Preserved Kidney Function Research Articles

Adamts1 and Cyst Expansion in Polycystic Kidney Disease

Background: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by mutations in either the Pkd1 or Pkd2 genes leading to progressive cyst growth and often kidney failure. We have previously demonstrated that tubules can enlarge following loss of Pkd1 without an increase in tubular cell numbers, suggesting that tubular basement membrane remodeling is important for cystic dilation. RNA sequencing of Pkd1 null kidneys revealed increased expression of 17 metalloproteinases, of which A Disintegrin and Metalloproteinase with Thrombospondin Motif 1 (Adamts1) is the most highly expressed and upregulated. Methods: Mice were generated with inducible tubule-specific knockout of Adamts1 alone (AtsTKO), Pkd1 alone (PkdTKO), or both (P/ATKO) following doxycycline induction from 4-6 weeks age. Uninduced mice were used as controls. AtsTKO mice had no detectable phenotype through 12 weeks age. Results: Upregulation of Adamts1 in PkdTKO kidneys correlated with a significant increase in the 70 kDa cleavage product of the V1 isoform of versican, which localized to the tubular basement membrane and adjacent interstitial mononuclear cells. Simultaneous deletion of both Adamts1 and Pkd1 (P/ATKO) reduced Adamts1 expression levels by >90%, prevented V1 versican cleavage, and reduced interstitial macrophage accumulation and activation. P/ATKO mice demonstrated reduced cystic enlargement, improved BUN and creatinine and better survival than did PkdTKO mice. Conclusions: Preventing Adamts1 upregulation following loss of tubular Pkd1 effectively reduced cyst growth and preserved kidney function.

The cardiovascular unphysiology of thrice weekly hemodialysis.

This review examines the unphysiological nature of conventional intermittent hemodialysis (IHD) and explores alternative dialysis modalities that more closely mimic natural kidney function. As cardiovascular complications remain a leading cause of morbidity and mortality in dialysis patients, understanding and addressing the limitations of IHD is crucial for improving outcomes. IHD's intermittent nature leads to significant fluctuations in metabolites, electrolytes, and fluid status, contributing to hemodynamic instability and increased cardiovascular risk. More frequent dialysis modalities, such as short daily hemodialysis and nocturnal hemodialysis have numerous benefits including reduced left ventricular hypertrophy, improved blood pressure control, and potentially decreasing mortality. Peritoneal dialysis offers a more continuous approach to treatment, which may provide cardiovascular benefits through gentler fluid removal and residual kidney function preservation. Conventional thrice weekly intermittent hemodialysis offers a fundamentally unphysiologic equilibrium of uremic solutes. Alternate approaches have demonstrated cardiovascular benefits.

Lupus Nephritis: Redefining the treatment goals

The course of proliferative lupus nephritis (LN) is characterized by flares of activity alternating with periods of quiescence, against a background of chronic immune dysregulation. An accurate assessment of disease activity is of unassailable importance to tailor therapy. In the present communication, we discuss the available clinical, serological and histological tools to evaluate disease activity and how they may be applied to redefine the treatment goals in LN. Traditionally, treatment response is judged by the degree of proteinuria reduction and improvement of kidney function, but this fails to differentiate ongoing inflammatory disease from chronic damage. Despite intensive research, no novel biomarker has proved useful for clinical practice, and we continue to rely on anti-double-stranded DNA antibody levels (anti-dsDNA) to assess serological activity. Repeat kidney biopsies sometimes reveal persistent inflammation despite apparent clinical remission, giving credibility to the conviction that histological remission should be a treatment goal and protocol biopsies part of the decision-making process. However, the discrepancies between clinical and histological responses to therapy can be explained by persistent systemic autoimmunity with low-grade immune complex deposition or, alternatively, by delayed clearance of intrarenal inflammation once immunological remission has been achieved. Since persistent immune dysregulation is the motor of disease activity in LN, it should be the principal focus of therapy and monitoring. We propose to replace the traditional induction-remission maintenance protocol by a more dynamic and individualized approach, and aim for 3 treatment goals, concomitantly rather than sequentially: 1) Clinical remission, by attenuating renal inflammation, using microscopic hematuria, proteinuria, eGFR and complement levels as biomarkers; 2) Immunological remission, by decreasing immune complex generation, using anti-dsDNA as biomarker; 3) Preservation of kidney function, by curtailing chronic kidney damage, using eGFR slope as biomarker.

Diet as a treatment for chronic kidney disease

The management of chronic kidney disease (CKD) includes nutritional interventions aimed at slowing disease progression and mitigating complications. This review examines various dietary approaches for CKD treatment, focusing on carbohydrate intake modulation, ketogenic diets, and plant-based diets. Standard guidelines recommend carbohydrate intake within 45% to 65% of total calories, but there is growing interest in reducing carbohydrate consumption to preserve kidney function. Low-carbohydrate diets (<25% of total calories) have shown benefits in glycemic control and weight reduction but may pose long-term adherence challenges. High-protein, low-carbohydrate diets are discouraged due to associations with hyperfiltration and CKD progression. Limiting fructose intake has been linked to reductions in blood pressure and uric acid levels. Intermittent fasting and ketogenic diets, which promote ketone body production and reduce inflammation, have shown promise in animal models and some human studies, particularly in autosomal dominant polycystic kidney disease, though more research is needed. Plantbased diets, such as the Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets, offer cardiovascular benefits and may reduce CKD risk but require careful management of potassium intake. Overall, dietary interventions should be individualized, considering potential risks like hyperkalemia and ensuring nutritional adequacy.

Primary hyperoxaluria type 3: from infancy to adulthood in a genetically unique cohort.

Primary hyperoxaluria type 3 (PH3) is a rare autosomal recessive disorder caused by bi-allelic genetic variants in the 4 hydroxy-2 oxoglutarate aldolase (HOGA-1) gene. We report the natural history of PH3 in a 16-patient cohort, 15 from a unique genetically isolated population. This retrospective single-center study followed PH3 patients between 2003 and 2023 with demographic, clinical, radiographic, genetic, and biochemical parameters. Genetic population screening was performed in four villages to determine carrier frequency and identify couples at risk in a genetically isolated population. Sixteen patients with biallelic (or homozygous) pathogenic variants (PV) in HOGA-1 (c.944_946 del, c.119C > A, c.208C > T) were included in the study, 15 Druze and one Jewish, aged 0-63years at diagnosis (4 adults and 12 pediatric patients). All symptomatic patients had clinical or imaging signs of nephrolithiasis. One developed chronic kidney disease (CKD) stage 5; biopsy showed focal mesangial sclerosis and chronic tubulo-interstitial changes with few oxalate deposits. Two other patients had CKD stage 2 (eGFR 87 and 74mL/min/1.73m2) upon their last visit. The remaining cohort showed preserved kidney function until the latest follow-up. Of 1167 healthy individuals screened, 90 carriers were found, a rate of 1:13 in the genetically unique cohort screened. A high prevalence of PH3 patients was found among a unique cohort, but probably still underdiagnosed due to relatively mild disease course. The carrier rate is high. There is no specific therapy for PH3, but early diagnosis can prevent redundant diagnostic efforts and provide early treatment for kidney stone disease. Even in our homogeneous cohort, kidney stone disease severity and CKD degree were variable, supporting a suspected contribution of yet unknown genetic or environmental factors.

Future of Uremic Toxin Management

During the progression of chronic kidney disease (CKD), the retention of uremic toxins plays a key role in the development of uremic syndrome. Knowledge about the nature and biological impact of uremic toxins has grown exponentially over the past decades. However, the science on reducing the concentration and effects of uremic toxins has not advanced in parallel. Additionally, the focus has remained for too long on dialysis strategies, which only benefit the small fraction of people with CKD who suffer from advanced kidney disease, whereas uremic toxicity effects are only partially prevented. This article reviews recent research on alternative methods to counteract uremic toxicity, emphasizing options that are also beneficial in the earlier stages of CKD, with a focus on both established methods and approaches which are still under investigation or at the experimental stage. We will consequently discuss the preservation of kidney function, the prevention of cardiovascular damage, gastro-intestinal interventions, including diet and biotics, and pharmacologic interventions. In the final part, we also review alternative options for extracorporeal uremic toxin removal. The future will reveal which of these options are valid for further development and evidence-based assessment, hopefully leading to a more sustainable treatment model for CKD than the current one.

Bidirectional Impact of Varying Severity of Acute Kidney Injury on Calcium Oxalate Stone Formation.

Acute Kidney Injury (AKI) is a prevalent renal disorder. The occurrence of AKI may promote the formation of renal calcium oxalate stones by exerting continuous effects on renal tubular epithelial cells. We aimed to delineate the molecular interplay between AKI and nephrolithiasis. A mild (20 min) and severe (30 min) renal ischemia-reperfusion injury model was established in mice. Seven days after injury, calcium oxalate stones were induced using glyoxylate (Gly) to evaluate the impact of AKI on the formation of kidney stones. Transcriptome sequencing was performed on tubular epithelial cells (TECs) to elucidate the relationship between AKI severity and kidney stones. Key transcription factors (TF) regulating differential gene transcription levels were identified using motif analysis, and pioglitazone, ginkgetin, and fludarabine were used for targeted therapy to validate key transcription factors as potential targets for kidney stone treatment. Severe AKI led to increased deposition of calcium oxalate crystals in renal, impaired kidney function, and upregulation of kidney stone-related gene expression. In contrast, mild AKI was associated with decreased crystal deposition, preserved kidney function, and downregulation of similar gene expression. Transcriptomic analysis revealed that genes associated with inflammation and cell adhesion pathways were significantly upregulated after severe AKI, while genes related to energy metabolism pathways were significantly upregulated after mild AKI. An integrative bioinformatic analysis uncovered a TF regulatory network within TECs, pinpointing that PKNOX1 was involved in the upregulation of inflammation-related genes after severe AKI, and inhibiting PKNOX1 function with Pioglitazone could simultaneously reduce the increase of calcium oxalate crystals after severe AKI in kidney. On the other hand, motif analysis also revealed the protective role of STAT1 in the kidneys after mild AKI, enhancing the function of STAT1 with Ginkgetin could reduce kidney stone formation, while the specific inhibitor of STAT1, Fludarabine, could eliminate the therapeutic effects of mild AKI on kidney stones. Inadequate repair of tubular epithelial cells after severe AKI increases the risk of kidney stone formation, with the upregulation of inflammation-related genes regulated by PKNOX1 playing a role in this process. Inhibiting PKNOX1 function can reduce kidney stone formation. Conversely, after mild AKI, effective cell repair through upregulation of STAT1 expression can protect TEC function, reduce stone formation, and activating STAT1 function can also achieve the goal of treating kidney stones.

A case report with literature review: long-term follow-up of kidney autotransplantation in fibromuscular dysplasia.

Fibromuscular dysplasia is a rare, idiopathic, systemic, non-inflammatory, and non-atherosclerotic vascular disease that primarily affects young women. It often presents as renal artery stenosis. Fibromuscular dysplasia can induce tissue damage in the post-stenotic kidney. Treatment options include antihypertensive therapy, surgical revascularization, and transluminal angioplasty with stent implantation. However, kidney autotransplantation is an alternative when these treatments are not feasible. This study presents a case report of a 22-year-old woman with fibromuscular dysplasia, highlighting the long-term success of kidney autotransplantation and reviewing the related literature. A multidisciplinary approach was employed in the treatment of this patient presenting with intermittent headaches, hypertension, and acute kidney disease, andwho was diagnosed with fibromuscular dysplasia. She underwent left aorta-renal bypass and right autotransplantation. Following the procedure, her serum creatinine level decreased from 2.74 to 1.1mg/dL, with an eight-year follow-up confirming the favorableoutcome. Renal artery stenosis is a significant contributor to secondary hypertension, with fibromuscular dysplasia being a rarecause. While medical and interventional treatments are usually effective, complex cases may necessitate alternative approaches. Kidney autotransplantation, albeit uncommon, is an effective option for patients who are unresponsive to conventional therapies. This case demonstrates the successful management of fibromuscular dysplasia-associated renovascular hypertension via kidney autotransplantation, resulting in controlled blood pressure and preserved kidney function. In conclusion, kidney autotransplantation represents a valuable therapeutic option for severe renal artery stenosis caused by fibromuscular dysplasia, particularly when percutaneous procedures are impractical.

Nephroprotective and hepatoprotective effects of lemongrass essential oil and citral on diclofenac-induced toxicity in mice

The present study was carried out to evaluate and compare the protective potential of two well-known antioxidants of herbal origin in a mouse model of acute DIC-induced nephro- and hepatotoxicity. The tested antioxidants included lemongrass essential oil (LO) and its predominant bioactive constituent citral (CIT). A third herbal product, silymarin (SILY), was used as a reference hepato-renal protective agent. DIC administration led to elevated serum urea and creatinine levels, and prompted oxidative stress along with histopathological changes in the kidney tissue. In parallel, DIC administration increased serum liver enzyme activity, decreased total protein, albumin, and globulin levels, and caused oxidative stress with associated histopathological changes in the liver tissue. Pre-treatment with LO or CIT mitigated DIC-induced alterations in all serum biochemical markers of kidney and liver health (except albumin). High-dose LO, like SILY, within kidney and liver tissues, counteracted DIC-induced oxidative stress and histomorphological alterations. By contrast, CIT failed to mitigate DIC-induced oxidative stress in the kidneys and provided only partial control of DIC-induced oxidative stress in the liver, resulting in less efficient preservation of kidney function and liver structural integrity than LO. Besides confirming the efficacy of SILY at protecting kidneys and liver against the toxicity of DIC in a rodent species different from the one tested so far (rat), this study demonstrated the preventive properties of LO and, to a lesser extent, of CIT against DIC-induced hepato-renal toxicity in mice, supporting their developmental potential as therapeutics.

Impact of the Preservation of Residual Kidney Function on Hemodialysis Survival: Results from the BISTRO Trial.

Preservation of residual kidney function (RKF) in dialysis patients has been associated with improved survival. RKF in the BISTRO trial was relatively well preserved and here we describe its association with survival during the trial and extended follow-up. RKF, measured as the average urea and creatinine clearance (GFR) or 24-hour urine volume was assessed at baseline, one, two and three months and three-monthly up to 2 years in incident haemodialysis patients. Time to event survival data or competing events (transplantation, modality change) were obtained for 50 months post enrolment via data linkage with the UK Renal Registry. Cox proportional hazards regression survival models, including those incorporating change in GFR from baseline as a time-varying variable and joint regression models for longitudinal and survival data (longitudinal models for GFR or urine volume) were used to explore the relationship of RKF preservation with survival. Analyses were adjusted for age, sex, comorbidity and ethnicity. 2919 measures of RKF were made in 387 patients from 32 UK dialysis units. Higher age and comorbidity score associated with increased mortality in all models. Baseline GFR reduced the risk of death (Hazard Ratio: 0.918 95%CI: 0.844, 0.999) per ml/min/1.73m2. A greater fall in GFR and urine volume from baseline was associated with a non-significant increased risk of death as visualised on spline plots. In the joint survival models higher GFR (adjusted HR: 0.88 95%CI 0.80, 0.97) or urine volume (adjusted HR: 0.75 95%CI 0.57, 0.95 per L) at any time point associated with better survival. Lower RKF during the first two years of haemodialysis is associated with an increased death risk for up to 50 months following dialysis initiation. This adds to a growing body of evidence that interventions to preserve RKF should be developed and tested in clinical trials.

Acetazolamide Therapy and Kidney Function in Persons with Nonalbuminuric Diabetes Mellitus Type 1.

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) lower the risk of kidney failure in persons with type 2 diabetes. The presumed mechanism of action is through greater delivery of sodium to the distal tubule, activation of tubuloglomerular feedback which lowers glomerular filtration rate (GFR) and intra-glomerular pressure. SGLT2is are not approved for use in persons with type 1 diabetes due to the risk of diabetic ketoacidosis. Acetazolamide, a proximal tubule diuretic, delivers more sodium to the distal nephron, and may activate tubuloglomerular feedback in a similar way to SGLT2is without a higher risk of diabetic ketoacidosis. The kidney effects and safety of acetazolamide in persons with type 1 diabetes have not been well studied. Methods: We conducted a dose-escalation trial to determine the effects of 3 dosages of oral acetazolamide (62.5mg, 125mg, and 250mg, all twice-daily) in 12 persons with type 1 diabetes. Participants were treated for 2 weeks followed by a 2-week washout before exposure to the next dosage level. Blood and urine chemistries, as well as iohexol measured GFR, were assessed before and after each treatment interval. We aimed to identify a dose that maximized measured GFR reductions while minimizing adverse effects. Results: The mean age was 46±17 years, 100% were White, and 75% were female. The mean measured GFR was 89±18ml/min/1.73m2 at baseline. Acetazolamide reduced measured GFR by 15% (95% CI 9, 21), 14% (95% CI 7, 21), and 15% (95% CI 10, 21) after 2 weeks at the 62.5mg, 125mg, and 250mg twice-daily dosage levels respectively. The measured GFR reduction was fully reversed after each 2-week washout. Serum bicarbonate was reduced by 2.3, 4.2 and 4.4 mEq/L with escalating doses, and no episodes of hypokalemia (< 3.5 mEq/L) were observed. Conclusions: Among persons with type 1 diabetes and preserved kidney function, acetazolamide caused an acute, reversible reduction in measured GFR without effects on glucose metabolism.

Aldehyde dehydrogenase 2 preserves kidney function by countering acrolein-induced metabolic and mitochondrial dysfunction.

The prevalence of chronic kidney disease (CKD) varies by race because of genetic and environmental factors. The Glu504Lys polymorphism in aldehyde dehydrogenase 2 (ALDH2), commonly observed among East Asian people, alters the enzyme's function in detoxifying alcohol-derived aldehydes, affecting kidney function. This study investigated the association between variations in ALDH2 levels within the kidney and the progression of kidney fibrosis. Our clinical data indicate that diminished ALDH2 levels are linked to worse CKD outcomes, with correlations between ALDH2 expression, estimated glomerular filtration rate, urinary levels of acrolein - an aldehyde metabolized by ALDH2 - and fibrosis severity. In mouse models of unilateral ureteral obstruction and folic acid nephropathy, reduced ALDH2 levels and elevated acrolein were observed in kidneys, especially in ALDH2 Glu504Lys-knockin mice. Mechanistically, acrolein modifies pyruvate kinase M2, leading to its nuclear translocation and coactivation of HIF-1α, shifting cellular metabolism to glycolysis, disrupting mitochondrial function, and contributing to tubular damage and the progression of kidney fibrosis. Enhancing ALDH2 expression through adeno-associated virus vectors reduced acrolein and mitigated fibrosis in both WT and Glu504Lys-knockin mice. These findings underscore the potential therapeutic significance of targeting the dynamic interaction between ALDH2 and acrolein in CKD.

Prospects for gene therapy in polycystic kidney disease.

We aim to provide an updated perspective on the recent advancements in gene therapy for polycystic kidney disease (PKD), a genetic disorder with significant morbidity. Given the rapid evolution of gene therapy technologies and their potential for treating inherited diseases, this review explores the therapeutic prospects and challenges in applying these technologies to PKD. Significant progress has been made in understanding the genetic underpinnings of PKD, making it a prime candidate for gene therapy. Re-expression of the PKD genes, treatment with the C-terminal tail of polycystin 1 protein and antagomir therapy against miR-17 have shown promise in reducing cyst formation and preserving kidney function. The rapid development of gene-editing tools, antisense oligonucleotide-based strategies, programmable RNA, and advanced gene delivery systems has opened new possibilities for PKD treatment. However, challenges such as off-target effects, delivery efficiency, and long-term safety remain significant barriers to clinical application. Current research highlights the transformative potential of gene therapy for PKD. Ongoing studies are crucial to overcoming existing challenges and translating these findings into clinical practice. We highlight the need for multidisciplinary efforts to optimize gene-editing technologies and ensure their safety and efficacy in treating PKD.

The Increasing Problem of Resistant Hypertension: We'll Manage till Help Comes!

Arterial hypertension remains the major cardiovascular risk worldwide. It is estimated that under 50 years of age one in every three adults is hypertensive while beyond the age of 50 the prevalence is almost 50% globally. The latest World Health Organization (WHO) Global Report on Hypertension indicated that the global number of hypertensive patients almost doubled in the last three decades, with related increasing deaths, disability, and costs annually. Because of this global increase, early diagnosis and timely treatment is of great importance. However, based on the WHO Global Report, it is estimated that up to 46% of individuals were never diagnosed. Of those diagnosed, less than 50% were on treatment, with nearly half among these at target according to the current guidelines. It is also important to note that an increasing number of hypertensive patients, despite the use of three or more drugs, still do not achieve a blood pressure normalization, thus defining the clinical scenario of resistant hypertension (RH). This condition is associated to a higher risk of hypertension-mediated organ damage and hospitalization due to acute cardiovascular events. Current guidelines recommend a triple combination therapy (renin angiotensin system blocking agent + a thiazide or thiazide-like diuretic + a dihydropyridinic calcium-channel blocker) to all patients with RH. Beta-blockers and mineralocorticoid receptor antagonists, alone or in combination, should be also considered based on concomitant conditions and potential contraindications. Finally, the renal denervation is also proposed in patients with preserved kidney function that remain hypertensive despite the use of maximum tolerated medical treatment. However, the failure of this procedure in the long term and the contraindication in patients with kidney failure is a strong call for a new therapeutic approach. In the present review, we will discuss the pharmacological novelties to come for the management of hypertension and RH in the next future.

Study Design and Baseline Characteristics of ALIGN, a Randomized Controlled Study of Atrasentan in Patients With IgA Nephropathy

IntroductionEndothelin A (ETA) receptor activation is a driver of proteinuria, kidney inflammation and fibrosis in IgA nephropathy (IgAN). Atrasentan, a selective ETA receptor antagonist, has potential to reduce proteinuria and preserve kidney function in IgAN. ALIGN (NCT04573478) is a phase 3, randomized, double-blind, placebo-controlled clinical trial of atrasentan in patients with IgAN at high risk of kidney function loss. MethodsEligibility criteria for the ALIGN main stratum included patients with biopsy-proven IgAN, total protein excretion ≥1g/d, eGFR ≥30 mL/min/1.73m2, receiving a maximally-tolerated stable dose of a renin-angiotensin system inhibitor (RASi). An exploratory stratum enrolled participants also receiving a stable dose of sodium glucose cotransporter-2 inhibitors (SGLT2i). Participants were randomized to 0.75 mg atrasentan or placebo orally daily for 132 weeks followed by a 4-week wash-out period. The primary outcome is proteinuria change from baseline (24h urine protein–creatinine ratio UPCR) to Week 36 in the main stratum. Key secondary endpoints include eGFR change from baseline to Week 136, safety and tolerability. ResultsEnrolment occurred across 20 countries; 404 patients are randomized: 340 in the main stratum and 64 in the SGLT2i stratum. At baseline in the main stratum, mean age was 44.7 years, 42.4% were female, mean eGFR and median UPCR were 58.9 mL/min/1.73 m2 and 1.4 g/g, respectively. ConclusionThe ongoing ALIGN trial evaluates the efficacy and safety of atrasentan in a representative global IgAN population at risk for disease progression despite optimized RASi therapy and includes an exploratory stratum evaluating atrasentan use in combination with an SGLT2i.

Effect of Expanded Hemodialysis with Theranova Dialyzer on Preservation of Residual Kidney Function in Incident Hemodialysis Patients: THREAD Randomized Controlled Trial

Effect of Expanded Hemodialysis with Theranova Dialyzer on Preservation of Residual Kidney Function in Incident Hemodialysis Patients: THREAD Randomized Controlled Trial

Cost-effectiveness of bioimpedance-guided fluid management in patients undergoing haemodialysis: the BISTRO RCT.

The BioImpedance Spectroscopy to maintain Renal Output randomised controlled trial investigated the effect of bioimpedance spectroscopy added to a standardised fluid management protocol on the risk of anuria and preservation of residual kidney function (primary trial outcomes) in incident haemodialysis patients. Despite the economic burden of kidney disease, the cost-effectiveness of using bioimpedance measurements to guide fluid management in haemodialysis is not known. To assess the cost-effectiveness of bioimpedance-guided fluid management against current fluid management without bioimpedance. Within-trial economic evaluation (cost-utility analysis) carried out alongside the open-label, multicentre BioImpedance Spectroscopy to maintain Renal Output randomised controlled trial. Thirty-four United Kingdom outpatient haemodialysis centres, both main and satellite units, and their associated inpatient hospitals. Four hundred and thirty-nine adult haemodialysis patients with > 500 ml urine/day or residual glomerular filtration rate > 3 ml/minute/1.73 m2. The study intervention was the incorporation of bioimpedance technology-derived information about body composition into the clinical assessment of fluid status in patients with residual kidney function undergoing haemodialysis. Bioimpedance measurements were used in conjunction with usual clinical judgement to set a target weight that would avoid excessive fluid depletion at the end of a dialysis session. The primary outcome measure of the BioImpedance Spectroscopy to maintain Renal Output economic evaluation was incremental cost per additional quality-adjusted life-year gained over 24 months following randomisation. In the main (base-case) analysis, this was calculated from the perspective of the National Health Service and Personal Social Services. Sensitivity analyses explored the impact of different scenarios, sources of resource use data and value sets. The bioimpedance-guided fluid management group was associated with £382 lower average cost per patient (95% CI -£3319 to £2556) and 0.043 more quality-adjusted life-years (95% CI -0.019 to 0.105) compared with the current fluid management group, with neither values being statistically significant. The probability of bioimpedance-guided fluid management being cost-effective was 76% and 83% at commonly cited willingness-to-pay threshold of £20,000 and £30,000 per quality-adjusted life-year gained, respectively. The results remained robust to a series of sensitivity analyses. The missing data level was high for some resource use categories collected through case report forms, due to COVID-19 disruptions and a significant dropout rate in the informing BioImpedance Spectroscopy to maintain Renal Output trial. Compared with current fluid management, bioimpedance-guided fluid management produced a marginal reduction in costs and a small improvement in quality-adjusted life-years. Results from both the base-case and sensitivity analyses suggested that use of bioimpedance is likely to be cost-effective. Future work exploring the association between primary outcomes and longer-term survival would be useful. Should an important link be established, and relevant evidence becomes available, it would be informative to determine whether and how this might affect longer-term costs and benefits associated with bioimpedance-guided fluid management. This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number HTA 14/216/01 (NIHR136142).

CGS-21680 defers cisplatin-induced AKI-CKD transition in C57/BL6 mice

Acute kidney injury (AKI), with a high mortality and morbidity, is known as a risk factor for developing progressive chronic kidney disease (CKD). Targeting transition of AKI to CKD displays an excellent therapeutic potential. This study aims at investigating the role of CGS-21680, selective A2AR agonist, in deferring Cis-induced AKI-CKD transition. The AKI-CKD transition model was induced in C57/BL6 mice by repeated low doses of Cis (2.5 mg/kg i.p for 5 consecutive days in two cycles with a recovery phase of 16 days between two cycles). CGS-21680 was administered daily for 6 weeks (0.1 mg/kg, i.p). Urine, blood, and kidney were collected at three different time points to track the disease progression. CGS-21680 administration preserved kidney function and attenuated tubular damage as evidenced by hematoxylin-eosin (H&E) histopathology. CGS-21680 significantly restored oxidative status as reflected by reduced malondialdehyde (MDA) content and increased total antioxidant capacity (TAC). CGS-21680 showed anti-inflammatory effect as indicated by decreased TNF-α and iNOS. Additionally, CGS-21680 ameliorated endothelial dysfunction and enhanced renal vasodilation as evidenced by upregulation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) expression and down regulation of endothelin-1 (ET-1) and its receptor endothelin-A (ET-A) receptor expression. CGS-21680 also attenuated renal fibrosis as reflected by the reduction of percentage of fibrosis in Masson's trichome-stained renal sections and down regulation of transforming growth factor beta1 (TGF-β1) protein expression in IHC-stained renal sections. In conclusion, CGS-21680 could defer Cis-induced AKI-CKD transition via its vasodilatory, antioxidant, anti-inflammatory, and anti-fibrotic effects.

Safety and impact of the Mediterranean diet in patients with chronic kidney disease: a pilot randomized crossover trial.

Emerging evidence highlights the potential advantages of the Mediterranean diet (MD) in preserving kidney function and slowing chronic kidney disease (CKD) progression. However, interventional studies on the MD are scarce in East Asian populations. This randomized crossover trial aimed to assess the safety and short-term impact of the Mediterranean Proper Optimal Balance (MEDi-POB) diet in Korean patients with stage 3-4 CKD. Kidney function was assessed using the estimated glomerular filtration rate, which was calculated using the CKD Epidemiology Collaboration equation. Fifty patients with CKD were randomly assigned to two groups, each starting with a different 4-week intervention, followed by a 4-week washout period, followed by a switch to the other 4-week intervention. During the MEDi-POB intervention, patients received home delivery of meals twice daily, 5 days a week, while the control intervention comprised a conventional diet. Forty-six patients successfully completed the entire 12-week trial. Paired t-tests were conducted to assess mean differences between the two groups. A linear mixed model was used to adjust for sequence and period. Dietary fat, fiber, and niacin intake were significantly higher following the MEDi-POB diet than following the control diet (p = 0.001 for fat, p < 0.001 for fiber, and p = 0.007 for niacin). The MEDi-POB diet also yielded slightly increased total CO2 levels (p = 0.043), indicating effective management of metabolic acidosis. Conversely, sodium and copper intake were significantly lower with the MEDi-POB diet (p = 0.032 and p = 0.037, respectively). Caloric intake increased, but body mass index slightly decreased from baseline after consuming the MEDi-POB diet. Dietary potassium intake exhibited a non-significant increase (p = 0.053), and no significant changes in serum (p = 0.883) and urine potassium levels (p = 0.087) occurred. Kidney function remained well-preserved following the MEDi-POB diet. These results indicate that the MEDi-POB diet is safe even in patients with advanced CKD, as it does not adversely affect serum and urine potassium levels and helps maintain kidney function.

Sparsentan improves glomerular hemodynamics, cell functions, and tissue repair in a mouse model of FSGS.

Dual endothelin-1 (ET-1) and angiotensin II (AngII) receptor antagonism with sparsentan has strong antiproteinuric actions via multiple potential mechanisms that are more pronounced, or additive, compared with current standard of care using angiotensin receptor blockers (ARBs). Considering the many actions of ET-1 and AngII on multiple cell types, this study aimed to determine glomeruloprotective mechanisms of sparsentan compared to the ARB losartan by direct visualization of its effects in the intact kidney in focal segmental glomerulosclerosis (FSGS) using intravital multiphoton microscopy. In both healthy and FSGS models, sparsentan treatment increased afferent/efferent arteriole diameters; increased or preserved blood flow and single-nephron glomerular filtration rate; attenuated acute ET-1 and AngII-induced increases in podocyte calcium; reduced proteinuria; preserved podocyte number; increased both endothelial and renin lineage cells and clones in vasculature, glomeruli, and tubules; restored glomerular endothelial glycocalyx; and attenuated mitochondrial stress and immune cell homing. These effects were either not observed or of smaller magnitude with losartan. The pleiotropic nephroprotective effects of sparsentan included improved hemodynamics, podocyte and endothelial cell functions, and tissue repair. Compared with losartan, sparsentan was more effective in the sustained preservation of kidney structure and function, which underscores the importance of the ET-1 component in FSGS pathogenesis and therapy.