Nondiabetic Kidney Research Articles

Design and baseline characteristics of the Finerenone, in addition to standard of care, on the progression of kidney disease in patients with Non-Diabetic Chronic Kidney Disease (FIND-CKD) randomized trial

ABSTRACT Background Finerenone, a non-steroidal mineralocorticoid receptor antagonist, improved kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes in two phase 3 outcome trials. The Finerenone, in addition to standard of care, on the progression of kidney disease in patients with Non-Diabetic Chronic Kidney Disease (FIND-CKD) study investigates the effect of finerenone in adults with CKD without diabetes. Methods FIND-CKD (NCT05047263 and EU CT 2023-506897-11-00) is a randomized, double-blind, placebo-controlled phase 3 trial in patients with CKD of non-diabetic aetiology. Adults with a urinary albumin:creatinine ratio (UACR) ≥200–≤3500 mg/g and an estimated glomerular filtration rate (eGFR) ≥25–<90 ml/min/1.73 m2 receiving a maximum tolerated dose of a renin–angiotensin system inhibitor were randomized 1:1 to once-daily placebo or finerenone 10 or 20 mg depending on eGFR >60 or <60 ml/min/1.73 m2. The primary efficacy outcome is total eGFR slope, defined as the mean annual rate of change in eGFR from baseline to month 32. Secondary efficacy outcomes include a combined cardiorenal composite outcome comprising time to kidney failure, sustained ≥57% decrease in eGFR, hospitalization for heart failure or cardiovascular death, as well as separate kidney and cardiovascular composite outcomes. Adverse events are recorded to assess tolerability and safety. Results Across 24 countries, 3231 patients were screened and 1584 were randomized to study treatment. The most common causes of CKD were chronic glomerulonephritis (57.0%) and hypertensive/ischaemic nephropathy (29.0%). Immunoglobulin A nephropathy was the most common glomerulonephritis (26.3% of the total population). At baseline, mean eGFR and median UACR were 46.7 ml/min/1.73 m2 and 818.9 mg/g, respectively. Diuretics were used by 282 participants (17.8%), statins by 851 (53.7%) and calcium channel blockers by 794 (50.1%). Sodium–glucose co-transporter 2 (SGLT2) inhibitors were used in 16.9% of patients; these individuals had a similar mean eGFR (45.6 versus 46.8 ml/min/1.73 m2) and a slightly higher median UACR (871.9 versus 808.3 mg/g) compared with those not using SGLT2 inhibitors at baseline. Conclusions FIND-CKD is the first phase 3 trial of finerenone in patients with CKD of non-diabetic aetiology.

Altered ECG parameters with loss of cardiac variability and prolonged QTc in a non-diabetic chronic kidney disease rat model

Altered ECG parameters with loss of cardiac variability and prolonged QTc in a non-diabetic chronic kidney disease rat model

Effects of Empagliflozin in Type 2 Diabetes With and Without Chronic Kidney Disease and Nondiabetic Chronic Kidney Disease: Protocol for 3 Crossover Randomized Controlled Trials (SiRENA Project).

Sodium-glucose-cotransporter 2 inhibitors (SGLT2is) have revolutionized the treatment of type 2 diabetes mellitus (DM2) and chronic kidney disease (CKD), reducing the risk of cardiovascular and renal end points by up to 40%. The underlying mechanisms are not fully understood. The study aims to examine the effects of empagliflozin versus placebo on renal hemodynamics, sodium balance, vascular function, and markers of the innate immune system in patients with DM2, DM2 and CKD, and nondiabetic CKD. We conducted 3 double-blind, crossover, randomized controlled trials, each with identical study protocols but different study populations. We included patients with DM2 and preserved kidney function (estimated glomerular filtration rate >60 mL/min/1.73 m2), DM2 and CKD, and nondiabetic CKD (both with estimated glomerular filtration rate 20-60 mL/min/1.73 m2). Each participant was randomly assigned to 4 weeks of treatment with either 10 mg of empagliflozin once daily or a matching placebo. After a wash-out period of at least 2 weeks, participants were crossed over to the opposite treatment. End points were measured at the end of each treatment period. The primary end point was renal blood flow measured with 82Rubidium positron emission tomography-computed tomography (82Rb-PET/CT). Secondary end points include glomerular filtration rate measured with 99mTechnetium-diethylene-triamine-pentaacetate (99mTc-DTPA) clearance, vascular function assessed by forearm venous occlusion strain gauge plethysmography, measurements of the nitric oxide (NO) system, water and sodium excretion, body composition measurements, and markers of the complement immune system. Recruitment began in April 2021 and was completed in September 2022. Examinations were completed by December 2022. In total, 49 participants completed the project: 16 participants in the DM2 and preserved kidney function study, 17 participants in the DM2 and CKD study, and 16 participants in the nondiabetic CKD study. Data analysis is ongoing. Results are yet to be published. This paper describes the rationale, design, and methods used in a project consisting of 3 double-blind, crossover, randomized controlled trials examining the effects of empagliflozin versus placebo in patients with DM2 with and without CKD and patients with nondiabetic CKD, respectively. EU Clinical Trials Register 2019-004303-12; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004303-12, EU Clinical Trials Register 2019-004447-80; https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004447-80, EU Clinical Trials Register 2019-004467-50; https://www.clinicaltrialsregister.eu/ctr-search/search?query=and+2019-004467-50. DERR1-10.2196/56067.

Linagliptin Mitigates TGF-β1 Mediated Epithelial-Mesenchymal Transition in Tacrolimus-Induced Renal Interstitial Fibrosis via Smad/ERK/P38 and HIF-1α/LOXL2 Signaling Pathways.

The dipeptidyl peptidase-4 (DPP-4) inhibitors, a novel anti-diabetic medication family, are renoprotective in diabetes, but a comparable benefit in chronic non-diabetic kidney diseases is still under investigation. This study aimed to elucidate the molecular mechanisms of linagliptin's (Lina) protective role in a rat model of chronic kidney injury caused by tacrolimus (TAC) independent of blood glucose levels. Thirty-two adult male Sprague Dawley rats were equally randomized into four groups and treated daily for 28 d as follows: The control group; received olive oil (1 mL/kg/d, subcutaneously), group 2; received Lina (5 mg/kg/d, orally), group 3; received TAC (1.5 mg/kg/d, subcutaneously), group 4; received TAC plus Lina concomitantly in doses as the same previous groups. Blood and urine samples were collected to investigate renal function indices and tubular injury markers. Additionally, signaling molecules, epithelial-mesenchymal transition (EMT), and fibrotic-related proteins in kidney tissue were assessed by enzyme-linked immunosorbent assay (ELISA) and Western blot analysis, immunohistochemical and histological examinations. Tacrolimus markedly induced renal injury and fibrosis as indicated by renal dysfunction, histological damage, and deposition of extracellular matrix (ECM) proteins. It also increased transforming growth factor β1 (TGF-β1), Smad4, p-extracellular signal-regulated kinase (ERK)1/2/ERK1/2, and p-P38/P38 mitogen-activated protein kinase (MAPK) protein levels. These alterations were markedly attenuated by the Lina administration. Moreover, Lina significantly inhibited EMT, evidenced by inhibiting Vimentin and α-smooth muscle actin (α-SMA) and elevating E-cadherin. Furthermore, Lina diminished hypoxia-related protein levels with a subsequent reduction in Snail and Twist expressions. We concluded that Lina may protect against TAC-induced interstitial fibrosis by modulating TGF-β1 mediated EMT via Smad-dependent and independent signaling pathways.

#1452 Halting the progression of chronic kidney disease; an audit of the use of renin-angiotensin-aldosterone blockers and SGLT-2 inhibitors

Abstract Background and Aims Sodium-glucose cotransporters-2 inhibitors (SGLT2i) were initially developed for the treatment of type 2 diabetes. Multiple studies have demonstrated the renoprotective effect of SGLT2i, with the capacity to slow diabetic kidney disease and non-diabetic proteinuric chronic kidney disease progression. More recently, the EMPA-KIDNEY trial demonstrated a benefit in patients with chronic kidney disease with a wider range of albuminuria and glomerular filtration rate. We aim to identify the proportion of patients on renin-angiotensin aldosterone system blockade (RAASb) such as angiotensin converting enzyme inhibitor (ACEi), and angiotensin II receptor blocker (ARB), and sodium-glucose transporter-2 inhibitor (SGLT2i) in our Nephrology outpatients clinic. We also aim to encourage awareness and prescribing of RAASb and SGLT2i in eligible patients with CKD. Method A prospective audit was performed in Galway University Hospital (GUH) from September 2023 to October 2023. The audit questionnaire was completed by doctors reviewing patients in OPD. The use of ACEi/ARB/SGLT2i was recorded during the consultation. Results 165 patients were included in the audit with a mean (±SD) age of 62.1 ± 18.6 years. The 3 most common primary renal diagnoses were diabetic kidney disease; 20/165 (12.1%), hypertensive renal disease; 18/165 (10.9%) and IgA nephropathy; 15/165 (9.1%). The mean estimated glomerular filtration rate (eGFR) was 46.8 ± 24.5 ml/min/1.73 m². At baseline, 94/165 (57%) were already on RAASb, none on dual RAASb agents. 20/165 (12.1%) were already on SGLT2i, amongst these, 15/20 (75%) were also on RAASb at the time of the OPD consultation. 13/165 (7.9%) patients were maximised on RAASb and 4/165 (2.4%) commenced an SGLT2i at the clinic visit. Guideline directed medical therapy according to the EMPA-Kidney and UK Kidney Association Clinical Practice Guidelines would suggest missed opportunity on therapeutic optimisation with RAASb and SGLT2i in 66/83 (79.5%) patients; 26/66 (39.4%) were neither on RAASb or SGLT2i, 34/66 (51.5%) were on RAASb but not on SGLT2i, 3/66 (4.5%) were on SGLT2i but not on RAASb, and 3/66 (4.5%) were on sub-maximal RAASb with an SGLT2i. Conclusion There is new evidence to support the use of SGLT2i, in those with chronic kidney disease with a wide range of albuminuria. SGLT2i use is underutilised in our clinic. Ideally, these patients should be initiated on an SGLT2i after being established on a RAASb early in their diagnosis to ensure the optimal renoprotective effects of SGLT2i.

For adults with early (stages 1 to 3) nondiabetic chronic kidney disease, how do angiotensin-converting enzyme inhibitors (ACEi) compare with placebo?

For adults with early (stages 1 to 3) nondiabetic chronic kidney disease, how do angiotensin-converting enzyme inhibitors (ACEi) compare with placebo?

#2265 The challenge of renal biopsy in diabetic patients: evaluation of a single center large cohort from North-West Italy

Abstract Background and Aims Diabetic kidney disease is one of the most severe long-term complications of diabetes. Currently, the international guidelines suggest diagnosis of diabetic nephropathy to be achieved on a clinical ground only. However, in the heterogeneous cluster of different conditions putatively co-existing with diabetes, renal biopsy is a unique tool for an accurate diagnosis and a guide for patient management. The aim of the study was to retrospectively analyze monocentric case history of kidney biopsies performed in diabetic patients over a period of 10 years. Patient's data were collected both at the time of histological examination and during follow-up. Method Data of renal biopsies (RB) performed in patients with diabetes mellitus from 1st January 2014 to 31th July 2023, were collected. Patient identification was performed by reviewing clinical histories and histopathological charts. Data on the indication for RB were collected from the medical report of the hospitalisation when the procedure was performed or from the visit when the indication was given. Atypical features were categorized according to an adaptation of the 2007 KDOQI guidelines for diabetes and chronic kidney disease. The significance of baseline differences was determined by the chi-squared test, Fisher's exact test or the unpaired t-test, as appropriate. Significance of univariate analysis were confirmed through the use of multivariate analysis. Correlation analysis, linear regression and Cox regression were also performed. A two-sided P-value <0.05 was statistically significant. All statistical analyses were performed using SPSS version 26.0 (IBM, Armonk, NY, USA). Results Among 1990 patients (pts) who underwent kidney biopsy during the study period, 297 had type 1 or type 2 DM (14.9%) and were therefore included in the study, regardless of diagnostic suspicion and histological findings. Histological examination revealed diabetic nephropathy (DN) in 112 cases (group 1), DN associated with another kidney disease in 56 cases (group 2) and nondiabetic renal diseases alone in the remaining 129 cases (62%) (group 3). In group 2 the kidney disease most frequently associated with DN was focal and segmental glomerulosclerosis, FSGS (24/56 pts) followed by IgA nephropathy, IgAN (14/56 pts). In this population the histological examination led to specific therapeutic indications in 22 patients. In group 3 the most frequently observed kidney disease was FSGS (37/112 pts) followed by ANCA-vasculitis (14/112 pts), membranous nephropathy (14/112 pts) and IgAN (10/112). In this population, histological examination led to a specific therapeutic indication in 67 pts. To determine predictors for histopathological diagnosis of DKD, we ran a logistic regression model. The covariates used in this model were the duration of diabetes, presence of retinopathy, hypertension, serum creatinine values, eGFR values and 24-hours proteinuria. None of them was found to be statistically significant. It should also be noted that 47 out of 112 pts (42%) with diabetic nephropathy had no retinopathy. In contrast, 9 pts (7%) with histological evidence of NDRD had diabetic retinopathy. 215 out of 297 pts had a follow-up of at least 6 months. During a mean follow up of 41.6±31.8 months, 53 pts (24 in group 1, 15 in group 2 and 14 in group 3) reached end stage kidney disease (16.5 months). In our population the presence of DN associated with another biopsy-proven nephropathy was especially prevalent. Having double nephropathy conferred a relative risk-RR for dialysis of 1.8089 (95% CI 1.0094 to 3.2415, P = .0464). Conclusion To our knowledge this is the largest cohorts of diabetic patients receiving renal biopsy even reported in a Western country. Our data proved kidney biopsy not to be an academic exercise in diabetic pts. Clinical and laboratory features do not predict histologic findings. Renal biopsy allowed the identification of unsuspecting nondiabetic kidney injuries and double nephropathies, which could be susceptible to different outcomes, and paved the pathway for treatment of potentially manageable histological changes.

#1626 The role of sodium-glucose cotransporter 2 inhibitors in diabetic nephropathy and non diabetic renal disease in diabetes mellitus type 2 patients

Abstract Background and Aims Diabetes Mellitus type 2 (DM2) leads to chronic kidney disease in a 30-40% of diabetic patients and it is the major cause of end stage renal disease (ESRD). The clinical course of diabetic kidney disease is very heterogeneous and there is a lack of agreement between clinical parameters and renal histology. Besides, lesions of non-diabetic kidney disease (NDRD) can coexist with lesions of diabetic nephropathy (DN) in two-thirds of kidney biopsies in patients with diabetes. There is not a specific treatment against diabetic kidney disease, treatment based in the blockade of renin-angiotensin-aldosterone system has demonstrated a delay of kidney function decline but the diabetic kidney disease is still the main cause of renal replacement by dialysis. Recently, a new class of oral glucose -lowering drugs, sodium-glucose cotransporter 2 (SGLT2) inhibitors, have shown beneficial effects into cardiovascular protection and chronic kidney disease in diabetic patients but it is not clear the beneficial effect in DN. The aim of this study is to evaluate the role of SGLT2 inhibitors in diabetic patients with DN biopsy-confirmed and compare with a group of diabetic patients with NDRD (DN and superimposed non diabetic renal disease lesions, NDRD). Method This is a retrospective study with DM2 patients and kidney biopsy performed. Patient demographic characteristics were recorded and diagnosis of Hypertension, duration of DM2, presence or absence of diabetic retinopathy (DR), macrovascular disease and treatment with renin–angiotensin– aldosterone system blockers (RAASB), oral hypoglycaemic agents, insulin, and aldosterone antagonists. Histological lesions were recorded according to the pathologic classification of DN. Renal function was based on estimated filtration rate CKD-EPI (eGFR mil/min/m2), the urine albumin-creatinine ratio (UACR mg/gr) and the 24 h proteinuria (g/24 h). Diabetic patients were classified according to the kidney biopsies in DN and NDRD. The follow up was assessed at the time of sodium-glucose cotransporter 2 (SGLT2) inhibitors started, 6, 12 and 24 months. Results A total of 64 DM2 patients with kidney biopsy were included in the study. Basal characteristics are summarized in Table 1. DN was diagnosed in 47% and NDRD in 53% of DM2 patients. DM2 patients with NDRD were older (64 ± 10 vs 70 ± 10, p = 0.017), and with more macrovascular disease than patients with DN, 6 (20%) vs 15 (44%), p = 0.04. Instead, DM2 patients with DN showed higher uACR levels than NDRD (2355 ± 2540 vs 706 ± 730, p = 0.02). A 40% of DM2 patients with DN were classified in nodular sclerosis class III of glomerular classification of DN. Interstitial fibrosis and tubular atrophy score were higher in DN versus NDRD patients, (interstitial fibrosis 12 (40%) vs 3 (9%), p = 0.006, tubular atrophy 10 (33%) vs 3 (9%), p = 0.02, Table 2. At the end of follow up, 20% of DM2 patients developed ESRD. According SGLT2 inhibitors treatment, a higher proportion of ESRD and death were observed in DM2 patients without SGLT2 inhibitors than patients with SGLT2 inhibitors, ESRD 11 (39%) vs 2 (6%), p = 0.001, death 9 (32%) vs 4 (11%), p = 0.03. Serum creatinine levels were lower in DM2 patients with SGLT2 inhibitors (118 ± 63.7 vs 203 ± 80.7, p = 0.001), but no differences was observed in uACR between groups. A significant reduction in serum creatinine levels with better eGFR were observed in both groups (DN and NDRD) under SGLT2 inhibitors comparing to group without SGLT2 inhibitors, serum creatinine levels 124 ± 78 vs 236 ± 83, p = 0.008, 107 ± 40 vs 201 ± 110, p = 0.02, and eGFR mil/min/m2 60.9 ± 27.5 vs 25.1 ± 7.2, p = 0.004, 62.6 ± 21.2 vs 33.7 ± 16.2, p = 0.005, Table 3. Conclusion A higher proportion of DM2 showed NDRD lesions in kidney biopsy. Treatment with SGLT2 inhibitors reduced progression of chronic renal disease in DN and NDRD DM2 patients. A reduced progression to ESRD and death were also observed in NDRD DM2 patients with SGLT2 treatment.

#1846 Oxalate nephropathy in diabetic kidney disease: another factor to take into account?

Abstract Background and Aims Patients with diabetes mellitus (DM) have an increased urinary excretion of oxalate. Around 40% of patients with oxalate nephropathy have DM. The aim of this study was to describe the prevalence of tubular deposits of calcium oxalate (CaOx) crystals in patients with diabetic kidney disease (DKD) and investigate its association with renal survival. Method We performed an observational retrospective study that included patients with DKD in renal biopsies performed at our centre between January 1999 and December 2021. We revised the biopsy specimens for the presence of intratubular CaOx crystals. We excluded patients with a histological findings of non-diabetic kidney disease and those lost to follow-up. Renal survival was defined as a state free from developing end-stage kidney disease (ESKD) requiring renal replacement therapy. Results The study included 87 patients with a mean age of 63.1 ± 13 years, 73.5% were male, and 88.5% had type 2 DM (11.5% type 1 DM). Baseline GFR at the moment of kidney biopsy was 38.5 ± 23 ml/min, and baseline median proteinuria was 3.46 (1.35-5.70) g/day. We found intratubular CaOx deposits in 11 biopsies (12.6%). These findings were only found in patients with type 2 DM (14.3% vs 0%), and was more frequently present in patients with a history of renal stones (33.3% vs 11.1%). There were no differences in baseline GFR, proteinuria or vintage of DM between patients with intratubular CaOx deposits and those with no signs of oxalte nephropathy. CaOx deposition was not associated with other histological lesions such as percentage of glomerular sclerosis, grade of interstitial fibrosis and/or tubular atrophy, interstitial inflammation, arterial hyalinosis or arteriosclerosis. After a median follow-up of 41 months, 49.4% of patients developed ESKD while 26.4% died without progressing to ESKD. The patients who progressed to ESKD had a higher baseline serum creatinine (2.56 ± 1.45 vs 1.98 ± 1.07 ml/min, p = 0.037) and lower serum albumin (3.08 ± 0.70 vs 3.57 ± 0.74 g/dl, p = 0.003). In the regression analysis there was no association between intratubular CaOx deposits and progression to ESKD (OR = 2.96, 95% CI 0.73-12.03). In the adjusted model, no histological lesions were associated with renal survival. In the survival analysis, the presence of intratubular CaOx deposits was not associated with neither renal nor patient survival. Conclusion Oxalate nephropathy, defined as the presence of intratubular CaOx deposits in kidney biopsies, may be found in patients with DKD. In our cohort, 14.3% of type 2 DM patients with DKD had concomitant oxalate nephropathy. Its presence was not associated with a worse renal or patient survival.

#2708 Impact of dialysis modality on bone phenotype

Abstract Background and Aims Literature data suggest that low bone turnover is the prevailing bone phenotype in patients treated with peritoneal dialysis (PD) and point to high sclerostin as the central culprit. Lack of adequate controls, diagnostic heterogeneity, and a changing mineral metabolism landscape and armamentarium call for a cautious interpretation and confirmation in contemporary patients. Method Laboratory parameters of mineral metabolism (biointact parathyroid hormone (PTH), fibroblast growth factor 23 [FGF23] and sclerostin), bone turnover markers (bone alkaline phosphatase [BALP], intact procollagen type I N-terminal propeptide [PINP], tartrate-resistant acid phosphatase 5b [TRAP5b]) and bone mineral density (BMD) were assessed in 636 non-diabetic kidney transplant candidates of whom 447 were treated with hemodialysis (HD) and 189 with PD. A bone biopsy was performed in 204 patients (n = 134 HD; n = 70 PD), with bone sclerostin expression assessed in a subset (n = 52). Results Patients treated with PD had lower levels of PINP (79.6 vs 99.5 ug/L; p < 0.01) and BALP (20.2 vs 23.7 ug/L; p = 0.04) compared to those treated with HD. Histomorphometric parameters of bone formation were numerically lower in patients treated with PD, but significance was not reached. Bone mineralization was impaired in HD patients (osteoid width: 7.90 vs 6.75 µM; p = 0.01; osteoid maturation: 9 vs 6 days; p = 0.03), while frank osteomalacia was rare in both modalities (6.0%, both groups). BMD was higher in patients treated with PD compared to HD at skeletal sites rich in cortical bone (Z-score midshaft radius −0.4 ± 1.3 vs −0.9 ± 1.7; p = 0.04). PTH levels were comparable (150 vs 144 pg/mL, PD vs HD), while patients treated with PD showed higher serum phosphate (4.9 ± 1.3 vs 4.5 ± 1.6 mg/dl; p < 0.01) and FGF23 levels (3852 pg/ml vs 2361 pg/ml; p = 0.01). Circulating (1.82 ng/mL, both groups) and bone tissue expression (205 ± 126 vs 206 ± 112 positive osteocytes per mm2) of sclerostin did not differ between groups. Conclusion Patients treated with PD present a lower bone turnover, better mineralization, and higher cortical BMD than counterparts treated HD. Overall, differences are marginal and most probably clinically irrelevant. We speculate that inferior phosphate control may be in the causal pathway.

#2572 Sodium-glucose transport protein 2 (SGLT-2) inhibitors in diabetic and non-diabetic kidney transplant recipients

Abstract Background and Aims The beneficial effects of administering sodium-glucose transport protein 2 (SGLT2i) inhibitors in patients with Chronic Kidney Disease, with or without Type 2 Diabetes (T2D), has been proven in large randomized controlled trials. Nevertheless, there is limited data considering Kidney Transplant Recipients (KTRs) with or without albuminuria. The purpose of this study was to evaluate the safety and efficacy of administering SGLT2i to KTRs in association to their kidney function and albuminuria. Method In this retrospective study we examined the effects of treatment with SGLT2i on kidney function (eGFR calculated with CKD-EPI formula), albuminuria (24h urine collection) and fasting serum glucose levels of KTRs. We included KTRs with T2D or without T2D and confirmed albuminuria (ACR >30 mg/gCr) in two consecutive ACR measurements. Kidney function and albuminuria monitoring was performed one month post-treatment initiation and in three month intervals thereafter. Moreover, immunosuppression trough levels were measured in each visit and active surveillance for adverse events was performed. Results Twenty-four KTRs (20 males) with a mean eGFR of 51.1 ± 14.2 ml/min/1.73 m2 were included in this study. Nine patients had T2D. Treatment was initiated 10 ± 5.4 years post transplant and all KTRs received dapagliflozin. Mean follow-up was 9 ± 2 months. Kidney function was non-significantly decreased directly after SGLT2i initiation and remained stable until the end of follow up (51.1 ± 14.2 vs. 51.4 ± 13.8 ml/min/1.73 m2). Overall, we found a significant reduction of albuminuria (371 ± 460 vs 235 ± 294 mg/24 h, p = 0.015). When KTRs were examined separately based on their diabetes status (KTRs with T2D vs. no T2D) we found that only those with T2D showed a significant decrease in albuminuria (450.4 ± 548 vs. 259.8 ± 332.5 mg/24 h, p = 0.008) at the end of follow up. Furthermore, a significant reduction of morning fasting glucose (106.4 ± 19.6 vs 99.9 ± 16.6 mg/dl, p = 0.0006) was noted. Trough levels of immunosuppression agents (tacrolimus, everolimus or cyclosporine) did not show any significant change after the initiation of SGLT2i and two patients had to discontinue the treatment, due to one episode of pyelonephritis and detection of funguria. Conclusion Prescription of SGTL2i in KTRs with T2D and albuminuria, seems to be a reliable option with significant efficacy on the decrease of albuminuria with minimal adverse effects.

Spectrum of non-diabetic kidney diseases in patients with type 2 DM who underwent kidney biopsy in Egypt.

Diabetic kidney disease (DKD) affects 30-40% of diabetic patients. The prevalence of non-diabetic kidney disease (NDKD) in patients with type 2 DM (T2D) in Egypt is unknown. This study aimed to assess the prevalence of NDKD in patients with T2D in Egypt. In this cross-sectional study, we searched the data of patients with T2D who underwent a native kidney biopsy between January 2010 and December 2020 in a kidney pathology laboratory in Egypt. Of 12,006 patients who underwent kidney biopsy, 677 patients had T2D. NDKD was found in 285 patients (42.7%), DKD in 220 patients (33%), and mixed DKD and NDKD in 162 patients (24.3%). The total prevalence of NDKD was 67% in patients with T2D in our study group. Membranous nephropathy (MN) was the most common histopathological disease in patients with NDKD (20.6%) followed by acute tubular injury (ATI) (19.2%) and focal segmental glomerulosclerosis (FSGS) (15.2%). The presence of ATI in kidney biopsy was associated with a significantly higher mean serum creatine level (P<0.001). Minimal change disease was associated with significantly higher proteinuria level (P>0.001). In multivariate analysis, the duration of diabetes was a significant predictor of NDKD, with longer duration decreasing the likelihood of the 'NDKD' outcome. NDKD is prevalent among patients with T2D. Kidney biopsy remains the gold standard for diagnosing NDKD in patients with T2D.

Vitamin D in kidney: a two-edged sword?

A wide variety of both calcium-dependent and calcium-non-dependent actions are attributed to the vitamin and hormone vitamin D. One of the most vital components of the human body, vitamin D is essential to both health and illness. It is a member of the fat-soluble secosteroid family, which is obtained from diets or direct sun exposure, which is what turns 7-hydroxycholesterol into the precursor of vitamin D. Bio-activation is an alternate phase that provides an active version of vitamin D that contributes to several notable processes like detoxification, fertility, glucose regulation, bone remodelling, and calcium regulation. Numerous research investigations examine the discernible function of vitamin D in kidney illness. The basic physiological and pathological roles of vitamin D in the kidneys of both diabetics and non-diabetics were examined in this study. In this study we analyzed a basic physiological and pathological roles of Vitamin D in kidney in terms of diabetic and non-diabetic proteinuric kidney diseases. Further research in this field is of high importance.

Renal tubular (pro)renin receptor deletion does not protect against kidney injury in db/db mice

Background: The (pro)renin receptor (PRR) is a multifunctional protein implicated in blood pressure regulation and kidney fibrosis. Previous studies report enhanced PRR expression in non-diabetic and diabetic kidney disease. In this study, we investigated whether deletion of renal tubular PRR attenuates kidney injury in type 2 diabetes. Methods: Floxed PRR mice were bred with mice expressing Pax8 rtTA and LC1 transgenes and db/db mice (B6.BKS) to obtain renal tubular PRR knockout (KO)-db/db mice. Age matched non-diabetic floxed controls, db/db mice and PRRKO-db/db mice were studied at 16, 20, 26 and 30 weeks of age. To induce PRR deletion, PRRKO-db/db mice were treated with 2 mg/ml doxycycline for 12 days at 8-10 weeks of age. Only male mice were included in this study. Results: All mice survived until the end of the study (N=5-7 mice/group). Compared to controls, db/db mice and PRRKO-db/db mice had higher body weights despite similar food intake throughout the study (p&lt;0.001 by one-way ANOVA). PRRKO-db/db mice had higher urine volume and water intake compared to controls and db/db mice (p &lt;0.01 by ANOVA). Db/db mice had elevated non-fasting blood glucose levels (average: 472 mg/dl at 16 weeks, 292 mg/dl at 30 weeks) while PRR KO-db/db mice had modestly elevated blood glucose levels (average 255 mg/dl at 20 and 30 weeks) relative to controls (average: 150 mg/dl). Urinary albumin excretion was markedly elevated in PRRKO-db/db mice relative to db/db mice and controls throughout the study (950 ug/day vs db/db:145 ug/day, controls: 50 ug/day, p&lt;0.001). At 30 weeks, kidney histology by PAS stain showed minimal tubular injury, glomerulosclerosis or interstitial inflammation among all 3 groups. Interestingly, podocin staining by immunofluorescence was reduced in db/db mice but not PRR-KO db/db mice. Compared to control mice, db/db mice had similar KIM-1, NGAL and collagen-1 mRNA expression in kidney cortex and inner medulla. PRR KO db/db mice had increased cortical KIM-1, NGAL and collagen-I expression compared to control and db/db mice (p&lt;0.01 by ANOVA). Plasma sPRR levels were almost two-fold higher in diabetic mice relative to controls with no difference between db/db mice and PRR KO-db/db mice. Urinary sPRR levels were undetectable in controls and mildly elevated in db/db mice (7.6 ± 0.7 pg/day) and PRR KO-db/db mice (47.6 ± 22.3 pg/ml). No differences in plasma prorenin/renin concentration was noted among the 3 groups while urinary prorenin/renin excretion was higher in PRRKO-db/db mice. Conclusion: Renal tubular deletion of PRR does not protect against kidney injury in type 2 diabetes. It is possible that loss of PRR impairs baseline tubular function which is exacerbated by type 2 diabetes. American Diabetes Association. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Determinants of non-diabetic kidney diseases in type 2 diabetic patients: Twenty years of single center experience.

Diabetic nephropathy is one of the most common complications associated with diabetes. However, non-diabetic kidney disease has been reported in patients with type 2 diabetes at varying incidence rates. The objective of our study is to investigate the occurrence, clinicopathological characteristics, and inflammatory markers linked to diabetic and non-diabetic nephropathy (NDN) in patients with type 2 diabetes mellitus (DM). Additionally, we aimed to explore the possibility of identifying non-diabetic pathology using different biopsy indications. A total of 159 patients with type 2 DM who underwent renal biopsy at a tertiary care nephrology clinic between January 2000 and January 2022 were enrolled in the study. We collected comprehensive data, including patient demographics, co-morbidities, diabetes duration, renal biopsy indications and results, serological markers, renal function, diabetic retinopathy (DRP), full blood count, blood biochemistry, urinalysis, and inflammatory markers. Patients were categorized based on their biopsy indications, and their biopsy results were classified into three groups: isolated NDN, isolated diabetic nephropathy (DN), and mixed nephropathy with concurrent NDN. We evaluated the relationship between biopsy indications and accompanying pathologies and statistically assessed the likelihood of each biopsy indication detecting non-diabetic renal pathology. Additionally, differences in other data, including demographic and laboratory results and medical histories, among the three groups were investigated. The most frequent indication of renal biopsy was atypical presentations of nephrotic syndrome or nephrotic range proteinuria (ANS/ANP) in 25.1% of patients. Other indications included unexplained renal failure (URF) in 22.6%, atypical presentations of non-nephrotic range proteinuria (ANNP) in 18.2%, acute kidney injury or rapidly progressive kidney dysfunction (AKI/RPKD) in 16.9%, microscopic hematuria in 15.7%, URF with ANNP in 11.3%, and severe nephrotic range proteinuria (SNP) in 9.4%. Renal biopsy revealed isolated NDN in 64.8%, DN in 25.1%, and mixed nephropathy in 10.1% of patients. Primary glomerular diseases were the main non-diabetic renal pathology, predominantly focal segmental glomerulosclerosis (FSGS) (36.4%) followed by MN (10.6%) and IgA nephropathy (7.5%). In comparison with the isolated DN and mixed nephropathy groups, patients in the isolated NDN group had significantly shorter diabetes duration, fewer DRP, as well as lower serum creatinine and neutrophil-to-lymphocyte ratio (NLR). Multivariate logistic regression analysis revealed that presence of hematuria (OR 4.40; 95% CI 1.34 - 14.46, p = 0.014), acute nephrotic range proteinuria (OR 11.93; 95% CI 1.56 - 90.77, p = 0.017), and AKI/APKD (OR 41.08; 95% CI 3.40 - 495.39, p = 0.003) were strong predictors of NDN. Lower NLR (OR 0.77; 95% CI 0.60 - 0.98, p = 0.035), shorter duration of diabetes (OR 0.90; 95% CI 0.84 - 0.97, p = 0.010), and absence of DRP (OR 0.35; 95% CI 0.12 - 0.98, p = 0.046) were also found to be independent indicators of NDN. Receiver operating characteristic curve (ROC) analysis revealed a cut-off value of ≤ 3.01 for NLR (sensitivity of 63.1%, specificity of 63.5%) with regards to predicting non-diabetic renal pathology (p = 0.006). Renal biopsy findings in patients with type 2 DM highlight that the prevalence of NDN may be higher than assumed, as presented mainly in the form of primary glomerular disease. The presence of AKI/RPKD, hematuria, and ANS/ANP serves as a reliable indicator of non-diabetic renal pathology. In more ambiguous situations, factors such as a shorter duration of diabetes, absence of DRP, and a lower NLR value may assist clinicians in biopsy decision.

SGLT2 inhibitors in diabetic and non-diabetic kidney transplant recipients: current knowledge and expectations.

The beneficial effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown recently in numerous randomized controlled trials (RCT) and systematic reviews. According to KDIGO guidelines, SGLT2i currently represent a first choice for diabetic patients with chronic kidney disease (CKD). In addition, a recent meta-analysis of 13 large led by the 'SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists' Consortium' (SMART-C) provided solid evidence of SGLT2i beneficial effects in CKD or in patients with heart failure, with and without diabetes. Collectively, the patients treated with SGLT2i had a decreased risk of CKD progression, acute kidney injury (AKI), end-stage kidney disease (ESKD) or death from heart failure. Whether these cardio-renal benefits should be extrapolated to kidney transplant recipients (KTR) needs to be assessed in further studies. In this article, we report recent data accumulated so far in the literature, looking at the efficacy and safety of SGLT2i in diabetic and non-diabetic KTR. We found encouraging data regarding the use of SGLT2i in KTR with diabetes. These agents appeared to be safe, and they reduced body weight and blood pressure in this group of patients. Potential effects on kidney graft function and survival are yet to be investigated.

Prevalence and Factors Predicting Nondiabetic Kidney Disease in Type 2 Diabetic Patients

ABSTRACT Background: Renal involvement in type 2 diabetes is mostly presumed to be due to diabetic nephropathy; however, a significant majority of diabetic patients can have pure nondiabetic kidney disease (NDKD) or NDKD superimposed on diabetic kidney disease (DKD). Kidney biopsy cannot be routinely performed for all diabetic patients, and hence, short of conclusive biomarkers, we need to explore various factors that can predict the occurrence of NDKD. Methods: We conducted a retrospective review of all native kidney biopsies conducted in patients with type 2 diabetes at our institute to identify the prevalence and factors that predict NDKD. The demographic data, clinical data, laboratory parameters, and histological results of the patients were obtained from their medical records. Binary logistic regression analysis was performed to evaluate the predictive factors for NDKD. Results: We analyzed a total of 69 patients. The mean (standard deviation) age of the cohort was 51.94 ± 12.7 years and males constituted the majority (68%). Patients with pure DKD, pure NDKD, and NDKD superimposed on DKD constituted 46.3%, 33.3%, and 20%, respectively, of the cohort. Around two-third of pure DKD patients in our cohort had diabetic retinopathy (DR), whereas only around one-fifth (26%) of pure NDKD patients had DR (P = 0.005). Membranous glomerulonephritis (MGN) was the most common histological lesion in the NDKD group (43%), followed by acute tubulointerstitial nephritis (ATIN) (17.3%). Among combined DKD and NDKD, the most common histological diagnosis was pyelonephritis (28.6%), followed by MGN and ATIN (14.3%). Independent factors predicting NDKD were shorter duration of diabetes (odds ratio [OR] = 0.74, confidence interval [CI] =0.59–0.94, P = 0.01) and absence of DR (OR = 0.15, 95% CI = 0.09–0.26, P = 0.01). Conclusion: Kidney biopsy revealed NDKD in nearly half of type 2 diabetes mellitus (T2DM) patients, especially in those with short duration of diabetes and absence of DR. Kidney biopsy is strongly recommended for T2DM patients with atypical presentation and in the absence of DR.

CLINICO-PATHOLOGICAL SPECTRUM OF BIOPSY PROVEN NATIVE KIDNEY DISEASE IN A TERTIARY HOSPITAL IN NEPAL

Background: Kidney biopsy has been regarded as an important tool for the diagnosis, management and monitoring the prognosis of renal diseases. We conducted this study to find out the clinico-pathological spectrum by native kidney biopsy in a relatively large scale. Methods: This was a hospital based, prospective, observational study carried out in a tertiary hospital of Kathmandu from January 2022 to December 2023. The biopsy specimens were reported by nephropathologists on the basis of light microscopy, direct immunofluorescence for all samples and electron microscopic examination whenever indicated. The patient`s demographic profile, indication and histological findings of kidney biopsy were studied and analyzed using appropriate statistical tools. Results: A total of 610 kidney biopsies were performed during the study period, of which 24 samples did not meet the inclusion criteria and 586 patients were included in the final analysis. The mean age of the patients was 42.08 ±9.09 years and 59.03% of the patients were younger than 40 years. Females outnumbered the males with female to male ratio of 1.09. The most common presentation was limb swelling (81.22%) and nephrotic syndrome was the most common indication for the biopsy and the most common histological finding was lupus nephritis, followed by IgA nephropathy and FSGS. Non-diabetic kidney disease was found in 54.28% of diabetic patients who underwent biopsy. Conclusions: Nephrotic syndrome was the most common indication for kidney biopsy with lupus nephritis being the most common histological finding. Non diabetic kidney disease (NDKD) was found in more than half of the patients with diabetes mellitus.

Endothelin receptor antagonists in diabetic and non-diabetic chronic kidney disease.

Chronic kidney disease (CKD) is one of the major causes of morbidity and mortality, affecting >800 million persons globally. While we still lack efficient, targeted therapies addressing the major underlying pathophysiologic processes in CKD, findings of several recent trials have brought about a shifting landscape of promising therapies. The endothelin system has been implicated in the pathophysiology of CKD and endothelin receptor antagonists are one class of drugs for which we have increasing evidence of efficacy in these patients. In this review we summarize the most recent findings on the safety and efficacy of endothelin receptor antagonists in diabetic and non-diabetic CKD, future directions of research and upcoming treatments.

Sodium Glucose Cotransporter-2 Inhibitors in Non-Diabetic Kidney Disease: Evidence in Experimental Models.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of glucose-lowering agents widely used for the treatment of type 2 diabetes mellitus. A number of clinical trials in type 2 diabetic patients with different degrees of renal impairment have clearly demonstrated that SGLT2 inhibitors reduce the progression rate of diabetic kidney disease. Furthermore, recent studies have shown that SGLT2 inhibitors also exert a protective effect in the case of non-diabetic kidney disease. Consequently, it has been hypothesized that the nephroprotective activity of these drugs could exceed the canonical impact on glycemic control and that the resulting beneficial effects could be the consequence of their pleiotropic properties (proven reduction of inflammation, fibrosis, oxidative stress and sympathetic nervous activity) both at systemic and tissue levels, suggesting that the efficacy of these drugs could also be extended to non-diabetic nephropathies. This review focuses on the nephroprotective effects of SGLT2 inhibitors in different experimental models of non-diabetic kidney disease. The different glucose-independent mechanisms potentially implemented by SGLT2 inhibitors to ultimately protect the non-diabetic kidney are described in detail, and conflicting results, when present, are discussed.