Non-diabetic Chronic Kidney Disease Research Articles

Value of SGLT-2 inhibitors in the treatment of chronic kidney disease : Clinical and practical implications.

Chronic kidney disease (CKD) drastically increases the risk for cardiovascular morbidity and mortality and its worldwide prevalence is still rising. Effective treatment slows CKD progression, prevents development of end-stage kidney disease and cardiovascular disease thereby prolonging survival of patients. Recently, several large-scale studies with sodium-glucose cotransport‑2 inhibitors (SGLT-2i) have demonstrated profound nephroprotective and cardioprotective properties in patients with type2diabetes mellitus with both CKD and heart failure. Recently, the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial demonstrated that the selective SGLT-2i dapagliflozin reduced the hazard ratio for acomposite renal and cardiovascular death endpoint in patients with CKD with or without type2diabetes. Furthermore, dapagliflozin exerted strong nephroprotection in CKD patients with diverse etiologies like IgA nephropathy. Furthermore, other promising CKD trials such as with empagliflozin are underway. Hence, individualized treatment with SGLT2i represents apromising therapeutic option for patients with both diabetic and non-diabetic CKD. Here we summarize the current knowledge on the treatment with SGLT-2i in CKD patients underscoring astrong rationale for SGLT2 inhibition to be incorporated into standard of care for most CKD patients also with non-diabetic kidney disease. Finally, we aim to translate the current evidence into recommendations for the clinical practice in the management of patients with CKD.

Investigation into the effect and mechanism of dapagliflozin against renal interstitial fibrosis based on transcriptome and network pharmacology

BackgroundRenal interstitial fibrosis (RIF) is the final pathway for chronic kidney diseases (CKD) to end-stage renal disease (ESRD). Dapagliflozin, a selective inhibitor of the sodium glucose co-transporter 2, reduced the risk of renal events in non-diabetic CKD patients in the DAPA-CKD trial. However, the effect and mechanism of dapagliflozin on RIF are not very clear. Currently, we evaluate the effects of dapagliflozin on RIF and systematically explore its mechanism. Methods and ResultsFirstly, unilateral ureteral obstruction (UUO) mouse model was established to evaluate effects of dapagliflozin on RIF, and results demonstrated dapagliflozin improved renal function and RIF of UUO mice independent of blood glucose control. Subsequently, transcriptome analysis was performed to explore the potential mechanism of dapagliflozin against RIF, which exhibited the therapeutic effect of dapagliflozin on RIF may be achieved through multiple pathways regulation. Then we verified the potential mechanisms with molecular biology methods, and found that dapagliflozin treatment significantly alleviated inflammation, apoptosis, oxidative stress and mitochondrial injury in kidneys of UUO mice. Furthermore, network pharmacology analysis was used to investigate the potential targets of dapagliflozin against RIF. Moreover, we also applied molecular docking and molecular dynamics simulation to predict the specific binding sites and binding capacity of dapagliflozin and hub target. ConclusionsDapagliflozin had therapeutic effect on RIF independent of blood glucose control, and the protective effects probably mediated by multiple pathways and targets regulation.

Predictive Value of HbA1c and Metabolic Syndrome for Renal Outcome in Non-Diabetic CKD Stage 1-4 Patients.

Glycated hemoglobin (HbA1c) levels are commonly used to indicate long-term glycemic control. An HbA1c level of 6.5–5.7% is defined as pre-diabetes and is proposed as a criterion for diagnosing metabolic syndrome (MetS). However, HbA1c levels can be affected by chronic kidney disease (CKD). Whether HbA1c is associated with clinical outcomes in nondiabetic CKD patients with or without MetS is still unknown. This study included 1270 nondiabetic CKD stage 1–4 Asian patients, divided by HbA1c and MetS. Through linear regression, HbA1c was positively associated with age, waist circumference, hemoglobin levels, and C-reactive protein and was negatively associated with malnutrition–inflammation. HbA1c levels were 5.5% (0.6%) and 5.7% (0.6%) in non-MetS and MetS, respectively (p < 0.001). In Cox regression, higher-level HbA1c was associated with worse composite renal outcome in MetS patients, but with better renal outcome in non-MetS patients: Hazard ratio (HR) (95% confidence interval [CI]) of HbA1c ≥5.7%, compared with HbA1c <5%, was 2.00 (1.06–3.78) in MetS and 0.25 (0.14–0.45) in non-MetS. An association between HbA1c and all-cause mortality was not found. In conclusion, higher HbA1c levels are associated with worse renal outcomes in nondiabetic CKD stage 1–4 patients modified by the presence of MetS.

Challenges in Diagnosis and Management of Glomerular Disease in Resource-Limited Settings

IntroductionGlomerular diseases are the leading drivers of nondiabetic chronic kidney disease disability-adjusted life years in resource-limited countries. Proper diagnosis and treatment relies on resources including kidney biopsy, ancillary testing, and access to evidence-based therapies.MethodsWe conducted a cross-sectional internet-based survey cascaded through society mailing lists among nephrologists in countries of Asia, Africa, and Eastern Europe. We collected the data on respondent demographics, their ability to perform and appropriately interpret a kidney biopsy, and their access to complementary investigations and treatment practices.ResultsA total of 298 kidney care specialists from 33 countries (53.3% from Asia and 44.6% from Africa; 64% from academic or university hospitals) participated in the survey. Of these specialists, 85% performed kidney biopsy. About 61% of the respondents could not obtain a kidney biopsy in more than 50% of patients with suspected glomerular disease. About 43% of the respondents from Africa had access to only light microscopy. Overall, the inability to undertake and fully evaluate a biopsy and perform ancillary investigations were more profound in Africa than in Asia. Overall, 59% of participants reported that more than 75% of their patients meet the cost of diagnosis and treatment by out-of-pocket payments. Empirical use of immunosuppression was higher in Africa than in Asia. The main barriers for diagnosis and treatment included delayed presentation, incomplete diagnostic work-up, and high cost of treatment.ConclusionMajor system-level barriers impede the implementation of guideline-driven approaches for diagnosis and treatment of patients with glomerular disease in resource-limited countries.

The non-steroidal mineralocorticoid receptor antagonist finerenone is a novel therapeutic option for patients with Type 2 diabetes and chronic kidney disease.

Despite strong preclinical data supporting the use of mineralocorticoid receptor antagonists (MRAs) to provide cardiorenal protection in rodent models of diabetes, the clinical evidence of their utility in treating chronic kidney disease (CKD) has been limited. Two major clinical trials (FIDELIO-DKD and FIGARO-DKD) including more than 13,000 patients with albuminuric CKD and Type 2 diabetes randomized to placebo or finerenone (MRA) have recently provided exciting results showing a significant risk reduction for kidney and cardiovascular outcomes. In this review, we will summarize the major findings of these trials, together with post-hoc and pooled analyses that have allowed evaluation of the efficacy and safety of finerenone across the spectrum of CKD, revealing significant protective effects of finerenone against kidney failure, new-onset atrial fibrillation or flutter, new-onset heart failure, cardiovascular death, and first and total heart-failure hospitalizations. Moreover, we will discuss the current evidence that supports the combined use of MRAs with sodium-glucose co-transporter-2 inhibitors, either by providing an additive cardiorenal benefit or by decreasing the risk of hyperkalemia. Although the mechanisms of protection by finerenone have only been partially explored in patients, rodent studies have shed light on its anti-inflammatory and anti-fibrotic effects in models of kidney disease, which is one of the main drivers for testing the efficacy of finerenone in non-diabetic CKD patients in the ongoing FIND-CKD trial.

Cardiovascular and Renal Outcomes with Finerenone, a Selective Mineralocorticoid Receptor Antagonist.

Overactivation of the renin–angiotensin–aldosterone system (RAAS) has been shown to be pathologic in heart failure and albuminuric chronic kidney disease (CKD), triggering pro-inflammatory and pro-fibrotic cellular pathways. The standard of care in these disease states includes treatment with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers. Mineralocorticoid receptor antagonists (MRAs) are also a mainstay in the treatment of heart failure with reduced ejection fraction; however, therapy is often limited by treatment-related hyperkalemia. In albuminuric CKD, the risk of hyperkalemia, acute kidney injury (AKI), and hypotension also remains significant. Finerenone is a novel non-steroidal MRA that may obviate some of these concerns and have therapeutic potential in additional patient populations. Finerenone was developed using the chemical structure of a dihydropyridine channel blocker but optimized to create a bulky MRA without any activity at the L-type calcium channel. It has several novel cellular mechanisms that may account for its ability to reduce cardiac hypertrophy and proteinuria more efficiently than an equinatriuretic dose of a steroidal MRA, while retaining anti-inflammatory and anti-fibrotic properties. Finerenone also has a lower rate of treatment-related hyperkalemia and AKI than steroidal MRAs with a smaller effect on systolic blood pressure, greatly expanding its therapeutic utility. The recently published FIGARO-DKD and FIDELIO-DKD trials demonstrate that treatment with finerenone in patients with type II diabetes and albuminuric CKD results in improved cardiovascular outcomes and a lower risk of CKD progression. Patients enrolled in these studies were already on maximally tolerated ACE inhibitor or angiotensin receptor blocker therapy. Trials investigating finerenone’s therapeutic effect in patients with heart failure with preserved ejection fraction (HFpEF) and non-diabetic CKD, as well sodium–glucose cotransporter 2 (SGLT2) and finerenone combination therapy in patients with diabetic nephropathy, are ongoing.

Review of SGLT2i for the Treatment of Renal Complications: Experience in Patients with and Without T2D

The management of type 2 diabetes (T2D) involves decreasing plasma glucose levels and reducing cardiovascular and microvascular complications. Diabetic kidney disease (DKD), defined as presence of albuminuria, impaired glomerular filtration, or both, is an insidious microvascular complication of diabetes that generates a substantial personal and clinical burden. The progressive reduction in renal function and increased albuminuria results in an increase of cardiovascular events. Thus, patients with DKD require exhaustive control of the associated cardiovascular risk factors. People with diabetes and renal impairment have fewer options of antidiabetic drugs because of contraindications, adverse effects, or altered pharmacokinetics. Sodium–glucose cotransporter type 2 inhibitors (SGLT2i) reduce blood glucose concentrations by blocking the uptake of sodium and glucose in the proximal tubule and promoting glycosuria, and these agents now have an important role in the management of T2D. The results of several cardiovascular outcomes trials suggested that SGLT2i are associated with improvements in renal endpoints in addition to their reduction in cardiovascular events and mortality, which represents a major advance in the care of this population. The dedicated kidney outcomes trials have confirmed the renoprotective action of SGLT2i across different glomerular filtration and albuminuria values, even in patients with non-diabetic chronic kidney disease. Notably, this improvement in kidney function may indirectly benefit cardiac function through multifaceted interorgan cross talk, which can break the cardiorenal vicious circle linked to T2D. In this article, we briefly review the different mechanisms of action that may explain the renal beneficial effects of SGLT2i and disclose the results of the key renal outcome trials and the subsequent update of related clinical guidelines.

Cholecalciferol supplementation and angiogenic markers in chronic kidney disease.

Vitamin D plays an important role in proliferation and differentiation of cells and deficiency of vitamin D disturbs angiogenic balance. Previous studies in animal models have reported an association between serum levels of vitamin D and balance between pro- and anti-angiogenic factors. There is insufficient evidence about the effect of vitamin D on mediators of angiogenesis in patients with CKD. We investigated the effect of cholecalciferol supplementation on serum levels of angiogenic markers in non-diabetic patients with CKD stage 3–4. In this secondary analysis on stored samples of our previously published randomized, double-blind, placebo-controlled trial, stable patients of either sex, aged 18–70 years, with non-diabetic CKD stage 3–4 and vitamin D deficiency (serum 25-hydroxyvitamin D ≤20 ng/ml) were randomized to receive either two directly observed oral doses of cholecalciferol (300,000 IU) or matching placebo at baseline and 8 weeks. The primary outcome was change in brachial artery flow-mediated dilatation at 16 weeks. Changes in levels of serum angiogenesis markers (angiopoietin-1, angiopoietin-2, VEGF-A, VEGEF-R, and Tie-2) between groups over 16 weeks were compared. A total 120 patients were enrolled. Supplementation with cholecalciferol led to significant improvement in FMD. Serum 25(OH)D levels were similar in both groups at baseline (13.21±4.78 ng/ml and 13.40±4.42 ng/ml; p = 0.888). At 16 weeks, the serum 25(OH)D levels increased in the cholecalciferol group but not in the placebo group (between-group difference in mean change:23.40 ng/ml; 95% CI, 19.76 to 27.06; p<0.001). Serum levels of angiogenic markers were similar at baseline. At 16 weeks, angiopoietin-2 level decreased in cholecalciferol group (mean difference:-0.73 ng/ml, 95%CI, -1.25 to -0.20, p = 0.002) but not in placebo group (mean difference -0.46 ng/ml, 95%CI, -1.09 to 0.17, p = 0.154), however there was no between-group difference at 16 weeks (between-group difference in mean change: -0.27 ng/ml, 95%CI, -1.09 to 0.55, p = 0.624). Serum angiopoietin-1 level increased [mean change: 5.63 (0.51 to 10.75), p = 0.018] and VEGF-R level decreased [mean change: -87.16 (-131.89 to -42.44), p<0.001] in placebo group but did not show any change in cholecalciferol group. Our data shows the changes in Ang-1, Ang-2 and Ang-1/Ang-2 ratio after high dose oral cholecalciferol supplementation in patients with non-diabetic G3-4 CKD. The data suggests changes in circulating levels of angiogenic markers which needs to be confirmed through an adequately powered study.

IMBALANCE IN BONE MORPHOGENIC PROTEINS 2 AND 7 IS ASSOCIATED WITH HYPERTENSION AND ARTERIAL STIFFNESS IN CHRONIC KIDNEY DISEASE

Objective: Patients with chronic kidney disease (CKD) exhibit an elevated cardiovascular risk from the early stages (I-III) with an exponentially increasing risk of cardiovascular death as kidney function worsens. The hypothesis of this study is that there is a imbalance in bone morphogenetic proteins BMP-2 (procalcifying) and BMP-7 (renoprotective) at early CKD stages associated with the development of hypertension, vascular stiffness and progressive kidney damage. Design and method: BMP-2 and BMP-7 levels were determined by ELISA in samples of CKD patients (stages I-III; n = 95) and of Munich Wistar Frömter (MWF) rats (22 weeks old; n = 6), a genetic model with spontaneous nondiabetic CKD, compared to age-matched Wistar rats. Results: Plasma BMP-2 levels were significantly higher in stage III CKD patients compared to controls. BMP-7 was, however, significantly lower at any stage of CKD compared to the control group with a significant further reduction in stage III patients. MWF rats presented significantly higher BMP-2 plasma levels compared to Wistar rats, whereas BMP-7 level was lower. The MWF strain showed an elevation of both systolic (SBP) and diastolic blood pressure (DBP), as well as pulse wave velocity (PWV) compared to the Wistar group. A positive correlation was observed between the BMP-2/BMP-7 ratio and SBP, DBP, and PWV, respectively. Plasma 25-OH cholecalciferol concentration was lower in MWF showing a negative correlation with the BMP-2/BMP-7 plasma ratio. Urinary albumin excretion (UAE), tubular damage markers, Kim-1 and Ngal, as well as renal BMP-2 were significantly higher in the MWF group compared to Wistar, whereas renal BMP-7 expression was significantly lower. A positive correlation was detected between the BMP-2/BMP-7 ratio and both the UAE and plasma creatinine level. Periaortic and mesenteric perivascular adipose tissue (PVAT) from MWF rats showed an altered expression of BMP-2, BMP-7, profibrotic and calcification markers. Conclusions: Our data show an imbalance in plasma, kidney and PVAT-derived BMP-2 and BMP-7 levels associated with hypertension and arterial stiffness. This might reflect a profibrotic/pro-calcifying propensity related with progressive CKD.

FINERENONE PREVENTS RENAL AND VASCULAR DAMAGE IN A NOVEL MODEL OF TYPE 1 DIABETES MELLITUS

Objective: The non-steroidal mineralocorticoid receptor antagonist (MRA), finerenone (FIN) improves renal and cardiovascular outcomes in patients with chronic kidney disease (CKD) in type 2 diabetes (T2D). We explored the effects of FIN in a novel model of CKD in type 1 diabetes (T1D). Design and method: We employed the Munich Wistar Frömter (MWF) rat model of non-diabetic CKD with mild hypertension and albuminuria to generate a novel model of CKD with T1D. This was achieved by an intra-peritoneal injection of streptozotocin (15 mg/kg) and additional exposure to a high-fat/high-sucrose diet. Oral treatment with FIN (10 mg/kg/day in rat chow) in diabetic animals (MWF-DKD-FIN) was compared to a group of diabetic rats receiving no treatment (MWF-DKD-Control) and a group of non-diabetic untreated MWF rats (MWF). Dietary exposure with or without pharmacological treatment was maintained for 6 weeks (n = 7–10 animals per group). Results: After 6 weeks, MWF-DKD-Control and MWF-DKD-FIN exhibited significantly elevated blood glucose levels (271.7 ± 67.1 mg/dl and 266.3 ± 46.8 mg/dl) as compared to MWF (110.3 ± 4.4 mg/dl; p &lt; 0.05). MWF-DKD-Control showed a 10-fold higher expression of renal damage markers Kim-1 and Ngal compared to MWF. This upregulation was significantly suppressed in MWF-DKD-FIN. FIN treatment resulted in a significant reduction of blood pressure and pulse wave velocity compared to MWF-DKD-Control (p &lt; 0.05). Vascular function studies showed an improvement in endothelial function in MWF-DKD-FIN compared to MWF-DKD-Control due to a reduction in pro-contractile prostaglandins, oxidative stress, and inflammatory cytokines (including IL-1, IL-6, TNFalpha and TGFbeta). FIN induced no changes in blood glucose levels, glucose tolerance or the increase in HOMA index compared to MWF-DKD-Control. Conclusions: Our data show that treatment with FIN improves renal and vascular damage in a new rat model of CKD with T1D. These beneficial effects associated with a reduction in inflammation and oxidative stress and was independent from changes in glucose homeostasis.

Clinical characteristics and disease outcomes in non-diabetic chronic kidney disease: retrospective analysis of a US healthcare claims database

BackgroundThe observational, real-world evidence FLIEDER study aimed to describe patient clinical characteristics and investigate clinical outcomes in non-diabetic patients with chronic kidney disease (CKD) using data collected from routine clinical practice in the United States.MethodsBetween 1 January, 2008–31 December, 2018, individuals aged ≥ 18 years, with non-diabetic, stage 3–4 CKD were indexed in the Optum® Clinformatics® Data Mart US healthcare claims database using International Classification of Diseases-9/10 codes for CKD or by laboratory values (estimated glomerular filtration rate [eGFR] 15–59 mL/min/1.73 m2). The primary outcomes were hospitalization for heart failure, a composite kidney outcome of end-stage kidney disease/kidney failure/need for dialysis and worsening of CKD stage from baseline. The effects of the intercurrent events of a sustained post-baseline decline in eGFR ≥ 30%, ≥ 40%, and ≥ 57% on the subsequent risk of the primary outcomes were also assessed.ResultsIn the main study cohort (N = 504,924), median age was 75.0 years, and 60.5% were female. Most patients (94.7%) had stage 3 CKD at index. Incidence rates for hospitalization for heart failure, the composite kidney outcome, and worsening of CKD stage from baseline were 4.0, 10.3, and 4.4 events/100 patient-years, respectively. The intercurrent event analysis demonstrated that a relative decline in kidney function from baseline significantly increased the risk of cardiorenal events.ConclusionsThis real-world study highlights that patients with non-diabetic CKD are at high risk of serious adverse clinical outcomes, and that this risk is amplified in patients who experienced greater post-baseline eGFR decline.Graphical abstract

MO074: SGLT2 Inhibition Promotes Intrinsic Kidney Regeneration by Cells of the Renin Lineage

Abstract BACKGROUND AND AIMS With chronic kidney disease (CKD) prevalence rapidly increasing, the need for novel therapies is rising. Sodium glucose co-transporter-2 (SGLT2) inhibitors were originally developed to treat hyperglycemia in patients with type 2 diabetes mellitus. Clinical trials with the SGLT2 inhibitor empagliflozin revealed a marked attenuation of the slope of kidney function decline, also in patients with non-diabetic CKD. The exact mechanism of this kidney sparing effect still remains to be clarified. Interestingly, cells of renin lineage (CoRL), residing in the juxtaglomerular apparatus to regulate blood pressure and fluid balance, have been demonstrated to harbor a stem cell like potential. CoRL have the ability to replenish glomerular cell number by dedifferentiating, migrating and subsequently replacing various glomerular cell types in different kidney injury mouse models. Considering that empagliflozin treatment affects renin plasma levels and electrolyte balance in patients, we hypothesized that empagliflozin could have an effect on CoRL-induced glomerular regeneration. METHOD Experiments were performed in a Ren1cre; tdTomato lineage-trace mouse strain that expresses a tomato fluorescent label in all cells derived from renin lineage. Two kidney injury mouse models were applied; bilateral ischemia reperfusion injury (bIRI) and 5/6 nephrectomy (5/6NTx). Empagliflozin (10 mg/kg) was administered daily via oral gavage for 14 days. Subsequently, mice were sacrificed and kidneys were harvested for histological analysis. RESULTS In both the bIRI and 5/6NTx model, empagliflozin intake led to an increase (&amp;gt;2-fold) of CoRL found in the intraglomerular regions compared with vehicle control littermates. These CoRL seemed to selectively differentiate towards different glomerular cell types per model: bIRI combined with empagliflozin administration resulted in an increase of claudin- (10-fold) and integrin-α8- (1.5-fold) tomato double positive cells, suggesting favored differentiation from CoRL to respectively a parietal epithelial or mesangial cell type. In contrast, in the empagliflozin treated 5/6NTx model, an increase (1.5-fold) in tomato-podocyn double positive cells was observed, implying more restocking of glomerular podocytes by CoRL in this model. CONCLUSION SGLT2 inhibition by empagliflozin treatment leads to increased CoRL-mediated intrinsic regeneration potential and provides the kidney with different replenished cell types in different kidney disease models. Our findings demonstrate a novel mechanism via which SGLT2 inhibition might protect against kidney injury.

MO387: Dapagliflozin and Kidney Outcomes in CKD Patients with and without Type 2 Diabetes: Real Life Data (Precursor Announcement)

Abstract BACKGROUND AND AIMS Globally, diabetes mellitus is a leading cause of kidney disease, with a critical % of patients approaching end-stage kidney disease. At the same time, chronic kidney disease (CKD) is a major contributor to illness and is associated with impaired quality of life. Until recently, the only classes of medication that have been shown to slow a decline in kidney function were angiotensin-converting–enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs). Sodium-glucose cotransporter 2 (SGLT2) inhibitors leading to a reduction in intraglomerular pressure may also preserve kidney function in persons with kidney diseases due to causes other than type 2 diabetes. We investigated the impact of Dapagliflozin on kidney function in CKD patients with and without type 2 diabetes. METHOD We monitored kidney function and proteinuria in 10 CKD patients (6 male) with and without type 2 diabetes that received Dapagliflozin. All the participants were required to be receiving a stable dose of an ACE inhibitor or ARB for the study period. All of our patients were clinically stable and there was no need for hospitalization for any reason. RESULTS A total of 9/10 patients were diabetic. One patient had focal segmental glomerulosclerosis (FSGS). The mean age of our patients was 70 years (range: 50–80 years) and were monitored for an average period of 21 months (range: 3–72 months). A total of 5 of them were receiving an ACE inhibitor and the other 5 an ARB. The mean eGFR of our patients at the initiation of the study was 49.62 ± 24.35 mL/min, turned to be 41.42 ± 11.34 mL/min (P = NS) after a year and 54.2 ± 26.97 mL/min after 24 months (P = NS). Mean proteinuria of our patients at the initiation of the study was 1573.33 ± 959 mg/24-h, which turned to be 800.33 ± 575.33 mg/24-h (P = 0.122) after a year and 953.25 ± 1062.93 mg/24-h after 24 months (P = NS). No major kidney event happened in any of our patients. CONCLUSION Dapagliflozin preserved and slightly increased kidney function in our study population for the duration of our noticing period. Proteinuria, on the other hand, showed downward trends. Our study is in progress, but for sure long-term clinical studies in evaluating the potential benefit of SGLT2i, especially, in non-diabetic CKD patients are required before reaching a meaningful and solid conclusion.

MO569: Assessment of Inflammation Using Neutrophil-Lymphocyte Ratio Among Non-Dialyzed Chronic Kidney Disease Patients—A Prospective Observational Study

Abstract BACKGROUND AND AIMS Persistent low-grade inflammation is intimately linked to the pathophysiology of chronic kidney disease and contributes grossly to poor nutritional status and mortality. There is insufficient evidence on inflammation in relation to diabetic status, stages of CKD among chronic kidney disease patients before the commencement of dialysis. This study has characterized the prevalence and factors of inflammation among pre-dialysis chronic kidney disease patients at a tertiary care public teaching hospital. METHOD This longitudinal observational study adopted neutrophil–lymphocyte ratio (&amp;gt;3.53) to evaluate the inflammatory status among pre-dialysis chronic kidney disease patients. Glomerular filtration rate (eGFR) calculated by CKD-EPI equation from National Kidney Foundation was used as a measure of renal function. Multiple/multinomial regression analysis was also performed to determine the predictors of inflammatory status. RESULTS A total of 450 non-dialysis chronic kidney disease patients with or with diabetes were recruited during the period of study, consisting of 265 males and 185 females. Patients were aged 53.9 ± 14.2 years. According to neutrophil–lymphocyte ratio, the prevalence of inflammation among chronic kidney disease patients was found to be 91 (20.2%). The chronic kidney disease patients with diabetes 51(11.3%) were found to have higher rates of inflammation than non-diabetic chronic kidney disease patients 40 (8.9%). The adult age group 57 (12.7%) suffered more with inflammation than the elderly 34 (7.6%). Patients with severe malnutrition 42 (9.3%) were noted to have higher prevalence of inflammation followed by well-nourished 27 (6.0%) and mild/moderately malnourished population 22 (4.9%). The extent of inflammation was found to increase {CKD stage 1–2 (0.6%), CKD stage 3a-3b 34 (7.6%), CKD stage 4–5 54 (12.0%)} with decrease in renal residual function. Serum albumin, nutritional status and serum phosphorous have shown a significant association with the inflammatory status among chronic kidney disease patients. CONCLUSION The current findings demonstrate that the inflammation should be regarded as a familiar comorbid condition in chronic kidney disease. The intensity of inflammation is greater in patients with poorer renal function, comorbid diabetes and higher age. Future work needs to be aligned with respect to comprehensive understanding of inflammation mechanisms among patients with chronic kidney disease.

MO392: Mildly Impaired Kidney Function May Be Associated With the Risk of Hippocampal Atrophy in Young and Midlife Adults

Abstract BACKGROUND AND AIMS To date, associations between kidney function and brain structural abnormalities have been described in several studies [1]. Reports of renal function in relation to hippocampal atrophy have been scarce and the majority of studies have been focussed on older end-stage renal disease populations [2]. Particularly, with the ageing process, the hippocampus has a greater propensity to atrophy than other cerebral structures.The purpose of this study was to evaluate the relationship between kidney function assessed by estimated glomerular filtration rate (eGFR) and the degrees of hippocampal atrophy among young and midlife adults. METHOD In this cross-sectional study, the risk factors for hippocampal atrophy were evaluated in a cohort of 219 non-diabetic chronic kidney disease (CKD) patients, age ≤ 55 years, who had undergone magnetic resonance imaging (MRI) of the brain. The eGFR was calculated using the CKD-EPI formula. Hippocampal volume (HV) was assessed in brain MRIs with the Scheltens’ Medial Temporal Atrophy score, including a 5-stage escalation—0: no atrophy, 1: only widening of choroid fissure, 2: also widening of the temporal horn of lateral ventricle, 3: moderate loss of HV (decrease in height) and 4: severe loss of HV [3]. RESULTS In our group, the median and interquartile ranges (IQR) of age was 45 (14) years, 57.53% (126 patients) being males. The median eGFR was 100.6 (34.7) mL/min/1.73m2 and 46.75% (102 patients) presented with mild reduction in eGFR (eGFR between 60 to 89 mL/min/1.73m2). In univariable regression analysis, eGFR (R2 = 0.207, P &amp;lt; 0.001), arterial hypertension (R2 = 0.018, P = 0.045), dyslipidaemia (R2 = 0.044, P = 0.002), haematocrit (R2 = 0.021, P = 0.032), natrium levels (R2 = 0.018, P = 0.047), and potassium levels ( R2 = 0.019, P = 0.042) were associated with smaller HV. In multivariable regression analysis, eGFR [odds ratio (OR), 0.95; 95% confidence interval (CI), 0.94–0.97; P &amp;lt; 0.001) and serum natrium (OR, 0.91; 95% CI, 0.83–0.98; P = 0.027) were significantly associated with hippocampal atrophy. CONCLUSION This cross-sectional study shows that mild decrease in eGFR is independently associated with hippocampal atrophy. Our results suggest that brain imaging tests should be routinely performed in patients with mild reduction of eGFR, as the hippocampal atrophy process appears to be due, in part, to the mild renal dysfunction itself.

Mineralocorticoid Receptor Antagonism Prevents the Synergistic Effect of Metabolic Challenge and Chronic Kidney Disease on Renal Fibrosis and Inflammation in Mice.

Obesity and/or metabolic diseases are frequently associated with chronic kidney disease and several factors associated with obesity may contribute to proteinuria and extracellular matrix production. Mineralocorticoid receptor antagonists have proven their clinical efficacy in diabetic kidney disease with preclinical data suggesting that they may also be efficient in non-diabetic chronic kidney disease associated to metabolic diseases. In the present study we developed a novel mouse model combining severe nephron reduction and High Fat Diet challenge that led to chronic kidney disease with metabolic alterations. We showed that the Mineralocorticoid Receptor antagonist canrenoate improved metabolic function, reduced albuminuria and prevented the synergistic effect of high fat diet on renal fibrosis and inflammation in chronic kidney disease mice.

Comparison of peripapillary retinal nerve fiber layer and macular thickness in non-diabetic chronic kidney disease and controls.

ObjectiveThis study aimed to compare the peripapillary retinal nerve fiber layer (pRNFL) thickness and macular thickness (MT) between patients with non-diabetic chronic kidney disease (NDCKD) and controls, as well as between different stages of NDCKD. We also evaluated the correlation between pRNFL thickness and MT with duration of NDCKD.MethodsThis was a comparative cross-sectional study. Subjects were divided into NDCKD and control groups. Both pRNFL thickness and MT, including center subfield thickness (CST), average MT as well as average ganglion cell-inner plexiform layer (GC-IPL) were measured using spectral-domain optical coherence tomography. One-way ANCOVA test was used to compare the differences in pRNFL and MT between NDCKD and controls, as well as between the different stages of NDCKD. Spearman rank-order correlation coefficients were employed to determine the effects of NDCKD duration on pRNFL thickness and MT.ResultsA total of 132 subjects were recruited, 66 with NDCKD and 66 controls. There was a statistically significant difference in superior (110.74 ± 23.35 vs 117.36 ± 16.17 μm, p = 0.022), nasal (65.97 ± 12.90 vs 69.35 ± 10.17 μm, p = 0.006), inferior quadrant (117.44 ± 23.98 vs 126.15 ± 14.75 μm, p = 0.006), average pRNFL (90.36 ± 14.93 vs 95.42 ± 9.87 μm, p = 0.005), CST (231.89 ± 26.72 vs 243.30 ± 21.05 μm, p = 0.006), average MT (268.88 ± 20.21 vs 274.92 ± 12.79 μm, p = 0.020) and average GC-IPL (75.48 ± 12.44 vs 81.56 ± 6.48, p = 0.001) values between the NDCKD group and controls. The superior quadrant (p = 0.007), nasal quadrant (p = 0.030), inferior quadrant (p = 0.047), average pRNFL (p = 0.006), average MT (p = 0.001) and average GC-IPL (p = 0.001) differed significantly between different stages of NDCKD. There was no correlation between pRNFL thickness and MT with duration of NDCKD.ConclusionCST, average MT, average GC-IPL thickness, average pRNFL and all quadrants of pRNFL except the temporal quadrant were significantly thinner in NDCKD patients compared to controls. These changes were associated with the severity of CKD, but not its duration.

A Podcast Discussing Aldosterone and Mineralocorticoid Receptor Antagonists in 2021: A Paradigm Shift.

The classic focus on the mechanisms of action of aldosterone was directed primarily on its role in modulating renal excretory function and maintaining volume homeostasis. In contrast, many recent studies have demonstrated a much wider and expanded role for aldosterone and for the mineralocorticoid receptor (MR). Activation of the MR promotes inflammation, collagen formation, fibrosis, and necrosis with consequent renal injury. Increasing evidence has accrued that implicates the pathophysiological overactivation of the MR as a major determinant of progression of both diabetic and nondiabetic chronic kidney disease (CKD). By promoting cascades of injury encompassing inflammation and fibrosis, MR overactivation constitutes a pivotal determinant of CKD progression and consequently its associated morbidity and mortality. Based on this mechanism of action, blockade of the MR with the nonsteroidal MR antagonist finerenone is currently being investigated as a novel treatment regimen to slow the progression of CKD. The recently reported FIDELIO-DKD (FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease) study demonstrated that patients with CKD and type 2 diabetes (T2D) who were treated with finerenone manifested a lower risk of a composite primary outcome event compared with patients in the placebo arm (defined as kidney failure or a sustained decrease of ≥ 40% in the estimated glomerular filtration rate from baseline, or death from renal causes). In addition, patients in the finerenone group also manifested a lower risk of a key secondary outcome event (defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure). Based on the success of these major clinical trials, finerenone was approved by the FDA on 9 July 2021 as a novel treatment for retarding CKD progression in patients with T2D (https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-drug-reduce-risk-serious-kidney-and-heart-complications-adults-chronic-kidney-disease). Podcast Video (MP4 258973 KB)Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-022-01236-w.

Effects of an SGLT Inhibitor on the Production, Toxicity, and Elimination of Gut-Derived Uremic Toxins: A Call for Additional Evidence.

Sodium–glucose cotransporter (SGLT) inhibitors are a class of oral hypoglycemic agents, which, in recent years, have been shown to improve renal and cardiovascular outcomes in patients with diabetic and non-diabetic chronic kidney disease. There remains considerable debate regarding the potential glucose-independent mechanisms by which these benefits are conferred. SGLT inhibitors, to a variable extent, impair small intestinal glucose absorption, facilitating the delivery of glucose into the colon. This suppresses protein fermentation, and thus the generation of uremic toxins such as phenols and indoles. It is acknowledged that such a shift in gut microbial metabolism yields health benefits for the host. SGLT inhibition, in addition, may be hypothesized to foster the renal clearance of protein-bound uremic toxins. Altered generation and elimination of uremic toxins may be in the causal pathway between SGLT inhibition and improved cardiometabolic health. Present review calls for additional research.

Triglycerides-glucose index and the risk of cardiovascular events in persons with non-diabetic chronic kidney disease.

ABSTRACTBackgroundChronic kidney disease (CKD) is associated with high rates of cardiovascular events. We here explored whether the recently described triglycerides–glucose index (TyG) predicted the incidence of major adverse cardiovascular events (MACE) in these patients.MethodsThis observationa study was undertaken of 1142 persons with CKD and free from diabetes and 460 controls from the prospective NEFRONA study. The study exposure was the TyG index at cohort inclusion. The study outcome was MACE (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and hospitalization for unstable angina). Covariates included demographics, comorbidities, lipid profile, renal function and glycaemic control. Cox regression models evaluated the association between TyG index and 4-point MACE in patients with CKD.ResultsTyG was higher [median 8.63 (interquartile range 8.32–8.95)] in patients with CKD compared with controls (P < 0.001). TyG increased across albuminuria categories but was similar for glomerular filtration rate categories among patients with CKD stages 3–5. During 46 ± 13 months of follow-up, 49 (4.3%) MACE were registered. TyG predicted the occurrence of MACE {hazard ratio (HR) 1.95 [95% confidence interval (CI) 1.11–3.40] per TyG unit increase; and HR 2.29 (95% CI 1.24–4.20] for TyG values above the median of 8.63 units}. Sensitivity analysis for subgroups of participants according to age, kidney function, body mass index and imaging evidence of atherosclerosis yielded similar results, as did adjusted analysis. Neither triglycerides nor glucose alone was associated with MACE.ConclusionsThe TyG index is associated with the occurrence of major cardiovascular events in persons free from diabetes with non-dialysis dependent CKD.