Cause Of Chronic Kidney Disease Research Articles

Abstract 02: Time restricted feeding reduces kidney fibrosis in diet-induced obesity through limiting kidney CD8+ T cell infiltration

Obesity is a leading cause of chronic kidney disease (CKD). Our lab previously showed that a 20 week diet-induced obesity (DIO) protocol (45% high fat) significantly increased kidney medullary fibrosis in male mice. Further, we found that time restricted feeding (TRF, feeding during 12-hr dark phase only) during the final 2 weeks of the 20-week DIO protocol significantly reduced kidney fibrosis. DIO mice showed significantly greater CD8+ T cells, compared to mice on a normal diet (ND) only during the dark phase. TRF in the DIO mice normalized the CD8+ T cell to that similar to ND mice. We hypothesized that pro-fibrotic CD8+ T cells infiltrate the kidney and mediate damage in the DIO mice. We used anti (a)-CD8 treatment during the final 2 weeks of DIO to deplete all CD8+ T cells. Separate cohorts of ND and DIO mice received control a-IgG treatment during the final 2 weeks of the protocol. DIO mice treated with a-CD8 showed significantly reduced kidney fibrosis compared to DIO mice treated with a-IgG and similar to ND mice treated with a-IgG (assessed by blue trichrome and picrosirius red staining; one-way ANOVA, p=0.018; NDa-IgG vs DIOa-IgG: p=0.033; DIOa-IgG vs DIOa-CD8: p=0.032). We next investigated the intestinal mucosa (IM) as a source of the kidney-infiltrating CD8+ T cells in DIO mice since the IM is one of the primary non-lymphoid sites of T cells in the body. Previous studies have shown that migration of T cells from the IM to the kidney can drive acute kidney injury, but it is unclear if this occurs with chronic models such as DIO. We used the KikumeGreen (KikGr) mouse model to identify migrating cells into the kidney. When KikGR protein is exposed to 408 nm blue light it is photoconverted to a KikRed. We photoconverted the IM at the end of the ND, DIO, and DIO+TRF protocols. Kidneys were analyzed by flow cytometry at 2.5 days post-photoconversion. We detected significantly higher KikRed+ CD8+ T cells in the kidneys of DIO mice compared to ND mice indicating that CD8+ T cells migrate to the kidney from the IM. DIO+TRF mice showed reduced KikRed+ CD8+ T cells in the kidney compared to DIO mice (one-way ANOVA: p=0.006, ND vs DIO: p=0.008; DIO vs TRF: p=0.047). DIO did not have any significant effect on CD4+ T cell migration (one-way ANOVA: p=0.997). This study indicates that DIO induces migration and infiltration of pro-fibrotic CD8+ T cells from the IM to the kidney, while TRF specifically limits migration and infiltration of CD8+ T cells.

Expression of Autophagy Markers LC3B, LAMP2A, and GRP78 in the Human Kidney during Embryonic, Early Fetal, and Postnatal Development and Their Significance in Diabetic Kidney Disease.

Autophagy is the primary intracellular degradation system, and it plays an important role in many biological and pathological processes. Studies of autophagy involvement in developmental processes are important for understanding various processes. Among them are fibrosis, degenerative diseases, cancer development, and metastasis formation. Diabetic kidney disease is one of the main causes of chronic kidney disease and end-stage renal failure. The aim of this study was to investigate the immunohistochemical expression patterns of LC3B, LAMP2A, and GRP78 during different developmental stages of early-developing human kidneys and in samples from patients with type II diabetes mellitus. During the 7/8th DW, moderate expression of LC3B and LAMP2A and strong expression of GRP78 were found in the mesonephric glomeruli and tubules. In the 9/10th DW, the expression of LC3B and LAMP2A was even more pronounced in the mesonephric tubules. LC3B, LAMP2A, and GRP78 immunoreactivity was also found in the paramesonephric and mesonephric ducts and was stronger in the 9/10th DW compared with the 7/8th DW. In addition, the expression of LC3B, LAMP2A, and GRP78 also appeared in the mesenchyme surrounding the paramesonephric duct in the 9/10th DW. In the 15/16th DW, the expression of LC3B in the glomeruli was weak, that of LAMP2A was moderate, and that of GRP78 was strong. In the tubuli, the expression of LC3B was moderate, while the expression of LAMP2A and GRP78 was strong. The strongest expression of LC3B, LAMP2A, and GRP78 was observed in the renal medullary structures, including developing blood vessels. In postnatal human kidneys, the most extensive LC3B, LAMP2A, and GRP78 expression in the cortex was found in the epithelium of the proximal convoluted tubules, with weak to moderate expression in the glomeruli. The medullary expression of LC3B was weak, but the expression of LAMP2A and GRP78 was the strongest in the medullary tubular structures. Significantly lower expression of LC3B was found in the glomeruli of the diabetic patients in comparison with the nondiabetic patients, but there was no difference in the expression of LC3B in the tubule-interstitial compartment. The expression of LAMP2A was significantly higher in the tubule-interstitial compartments of the diabetic patients in comparison with the nondiabetic patients, while its expression did not differ in the glomeruli. Extensive expression of GRP78 was found in the glomeruli and the tubule-interstitial compartments, but there was no difference in the expression between the two groups of patients. These data give us new information about the expression of LC3B, LAMP2A, and GRP78 during embryonic, fetal, and early postnatal development. The spatiotemporal expression of LC3B, LAMP2A, and GRP78 indicates the important role of autophagy during the early stages of renal development. In addition, our data suggest a disturbance in autophagy processes in the glomeruli and tubuli of diabetic kidneys as an important factor in the pathogenesis of diabetic kidney disease.

High lipoprotein(s) as a cause of chronic kidney disease: A population-based Mendelian randomization study

High lipoprotein(s) as a cause of chronic kidney disease: A population-based Mendelian randomization study

The impact of social deprivation on development and progression of diabetic kidney disease

Introduction Diabetes is one of the leading causes of chronic kidney disease. Social deprivation is recognised as a risk factor for complications of diabetes, including diabetic kidney disease. The effect of deprivation on rate of decline in renal function has not been explored in the Irish Health System to date. The objective of this study is to explore the association between social deprivation and the development/progression of diabetic kidney disease in a cohort of adults living with diabetes in Ireland. Methods This is a retrospective cohort study using an existing dataset of people living with diabetes who attended the diabetes centre at University Hospital Galway from 2012 to 2016. The variables included in this dataset include demographic variables, type and duration of diabetes, clinical variables such as medication use, blood pressure and BMI and laboratory data including creatinine, urine albumin to creatinine to ratio, haemoglobin A1c and lipids. This dataset will be updated with laboratory data until January 2023. Individual’s addresses will be used to calculate deprivation indices using the Pobal Haase Pratschke (HP) deprivation index. Rate of renal function decline will be calculated using linear mixed-effect models. The relationship between deprivation and renal function will be assessed using linear regression (absolute and relative rate of renal function decline based on eGFR) and logistic regression models (rapid vs. non-rapid decline).

Investigating Interleukin-6 Levels in Type 2 Diabetes Mellitus Patients With and Without Diabetic Nephropathy.

Diabetic nephropathy (DN), a severe complication affecting 40% of diabetic individuals, is a leading cause of chronic kidney disease (CKD). It involves a progressive increase in urinary albumin and a decline in the glomerular filtration rate. Early detection and intervention are crucial to preventing CKD progression. The current marker, albuminuria, measured as the urine albumin-to-creatinine ratio (UACR), has limitations, highlighting the need for alternative biomarkers. Researchers have linked the proinflammatory cytokine interleukin-6 (IL-6) to the progression of DN, observing elevated levels in DN patients compared to those without DN. IL-6 also regulates glucose metabolism, promoting insulin effectiveness and secretion. Inflammation and glucose control are two things that IL-6 does. This makes it a promising biomarker and therapeutic target for DN and type 2 diabetes mellitus (T2DM). This study focuses on IL-6 levels in T2DM patients with and without DN. From September 2022 to June 2024, the Department of General Medicine, Dr. D. Y. Patil Medical College, Hospitaland Research Centre, Dr. D. Y. Patil Vidyapeeth (Deemed to be University),Pune, conducted an observational cross-sectional comparative study on 80 T2DM patients, with 40 in group A (cases = T2DM patients with DN) and 40 in group B (controls = T2DM patients without DN). The study included patients with T2DM between the ages of 40 and 80. The study excludes conditions such as diabetic ketoacidosis, patients with end-stage renal disease, and conditions that increase IL-6, such as COVID-19. The study excluded autoimmune conditions with elevated IL-6, such as rheumatoid arthritis, systemic lupus erythematous, ankylosing spondylitis, psoriasis, and Crohn's disease. We obtained ethical approval and written consent from participants. In the current study, 61 patients (76.2%) were 60 years old or younger, while 19 patients (23.8%) were older than 60 years. Among the participants, 38 were females (47.5%) and 42 were males (52.5%). The case group, which consisted of 40 T2DM patients with DN, had a mean glycated hemoglobin (HbA1c) of 7.1700 ± 0.71044. In contrast, the control group, comprising 40 T2DM patients without DN, had a mean HbA1c of 6.8650 ± 0.57179. This difference was statistically significant, with a p value of 0.038. Additionally, the mean UACR in the case group was 134.34 ± 95.56, significantly higher than the control group's mean UACR of 22.32 ± 9.90. This difference was highly significant, with a p value of 0.001. Furthermore, the case group exhibited elevated mean IL-6 levels of 15.48 ± 4.27 compared to the control group's 7.02 ± 2.46, which is also highly significant, reflected by a p value of 0.001. As the concentration of IL-6 rises in diabetic patients with nephropathy, this study suggests that IL-6 may have an effect on the development of DN. This cytokine is necessary for both the initiation and progression of the condition. Using IL-6 as a supportive diagnostic test could help rule out other potential causes of DN in T2DM. Moreover, this marker does not require invasive procedures, and early measurement may help reduce mortality and morbidity.

Vaccarin suppresses diabetic nephropathy through inhibiting the EGFR/ERK1/2 signaling pathway.

Diabetic nephropathy (DN) is recognized as one of the primary causes of chronic kidney disease and end-stage renal disease. Vaccarin (VAC) confers favorable effects on cardiovascular and metabolic diseases, including type 2 diabetes mellitus (T2DM). Nonetheless, the potential role and mechanism of VAC in the etiology of DN have yet to be completely elucidated. In this study, a classical mouse model of T2DM is experimentally induced via a high-fat diet (HFD)/streptozocin (STZ) regimen. Renal histological changes are assessed via H&E staining. Masson staining and immunohistochemistry (IHC) are employed to assess renal fibrosis. RT-PCR is utilized to quantify the mRNA levels of renal fibrosis, oxidative stress and inflammation markers. The levels of malondialdehyde (MDA) and reactive oxygen species (ROS), as well as the content of glutathione peroxidase (GSH-Px), are measured. The protein expressions of collagen I, TGF-β1, α-SMA, E-cadherin, Nrf2, catalase, SOD3, SOD2, SOD1, p-ERK, p-EGFR (Y845), p-EGFR (Y1173), p-NFκB P65, t-ERK, t-EGFR and t-NFκB P65 are detected by western blot analysis. Our results reveal that VAC has a beneficial effect on DN mice by improving renal function and mitigating histological damage. This is achieved through its inhibition of renal fibrosis, inflammatory cytokine overproduction, and ROS generation. Moreover, VAC treatment effectively suppresses the process of epithelial-mesenchymal transition (EMT), a crucial characteristic of renal fibrosis, in high glucose (HG)-induced HK-2 cells. Network pharmacology analysis and molecular docking identify epidermal growth factor receptor (EGFR) as a potential target for VAC. Amino acid site mutations reveal that Lys-879, Ile-918, and Ala-920 of EGFR may mediate the direct binding of VAC to EGFR. In support of these findings, VAC reduces the phosphorylation levels of both EGFR and its downstream mediator, extracellular signal-regulated kinase 1/2 (ERK1/2), in diabetic kidneys and HG-treated HK-2 cells. Notably, blocking either EGFR or ERK1/2 yields renal benefits similar to those observed with VAC treatment. Therefore, this study reveals that VAC attenuates renal damage via inactivation of the EGFR/ERK1/2 signaling axis in T2DM patients.

Nadir Creatinine in Congenital Anomalies of the Kidney and Urinary Tract (CAKUT): A Single-Center Experience.

Congenital anomalies of the kidney and urinary tract (CAKUT) are the main cause of chronic kidney disease (CKD) requiring renal replacement therapy (RRT) in children, being the leading cause (50-70%) of end-stage renal disease (ESRD) in children and young adults. Our study aimed to assess the natural evolution of various antenatally diagnosed renal malformations and to identify potential prognostic factors to guide the therapeutic management of patients with CAKUT. We conducted a retrospective study on 205 children with CAKUT. For each patient, analyzing their medical records, we established the nadir value of serum creatinine, defined as the lowest creatinine level during the first year of life. We assessed the value of nadir creatinine as a prognostic marker in patients with CAKUT, and using an ROC curve, we also determined a threshold value of nadir creatinine that predicted progression to ESRD. The male-to-female ratio was 2.8 to 1. The mean gestational age at detection was 29.85 weeks (±6.71). A total of 36 patients (17.6%) had impaired renal function, of which 8 (3.9% of the total) progressed to ESRD. The mean nadir creatinine in patients with ESRD was 1.39 mg/dL. A nadir creatinine cut-off of 0.98 mg/dL had high sensitivity and specificity in identifying patients with progression to ESRD, with an AUC of 0.95 and a 95% confidence interval between 0.86 and 1.05 mg/dL. Our results support the value of nadir creatinine in predicting progression to ESRD, consistent with previously published data.

Routine cardiac biomarkers for the prediction of incident major adverse cardiac events in patients with glomerulonephritis: a real-world analysis using a global federated database

Rationale & objectiveGlomerulonephritis (GN) is a leading cause of chronic kidney disease (CKD). Major adverse cardiovascular events (MACE) are prolific in CKD. The risk of MACE in GN cohorts is multifactorial. We investigated the prognostic significance of routine cardiac biomarkers, Troponin I and N-terminal pro-BNP (NT-proBNP) in predicting MACE within 5 years of GN diagnosis.Study DesignRetrospective cohort study.Setting & participantsData were obtained from TriNetX, a global federated health research network of electronic health records (EHR).Exposure or predictorBiomarker thresholds: Troponin I: 18 ng/L, NT-proBNP: 400 pg/mL.OutcomesPrimary outcome: Incidence of major adverse cardiovascular events (MACE). Secondary outcome: was the risk for each individual component of the composite outcome.Analytical Approach1:1 propensity score matching using logistic regression. Cox proportional hazard models were used to assess the association of cardiac biomarkers with the primary and secondary outcomes, reported as Hazard Ratio (HR) and 95% confidence intervals (CI). Survival analysis was performed which estimates the probability of an outcome over a 5-year follow-up from the index event.ResultsFollowing PSM, 34,974 and 18,218 patients were analysed in the Troponin I and NTproBNP cohorts, respectively. In the Troponin I all cause GN cohort, 3,222 (9%) developed composite MACE outcome HR 1.79; (95% CI, 1.70, 1.88, p < 0.0001). In the NTproBNP GN cohort, 1,686 (9%) developed composite MACE outcome HR 1.99; (95% CI, 1.86, 2.14, p < 0.0001).LimitationsThe data are derived from EHR for administrative purposes; therefore, there is the potential for data errors or missing data.ConclusionsIn GN, routinely available cardiac biomarkers can predict incident MACE. The results suggest the clinical need for cardiovascular and mortality risk profiling in glomerular disease using a combination of clinical and laboratory variables.

Potential Role of Mineralocorticoid Receptor Antagonists in Nondiabetic Chronic Kidney Disease and Glomerular Disease.

Glomerular disease is a leading cause of CKD and ESKD. Although diabetic kidney disease is the most common cause of glomerular disease, nondiabetic causes include malignancy, systemic autoimmune conditions, drug effects, or genetic conditions. Nondiabetic glomerular diseases are rare diseases, with a paucity of high-quality clinical trials in this area. Furthermore, late referral can result in poor patient outcomes. This article reviews the current management of nondiabetic glomerular disease and explores the latest developments in drug treatment in this area. Current treatment of nondiabetic glomerular disease aims to manage complications (edema, hypertension, proteinuria, hyperlipidemia, hypercoagulability, and thrombosis) as well as target the underlying cause of glomerular disease. Treatment options include renin-angiotensin-aldosterone system inhibitors, statins/nonstatin alternatives, loop diuretics, anticoagulation agents, immunosuppressives, and lifestyle and dietary modifications. Effective treatment of nondiabetic glomerular disease is limited by heterogeneity and a lack of understanding of the disease pathogenesis. Sodium-glucose cotransporter-2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists (ns-MRAs, such as finerenone), with their broad anti-inflammatory and antifibrotic effects, have emerged as valuable therapeutic options for a range of cardiorenal conditions, including CKD. ns-MRAs are an evolving drug class of particular interest for the future treatment of nondiabetic glomerular disease, and there is evidence that these agents may improve kidney prognosis in various subgroups of patients with CKD. The benefits offered by ns-MRAs may present an opportunity to reduce the progression of CKD from a spectrum of glomerular disease. Several novel ns-MRA are in clinical development for both diabetic and nondiabetic CKD.

Evaluation of serum levels of sestrin 2 and betatrophin in type 2 diabetic patients with diabetic nephropathy

BackgroundDiabetic kidney disease (DKD) is one of the most serious microvascular complications of diabetes mellitus (DM) and the leading cause of chronic kidney disease (CKD) worldwide. Since obesity and type 2 DM (T2DM) are considered as inflammatory conditions, thus reducing their accompanied systemic inflammation may lessen their complications. Sestrin 2 belongs to a group of stress induced proteins which are produced in response to oxidative stress, inflammation and DNA damage. Betatrophin; a hormone that stimulates the growth, proliferation and mass expansion of pancreatic beta-cells and improves glucose tolerance. The objective of the study was to evaluate levels of serum Sestrin 2 and betatrophin in patients with different stages of diabetic nephropathy (DN)) and compare results with healthy control.MethodsThis cross sectional study was carried out on 60 patients above 18 years old, recruited from Tanta University hospitals out patients clinics and 20 apparently healthy individuals of matched sex and age as a control group. Participants were divided into two groups: group I: 20 normal subjects as control group and group II: 60 patients with type 2 DM,. further subdivided in to three equal groups: group 1IIA(20 patients) with normo-albuminuria (ACR < 30 mg/g), group IIB (20 patients) with micro albuminuria (ACR = 30 to 300 mg/g) and group IIC (20 patients) with macro albuminuria (ACR > 300 mg/g). They were subjected to detailed history taking, careful clinical examination and laboratory investigations including blood urea, serum creatinine, estimated glomerular filtration rate (eGFR), urinary albumin creatinine ratio, and specific laboratory tests for Sestrin 2 and Betatrophin by using ELISA technique.ResultsSerum Sestrin 2 significantly decreased, while serum betatrophin level significantly increased in macroalbuminuric group compared to control and other 2 diabetic groups (P value < 0.05). The cut off value of serum sestrin 2 was 0.98 ng/ml with sensitivity 99%, specificity 66% while the cut off value of serum betatrophin was > 98.25 ng/ml with sensitivity 98%, specificity 82%. Serum betatrophin positively correlated with age, fasting, 2 h postprandial, BMI, triglyceride, total cholesterol, serum creatinine, blood urea, UACR, and negatively correlated with eGFR and serum albumin. Serum Sestrin 2 positively correlated with serum albumin. BMI, serum urea, UACR and serum albumin. Serum betatrophin are found to be risk factors or predictors for diabetic nephropathy.ConclusionsPatients with DN, particularly the macroalbuminuria group, had a significant increase in betatrophin levels and a significant decrease in serum Sestrin 2 level. The function of Sestrin 2 is compromised in DN, and restoring it can reverse a series of molecular alterations with subsequent improvement of the renal functions, albuminuria and structural damage.

Differentiated metabolomic profiling reveals plasma amino acid signatures for primary glomerular disease

Primary glomerular disease (PGD) is an idiopathic cause of renal glomerular lesions that is characterized by proteinuria or hematuria and is the leading cause of chronic kidney disease (CKD). The identification of circulating biomarkers for the diagnosis of PGD requires a thorough understanding of the metabolic defects involved. In this study, ultra-high performance liquid chromatography–tandem mass spectrometry was performed to characterize the amino acid (AA) profiles of patients with pathologically diagnosed PGD, including minimal change disease (MCD), focal segmental glomerular sclerosis (FSGS), membranous nephropathy, and immunoglobulin A nephropathy. The plasma concentrations of asparagine and ornithine were low, and that of aspartic acid was high, in patients with all the pathologic types of PGD, compared to healthy controls. Two distinct diagnostic models were generated using the differential plasma AA profiles using logistic regression and receiver operating characteristic analyses, with areas under the curves of 1.000 and accuracies up to 100.0% in patients with MCD and FSGS. In conclusion, the progression of PGD is associated with alterations in AA profiles, The present findings provide a theoretical basis for the use of AAs as a non-invasive, real-time, rapid, and simple biomarker for the diagnosis of various pathologic types of PGD.

Treatment of Type 2 Diabetes Mellitus in Advanced Chronic Kidney Disease for the Primary Care Physician.

Diabetes mellitus (DM) is a common cause of chronic kidney disease (CKD), leading to the need for renal replacement therapy (RRT). RRT includes hemodialysis (HD), peritoneal dialysis (PD), kidney transplantation (KT), and medical management. As CKD advances, the management of DM may change as medication clearance, effectiveness, and side effects can be altered due to decreasing renal clearance. Medications like metformin that were safe to use early in CKD may build up toxic levels of metabolites in advanced CKD. Other medications, like sodium-glucose co-transporter 2 inhibitors, which work by excreting glucose in the urine, may not be able to work effectively in advanced CKD due to fewer working nephrons. Insulin breakdown may take longer, and both formulation and dosing may need to be changed to avoid hypoglycemia. While DM control contributes to CKD progression, effective DM control continues to be important even after patients have been placed on RRT. Patients on RRT are frequently taken care of by a team of providers, including the primary care physician, both in and outsidethe hospital. Non-nephrologists who are involved with the care of a patient treated with RRT need to be adept at managing DM in this population. This paper aims to outline the management of type 2 DM in advanced CKD.

Phenotypic quantification of Nphs1-deficient mice.

Steroid-resistant nephrotic syndrome (SRNS) is the second most frequent cause of chronic kidney disease in children and young adults. The most severe form of steroid-resistant nephrotic syndrome is congenital nephrotic syndrome Finnish type (CNSF), caused by biallelic loss-of-function variants inNPHS1,encoding nephrin. Since each of the 68 monogenic causes of steroid-resistant nephrotic syndrome represents a rare cause of the disease, tailoring therapeutic interventions to multiple molecular targets remains challenging, suggesting gene replacement therapy (GRT) as a viable alternative. To set the ground for a gene replacement study in vivo, we established rigorous, quantifiable, and reproducible phenotypic assessment of a conditional Nphs1 knockout mouse model. By breeding a floxed Nphs1fl/- mouse (Nphs1tm1Afrn/J) previously studied for pancreatic β-cell survival with a podocin promoter-driven Cre recombinase mouse model (Tg(NPHS2-Cre)295Lbh/J), we generated mice with podocyte-specific nephrin deficiency (Nphs1fl/fl NPHS2-Cre +). We observed a median survival to postnatal day P5 in nephrin-deficient mice, whereas heterozygous control mice and wild type (WT) control group showed 90% and 100% survival, respectively (at P50 days). Light microscopy analysis showed a significantly higher number of renal-tubular microcysts per kidney section in nephrin-deficient mice compared to the control groups (P < 0.0022). Transmission electron microscopy demonstrated reduced foot process (FP) density in nephrin-deficient mice compared to controls (P < 0.0001). Additionally, proteinuria quantitation using urine albumin-to-creatinine ratio (UACR) was significantly higher in nephrin-deficient mice compared to controls. This study represents the first comprehensive description of the kidney phenotype in anephrin-deficient mouse model, laying the foundation for future gene replacement therapy endeavors.

Advancements in Research on Genetic Kidney Diseases Using Human-Induced Pluripotent Stem Cell-Derived Kidney Organoids.

Genetic or hereditary kidney disease stands as a pivotal cause of chronic kidney disease (CKD). The proliferation and widespread utilization of DNA testing in clinical settings have notably eased the diagnosis of genetic kidney diseases, which were once elusive but are now increasingly identified in cases previously deemed CKD of unknown etiology. However, despite these diagnostic strides, research into disease pathogenesis and novel drug development faces significant hurdles, chiefly due to the dearth of appropriate animal models and the challenges posed by limited patient cohorts in clinical studies. Conversely, the advent and utilization of human-induced pluripotent stem cells (hiPSCs) offer a promising avenue for genetic kidney disease research. Particularly, the development of hiPSC-derived kidney organoid systems presents a novel platform for investigating various forms of genetic kidney diseases. Moreover, the integration of the CRISPR/Cas9 technique into this system holds immense potential for efficient research on genetic kidney diseases. This review aims to explore the applications of in vitro kidney organoids generated from hiPSCs in the study of diverse genetic kidney diseases. Additionally, it will delve into the limitations of this research platform and outline future perspectives for advancing research in this crucial area.

Targeting senescence to prevent diabetic kidney disease: Exploring molecular mechanisms and potential therapeutic targets for disease management.

As a microvascular complication, diabetic kidney disease is the leading cause of chronic kidney disease and end-stage renal disease worldwide. While the underlying pathophysiology driving transition of diabetic kidney disease to renal failure is yet to be fully understood, recent studies suggest that cellular senescence is central in disease development and progression. Consequently, understanding the molecular mechanisms which initiate and drive senescence in response to the diabetic milieu is crucial in developing targeted therapies that halt progression of renal disease. To understand the mechanistic pathways underpinning cellular senescence in the context of diabetic kidney disease, we reviewed the literature using PubMed for English language articles that contained key words related to senescence, inflammation, fibrosis, senescence-associated secretory phenotype (SASP), autophagy, and diabetes. Aberrant accumulation of metabolically active senescent cells is a notable event in the progression of diabetic kidney disease. Through autocrine- and paracrine-mediated mechanisms, resident senescent cells potentiate inflammation and fibrosis through increased expression and secretion of pro-inflammatory cytokines, chemoattractants, recruitment of immune cells, myofibroblast activation, and extracellular matrix remodelling. Compounds that eliminate senescent cells and/or target the SASP - including senolytic and senomorphics drugs - demonstrate promising results in reducing the senescent cell burden and associated pro-inflammatory effect. Here we evidence the link between senescence and diabetic kidney disease and highlight underlying molecular mechanisms and potential therapeutic targets that could be exploited to delay disease progression and improve outcomes for individuals with the disease. Trials are now required to translate their therapeutic potential to a clinical setting.

Fabry nephropathy: a treatable cause of chronic kidney disease

Fabry disease is a rare X-linked inborn error of metabolism that has a high prevalence of chronic kidney disease (CKD) and renal failure. It is due to the deficiency of the α-galactosidase A (α-Gal) lysosomal enzyme with subsequent accumulation of globotriaosylceramide (Gb3) in lysosomes. In the kidney, the podocyte is the main target of this disease, although all cell types are involved. The podocyte, being terminally differentiated, does not replicate and thus accumulates Gb3 throughout life. Podocytes are injured by Gb3, leading to their detachment from the glomerular basement membrane and subsequent loss in the urine. Albuminuria starts in childhood and progresses to overt proteinuria in the teens and 20 s. CKD ensues with adults starting dialysis at an average age of 42 years. Patients have a high prevalence of stroke and cardiomyopathy with hypertrophic change, heart failure, and dysrhythmias. Patient survival is limited in both genders. Diagnosis is based on the demonstration of a low α-Gal activity and a pathogenic GLA mutation. Clinical features are highly variable, which makes recognition of this condition difficult. Treatment with intravenous recombinant human enzyme replacement therapy (ERT) and oral pharmacologic chaperone are available. Control of proteinuria to 0.5 g/day or less is of critical importance to limit progression to end-stage renal disease. Early initiation of treatment gives the best results, but the optimal age to start is uncertain. Fabry nephropathy remains a challenge due to its multisystem nature, difficult diagnosis, and complicated management. It is important as a treatable cause of CKD.

From pathophysiology to personalized care: A comprehensive review of diabetic kidney disease

Diabetic kidney disease (DKD) stands as a prevalent and significant complication in individuals with type 2 diabetes, impacting nearly half of this population. It holds the primary position as the cause of chronic kidney disease and end-stage kidney disease globally, associated with heightened cardiovascular morbidity and mortality. Despite the array of available interventions to prevent and manage DKD, such as regulating blood sugar levels, controlling blood pressure, and inhibiting the renin-angiotensin system, numerous patients continue to grapple with the ongoing decline in kidney function and unfavorable outcomes. This comprehensive review offers an updated exploration of the pathophysiology, diagnosis, prevention, and treatment of DKD. Special attention is devoted to emerging treatment modalities displaying promising outcomes in clinical trials, notably sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, non-steroidal mineralocorticoid receptor antagonists, and innovative agents addressing inflammation and fibrosis. The discourse also delves into the complexities and opportunities associated with integrating these therapies into clinical practice, emphasizing the necessity for personalized and all-encompassing care for DKD patients. The conclusion outlines future directions, urging further research and providing recommendations to advance both understanding and practical approaches in this domain. Keywords: pathophysiology; personalized care; diabetic kidney disease

The Functional Role of microRNAs and mRNAs in Diabetic Kidney Disease: A Review.

Diabetes is a group of diseases marked by poor control of blood glucose levels. Diabetes mellitus (DM) occurs when pancreatic cells fail to make insulin, which is required to keep blood glucose levels stable, disorders, and so on. High glucose levels in the blood induce diabetic effects, which can cause catastrophic damage to bodily organs such as the eyes and lower extremities. Diabetes is classified into many forms, one of which is controlled by hyperglycemia or Diabetic Kidney Disease (DKD), and another that is not controlled by hyperglycemia (nondiabetic kidney disease or NDKD) and is caused by other factors such as hypertension, hereditary. DKD is associated with diabetic nephropathy (DN), a leading cause of chronic kidney disease (CKD) and end-stage renal failure. The disease is characterized by glomerular basement membrane thickening, glomerular sclerosis, and mesangial expansion, resulting in a progressive decrease in glomerular filtration rate, glomerular hypertension, and renal failure or nephrotic syndrome. It is also represented by some microvascular complications such as nerve ischemia produced by intracellular metabolic changes, microvascular illness, and the direct impact of excessive blood glucose on neuronal activity. Therefore, DKD-induced nephrotic failure is worse than NDKD. MicroRNAs (miRNAs) are important in the development and progression of several diseases, including diabetic kidney disease (DKD). These dysregulated miRNAs can impact various cellular processes, including inflammation, fibrosis, oxidative stress, and apoptosis, all of which are implicated during DKD. MiRNAs can alter the course of DKD by targeting several essential mechanisms. Understanding the miRNAs implicated in DKD and their involvement in disease development might lead to identifying possible therapeutic targets for DKD prevention and therapy. Therefore, this review focuses specifically on DKD-associated DN, as well as how in-silico approaches may aid in improving the management of the disease.

Patient Characteristics and Outcomes of Hospitalized Chronic Kidney Disease Patients with and without Type 2 Diabetes Mellitus: Observations from the German Claims Data-Based Cohort of the CaReMe-CKD Multinational Study.

Type 2 diabetes mellitus (T2DM) is a leading cause of chronic kidney disease (CKD) globally. Both conditions substantially worsen patients' prognosis. Current data on German in-hospital CKD cohorts are scarce. The multinational CaReMe study was initiated to evaluate the current epidemiology and healthcare burden of cardiovascular, renal and metabolic diseases. In this substudy, we share real-world data on CKD inpatients stratified for coexisting T2DM derived from a large German hospital network. This study used administrative data of inpatient cases from 89 Helios hospitals from 01/01/2016 to 28/02/2022. Data were extracted from ICD-10-encoded discharge diagnoses and OPS-encoded procedures. The first case meeting a previously developed CKD definition (defined by ICD-10- and OPS-codes) was considered the index case for a particular patient. Subsequent hospitalizations were analysed for readmission statistics. Patient characteristics and pre-defined endpoints were stratified for T2DM at index case. In total, 48,011 patients with CKD were included in the present analysis (mean age ± standard deviation, 73.8 ± 13.1 years; female, 44%) of whom 47.9% had co-existing T2DM. Patients with T2DM were older (75 ± 10.6 vs 72.7 ± 14.9 years, p < 0.001), but gender distribution was similar to patients without T2DM. The burden of cardiovascular disease was increased in patients with T2DM, and index and follow-up in-hospital mortality rates were higher. Non-T2DM patients were characterised by more advanced CKD at baseline. Patients with T2DM had consistently higher readmission numbers for all events of interest, except for readmissions due to kidney failure/dialysis, which were more common in non-T2DM patients. In this study, we present recent data on hospitalized patients with CKD in Germany. In this CKD cohort, nearly half had T2DM, which substantially affected cardiovascular disease burden, rehospitalization frequency and mortality. Interestingly, non-diabetic patients had more advanced underlying renal disease, which affected renal outcomes.

Stepping Stones In Prevention of Kidney Stone Disease In Pakistan

The prevalence and incidence of kidney stone disease (KSD) has increased in Pakistan since last 5 decades, it is not only the cause of pain, hematuria and fever but is also an important cause of chronic kidney disease, Morbidity and mortality as well if left untreated. It is recurrent disease and can be manifestation of systemic diseases, (D.M, obesity, HTN) genetic and environmental factors play a role in etiology of disease. In spite of modern methods of surgical removal available in Pakistan there is constant increase in number of patients. Economic burden of disease is quite significant, so established metaphylaxsis program is essential part of management of this surgical and medical disease. Main therapies based on history, stone analysis, 24 hour urine metabolic study constitutes the basis of prevention. Increasing fluid intake dietary modification, Pharmacotherapy is the main stay of metaphylaxsis. Compliance of the patient and establishment of specialized stone clinics should be managed jointly by urologist, nephrologist, dietitians, metabolic laboratory expert and Medical Social officers. Prevention is possible in many cases if these patients are managed jointly by multidisciplinary team.