Cause Of End-stage Kidney Disease Research Articles

Novel Biomarkers of Diabetic Kidney Disease

Diabetic kidney disease (DKD) is a highly prevalent condition worldwide. It represents one of the most common complications arising from diabetes mellitus (DM) and is the leading cause of end-stage kidney disease (ESKD). Its development involves three fundamental components: the hemodynamic, metabolic, and inflammatory axes. Clinically, persistent albuminuria in association with a progressive decline in glomerular filtration rate (GFR) defines this disease. However, as these alterations are not specific to DKD, there is a need to discuss novel biomarkers arising from its pathogenesis which may aid in the diagnosis, follow-up, therapeutic response, and prognosis of the disease.

Neural and central mechanisms of kidney fibrosis after relief of ureteral obstruction

Obstructive uropathy from nephrolithiasis remains a leading cause of end-stage kidney disease. Mechanisms of kidney fibrosis after relief of ureteral obstruction represent opportunities for therapeutic intervention. Here, in mouse models of ureteral obstruction, we have combined methods of virus tracing and optogenetic techniques to identify an overactive central pathway in the paraventricular nucleus (PVN)-rostral ventrolateral medulla (RVLM) that determines the fibrotic fate of kidney after relief of the obstruction. The overactive pathway is driven by kidney afferent nerves that activate angiotensin II signaling in RVLM-projecting PVN neurons to drive sympathetic discharge back to the kidney. This causes the kidney to undergo fibrosis with loss of function. Blockade of sympathetic traffic or deletion of AT1a in PVN preserves the structure of the post-obstructed kidney. Human post-obstructed kidneys also demonstrate evidence of increased sympathetic nerve activity associated with a fibrotic outcome. Manipulating these neural elements is a potential treatment strategy.

Broadening horizons in mechanisms, management, and treatment of diabetic kidney disease

Diabetic kidney disease (DKD) is the first cause of end-stage kidney disease in patients with diabetes and its prevalence is increasing worldwide. It encompasses histological alterations that mainly affect the glomerular filtration unit, which include thickening of the basement membrane, mesangial cell proliferation, endothelial alteration, and podocyte injury. These morphological abnormalities further result in a persistent increase of urinary albumin-to-creatinine ratio and in a reduction of the estimated glomerular filtration rate. Several molecular and cellular mechanisms have been recognized, up to date, as major players in mediating such clinical and histological features and many more are being under investigation. This review summarizes the most recent advances in understanding cell death mechanisms, intracellular signaling pathways and molecular effectors that play a role in the onset and progression of diabetic kidney damage. Some of those molecular and cellular mechanisms have been already successfully targeted in preclinical models of DKD and, in some cases, strategies have been tested in clinical trials. Finally, this report sheds light on the relevance of novel pathways that may become therapeutic targets for future applications in DKD.

A prediction model on incident ESKD among individuals with T2D and CKD

BackgroundDiabetes is the leading cause of end-stage kidney disease (ESKD). This study aimed to predict incident ESKD among individuals with T2D and CKD. MethodThe Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial data were split into a training set and a validation set by a ratio of 7:3. A dynamic time-varying Cox model was fit to predict the development of incident ESKD. Significant predictors were identified from a list of candidate variables, including demographic characteristics, physical exam results, laboratory results, medical history, drug information, and healthcare utilization. Model performance was evaluated by Brier score and C statistics. Decomposition analysis was conducted to assess the variable importance. Patient-level data from Harmony Outcome clinical trial and CRIC study were used for external validation. ResultsA total of 6982 diabetes patients with CKD were used for model development, with a median follow-up of four years and 312 ESKD events. The significant predictors for the final model were female sex, race, smoking status, age at T2D diagnosis, SBP, HR, HbA1c, estimated glomerular filtration rate (eGFR), urine albumin-creatinine ratio (UACR), retinopathy event occurring in last year, antihypertensive drug use, and an interaction term between SBP and female. The model demonstrated good performance in discrimination (C-statistic 0.764 [95 % CI 0.763–0.811]) and calibration (Brier Score 0.0083 [95 % CI 0.0063–0.0108]). The top 3 most important predictors in the prediction model were eGFR, retinopathy event, and UACR. Acceptable discrimination (C-statistic: 0.701 [95 % CI 0.665–0.716]; 0.86 [95 % CI 0.847–0.872]) and calibration (Brier Score: 0.0794 [95 % CI 0.0733–0.1022]; 0.0476 [95 % CI 0.0440, 0.0506]) were demonstrated in the Harmony Outcome and CRIC data, respectively. ConclusionThe dynamic risk prediction of incident ESKD among individuals with T2D can be a useful tool to support better disease management to lower the risk of developing ESKD.

Treatment with rituximab and hydroxychloroquine in a patient with membranous nephropathy and diabetic nephropathy: A case report

Abstract Nephrotic syndrome (NS), which includes primary and secondary types, is one of the causes of end-stage kidney disease. Common causes in adults include diabetic nephropathy (DN), membranous nephropathy (MN), and focal segmental glomerulosclerosis. About 30%–40% of diabetics can develop into DN. The incidence of primary nephrotic syndrome in diabetic patients was not significantly different from that in the general population. Herein we present a windfall from the treatment of rituximab combined with hydroxychloroquine in a patient with primary MN and DN. A 51-year-old Chinese man, diagnosed with type 2 diabetes mellitus (T2DM) 12 years ago, was admitted to the hospital due to edema of bilateral lower limbs and severe proteinuria. Serology showed the obvious elevation of the anti-phospholipase A2 receptor (anti-PLA2R) level and renal biopsy showed MN concomitant with DN. After low dosage of prednisone and standard dosage of rituximab, the patient’s proteinuria decreased; however, the effect was unsatisfactory and proteinuria was elevated again in 8 months. Thus, treatment with rituximab and hydroxychloroquine was initiated, which resulted in proteinuria diminishing significantly and albumin returning to normal level. Therefore, even complicated with DN, patients diagnosed with primary MN still have a promising remission after being treated with rituximab and hydroxychloroquine.

The association of plasma NT-proBNP level and progression of diabetic kidney disease

Aims Diabetic kidney disease (DKD) is the most common cause of end-stage kidney disease (ESKD). The identification of risk factors involved in the progression of DKD to ESKD is expected to result in early detection and appropriate intervention and improve prognosis. This study aimed to explore whether plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) was associated with kidney outcomes in patients with type 2 diabetes mellitus (T2DM) and biopsy-proven DKD. Methods Patients with biopsy-proven DKD who were followed up at West China Hospital over 12 months were enrolled. The kidney outcome was defined as progression to ESKD. The cutoff value of plasma NT-proBNP concentration was calculated by using receiver operating characteristic (ROC) curve analysis. The influence of NT-proBNP levels on kidney outcome in patients with DKD was assessed using Cox regression analysis. Results A total of 30 (24.5%) patients reached ESKD during a median follow-up of 24.1 months. The baseline serum NT-proBNP level had a significant correlation with baseline proteinuria, kidney function, glomerular lesions, interstitial fibrosis tubular atrophy (IFTA), and arteriolar hyalinosis. Multivariate Cox regression analysis indicated that increased NT-proBNP level was significantly associated with a higher risk of progression to ESKD (HR 6.43; 95% CI (1.65–25.10, p = 0.007), and each 1 SD increase in LG (NT-proBNP) was also associated with a higher risk (HR 2.43; 95% CI 1.94–5.29, p = 0.047) of an adverse kidney outcome after adjusting for confounding factors. Conclusions A higher level of plasma NT-proBNP predicts kidney prognosis in patients with biopsy-proven DKD. This warrants further investigation into the potential mechanisms.

Sex differences in risk factors for end-stage kidney disease and death in type 2 diabetes: A retrospective cohort study.

This study investigated the sex differences in the risk of end-stage kidney disease (ESKD) and mortality, as well as the effect modification of sex on associated factors in patients with type 2 diabetes. This multicenter observational cohort study included 4328 patients with type 2 diabetes. Hazard ratios (HRs) with 95% confidence intervals (CIs) of sex for ESKD and death were estimated using Cox proportional regression with adjustment for baseline covariates. For assessing risk modification, HRs and incidence rates for ESKD and death were compared between sexes across patient characteristics using Cox proportional and Poisson regression models. During a median follow-up of 7 years, 276 patients (70% men) developed ESKD, and 241 patients (68% men) died. Men had higher risks of ESKD (HR 1.34; 95% CI 1.02-1.75; p=.034) and death (HR 1.64; 95% CI 1.24-2.16; p=.001) versus women after adjusting for multiple covariates. Among patients with microalbuminuria, men had a substantially higher risk of ESKD versus women, compared to those with normo- and macroalbuminuria (p for interaction .04). Incidence rates were also increased in men versus women with albuminuria of around 300 mg/g. No differences were detected in the association of sex and death across baseline patient subgroups. In type 2 diabetes, men had an increased risk of ESKD and death versus women. Moderately increased albuminuria was strongly associated with sex difference in developing ESKD.

Urinary Biomarkers of Tubular Health and Risk for Kidney Function Decline or Mortality in Diabetes

Introduction: Diabetes is a leading cause of end-stage kidney disease (ESKD). Biomarkers of tubular health may prognosticate chronic kidney disease (CKD) progression beyond estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). Methods: We examined associations of five urinary biomarkers of tubular injury and repair (NGAL, KIM-1, IL-18, MCP-1, YKL-40) with kidney function decline (first occurrence of a decrease in eGFR ≥30 mL/min/1.73 m2 if randomization eGFR ≥60 or ≥50% if randomization eGFR <60; ESKD) and all-cause mortality among 1,135 VA NEPHRON-D trial participants with baseline UACR ≥300 mg/g and available urine samples. Covariates included age, sex, race, BMI, systolic BP, HbA1c, treatment arm, eGFR, and UACR. In a subset of participants with 12-month samples (n = 712), we evaluated associations of KIM-1, MCP-1, and YKL-40 change (from baseline to 12 months) with eGFR decline (from 12 months onward). Results: At baseline, mean age was 65 years, mean eGFR was 56 mL/min/1.73 m2, and median UACR was 840 mg/g. Over a median of 2.2 years, 13% experienced kidney function decline and 9% died. In fully adjusted models, the highest versus lowest quartiles of MCP-1 and YKL-40 were associated with 2.18- and 1.76-fold higher risks of kidney function decline, respectively. One-year changes in KIM-1, MCP-1, and YKL-40 were not associated with subsequent eGFR decline. Higher baseline levels of NGAL, IL-18, MCP-1, and YKL-40 levels (per 2-fold higher) were independently associated with 10–40% higher risk of mortality. Conclusion: Among Veterans with diabetes and CKD, urinary biomarkers of tubular health were associated with kidney function decline and mortality.

Kidney transplant access for children and young adults with congenital anomalies of the kidney and urinary tract

PurposeAlthough congenital anomalies of the kidney and urinary tract (CAKUT) are among the leading causes of end-stage kidney disease (ESKD) in children and young adults, kidney transplantation access for this population has not been well studied in the US. We compared transplantation access in the US based on whether the etiology of kidney disease was secondary to CAKUT, and additionally by CAKUT subgroups (anatomic vs. inherited causes of CAKUT).MethodsUsing the United States Renal Data System, we conducted a retrospective cohort study of 80,531 children and young adults who started dialysis between 1995 and 2015. We used adjusted Cox models to examine the association between etiology of kidney disease (CAKUT vs. non-CAKUT, anatomic vs. inherited) and receipt of kidney transplantation, and secondarily, receipt of a living vs. deceased donor kidney transplant.ResultsOverall, we found an increased likelihood of kidney transplantation access for participants with CAKUT compared to those without CAKUT (HR 1.23; 95% CI 1.20–1.27). Among the subset of individuals with CAKUT as the attributed cause of ESKD, we found a lower likelihood of kidney transplantation in those with anatomic causes of CAKUT compared to those with inherited causes of CAKUT (adjusted HR 0.85; 0.81–0.90).ConclusionThere are notable disparities in kidney transplantation rates among CAKUT subgroups. Those with anatomic causes of CAKUT started on dialysis have significantly reduced access to kidney transplantations compared to individuals with inherited causes of CAKUT who were initiated on dialysis. Further studies are needed to understand barriers to transplantation access in this population.

PS-P10-9: INCIDENCE OF DIALYSIS AFTER MASSIVE NATURAL DISASTER DUE TO END-STAGE KIDNEY DISEASE ASSOCIATED WITH HYPERTENSION

Objective: The relationships between a massive disaster and the development of end-stage kidney disease (ESKD) is still unknown. We investigated the incidence and the causes of dialysis initiation in a city affected by the Great East Japan Earthquake (GEJE). Design and method: Single-center, retrospective observational study. All patients who initiated or were treated with dialysis in Kesennuma City Hospital between 2007 and 2021 were enrolled. The year of the dialysis initiation was determined retrospectively based on the initiation date. The causes of ESKD were clinically and conveniently divided into four groups; diabetic nephropathy (DN), hypertensive renal disease (HRD), glomerulonephritis (GN) and others. Results: The increasing number of dialysis initiation after GEJE were recognized around after the five years and peaked down after the ten years. The age at dialysis initiation among the four groups and the ratios of the four groups between before and after GEJE were significantly different (p = 0.0142, p = 0.0317). The age at the initiation by HRD was significantly increased than that by DN after GEJE (p = 0.0088), but not the before. The initiation by DN was high both before and after GEJE. No characteristic variation was seen in the initiation by GN. Notably the initiation by HRD was significantly increased around five years after GEJE and returned after the ten years. It looked like the increased initiation cause of HRD was related with GEJE. Conclusions: The influences of GEJE on dialysis initiations were sustained for up to 10 years after GEJE, that was probably associated with HRD. This is a first proposal the massive disaster could develop EKSD.

Management of adults with diabetes on dialysis: Summary of recommendations of the Joint British Diabetes Societies guidelines 2022.

Diabetes is the commonest cause of end-stage kidney disease in many parts of the world, and many people on dialysis programmes live with diabetes. Such people are vulnerable to complications from their diabetes, and their care may be fragmented due to the many specialists involved. This updated guidance from the Joint British Diabetes Societies aims to review and update the 2016 guidance, with particular emphasis on glycaemic monitoring in the light of recent advances in this area. In addition, the guidance covers clinical issues related to the management of diabetes in people on peritoneal dialysis, along with acute complications such as hypoglycaemia and ketoacidosis, and chronic complications such as foot and eye disease.

Prognostic value of the combination of neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio and platelet-to-lymphocyte ratio on mortality in patients on maintenance hemodialysis.

Hemodialysis (HD) is the most important renal replacement therapy for patients with end-stage kidney disease (ESKD). Systemic inflammation is a risk factor of mortality in HD patients. Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR) are new inflammatory markers. However, previous studies have inconsistent conclusions about the predictive value of NLR, MLR and PLR on mortality of HD patients. The aim of this study was to establish an inflammation scoring system by including NLR, MLR and PLR, and evaluate the association between the inflammation score and all-cause and cardiovascular mortality in HD patients. In this single center retrospective cohort study, 213 incident HD patients from January 1, 2015 to December 31, 2020 were included. Baseline demographic and clinical data and laboratory measurements were collected. According to the optimal cut-off values, NLR, MLR and PLR were assigned 0 or 1 point, respectively. Then, the inflammation score was obtained by adding the NLR, MLR and PLR scores. All patients were followed until July 31, 2021. The associations of the inflammation score with all-cause and cardiovascular mortality were assessed by multivariable-adjusted Cox models. Of 213 patients, the mean (± SD) age was 56.8 ± 14.4 years, 66.2% were men, and 32.9% with diabetes. The primary cause of ESKD was mainly chronic glomerulonephritis (46.5%) and diabetic nephropathy (28.6%). The median inflammation score was 2 (interquartile range = 1-3). During a median 30 months (interquartile range = 17-50 months) follow-up period, 53 patients had died, of which 33 deaths were caused by cardiovascular disease. After adjusting for demographics, primary diseases and other confounders in multivariable model, the inflammation score = 3 was associated with a hazard ratio for all-cause mortality of 4.562 (95% confidence interval, 1.342-15.504, P = 0.015) and a hazard ratio for cardiovascular mortality of 4.027 (95% confidence interval, 0.882-18.384, P = 0.072). In conclusion, an inflammation scoring system was established by including NLR, MLR and PLR, and the higher inflammation score was independently associated with all-cause mortality in HD patients.

Hemodialysis patients’ satisfaction with dialysis care: a cross-sectional prospective study conducted in a non-profitable care facility, Minia Egypt

BackgroundThe prevalence of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) is increasing continuously as a result of the dramatic growth in the prevalence of two main causes of ESKD which are diabetes mellitus (DM) and hypertension, hence, ESKD represents a global concern. Based on the sixth annual report of the Egyptian society of nephrology, the prevalence of ESKD in Egypt is estimated to be 375 per 1000,000. Meanwhile, other studies estimated the prevalence in El-Minia governorate to be around 308 per 1000,000. Hemodialysis (HD) represents the main modality of Kidney replacement therapy (KRT) for sufferers of ESKD in El-Minia governorate. Patients treated with in-center HD attend dialysis care usually three times per week for several hours each time, hence, their experiences during dialysis care will likely have a major impact on living with chronic illness. Hence, measuring patient satisfaction is very important as it is not only an outcome but also a contributor to other outcomes and objectives, it can provide valuable information about problem areas that can be modified to improve patient experience and outcomes.MethodsA single-center cross-sectional prospective study was conducted in the HD unit, Minia nephrology and urology university hospital. Demographic data were obtained through face-to-face interviews, Patients received a questionnaire to assess satisfaction with medical staff interactions, as well as care before, during, and after dialysis. An observational checklist of healthcare staff and equipment in the dialysis unit was also given to the patients.ResultsOne hundred nineteen patients participated in the study; patients were generally satisfied with the care provided in the dialysis unit (mean = 2.64), patients were most satisfied with aspects of care related to nurses, while they were neutral about aspects related to physicians, and were dissatisfied with nutritional care.ConclusionThere are multiple problem areas in the HD unit affecting patients’ experience, and further improvement in the care provided in the dialysis unit is required.

Re-understanding and focusing on normoalbuminuric diabetic kidney disease.

Diabetes mellitus (DM) has grown up to be an important issue of global public health because of its high incidence rate. About 25% of DM patients can develop diabetic foot/ulcers (DF/DFU). Diabetic kidney disease (DKD) is the main cause of end-stage kidney disease (ESKD). DF/DFU and DKD are serious complications of DM. Therefore, early diagnosis and timely prevention and treatment of DF/DFU and DKD are essential for the progress of DM. The clinical diagnosis and staging of DKD are mostly based on the urinary albumin excretion rate (UAER) and EGFR. However, clinically, DKD patients show normoalbuminuric diabetic kidney disease (NADKD) instead of clinical proteinuria. The old NADKD concept is no longer suitable and should be updated accordingly with the redefinition of normal proteinuria by NKF/FDA. Based on the relevant guidelines of DM and CKD and combined with the current situation of clinical research, the review described NADKD from the aspects of epidemiology, pathological mechanism, clinical characteristics, biomarkers, disease diagnosis, and the relationship with DF/DFU to arouse the new understanding of NADKD in the medical profession and pay attention to it.

Renal Proximal Tubular Cells: A New Site for Targeted Delivery Therapy of Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a major complication of diabetes mellitus (DM) and the leading cause of end-stage kidney disease (ESKD) worldwide. A significant number of drugs have been clinically investigated for the treatment of DKD. However, a large proportion of patients still develop end-stage kidney disease unstoppably. As a result, new effective therapies are urgently needed to slow down the progression of DKD. Recently, there is increasing evidence that targeted drug delivery strategies such as large molecule carriers, small molecule prodrugs, and nanoparticles can improve drug efficacy and reduce adverse side effects. There is no doubt that targeted drug delivery strategies have epoch-making significance and great application prospects for the treatment of DKD. In addition, the proximal tubule plays a very critical role in the progression of DKD. Consequently, the purpose of this paper is to summarize the current understanding of proximal tubule cell-targeted therapy, screen for optimal targeting strategies, and find new therapeutic approaches for the treatment of DKD.

Podocyte derived TNF-α mediates monocyte differentiation and contributes to glomerular injury.

Diabetes shortens the life expectancy by more than a decade, and the excess mortality in diabetes is correlated with the incidence of kidney disease. Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease. Macrophage accumulation predicts the severity of kidney injury in human biopsies and experimental models of DKD. However, the mechanism underlying macrophage recruitment in diabetes glomeruli is unclear. Elevated plasma growth hormone (GH) levels in type I diabetes and acromegalic individuals impaired glomerular biology. In this study, we examined whether GH-stimulated podocytes contribute to macrophage accumulation. RNA-seq analysis revealed elevated TNF-α signaling in GH-treated human podocytes. Conditioned media from GH-treated podocytes (GH-CM) induced differentiation of monocytes to macrophages. On the other hand, neutralization of GH-CM with the TNF-α antibody diminished GH-CM's action on monocytes. The treatment of mice with GH resulted in increased macrophage recruitment, podocyte injury, and proteinuria. Furthermore, we noticed the activation of TNF-α signaling, macrophage accumulation, and fibrosis in DKD patients' kidney biopsies. Our findings suggest that podocytes could secrete TNF-α and contribute to macrophage migration, resulting in DKD-related renal inflammation. Inhibition of either GH action or TNF-α expression in podocytes could be a novel therapeutic approach for DKD treatment.

Extracellular vesicles from focal segmental glomerulosclerosis pediatric patients induce STAT3 activation and mesangial cell proliferation.

Primary focal segmental glomerulosclerosis (FSGS), a major cause of end-stage kidney disease (ESKD) in adolescents and young adults, is attributable to recognized genetic mutations in a minority of cases. For the majority with idiopathic primary FSGS, the cause of the disease is unknown. We hypothesize that extracellular vesicle (EVs), that carry information between podocytes and mesangial cells, may play a key role in disease progression. A total of 30 participants (20 primary nephrotic syndrome/ 10 healthy controls) were enrolled in this study. Primary nephrotic syndrome subjects were grouped based on pathologic diagnosis. The FSGS group was compared to healthy control subjects based on demographic and clinical findings. EVs were isolated from the urine of each group before being characterized by Western blotting, transmission electron microscopy, and nanoparticle tracking analysis. The effects of the EVs from each group on normal human mesangial cells and activation of certain pathways were then investigated. Based on demographic and clinical findings, mean serum creatinine was significantly higher in the FSGS group than the normal healthy control group. The mean size of the EVs in the FSGS group was significantly higher than the healthy control group. The mesangial cells that were challenged with EVs isolated from FSGS patients showed significant upregulation of STAT-3, PCNA, Ki67, and cell proliferation. Our data demonstrate that EVs from FSGS patients stimulate mesangial cell proliferation in association with upregulation of the phospho-STAT-3 pathway. Additional studies are planned to identify the molecular cargo within the EVs from FSGS patients that contribute to the pathogenesis of FSGS.

Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of DKD. A three-marker panel was derived from a proteomics analysis of plasma samples by an unbiased machine learning approach from participants (N = 58) in the Clinical Phenotyping and Resource Biobank study. In combination with standard clinical parameters, this panel improved prediction of the composite outcome of ESKD or a 40% decline in glomerular filtration rate. The panel was validated in an independent group (N = 68), who also had kidney transcriptomic profiles. One marker, plasma angiopoietin 2 (ANGPT2), was significantly associated with outcomes in cohorts from the Cardiovascular Health Study (N = 3,183) and the Chinese Cohort Study of Chronic Kidney Disease (N = 210). Glomerular transcriptional angiopoietin/Tie (ANG-TIE) pathway scores, derived from the expression of 154 ANG-TIE signaling mediators, correlated positively with plasma ANGPT2 levels and kidney outcomes. Higher receptor expression in glomeruli and higher ANG-TIE pathway scores in endothelial cells corroborated potential functional effects in the kidney from elevated plasma ANGPT2 levels. Our work suggests that ANGPT2 is a promising prognostic endothelial biomarker with likely functional impact on glomerular pathogenesis in DKD.

Challenges in Management of Diabetic Patient on Dialysis

Diabetes mellitus is the leading cause of end-stage kidney disease in many countries. The management of diabetic patients who receive dialysis can be challenging. Diabetic dialysis patients have higher rates of cardiovascular events and mortality due to metabolic factors and accelerated vascular calcification. Diabetic haemodialysis patients have high rates of haemodynamic instability which leads to organ ischaemia and end organ damage; autonomic dysfunction seems to play an important role in haemodynamic instability and abnormal organ perfusion during haemodialysis. Poor glycaemic control contributes to fluid overload and worse cardiovascular outcome. Xerostomia and thirst are the main drivers for fluid overload in haemodialysis patients and in peritoneal dialysis a chronic state of hyperhydration that is related to absorption of glucose from the PD fluids, protein loss and malnutrition contributes to fluid overload. Glycaemic control is of great importance and adjustments to diabetic agents are required. In haemodialysis, a reduction in insulin dose is recommended to avoid hypoglycaemia whereas in peritoneal dialysis an increase in insulin dose is often required. Foot ulcers and infection are more common in diabetic dialysis patients compared to non-diabetic dialysis patients or diabetic patients with normal renal function and regular surveillance for early identification is important. Ultimately, a multi-disciplinary approach which includes diabetologist, nephrologist, dietitians, microbiologist, vascular surgeon, interventional radiologist is required to address the complicated aspects of diabetic patient care on dialysis.

Polymorphisms in glucose homeostasis genes are associated with cardiovascular and renal parameters in patients with diabetic nephropathy

Background Diabetic nephropathy (DN) has become the major cause of end-stage kidney disease and is associated to an extremely high cardiovascular (CV) risk. Methods We screened 318 DN patients for 23 SNPs in four glucose transporters (SLC2A1, SLC2A2, SLC5A1 and SLC5A2) and in KCNJ11 and ABCC8, which participate in insulin secretion. Regression models were utilised to identify associations with renal parameters, atherosclerosis measurements and CV events. In addition, 506 individuals with normal renal function were also genotyped as a control group. Results In the patient’s cohort, common carotid intima media thickness values were higher in carriers of ABCC8 rs3758953 and rs2188966 vs. non-carriers [0.78(0.25) vs. 0.72(0.22) mm, p < 0.05 and 0.79(0.26) vs. 0.72(0.22) mm, p < 0.05], respectively. Furthermore, ABCC8 rs1799859 was linked to presence of plaque in these patients [1.89(1.03-3.46), p < 0.05]. Two variants, SLC2A2 rs8192675 and SLC5A2 rs9924771, were associated with better [OR = 0.49 (0.30-0.81), p < 0.01] and worse [OR = 1.92 (1.15-3.21), p < 0.05] CV event-free survival, respectively. With regard to renal variables, rs841848 and rs710218 in SLC2A1, as well as rs3813008 in SLC5A2, significantly altered estimated glomerular filtration rate values [carriers vs. non-carriers: 30.41(22.57) vs. 28.25(20.10), p < 0.05; 28.95(21.11) vs. 29.52(21.66), p < 0.05 and 32.03(18.06) vs. 28.14(23.06) ml/min/1.73 m2, p < 0.05]. In addition, ABCC8 rs3758947 was associated with higher albumin-to-creatinine ratios [193.5(1139.91) vs. 160(652.90) mg/g, p < 0.05]. The epistasis analysis of SNP-pairs interactions showed that ABCC8 rs3758947 interacted with several SNPs in SLC2A2 to significantly affect CV events (p < 0.01). No SNPs were associated with DN risk. Conclusions Polymorphisms in genes determining glucose homeostasis may play a relevant role in renal parameters and CV-related outcomes of DN patients.