrolimus or vehicle for 28 days. Dosing was based on a pilot experiment to achieve clinically therapeutic concentrations. Drug effects were assessed by electrolyte handling at day 18 and 28, thiazide testing at day 20, telemetric BP recordings and analysis of messenger RNA (mRNA) and protein levels of distal tubular transporters at day 28. Results Compared with vehicle, tacrolimus but not voclosporin significantly increased the fractional excretions of calcium (>4-fold), magnesium and chloride (both 1.5-fold) and caused hypomagnesaemia. Tacrolimus but not voclosporin significantly reduced distal tubular transporters at the mRNA and/or protein level, including the sodium–chloride cotransporter, transient receptor melastatin 6, transient receptor potential vanilloid 5, cyclin M2, sodium–calcium exchanger and calbindin-D28K. Tacrolimus but not voclosporin reduced the mRNA level and urinary excretion of epidermal growth factor. The saluretic response to hydrochlorothiazide at day 20 was similar in the voclosporin and vehicle groups, whereas it was lower in the tacrolimus group. The phosphorylated form of the sodium–chloride cotransporter was significantly higher at day 28 in rats treated with voclosporin than in those treated with tacrolimus. Tacrolimus transiently increased BP, whereas voclosporin caused a gradual but persistent increase in BP that was further characterized by high renin, normal aldosterone and low endothelin-1. Conclusions In contrast to tacrolimus, voclosporin does not cause hypercalciuria and hypomagnesaemia, but similarly causes hypertension. Our data reveal differences between the distal tubular effects of tacrolimus and voclosporin and provide a pathophysiological basis for the clinically observed differences between the two CNIs. [ABSTRACT FROM AUTHOR]

The susceptibility of patients with chronic kidney disease to develop postprandial hyperkalemia suggests alterations in normal kidney sodium (Na+) and potassium (K+) handling, but the exact nature of these changes is largely unknown. To address this, we analyzed the natriuretic and kaliuretic responses to diuretics and acute K+ loading in rats who underwent 5/6 nephrectomy (5/6Nx) and compared this with the response in sham-operated rats. The natriuretic and kaliuretic responses to furosemide, hydrochlorothiazide, and amiloride were largely similar between 5/6Nx and sham rats except for a significantly reduced kaliuretic response to hydrochlorothiazide in 5/6Nx rats. Acute dietary K+ loading with either 2.5% potassium chloride or 2.5% potassium citrate caused lower natriuretic and kaliuretic responses in 5/6Nx rats compared with sham rats. This resulted in significantly higher plasma K+ concentrations in 5/6Nx rats, which were accompanied by corresponding increases in plasma aldosterone. Acute K+ loading caused dephosphorylation of Ste20-related proline/alanine-rich kinase and the sodium-chloride cotransporter both in sham and 5/6Nx rats. In contrast, the acute K+ load decreased the Na+/hydrogen exchanger 3 and increased serum- and glucocorticoid-regulated kinase 1 and the α-subunit of the epithelial sodium channel (ENaC) only in sham rats. Together, our data show that 5/6Nx impairs the natriuretic and kaliuretic response to an acute dietary K+ load, which is further characterized by a loss of ENaC adaptation and the development of postprandial hyperkalemia. NEW & NOTEWORTHY: Rats who underwent 5/6 nephrectomy demonstrate a reduced ability to excrete an acute K+ load with the development of postprandial hyperkalemia. 5/6 Nephrectomy attenuates K+-induced natriuresis and impairs ENaC regulation despite intact NCC dephosphorylation and increased plasma aldosterone. This offers a potential explanation for why patients with chronic kidney disease are predisposed to postprandial hyperkalemia. [ABSTRACT FROM AUTHOR]

Dietary potassium (K+) supplementation is associated with a lowering effect in blood pressure (BP), but not all studies agree. Here, we examined the effects of short- and long-term K+ supplementation on BP in mice, whether differences depend on the accompanying anion or the sodium (Na+) intake and molecular alterations in the kidney that may underlie BP changes. Relative to the control diet, BP was higher in mice fed a high NaCl (1.57% Na+) diet for 7 weeks or fed a K+-free diet for 2 weeks. BP was highest on a K+-free/high NaCl diet. Commensurate with increased abundance and phosphorylation of the thiazide sensitive sodium-chloride-cotransporter (NCC) on the K+-free/high NaCl diet, BP returned to normal with thiazides. Three weeks of a high K+ diet (5% K+) increased BP (predominantly during the night) independently of dietary Na+ or anion intake. Conversely, 4 days of KCl feeding reduced BP. Both feeding periods resulted in lower NCC levels but in increased levels of cleaved (active) α and γ subunits of the epithelial Na+ channel ENaC. The elevated BP after chronic K+ feeding was reduced by amiloride but not thiazide. Our results suggest that dietary K+ has an optimal threshold where it may be most effective for cardiovascular health.

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Context Thiazide-induced hyponatremia is one of the most common forms of hyponatremia, but its pathogenesis is incompletely understood. Recent clinical data suggest links with prostaglandin E2 (PGE2) and a single nucleotide polymorphism (SNP) in the prostaglandin transporter gene (SLCO2A1), but it is unknown if these findings also apply to the general population. Objective To study the associations between serum sodium, thiazide diuretics, urinary excretions of PGE2, and its metabolite (PGEM), and the rs34550074 SNP in SLCO2A1 in the general population. Design Prospective population-based cohort study (Rotterdam Study). Setting General population. Participants 2178 participants (65% female, age 64 ± 8 years) Intervention(s) None. Main Outcome Measure(s) Serum sodium levels. Results Higher urinary PGE2 excretion was associated with lower serum sodium: difference in serum sodium for each 2-fold higher PGE2 −0.19 mmol/L [95% confidence interval (CI) −0.31 to −0.06], PGEM −0.29 mmol/L (95% CI −0.41 to −0.17). This association was stronger in thiazide users (per 2-fold higher PGE2 −0.73 vs −0.12 mmol/L and PGEM −0.6 vs −0.25 mmol/L, P for interaction <.05 for both). A propensity score matching analysis of thiazide vs non-thiazide users yielded similar results. The SNP rs34550074 was not associated with lower serum sodium or higher urinary PGE2 or PGEM excretion in thiazide or non-thiazide users. Conclusion Serum sodium is lower in people with higher urinary PGE2 and PGEM excretion, and this association is stronger in thiazide users. This suggests that PGE2-mediated water reabsorption regulates serum sodium, which is relevant for the pathogenesis of hyponatremia in general and thiazide-induced hyponatremia specifically. [ABSTRACT FROM AUTHOR]

The prostaglandin E2 (PGE2) receptor EP3 has been detected in the thick ascending limb (TAL) and the collecting duct of the kidney, where its actions are proposed to inhibit water reabsorption. However, EP3 is also expressed in other cell types, including vascular endothelial cells. The aim here was to determine the contribution of EP3 in renal water handling in male and female adult mice by phenotyping a novel mouse model with doxycycline-dependent deletion of EP3 throughout the kidney tubule (EP3−/− mice). RNAscope demonstrated that EP3 was highly expressed in the cortical and medullary TAL of adult mice. Compared with controls EP3 mRNA expression was reduced by >80% in whole kidney (RT-qPCR) and nondetectable (RNAscope) in renal tubules of EP3−/− mice. Under basal conditions, there were no significant differences in control and EP3−/− mice of both sexes in food and water intake, body weight, urinary output, or clinical biochemistries. No differences were detectable between genotypes in handling of an acute water load or in their response to the vasopressin analog 1-deamino-8- d -arginine-vasopressin (dDAVP). No differences in water handling were observed when PGE2 production was enhanced using 1% NaCl load. Expression of proteins involved in kidney water handling was not different between genotypes. This study demonstrates that renal tubular EP3 is not essential for body fluid homeostasis in males or females, even when PGE2 levels are high. The mouse model is a novel tool for examining the role of EP3 in kidney function independently of potential developmental abnormalities or systemic effects. NEW & NOTEWORTHY: The prostanoid EP3 receptor is proposed to play a key role in the kidney tubule and antagonize the effects of vasopressin on aquaporin-mediated water reabsorption. Here, we phenotyped a kidney tubule-specific inducible knockout mouse model of the EP3 receptor. Our major finding is that, even under physiological stress, tubular EP3 plays no detectable role in renal water or solute handling. This suggests that other EP receptors must be important for renal salt and water handling. [ABSTRACT FROM AUTHOR]

Background A single dose of small interfering RNA (siRNA) targeting liver angiotensinogen eliminates hepatic angiotensinogen and lowers blood pressure. Angiotensinogen elimination raises concerns for clinical application because an angiotensin rise is needed to maintain perfusion pressure during hypovolemia. Here, we investigated whether conventional vasopressors can raise arterial pressure after angiotensinogen depletion. Methods and Results Spontaneously hypertensive rats on a low‐salt diet were treated with siRNA (10 mg/kg fortnightly) for 4 weeks, supplemented during the final 2 weeks with fludrocortisone (6 mg/kg per day), the α‐adrenergic agonist midodrine (4 mg/kg per day), or a high‐salt diet (all groups n=6–7). Pressor responsiveness to angiotensin II and norepinephrine was assessed before and after siRNA administration. Blood pressure was measured via radiotelemetry. Depletion of liver angiotensinogen by siRNA lowered plasma angiotensinogen concentrations by 99.2±0.1% and mean arterial pressure by 19 mm Hg. siRNA‐mediated blood pressure lowering was rapidly reversed by intravenous angiotensin II or norepinephrine, or gradually reversed by fludrocortisone or high salt intake. Midodrine had no effect. Unexpectedly, fludrocortisone partially restored plasma angiotensinogen concentrations in siRNA‐treated rats, and nearly abolished plasma renin concentrations. To investigate whether this angiotensinogen originated from nonhepatic sources, fludrocortisone was administered to mice lacking hepatic angiotensinogen. Fludrocortisone did not increase angiotensinogen in these mice, implying that the rise in angiotensinogen in the siRNA‐treated rats must have depended on the liver, most likely reflecting diminished cleavage by renin. Conclusions Intact pressor responsiveness to conventional vasopressors provides pharmacological means to regulate the blood pressure–lowering effect of angiotensinogen siRNA and may support future therapeutic implementation of siRNA.

The article "Cosmic kidney disease: a spaceflight-induced tubulopathy" published in the Clinical Kidney Journal explores the impact of spaceflight on kidney health, particularly focusing on the risk of kidney stones and radiation sensitivity. The study by Siew et al. identifies spaceflight-induced kidney perturbations, coining the term 'cosmic kidney disease', and highlights factors such as hypercalciuria, hyperoxaluria, and antidiuresis contributing to kidney stone formation. The research combines a 'pan-omics' approach with physiological and morphological analysis, revealing tubular remodelling and vascular damage in the kidney due to exposure to galactic cosmic radiation. Questions remain regarding the triggers of tubular remodelling and the potential benefits of thiazide diuretics for astronauts to prevent kidney stones and bone loss during space travel. [Extracted from the article]

Abstract Autosomal‐dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, leading to kidney failure in most patients. In approximately 85% of cases, the disease is caused by mutations in PKD1. How dysregulation of PKD1 leads to cyst formation on a molecular level is unknown. Induced pluripotent stem cells (iPSCs) are a powerful tool for in vitro modeling of genetic disorders. Here, we established ADPKD patient‐specific iPSCs to study the function of PKD1 in kidney development and cyst formation in vitro. Somatic mutations are proposed to be the initiating event of cyst formation, and therefore, iPSCs were derived from cystic renal epithelial cells rather than fibroblasts. Mutation analysis of the ADPKD iPSCs revealed germline mutations in PKD1 but no additional somatic mutations in PKD1/PKD2. Although several somatic mutations in other genes implicated in ADPKD were identified in cystic renal epithelial cells, only few of these mutations were present in iPSCs, indicating a heterogeneous mutational landscape, and possibly in vitro cell selection before and during the reprogramming process. Whole‐genome DNA methylation analysis indicated that iPSCs derived from renal epithelial cells maintain a kidney‐specific DNA methylation memory. In addition, comparison of PKD1+/− and control iPSCs revealed differences in DNA methylation associated with the disease history. In conclusion, we generated and characterized iPSCs derived from cystic and healthy control renal epithelial cells, which can be used for in vitro modeling of kidney development in general and cystogenesis in particular.

Background Consensus lacks concerning a bidirectional association between kidney function and atrial fibrillation (AF), but this is crucial information for prevention/treatment efforts for both chronic kidney disease and AF. Therefore, we investigated the bidirectional association between kidney function and AF. Methods and Results This study was a prospective cohort study including 9228 participants (mean age, 64.9 years; 57.2% women) with information on kidney function (estimated glomerular filtration rate [eGFR] based on serum creatinine [eGFRcreat], cystatin C [eGFRcys], or both [eGFRcreat‐cys], and urine albumin‐to‐creatinine ratio) and AF. Reduced kidney function was defined as eGFRcreat