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BACKGROUND: Diabetic kidney disease (DKD) is the most common cause of kidney failure in the world, and novel predictive biomarkers and molecular mechanisms of disease are needed. Endothelial cell-specific molecule-1 (Esm-1) is a secreted proteoglycan that attenuates inflammation. We previously identified that a glomerular deficiency of Esm-1 associates with more pronounced albuminuria and glomerular inflammation in DKD-susceptible relative to DKD-resistant mice, but its contribution to DKD remains unexplored. METHODS: Using hydrodynamic tail-vein injection, we overexpress Esm-1 in DKD-susceptible DBA/2 mice and delete Esm-1 in DKD-resistant C57BL/6 mice to study the contribution of Esm-1 to DKD. We analyze clinical indices of DKD, leukocyte infiltration, podocytopenia, and extracellular matrix production. We also study transcriptomic changes to assess potential mechanisms of Esm-1 in glomeruli. RESULTS: In DKD-susceptible mice, Esm-1 inversely correlates with albuminuria and glomerular leukocyte infiltration. We show that overexpression of Esm-1 reduces albuminuria and diabetes-induced podocyte injury, independent of changes in leukocyte infiltration. Using a complementary approach, we find that constitutive deletion of Esm-1 in DKD-resistant mice modestly increases the degree of diabetes-induced albuminuria versus wild-type controls. By glomerular RNAseq, we identify that Esm-1 attenuates expression of kidney disease–promoting and interferon (IFN)-related genes, including Ackr2 and Cxcl11. CONCLUSIONS: We demonstrate that, in DKD-susceptible mice, Esm-1 protects against diabetes-induced albuminuria and podocytopathy, possibly through select IFN signaling. Companion studies in patients with diabetes suggest a role of Esm-1 in human DKD.

Background Verinurad is a human uric acid (UA) transporter (URAT1) inhibitor known to decrease serum UA (sUA) levels and that may reduce albuminuria. In a Phase 2a study (NCT03118739), treatment with verinurad + febuxostat lowered urine albumin-to-creatinine ratio (UACR) at 12 weeks by 39% (90% confidence interval 4–62%) among patients with Type 2 diabetes mellitus, hyperuricaemia and albuminuria. The Phase 2b, randomized, placebo-controlled Study of verinurAd and alloPurinol in Patients with cHronic kIdney disease and hyperuRicaEmia (SAPPHIRE; NCT03990363) will examine the effect of verinurad + allopurinol on albuminuria and estimated glomerular filtration rate (eGFR) slope among patients with chronic kidney disease (CKD) and hyperuricaemia. Methods Adults (≥18 years of age) with CKD, eGFR ≥25 mL/min/1.73 m2, UACR 30–5000 mg/g and sUA ≥6.0 mg/dL will be enrolled. Approximately 725 patients will be randomized 1:1:1:1:1 to 12, 7.5 or 3 mg verinurad + allopurinol, allopurinol or placebo. An 8-week dose-titration period will precede a 12-month treatment period; verinurad dose will be increased to 24 mg at Month 9 in a subset of patients in the 3 mg verinurad + allopurinol arm. The primary efficacy endpoint the is change from baseline in UACR at 6 months. Secondary efficacy endpoints include changes in UACR, eGFR and sUA from baseline at 6 and 12 months. Conclusions This study will assess the combined clinical effect of verinurad + allopurinol on kidney function in patients with CKD, hyperuricaemia and albuminuria, and whether this combination confers renoprotection beyond standard-of-care.

Rationale & Objective Benefits of sodium-glucose co-transporter 2 inhibitors on kidney outcomes have been demonstrated in clinical trials. Among patients with type 2 diabetes and established cardiovascular (CV) disease enrolled in EMPA-REG Outcome Study (NCT01131676), empagliflozin added to standard of care (SoC) reduced the risk of incident or worsening nephropathy compared to SoC alone. This analysis evaluated the cost-effectiveness of empagliflozin versus SoC alone in the subpopulation with diabetic kidney disease (DKD) from the perspective of United States (US) commercial insurers and Medicare. Study Design Discrete event simulation model. Setting & Population Patients with DKD in a US healthcare system. Interventions Empagliflozin 10 or 25 mg with SoC versus SoC alone. SoC included glucose-lowering therapies and medications to treat CV risk factors. Outcomes Incremental cost-effectiveness ratios (ICERs, 2020 US dollars per quality-adjusted life-year [QALY] gained). Costs and QALYs were discounted 3.0%/year. Model, Perspective, & Timeframe: Cost-effectiveness analysis, commercial insurers and Medicare perspective, lifetime horizon. Results The ICER of empagliflozin with SoC versus SoC alone was $25,974/QALY. Empagliflozin added 0.67 QALYs and $17,322/patient over a lifetime horizon. Results were driven by fewer clinical events (including CV death, heart failure [HF] hospitalization, albuminuria progression, and a composite kidney outcome) experienced by patients receiving empagliflozin with SoC versus SoC alone. Results were sensitive to rates of CV death, non-fatal MI, and HF hospitalization, as well as to drug costs, and time horizon. Probabilistic sensitivity analyses indicated 91% of simulations falling below $50,000/QALY. Limitations The EMPA-REG Outcome Study was not powered to assess treatment benefits in a subgroup and excluded patients with estimated glomerular filtration rate Conclusion Based on EMPA-REG Outcome Study, this cost-effectiveness analysis suggests that for commercial insurers and Medicare, adding empagliflozin to SoC may be a cost-effective treatment option for patients with DKD.

The association between Takayasu’s arteritis and membranous nephropathy is uncommon. We present the case of a 46-year-old man with Takayasu’s arteritis treated over 10 years by a multidisciplinary medical team. He had an atrophic left kidney due to arterial stenosis, with a basal creatinine of 1.59 mg/dL (140.55 µmol/l). Three years ago, he presented with full nephrotic syndrome, uncontrolled blood pressure, creatinine increases to 4.5 mg/dL (basal: 1.59 mg/dL), severe hypoalbuminaemia (1.4 g/dL) and albuminuria of 24.6 g per day. He underwent percutaneous biopsy of the right kidney that showed membranous nephropathy with negative PLA2R1 and positive IgG 1, 3 and 4 subclasses. After therapy with oral prednisone and cyclophosphamide, the patient’s kidney function improved, without recurrence of disease after 3 years of follow-up. Here, we present this extremely uncommon association of Takayasu’s arteritis and membranous nephropathy.

Use of renin-angiotensin-aldosterone system inhibitors (RAASi) in patients with heart failure (HF) and reduced ejection fraction is associated with functional improvement, an increase in perceived quality of life, a reduction in the probability of cardiovascular death, and a decrease in the number of hospitalizations. Some of these drugs are also efficacious in patients with chronic kidney disease and albuminuria as well as in patients with resistant hypertension. Despite their numerous benefits, RAASi are associated with an increase in incidence of hyperkalemia, especially in patients with concomitant chronic kidney disease. Hyperkalemia is a common electrolyte disorder that is defined as an elevation in plasma concentrations of potassium above 5 mEq/L. It has been related to rehospitalizations, malignant arrhythmias, and an increase in mortality. On the other hand, optimized treatment with RAASi requires progressive dose increases which can in turn entail a greater probability of hyperkalemia. For all of these reasons, it is necessary to establish management and treatment guidelines for these patients. This consensus document arises from this objective. Its recommendations have been developed by a group of ten experts and reviewed by a panel of another ten specialists in the treatment of patients with HF (ten cardiologists and ten internists in total). This document has been endorsed by the Spanish Society of Cardiology (SEC, for its initials in Spanish) and the Spanish Society of Internal Medicine (SEMI, for its initials in Spanish).

OBJECTIVE: The aim of this study was to determine the haemodynamics of the intrarenal arteries from the relationship between resistivity index (RI) and kidney function, and to identify the predictors of high RI among patients with diabetic nephropathy (DN) and those with diabetes mellitus (DM) without DN. METHODS: This was a cross-sectional survey of 133 participants, comprising 40 subjects with DM without DN, 53 with DM with DN and 40 healthy controls. Information obtained was demographics, lifestyle, medical and medication histories, while anthropometric and blood pressure measurements were taken. Albuminuria and estimated glomerular filtration rate were determined and RI was measured using a Doppler ultrasound scan. RESULTS: The mean intrarenal artery RIs were higher among the patients with DM without DN (0.60 ± 0.04) and the group with DM with DN (0.61 ± 0.04) than in the controls (0.56 ± 0.04) (p = 0.02). Glycated haemoglobin (HbA(1c)) predicted high RI in the DM without DN group (OR 2.81; CI: 1.73–9.03) while hypertension (OR 3.60; CI: 1.06–12.22) predicted high RI in the DM with DN group. CONCLUSION: Elevated intrarenal artery RI was prevalent among patients with DM without DN and those with DM with DN, while elevated HbA(1c) level and hypertension predicted elevated RI in subjects with DM without DN and those with DM with DN.

To explore the association between retinal neurodegeneration and metabolic parameters in progressive dysglycemia.A cross-sectional study was performed on 68 participants: normal glucose tolerance (n = 23), prediabetes (n = 25), and Type 2 diabetes without diabetic retinopathy (n = 20). Anthropometric assessment and laboratory sampling for HbA1c, fasting glucose, insulin, c-peptide, lipid profile, renal function, and albumin-to-creatinine ratio were conducted. Central and pericentral macular thicknesses on spectral domain optical coherence tomography were compared with systemic parameters.Baseline demographic characteristics were similar across all groups. Cuzick's trend test revealed progressive full-thickness macular thinning with increasing dysglycemia across all three groups (P = 0.015). The urinary albumin-to-creatinine ratio was significantly correlated with full-thickness superior (R = -0.435; P = 0.0002), inferior (R = -0.409; P = 0.0005), temporal (R = -0.429; P = 0.003), and nasal (R = -0.493; P0.0001) pericentral macular thinning, after post hoc Bonferroni adjustment. There was no association between macular thinning and waist circumference, body mass index, blood pressure, lipid profile, or insulin resistance.Progressive dysglycemia is associated with macular thinning before the onset of visible retinopathy and occurs alongside microalbuminuria. Retinal neurodegenerative changes may help identify those most at risk from dysglycemic end-organ damage.

Nephrotic syndrome is characterized by severe proteinuria, hypoalbuminaemia, edema and hyperlipidaemia. Genetic studies of nephrotic syndrome have led to the identification of proteins playing a crucial role in slit diaphragm signaling, regulation of actin cytoskeleton dynamics and cell-matrix interactions. The laminin α5 chain is essential for embryonic development and, in association with laminin β2 and laminin γ1, is a major component of the glomerular basement membrane, a critical component of the glomerular filtration barrier. Mutations in LAMA5 were recently identified in children with nephrotic syndrome. Here, we have identified a novel missense mutation (E884G) in the uncharacterized L4a domain of LAMA5 where homozygous mice develop nephrotic syndrome with severe proteinuria with histological and ultrastructural changes in the glomerulus mimicking the progression seen in most patients. The levels of LAMA5 are reduced in vivo and the assembly of the laminin 521 heterotrimer significantly reduced in vitro. Proteomic analysis of the glomerular extracellular fraction revealed changes in the matrix composition. Importantly, the genetic background of the mice had a significant effect on aspects of disease progression from proteinuria to changes in podocyte morphology. Thus, our novel model will provide insights into pathologic mechanisms of nephrotic syndrome and pathways that influence the response to a dysfunctional glomerular basement membrane that may be important in a range of kidney diseases.

BACKGROUND: Endogenously formed advanced glycation end products (AGEs) may be important drivers of microvascular dysfunction and the microvascular complications of diabetes. AGEs are also formed in food products, especially during preparation methods involving dry heat.OBJECTIVES: We aimed to assess cross-sectional associations between dietary AGE intake and generalized microvascular function in a population-based cohort.METHODS: In 3144 participants of the Maastricht Study (mean ± SD age: 60 ± 8 y, 51% men) the dietary AGEs Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated using the combination of our ultra-performance LC-tandem MS dietary AGE database and an FFQ. Microvascular function was determined in the retina as flicker light-induced arteriolar and venular dilation and as central retinal arteriolar and venular equivalents, in plasma as a z score of endothelial dysfunction biomarkers (soluble vascular adhesion molecule 1 and soluble intracellular adhesion molecule 1, soluble E-selectin, and von Willebrand factor), in skin as the heat-induced skin hyperemic response, and in urine as 24-h albuminuria. Associations were evaluated using multiple linear regression adjusting for demographic, cardiovascular, lifestyle, and dietary factors.RESULTS: Overall, intakes of CML, CEL, and MG-H1 were not associated with the microvascular outcomes. Although higher intake of CEL was associated with higher flicker light-induced venular dilation (β percentage change over baseline: 0.14; 95% CI: 0.02, 0.26) and lower plasma biomarker z score (β: -0.04 SD; 95% CI: -0.08, -0.00 SD), the effect sizes were small and their biological relevance can be questioned.CONCLUSIONS: We did not show any strong association between habitual intake of dietary AGEs and generalized microvascular function. The contribution of dietary AGEs to generalized microvascular function should be further assessed in randomized controlled trials using specifically designed dietary interventions.

Background: Individuals with chronic kidney disease (CKD) have a high burden of cardiovascular disease (CVD). Abnormalities in cardiac structure and function represent subclinical CVD and can be assessed by cardiac magnetic resonance imaging (cMRI). Methods: We investigated differences in cMRI parameters in 140 individuals with CKD stages 3b-4 who participated in the CKD Optimal Management with BInders and NicotinamidE (COMBINE) trial and in 24 age-and sex matched healthy volunteers. Among COMBINE participants, we examined the associations of estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), phosphate, fibroblast growth factor 23 (FGF23), and parathyroid hormone (PTH) with baseline (N=140) and 12-month change (N=112) in cMRI parameters. Results: Mean (standard deviation [SD]) age of the COMBINE participants and healthy volunteers were 64.9 (11.9) and 60.4 (7.3) years. The mean (SD) baseline eGFR in COMBINE participants was 32.1 (8.0) and 85.9 (16.0) ml/ min/1.73m2 in healthy volunteers. The median (interquartile range [IQR]) UACR in COMBINE participants was 154 (20.3 - 540.0) mg/g. Individuals with CKD had lower mitral valve E/A ratio compared to healthy volunteers (β estimate -0.13 CKD vs. non-CKD, 95% confidence interval [CI] -0.24, -0.012). Among COMBINE participants, multivariable linear regression analyses showed that higher UACR was significantly associated with lower mitral valve E/A ratio (β-estimate per 1 unit increase in natural log UACR -0.06, 95% CI -0.09, -0.03). This finding was preserved among individuals without baseline CVD. UACR was not associated with 12-month change in any cMRI parameter. eGFR, phosphate, FGF23, and PTH were not associated with any cMRI parameter in cross-sectional or change analyses. Conclusions: Individuals with CKD stages 3b-4 have evidence of cMRI abnormalities. Albuminuria was independently associated with diastolic dysfunction assessed by mitral valve E/A ratio in individuals with CKD with and without clinical CVD, but was not associated with change in any cMRI parameter.

Background Cerebral small vessel disease (cSVD) is a late consequence of cerebral microvascular dysfunction (MVD). MVD is hard to measure in the brain due to its limited accessibility. Extracerebral MVD (eMVD) measures can give insights in the etiology of cerebral MVD, as MVD may be a systemic process. We aim to investigate whether a compound score consisting of several eMVD measures is associated with structural cSVD MRI markers. Methods Cross-sectional data of the population-based Maastricht Study was used (n = 1872, mean age 59 ± 8 years, 49% women). Measures of eMVD included flicker light-induced retinal arteriolar and venular dilation response (retina), albuminuria and glomerular filtration rate (kidney), heat-induced skin hyperemia (skin), and plasma biomarkers of endothelial dysfunction (sICAM-1, sVCAM-1, sE-selectin, and von Willebrand factor). These measures were standardized into z scores and summarized into a compound score. Linear and logistic regression analyses were used to investigate the associations between the compound score and white matter hyperintensity (WMH) volume, and the presence of lacunes and microbleeds, as measured by brain MRI. Results The eMVD compound score was associated with WMH volume independent of age, sex, and cardiovascular risk factors (St β 0.057 [95% CI 0.010–0.081], p value 0.01), but not with the presence of lacunes (OR 1.011 [95% CI 0.803–1.273], p value 0.92) or microbleeds (OR 1.055 [95% CI 0.896–1.242], p value 0.52). Conclusion A compound score of eMVD is associated with WMH volume. Further research is needed to expand the knowledge about the role of systemic MVD in the pathophysiology of cSVD.

Background: Acute changes in glomerular filtration rate (GFR) can occur following initiation of interventions for chronic kidney disease (CKD) progression. These complicate the interpretation of treatment effects on long term progression of (CKD). We sought to assess the magnitude and consistency of acute effects in randomized clinical trials (RCT) and explore factors that might impact them. Methods: We performed a meta-analysis of 53 RCTs for CKD progression enrolling 56,413 participants that had at least one estimated GFR measurement by six months following randomization. We defined acute treatment effects as the mean difference in GFR slope from baseline to 3 months between randomized groups. We performed univariable and multivariable meta-regression to assess the impact of intervention type, disease state, baseline GFR and albuminuria on the magnitude of acute effects. Results: The mean acute effect across all studies was -0.21 mL/min/1.73m2 (95% CI -0.63 to 0.22) over three months, with substantial heterogeneity across interventions (95% coverage interval across studies, -2.50 to +2.08 mL/min/1.73m2). Negative average acute effects were observed in renin angiotensin system blockade, blood pressure lowering and sodium-glucose cotransporter 2 inhibitor trials while positive acute effects were observed in trials of immunosuppressive agents. Larger negative acute effects were observed in trials with higher mean baseline GFR. Conclusion: The magnitude and consistency of acute GFR effects varies across different interventions, and is larger at higher baseline GFR. Understanding the nature and magnitude of the acute effects can help inform the optimal design of RCTs in CKD evaluating kidney disease progression.

Background: Long-term outcomes of live kidney donors remain controversial, although this information is crucial for selecting potential donors. Thus, this study compared the long-term risk of all-cause mortality between live kidney donors and healthy non-donors.Methods: We performed a retrospective cohort study including donors from seven tertiary hospitals in South Korea. Persons who underwent voluntary health screening were included as controls. We created a matched control group considering age, sex, era, body mass index, baseline hypertension, diabetes, estimated glomerular filtration rate, and dipstick albuminuria. The study outcome was progression to end-stage kidney disease (ESKD), and all-cause mortality as identified in the linked claims database. Results: We screened 1,878 kidney donors and 78,115 health screening examinees from 2003 to 2016. After matching, 1,701 persons remained in each group. The median age of the matched study subjects was 44 years, and 46.6% were male. Among the study subjects, 2.7% and 16.6% had underlying diabetes and hypertension, respectively. There were no ESKD events in the matched donor and control groups. There were 24 (1.4%) and 12 mortality cases (0.7%) in the matched donor and control groups, respectively. In the age-sex adjusted model, the risk for all-cause mortality was significantly higher in the donor group than in the control group. However, the significance was not retained after socioeconomic status was included as a covariate (adjusted hazard ratio, 1.82; 95% confidence interval, 0.87–3.80). Conclusion: All-cause mortality was similar in live kidney donors and matched non-donor healthy controls with similar health status and socioeconomic status in the Korean population.

Background Stopping renin-angiotensin system inhibitors (RASi) after an episode of hyperkalemia is common but may involve therapeutic compromises, in that the cessation of RASi deprives patients of their beneficial cardiovascular effects. Methods and results Observational study from the Stockholm Creatinine Measurements (SCREAM) project including patients initiating RASi in routine care and surviving a first-detected episode of hyperkalemia (potassium >5.0 mmol/L). We used target trial emulation techniques based on cloning, censoring and weighting to compare stopping vs. continuing RASi within 6 months after hyperkalemia. Outcomes were 3-year risks of mortality, major adverse cardiovascular events (MACE, composite of cardiovascular death, myocardial infarction and stroke hospitalization) and recurrent hyperkalemia. Of 5669 new users of RASi who developed hyperkalemia (median age 72 years, 44% women), 1425 (25%) stopped RASi therapy within 6 months. Compared with continuing RASi, stopping therapy was associated with a higher 3-year risk of death (absolute risk difference 10.8%; HR 1.49, 95% CI 1.34-1.64) and MACE (risk difference 4.7%; HR 1.29, 1.14-1.45), but a lower risk of recurrent hyperkalemia (risk difference -9.5%; HR 0.76, 0.69-0.84). Results were consistent for events following potassium of >5.0 or >5.5 mmol/L, after censoring when the treatment decision was changed, across prespecified subgroups, and after adjusting for albuminuria. Conclusion These findings suggest that stopping RASi after hyperkalemia may be associated with a lower risk of recurrence of hyperkalemia, but higher risk of death and cardiovascular events.

OBJECTIVE: To examine the effect of a telehealth intervention that used a dietary app, educational website, and weekly dietitian tele-counseling) on sodium intake, diet quality, blood pressure and albuminuria among individuals with diabetes and early stage chronic kidney disease. DESIGN AND METHODS: We examined the effects of a dietary app-supported tele-counseling intervention in a single center, single arm study of 44 participants with type 2 diabetes and stage 1–3a chronic kidney disease. Participants recorded and shared dietary data via MyFitnessPal with registered dietitians, who used motivational interviewing to provide telephone counseling weekly for 8 weeks. After the 8-week intensive intervention, participants were followed at 6 months and 12 months. Outcomes included 24-hour urine sodium (2 collections per timepoint), Healthy Eating Index (HEI) 2015 score (three 24-hour dietary recalls per timepoint), 24-hour systolic blood pressure (SBP) and diastolic blood pressure (DBP), and 24-hour urine albumin excretion. RESULTS: Out of 44 consented participants (mean age 60.3 +/− 11.9 years, 43% female, 89% white, median eGFR was 78.5 ml/min/1.73m(2), median urine albumin excretion 52.9 mg/day, 84% hypertension), 32 (73%) completed 8-week follow-up, 27 (61%) completed 6-month follow up, and 25 (57%) completed 12-month follow up. Among participants who completed 12-month follow up, reported sodium intake decreased by 638 mg/day from baseline of 2919 mg/day (p-value

The decline of the estimated glomerular filtration rate (eGFR) and the presence of albuminuria are the typical hallmarks of kidney disease arising as one of the most frequent diabetic complications over a long period of time, generally known as diabetic nephropathy or diabetes kidney disease (DKD). However, a decline in the renal function may occur in diabetic patients for other reasons unrelated to glycemic control, and this condition is known as non-diabetic kidney disease (NDKD). In this opinion paper we will review these conditions, and we outline the importance of other investigations, such as kidney biopsy and the measurement of novel biomarkers, in order to identify the disease progression early, and to allow a timely intervention. We will also focus on the actual limits of the quantitative measurements of albumin in urine, especially with regards to potential interferences due to the treatment of patients with statins.

The clinical research on BH4 is limited because of the difficulties on its measurement. In this study, we used our own established LC-MS/MS method to examine the plasma BH4 levels in diabetes to determine whether it could be used as a biomarker for the prediction of kidney injury in those patients.Hospitalized diabetes patients in Renmin Hospital of Wuhan University from Jan to Aug 2021 were recruited. To assess the association between plasma BH4 with ACR or eGFR in diabetes, a total of 142 patients with type 2 diabetes (T2DM) were enrolled. They were divided into three groups by albuminuria levels: normoalbuminuria (n = 68), microalbuminuria (n = 48), and macroalbuminuria (n = 26) according to ACR; or into two groups by eGFR: eGFR≥90 or eGFR90 ml/min for correlation and logistic regression analysis. Plasma BH4 level was measured by LC-MS/MS along with other biochemical indices.Plasma BH4 concentrations were decreased as ACR progressed. BH4 (r = -0.55, P 0.001) and 2h C-Peptide (CP-2h) (r = -0.248, P = 0.003) levels were negatively correlated with ACR. Moreover, multivariable logistic regression analysis showed BH4 concentrations (B = -0.468, P 0.001) and CP-2h (B = -0.257, P = 0.028) were independently associated with ACR progression. ROC curve showed that BH4 level has a predictive value on ACR (95%CI 0.686-0.841, sensitivity 69.1%, specificity 73%). Moreover, in diabetes patients with eGFR≥90 ml/min, plasma BH4 level (P = 0.008) is higher than those in diabetes with eGFR90 ml/min and BH4 was remained independently associated with eGFR after multivariable logistic regression analysis (B = -0.193, P = 0.048).Our established LC-MS/MS method could be used on human plasma BH4 measurements and our data suggested that BH4 level can be used as a biomarker for kidney injury in diabetes indicated by its association with ACR progression and early renal function decline.

PURPOSE Urinary stone disease (USD) has been associated with an increased risk of chronic kidney disease (CKD) and end-stage renal disease in Western populations. However, the metabolic disorders associated with unilateral and bilateral renal stones and the association of these types of stones with CKD and kidney tubular injury markers, such as urine N-acetyl-s-D-glucosaminidase (NAG) and alpha-1-microglobulin (α1-MG), have not been fully examined. MATERIALS AND METHODS We performed a cross-sectional study of 10,281 participants in rural China in 2014. All the subjects underwent renal ultrasound to detect USD; stone formers were divided into groups with unilateral or bilateral renal stones by ultrasound examinations. CKD was defined as a decreased estimated glomerular filtration rate (eGFR

Aims/Introduction The sodium–glucose cotransporter 2 inhibitor, canagliflozin, reduced kidney failure and cardiovascular events in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial. We carried out a post‐hoc analysis to evaluate the efficacy and safety of canagliflozin in a subgroup of participants in East and South‐East Asian (EA) countries who are at high risk of renal complications. Materials and Methods Participants with an estimated glomerular filtration rate of 30 to 300–5,000 mg/g were randomized to 100 mg of canagliflozin or a placebo. The effects of canagliflozin treatment on pre‐specified efficacy and safety outcomes were examined using Cox proportional hazards regression between participants from EA countries (China, Japan, Malaysia, the Philippines, South Korea and Taiwan) and the remaining participants. Results Of 4,401 participants, 604 (13.7%) were from EA countries; 301 and 303 were assigned to the canagliflozin and placebo groups, respectively. Canagliflozin lowered the risk of primary outcome (composite of end‐stage kidney disease, doubling of serum creatinine level, or renal or cardiovascular death) in EA participants (hazard ratio 0.54, 95% confidence interval 0.35–0.84). The effects of canagliflozin on renal and cardiovascular outcomes in EA participants were generally similar to those of the remaining participants. Safety outcomes were similar between the EA and non‐EA participants. Conclusions In the CREDENCE trial, the risk of renal and cardiovascular events was safely reduced in participants from EA countries at high risk of renal events., A post‐hoc analysis was carried out to evaluate the efficacy and safety of canagliflozin in a subgroup of participants in East and South‐East Asian countries in the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial. Canagliflozin lowered the risk of primary composite outcome (composite of end‐stage kidney disease, doubling of serum creatinine level, or death from renal or cardiovascular causes) in East and South‐East Asian participants (hazard ratio 0.54, 95% confidence interval 0.35–0.84). Canagliflozin safely reduced the risk of renal and cardiovascular events in participants from East and South‐East Asian countries at high risk of renal events.

Kidney dysfunction can profoundly influence many organ systems, and recent evidence suggests a potential role for increased albuminuria in the development of mild cognitive impairment (MCI) or dementia. Epidemiological studies conducted in different populations have demonstrated that the presence of increased albuminuria is associated with a higher relative risk of MCI or dementia both in cross-sectional analyses and in studies with long-term follow-up. The underlying pathophysiological mechanisms of albuminuria’s effect are as yet insufficiently studied, with several important knowledge gaps still present in a complex relationship with other MCI and dementia risk factors. Both the kidney and the brain have microvascular similarities that make them sensitive to endothelial dysfunction involving different mechanisms, including oxidative stress and inflammation. The exact substrate of MCI and dementia is still under investigation, however available experimental data indicate that elevated albuminuria and low glomerular filtration rate are associated with significant neuroanatomical declines in hippocampal function and grey matter volume. Thus, albuminuria may be critical in the development of cognitive impairment and its progression to dementia. In this review, we summarize the available evidence on albuminuria’s link to MCI and dementia, point to existing gaps in our knowledge and suggest actions to overcome them. The major question of whether interventions that target increased albuminuria could prevent cognitive decline remains unanswered. Our recommendations for future research are aimed at helping to plan clinical trials and to solve the complex conundrum outlined in this review, with the ultimate goal of improving the lives of patients with chronic kidney disease., Graphical Abstract Graphical Abstract

Diabetic nephropathy (DN) is the most common complication of diabetic patients, and has become a global healthcare problem. In this study, we used diabetic mice to evaluate the effect of Losartan on DN, in which the experimental animals were divided into three groups: non-diabetic mice (db/m group), untreated-diabetic mice (db/db group), and Losartan-treated diabetic mice (db/db-losartan). Next, immunohistochemistry and immunofluorescence were used to detect Wilms tumor protein 1 (WT-1) and synaptopodin expression, respectively. Protein levels of WT-1, synaptopodin, claudin1, and Pax-2 were assessed by Western blotting and real-time PCR. The miR-193a mRNA levels were quantitated by real-time PCR. The results showed that albuminuria was increased in diabetic mice compared with control animals and was significantly ameliorated by treatment with Losartan. In addition, Losartan significantly upregulated the immunopositive cell numbers of WT-1, the expression of WT-1 and synaptopodin in renal tissue. By contrast, expression of claudin1 and Pax-2 in renal tissue were decreased in db/db-losartan group. Besides, expression of miR-193a was decreased significantly in db/db-losartan group compared with the untreated diabetic group. Thus, Losartan has renoprotective effects on the control of tissue damage possibly by inhibiting the expression of miR-193a, thereby promoting the repair of podocyte injury in mice with DN.

A 47-year-old woman with history of seizure disorder (semiology of seizure unknown), not well controlled with antiepileptic drugs since last 30 years presented with 1-year history of intermittent throbbing headache. On the day prior to admission, she experienced worst headache, followed by loss of consciousness. On regaining consciousness, she had neck pain without any focal neurological deficit, but examination was marked by positive meningeal signs. She had history of oral ulceration, photosensitivity and small joints pain for which no medical consultancy was sought until. Following relevant investigations, this case came out to be moyamoya angiopathy secondary to underlying systemic lupus erythematosus. She was put on immunosuppressive and immunomodulator as per recommendations. Among neurological symptoms, headache improved dramatically without any further seizure recurrence till the 6 months of follow-up.

Hematuria or proteinuria may be just a normal transient finding in children, usually accompanying a non-specific viral infection, or it can be an indicator of a kidney or urinary tract disorder. In this chapter, the various causes and significance of discolored urine, hematuria and proteinuria in children are discussed. A pragmatic clinical approach to evaluate a child with isolated hematuria or isolated proteinuria is suggested to reduce unnecessary extensive workup in benign cases and yet not miss the cases with significant glomerular or urinary tract disease. Early detection and treatment of significant disorders would hopefully delay or prevent the onset of renal insufficiency in children.

Chronic kidney disease (CKD) is an important health issue that affects ~ 9.1% of the world adult population. Serum creatinine is the most commonly used biomarker for assessing kidney function and is utilized in different equations for estimating creatinine clearance or glomerular filtration rate (GFR). The Cockcroft-Gault formula for adults and "original" Schwartz formula for children have been the most commonly used equations for estimating kidney function during the last 3-4 decades. Introduction of standardized serum creatinine bioanalytical methodology has reduced interlaboratory variability but is not intended to be used with Cockcroft-Gault or original Schwartz equations. More accurate equations (for instance, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) for adults and bedside Schwartz or Chronic Kidney Disease in Children Schwartz equation for children) based on standardized serum creatinine values (and another biomarker-cystatin C) have been introduced and validated in recent years. Recently, the CKD-EPI equation refitted without a race variable was introduced. Clinical practice guidance in nephrology advocates a shift to these equations for managing health care of patients with CKD. The guidance also recommends use of albuminuria in addition to GFR for CKD diagnosis and management. Significant research with large data sets would be necessary to evaluate whether this paradigm would also be valuable in drug dose adjustments. This article attempts to highlight some important advancements in the field from a clinical pharmacology perspective and is a call to action to industry, regulators, and academia to rethink the current paradigm for assessing kidney function to enable dose recommendation in patients with CKD.

Background Physiologically regulated insulin secretion and euglycemia are achievable in type 1 diabetes (T1D) by islet or pancreas transplantation. However, pancreas transplant alone (PTA) remains a debated approach, with uncertainties on its relative benefits and risks. We determined the actual long-term (10 years) efficacy and safety of PTA in carefully characterized T1D subjects. Methods This is a single-centre, cohort study in 66 consecutive T1D subjects who received a PTA between April 2001 and December 2007, and were then all followed until 10 years since transplant. Main features evaluated were patient survival, pancreas graft function, C-peptide levels, glycemic parameters, and the function of the native kidneys. Results Ten-year actual patient survival was 92.4%. Optimal (insulin-independence) or good (minimal insulin requirement) graft function was observed in 57.4 and 3.2% of patients, respectively. Six (9.0%) patients developed stage 5 or 4 chronic kidney disease. In the remaining individuals bearing a successful PTA, eGFR decline per year was -2.29±2.69 ml/min/1.73m. Reduction of eGFR at 1 year post-PTA was higher in those with pre-PTA hyperfiltration and higher HbA1c concentrations; eGFR changes afterwards significantly correlated with diabetes duration. In recipients with normoglycemia at 10 years, 74% of normo- or micro-albuminuric subjects pre-PTA remained stable, and 26% progressed towards a worse stage; conversely, in 62.5% of the macro-albuminuric individuals albuminuria severity regressed. Conclusions These long-term effects of PTA on patient survival, graft function and the native kidneys support PTA as a suitable approach to treat diabetes in selected T1D patients.

Background Lymphatic abnormalities are observed in several types of kidney disease, but the relationship between the renal lymphatic system and renal function is unclear. The discovery of lymphatic-specific proteins, advances in microscopy, and available genetic mouse models provide the tools to help elucidate the role of renal lymphatics in physiology and disease. Methods We utilized a mouse model containing a missense mutation in Vegfr3 (dubbed Chy) that abrogates its kinase ability. Vegfr3Chy/+ mice were examined for developmental abnormalities and kidney-specific outcomes. Control and Vegfr3Chy/+ mice were subjected to cisplatin-mediated injury. We characterized renal lymphatics using tissue-clearing, light-sheet microscopy, and computational analyses. Results In the kidney, VEGFR3 is expressed not only in lymphatic vessels but also, in various blood capillaries. Vegfr3Chy/+ mice had severely reduced renal lymphatics with 100% penetrance, but we found no abnormalities in BP, serum creatinine, BUN, albuminuria, and histology. There was no difference in the degree of renal injury after low-dose cisplatin (5 mg/kg), although Vegfr3Chy/+ mice developed perivascular inflammation. Cisplatin-treated controls had no difference in total cortical lymphatic volume and length but showed increased lymphatic density due to decreased cortical volume. Conclusions We demonstrate that VEGFR3 is required for development of renal lymphatics. Our studies reveal that reduced lymphatic density does not impair renal function at baseline and induces only modest histologic changes after mild injury. We introduce a novel quantification method to evaluate renal lymphatics in 3D and demonstrate that accurate measurement of lymphatic density in CKD requires assessment of changes to cortical volume.

Background Cognitive impairment is common among persons with chronic kidney disease (CKD), due in part to reduced kidney function. Given that physical activity (PA) is known to mitigate cognitive decline, we examined whether associations between CKD stage and global/domain-specific cognitive function differ by PA. Methods We leveraged 3223 participants (≥60 years of age) enrolled in National Health and Nutrition Examination Survey (NHANES, 2011–2014), with at least one measure of objective cognitive function [immediate recall (CERAD-WL), delayed recall (CERAD-DR), verbal fluency (AF), executive function/processing speed (DSST), global (average of four tests) or self-perceived memory decline (SCD)]. We quantified the association between CKD stage {no CKD: estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2 and albuminuria [albumin:creatinine ratio (ACR)] Results Among NHANES participants, 34.9% had CKD stages G1–G3, 2.6% had stages G4 and G5 and 50.7% had low PA. CKD stages G4 and G5 were associated with lower global cognitive function {difference = −0.38 standard deviation [SD] [95% confidence interval (CI) −0.62 to −0.15]}. This association differed by PA (Pinteraction = 0.01). Specifically, among participants with low PA, those with CKD stages G4 and G5 had lower global cognitive function [difference = −0.57 SD (95% CI −0.82 to −0.31)] compared with those without CKD. Among those with high PA, no difference was found [difference = 0.10 SD (95% CI −0.29–0.49)]. Similarly, the CKD stage was only associated with immediate recall, verbal fluency, executive function and processing speed among those with low PA; no associations were observed for delayed recall or self-perceived memory decline. Conclusions CKD is associated with lower objective cognitive function among those with low but not high PA. Clinicians should consider screening older patients with CKD who have low PA for cognitive impairment and encourage them to meet PA guidelines.

Background: diabetic nephropathy is one of the most leading disorder in patients with type 2 diabetes mellitus. Urinary albuminuria used for detection of nephropathy in type 2 diabetes mellitus but its not an a sensitive and specific biomarker for DN. Recent studies found some of the sensitive and specific biomarker for early detection and progression of nephropathy in type 2 diabetes mellitus patients. Materials and Methods: A total 150 subjects included in the present study in that 100 patients diagnosed with type 2 diabetes mellitus and 50 healthy controls. All the subjects included after informed consent and blood, urine samples were collected from the all the subjects. FBS, PPBS, Urea, Creatinine, Uric acid, HbA1C and Urinary Albumin was analysed by using laboratory standard methods. Results: statistically elevated levels of plasma FBS, PPBS, HbA1C in both the groups of type 2 diabetes mellitus when compared to healthy controls. Serum Urea, Creatinine and Uric Acid levels elevated in type 2 diabetes mellitus with microalbuminuria when compared to other two groups of study subjects. The Glycosylated hemoglobin positively correlated with urinary microalbuminuria in patients with two groups of type 2 diabetes mellitus. Conclusion: This study suggest that the poor glycemic control leads to increased further complications in patients with type 2 diabetes mellitus. Continuous monitoring of HbA1C and Urinary Albumin Levels were useful for progression and treatment of patients with type 2 diabetes mellitus. Keywords: Type 2 diabetes mellitus, HbA1C, Urinary albumin.

Introduction Patients with chronic kidney disease (CKD) remain at risk for kidney and cardiovascular events resulting from residual albuminuria, despite available treatments. Leukotrienes are proinflammatory and vasoconstrictive lipid mediators implicated in the etiology of chronic inflammatory diseases. AZD5718 is a potent, selective, and reversible 5-lipoxygenase activating protein (FLAP) inhibitor that suppresses leukotriene production. Methods FLAIR (FLAP Inhibition in Renal disease) is an ongoing phase 2b, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of AZD5718 in patients with proteinuric CKD with or without type 2 diabetes. Participants receive AZD5718 at 3 different doses or placebo once daily for 12 weeks, followed by an 8-week extension in which they also receive dapagliflozin (10 mg/d) as anticipated future standard of care. The planned sample size is 632 participants, providing 91% power to detect 30% reduction in urinary albumin-to-creatinine ratio (UACR) between the maximum dose of AZD5718 and placebo. The dose–response effect of AZD5718 on UACR after the dapagliflozin extension is the primary efficacy objective. Key secondary objectives are the dose–response effect of AZD5718 plus current standard of care on UACR and acute effects of treatment on the estimated glomerular filtration rate. Safety, tolerability, AZD5718 pharmacokinetics, and analyses of biomarkers that may predict or reflect response to AZD5718 are additional objectives. Conclusion FLAIR will provide data on the effects of 5-lipoxygenase pathway inhibition in patients with proteinuric CKD with or without type 2 diabetes, and will form the basis for future clinical trials (ClinicalTrials.gov: NCT04492722)., Graphical abstract

Lulu Song,1 Xiaomu Kong,2 Zhaojun Yang,1 Jinping Zhang,1 Wenying Yang,1 Bo Zhang,1 Xiaoping Chen,1 Xin Wang1 1Department of Endocrinology, China-Japan Friendship Hospital, Beijing, People’s Republic of China; 2Clinical Laboratory, China-Japan Friendship Hospital, Beijing, People’s Republic of ChinaCorrespondence: Xin WangDepartment of Endocrinology, China-Japan Friendship Hospital, 2 Yinghua East Road, Beijing, 100029, People’s Republic of ChinaTel +86 1084205254Email xiangpian11@163.comPurpose: To assess the effect of acarbose in lowering low-grade albuminuria compared to metformin in newly diagnosed Chinese type 2 diabetes (T2DM) patients.Patients and Methods: The Metformin and AcaRbose Clinical Trial was a randomized, open-label trial in newly diagnosed T2DM patients. Participants received 48 weeks of monotherapy with acarbose (100 mg three times a day) or metformin (1500 mg once a day). As the hypoglycemic effect of acarbose and metformin has been evaluated in previous reports. This analysis studied the effect of the two antidiabetic drugs on reducing urinary albumin. The percent change in the urinary albumin/creatinine ratio (uACR) from baseline to week 48 was analyzed, and ANCOVA was employed to establish whether the effect in decreasing uACR was mediated by metabolic improvement.Results: Acarbose reduced the adjusted mean percent uACR by − 31.5% (95% confidence interval [CI] − 48.4 to − 7.5) compared with metformin. When adjusting for changes in glycated hemoglobin, body weight, systolic blood pressure and triglycerides or changes in area under the curve of glucagon-like peptide 1 (AUCGLP-1) in the standard meal test, the uACR-lowering effect was not attenuated. If stratified by eGFR, blood glucose level, sex or uACR level, the effect of acarbose versus metformin was consistent across subgroups. The proportion of patients with a reduction in uACR of at least 70% was 48.6% in the acarbose group and 34.1% in the metformin group.Conclusion: Acarbose lowered the uACR compared to metformin in newly diagnosed T2DM patients independent of improvements in hyperglycemia, blood pressure, body weight and triglycerides.Keywords: diabetes mellitus, type 2, diabetic nephropathies, hypoglycemic agents

Background In the critical care environment, elevated albuminuria values show capacity to reflect illness severity and predict mortality and hence assessing albumin/creatinine ratio (ACR) at the bedside has potential clinical benefit Point-of-care (POC) analysers offer rapid results but may be less accurate then laboratory analysis. Methods Critically ill adult patients with a urinary catheter in situ had albumin, creatinine, and ACR measurements performed via laboratory and POC analysis. Data are presented as mean (standard deviation) or median [interquartile range]. Measurement agreement was assessed by Lin's concordance correlation coefficient, Bland Altman 95% limits of agreement, and classification by Cohen's kappa statistic. Results/Findings Albumin, creatinine, and ACR analysis was performed for 30 patients. Lin's correlation coefficient showed ‘substantial’ agreement for albumin and ACR and ‘almost perfect’ agreement for creatinine for POC vs laboratory analysis. POC vs laboratory analysis also showed poor agreement for identification of normal ACR (>1 mg/mmol) and mild urine ACR (1–3 mg/mmol) and ‘substantial’ agreement for moderately increased urine ACR (3–30 mg/mmol). Conclusions ACR POC values appear to provide an accurate and rapid method that has potential to provide an early indication of injury severity and mortality risk in the critically ill.

Diabetic kidney disease (DKD) is one of the most common complications of diabetes and is clinically featured by progressive albuminuria, consequent to glomerular destruction that involves podocyte senescence. Burgeoning evidence suggests that ketosis, in particular β-hydroxybutyrate, exerts a beneficial effect on aging and on myriad metabolic or chronic diseases, including obesity, diabetes and chronic kidney diseases. Its effect on DKD is largely unknown. In vitro in podocytes exposed to a diabetic milieu, β-hydroxybutyrate treatment substantially mitigated cellular senescence and injury, as evidenced by reduced formation of γH2AX foci, reduced staining for senescence-associated-β-galactosidase activity, diminished expression of key mediators of senescence signaling like p16INK4A and p21, and preserved expression of synaptopodin. This beneficial action of β-hydroxybutyrate coincided with a reinforced transcription factor Nrf2 antioxidant response. Mechanistically, β-hydroxybutyrate inhibition of glycogen synthase kinase 3β (GSK3β), a convergent point for myriad signaling pathways regulating Nrf2 activity, seems to contribute. Indeed, trigonelline, a selective inhibitor of Nrf2, or ectopic expression of constitutively active mutant GSK3β abolished, whereas selective activation of Nrf2 was sufficient for the anti-senescent and podocyte protective effects of β-hydroxybutyrate. Moreover, molecular modeling and docking analysis revealed that β-hydroxybutyrate is able to directly target the ATP-binding pocket of GSK3β and thereby block its kinase activity. In murine models of streptozotocin-elicited DKD, β-hydroxybutyrate therapy inhibited GSK3β and reinforced Nrf2 activation in glomerular podocytes, resulting in lessened podocyte senescence and injury and improved diabetic glomerulopathy and albuminuria. Thus, our findings may pave the way for developing a β-hydroxybutyrate-based novel approach of therapeutic ketosis for treating DKD.

Introduction We have previously showed that albuminuria was associated with low birthweight in young adults in a remote Australian Aboriginal community that has high rates of kidney disease. Here we describe the association of birthweight with incidence and progression of kidney disease over time. Methods Among 695 members of an Aboriginal community with recorded birthweights, urine albumin creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were measured at ages 5 to 40 years, and follow-up values were measured or imputed again a median of 11.6 years later. Prevalence of markers on each occasion and change over time were evaluated in the context of birthweights and other potentially significant factors. Results On the second screen, ACR was inversely and significantly correlated with birthweight and eGFR was directly correlated with birthweight. Increases in ACR and in proportions of persons who developed new-onset (incident) albuminuria between screens were higher in those of lower birthweights (, Graphical abstract

Sodium-glucose cotransporter-2 (SGLT2) inhibitors lower risk of cardiovascular and kidney events in people with type 2 diabetes. In the empagliflozin in type 1 diabetes clinical program (Empagliflozin as Adjunctive to inSulin thErapy [EASE]), glycemic control, body weight, and BP improved with

BACKGROUND Patients with normoalbuminuria and a reduced estimated glomerular filtration rate (eGFR) account for a considerable proportion of type 2 diabetes patients. The aim of this research was to investigate the epidemiological and clinical characteristics of normoalbuminuric kidney disease in a Chinese population. METHODS We included 8131 diabetic patients from a multicenter prospective study in China. Based on eGFR and urinary albumin-to-creatinine ratio (UACR), participants were stratified into four groups-normal albuminuria, albuminuria, normoalbuminuria with eGFR

Increased oxidative stress in glomerular endothelial cells (GEnCs) contributes to early diabetic kidney disease (DKD). While mitochondrial respiratory complex IV activity is reduced in DKD, it remains unclear whether this is a driver or a consequence of oxidative stress in GEnCs. Synthesis of cytochrome C oxidase 2 (SCO2), a key metallochaperone in the electron transport chain, is critical to the biogenesis and assembly of subunits required for functional respiratory complex IV activity. Here, we investigated the effects of Sco2 hypomorphs (Sco2KO/KI, Sco2KI/KI), with a functional loss of SCO2, in the progression of DKD using a murine model of Type II Diabetes Mellitus, db/db mice. Diabetic Sco2KO/KI and Sco2KI/KI hypomorphs exhibited a reduction in complex IV activity, but an improvement in albuminuria, serum creatinine, and histomorphometric evidence of early DKD as compared to db/db mice. Single-nucleus RNA sequencing with gene set enrichment analysis of differentially expressed genes in the endothelial cluster of Sco2KO/KI;db/db mice demonstrated an increase in genes involved in VEGF-VEGFR2 signaling and reduced oxidative stress as compared to db/db mice. These data suggest that reduced complex IV activity due to a loss of functional SCO2 might be protective in GEnCs in early DKD.

BACKGROUND Mineralocorticoid receptor antagonist (MRA) when combined with either angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) may provide additional benefits of cardiovascular and kidney disease risk reduction in patients with diabetic kidney disease (DKD) and hypertension. We evaluated the effectiveness of combination therapy (MRAs, either spironolactone or eplerenone, plus ACEI/ARB) compared with monotherapy (ACEI/ARB only) in patients with DKD and hypertension. METHODS Retrospective cohort study was performed in patients (age ≥ 18 years) with hypertension, diabetes, and albuminuria between 2008 and 2018 within an integrated health system. MRA with ACEI/ARB compared to ACEI/ARB alone was evaluated on composite of cardiovascular events, progression to end-stage kidney disease, or all-cause mortality. Hyperkalemia was compared as a safety outcome. RESULTS We identified 1282 patients who received MRAs with ACEI/ARBs and 5484 patients who received ACEI/ARBs alone. Median exposure time for combination therapy was 126 days. The rates per 100 person-years of cardiovascular, kidney, or all-cause mortality outcomes were 12.2 and 9.2 for combination therapy and monotherapy, respectively (hazard ratios = 1.24, 95% Confidence Interval (CI):0.94, 1.63). Patients receiving combination therapy had greater reduction in urine albumin-to-creatinine ratio compared with monotherapy (Mean reduction: 823 and 585 mg/g; p

Introduction: Anemia is a modifiable and very common complication of chronic kidney disease that could be difficult to manage, more so in low income settings due to late recognition, and cost of undergoing required investigations and treatment. Methods: A cross sectional study in which participants with chronic kidney disease and with glomerular filtration rate (GFR)

Type 2 Diabetes mellitus (T2DM) is a syndrome of disorders characterized by hyperglycemia caused due to a relative or absolute deficiency of insulin, decreased glucose utilization. The metabolic derangements in diabetes lead to secondary complications that affect multiple organ systems particularly on kidney. For early detection of kidney damage in T2DM patients are important by using certain type of urinary proteins. We aimed to evaluate the glomerular basement membrane damage and leaking of structural proteins in among different stages of type 2 diabetes mellitus patients. A total 150 type 2 diabetes mellitus patients were included in the present study and again sub classified into 2 types (Normoalbuminuria 50, Microalbuminuria 50) based on their urinary ACR and also included 50 age, gender matched healthy controls. The FBS, PPBS, Urea, Creatinine, HbA1C, Urinary Albumin was analysed by using laboratory standard methods and Urinary Adiponectin was measured by using were collected from the all subjects. A statistical was performed by using SPSS Version 21.0 and P value considers < 0.05 is statistically significant. The significantly elevated levels of plasma FBS, PPBS, Serum Urea, Creatinine, HbA1c, Urinary albuminuria and Urinary Adiponectin observed in two groups of type 2 diabetes mellitus when compared to healthy controls. The Urinary Adiponectin was positively correlated with blood sugar levels and urinary albumin in two groups of diabetes mellitus. The data showed a significantly damaged foot process of podocytes and glomerular basement membrane leads to leaking of certain urinary proteins.The elevated levels of Urinary Proteins and HbA1c, Urinary Albuminuria directly indicate the damage of podocytes and glomerular basement membrane in the kidney. These studies suggest continuous monitoring of these parameters may helpful for progression of type 2 diabetes mellitus complications.

Diabetic nephropathy is a one of the microvascular complication in patients with type 2 diabetes mellitus due to increased production of free radicals and decreased levels of anti oxidants. The seviority of the disease totally depends on due to damage of foot process of podocytes. Hence, we need to evaluate the altered structural changes of podocytes, glomerular basement membrane in patients with type 2 diabetes mellitus. A total 60 type 2 diabetes mellitus patients were included in the present study and again sub classified into 2 types (Normoalbuminuria 30, Microalbuminuria 30) based on their urinary ACR. Basic laboratory investigations and radio graphical data were collected from the all subjects. A statistical was performed by using SPSS Version 21.0 and P value considers < 0.05 is statistically significant. The significantly elevated levels of plasma FBS, PPBS, Serum Urea, Creatinine, Uric Acid and HbA1c, Urinary albuminuria observed in type 2 diabetes mellitus with microalbuminuria when compared to normoalbuminuria. The radiographical data showed a significantly damaged foot process of podocytes and glomerular basement membrane are observed in patients with microalbuminuria when compared to normoalbuminuria. The increased levels blood sugar and HbA1c, Urinary Albuminuria directly indicates the damage of podocytes and glomerular basement membrane in the kidney. This study suggest continuous monitoring of these parameters may helpful for progression of type 2 diabetes mellitus complications.

Renal parenchymal fibrosis is the most important determinant of kidney disease progression and it is determined via biopsy. The aim of this study is to evaluate the renal stiffness noninvasively by magnetic resonance elastography (MRE) and to compare it with clinicopathologic parameters in glomerulonephritis and AA amyloidosis patients. Thirty-four patients with glomerular filtration rate (GFR) over 20 ml/min/1.73m2 had non-contrast MRE prospectively. Kidney stiffness values were obtained from whole kidney, cortex, and medulla. Values were correlated with GFR, albuminuria, proteinuria, and degree of fibrosis that are assessed via renal biopsy. Patients were grouped clinicopathologically to assess the relation between stiffness and chronicity. Mean whole kidney, cortex, and medulla stiffnesses were 3.78 (± 1.26), 3.63 (± 1.25), and 4.77 (± 2.03) kPa, respectively. Mean global glomerulosclerosis was 22% (± 18%) and median segmental glomerulosclerosis was 4% (min–max: 0%–100%). Extent of tubulointerstitial fibrosis was less than 25% in 26 of the patients (76.5%), 25%–50% in 6 of the patients (17.6%), and higher than 50% in 2 of the patients (5.9%). Fourteen patients were defined to have chronic renal parenchymal injury. MRE-derived stiffness values correlated negatively with parameters of fibrosis. Lower stiffness values were observed in patients with chronic renal injury compared to those without (P

Individuals with Chronic Kidney Disease (CKD) are at high risk for cardiovascular morbidity and mortality. The aim of this study was to examine the relationship between renal dysfunction and all-cause mortality in a sample of subjects undergoing coronary angiography (CA). We evaluated 1017 subjects who consecutively underwent CA. Glomerular filtration rate (eGFR) was estimated by CKD-EPI and urinary albumin excretion reported as urinary albumin-to-creatinine ratio. Vital status was ascertained by interrogating the Italian Health Card Database. One-thousand-seventeen subjects (759 M/258F) were enrolled into the study from 2016 to 2018. One-hundred-fourteen deaths occurred during a median follow-up of 44 months. The whole population was divided in two subgroups according to the presence/absence of low eGFR (i.e.

Background Proteinuria is a well-known risk factor for progressive kidney impairment. Recently, C-terminal cubilin (CUBN) variants have been associated with isolated proteinuria without progression of kidney disease. Methods Genetic testing of 347 families with proteinuria of suspected monogenic cause was performed by next-generation sequencing of a custom-designed kidney disease gene panel. Families with CUBN biallelic proteinuria-causing variants were studied at the clinical, genetic, laboratory and pathologic levels. Results Twelve families (15 patients) bearing homozygous or compound heterozygous proteinuria-causing variants in the C-terminal CUBN gene were identified, representing 3.5% of the total cohort. We identified 14 different sequence variants, five of which were novel. The median age at diagnosis of proteinuria was 4 years (range 9 months to 44 years), and in most cases proteinuria was detected incidentally. Thirteen patients had moderate to severe proteinuria at diagnosis without nephrotic syndrome. These patients showed lack of response to angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) treatment, normal kidney biopsy and preservation of normal kidney function over time. The two remaining patients presented a more severe phenotype, likely caused by associated comorbidities. Conclusions Identification of C-terminal pathogenic CUBN variants is diagnostic of an entity characterized by glomerular proteinuria, normal kidney histology and lack of response to ACEi/ARB treatment. This study adds evidence and increases awareness about albuminuria caused by C-terminal variants in the CUBN gene, which is a benign condition usually diagnosed in childhood with preserved renal function until adulthood.

The aim of this study was to determine whether carbohydrate antigen 72–4 (CA72–4) is elevated in diabetic kidney disease (DKD), and examine the association between urinary albumin-to-creatinine ratio (UACR) and CA72–4 in patients with type 2 diabetes mellitus (T2DM). Non-dialysis patients with T2DM (n=296) and 90 healthy controls were recruited in this study. CA72–4 level was measured by electrochemiluminescence immunoassay. DKD was defined as UACR≥ 30 mg/g in the absence of a urinary infection or other renal diseases. We found that patients with DKD had significantly higher serum CA72–4 levels compared to those with normoalbuminuria and healthy controls. Positive rates of CA72–4 increased gradually and markedly from normoalbuminuria to microalbuminuria and to macroalbuminuria in diabetic patients (7.5, 11.2, and 17.4%, respectively; P for trend< 0.05). CA72–4 also showed a positive correlation with UACR (r=0.288, P< 0.01). Logistic regression analysis revealed the association of increased UACR with an increased odds ratio of elevation of CA72–4 levels (P for trend< 0.05) after multivariable adjustment. In conclusion, serum levels of CA72–4 increase abnormally with the increase in urinary albumin excretion, which affects the specificity of diagnosis of malignancies. An appropriate interpretation of CA72–4 is essential to prevent unnecessary and even hazardous diagnostic procedures in patients with T2DM.

Urinary progranulin is an inflammatory marker that may indicate renal damage at an early stage of diabetic nephropathy. To determine urinary level of progranulin in patients with type 2 diabetic nephropathy and to ascertain its correlation with renal function. This was a cross-sectional comparative study that was carried out at Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), Pondicherry, India. Thirty-three control subjects and 99 diabetic patients (divided into 3 equal groups based on urinary albumin excretion) were included. Albuminuria was detected by dipstick method in a spot urine sample for all subjects. Urinary albumin level was estimated by nephelometry for diabetic subjects who had trace or no albuminuria by dipstick method. Urinary progranulin was estimated by ELISA technique for all study subjects. eGFR (estimated glomerular filtration rate) was calculated by chronic kidney disease epidemiology collaboration (CKD-EPI) formula for all study subjects. Urinary progranulin levels were found to be significantly elevated in diabetic patients as compared to the control subjects (p

The glomerulus is the accessible window to visualize the endothelial status of the whole body. Minimal level of albuminuria even below the cutoff point of microalbuminuria might be a marker of endothelial dysfunction. Exposure to Bisphenol A may be a risk factor of developing low-grade albuminuria in pediatrics. Aim: This study investigated the association of exposure to Bisphenol A and the presence of low-grade albuminuria. Methods: A cross-sectional study enrolling 158 children; 91 boys and 67 girls. Children with hepatic disease, kidney disease and endocrinopathies were excluded from the study. Urinary albumin and creatinine were measured in a first morning urine specimen. Urinary albumin/creatinine ratio was calculated in mg/gm and was stratified into: macroalbuminuria of ˃300mg/gm, microalbuminuria of 30-300mg/gm and low grade albuminuria of ˂30mg/gm. Urinary Bisphenol A was measured by high performance liquid chromatography using florescent detector. Results: Low grade albuminuria was detected in 141 participants (89.24%), while microalbuminuria and macroalbuminuria were detected in 15 (9.5%) and 2 (1.26%) participants, respectively. The total urinary Bisphenol A in candidates with low grade albuminuria was categorized into four quartiles (1.215) ng/mL and similarly their low grade albuminuria into (7.3870) mg/gm. Children with the highest compared to the lowest quartile of urinary Bisphenol A had comparable mean of low grade albuminuria with insignificant P value. Conclusion: low grade albuminuria was found in 141 out of 158 children. A direct cause effect of exposure to Bisphenol A could not be proved. Further studies are needed to investigate the pathophysiology of low grade albuminuria and its significance

Albuminuria is an under-recognized component of chronic kidney disease definition, staging, and prognosis. Guidelines, particularly for hypertension, conflict on recommendations for urine albumin-to-creatinine ratio (ACR) measurement. Separately among 1 344 594 adults with diabetes and 2 334 461 nondiabetic adults with hypertension from the chronic kidney disease Prognosis Consortium, we assessed ACR testing, estimated the prevalence and incidence of ACR ≥30 mg/g and developed risk models for ACR ≥30 mg/g. The ACR screening rate (cohort range) was 35.1% (12.3%–74.5%) in diabetes and 4.1% (1.3%–20.7%) in hypertension. Screening was largely unrelated to the predicted risk of prevalent albuminuria. The median prevalence of ACR ≥30 mg/g across cohorts was 32.1% in diabetes and 21.8% in hypertension. Higher systolic blood pressure was associated with a higher prevalence of albuminuria (odds ratio [95% CI] per 20 mm Hg in diabetes, 1.50 [1.42–1.60]; in hypertension, 1.36 [1.28–1.45]). The ratio of undetected (due to lack of screening) to detected ACR ≥30 mg/g was estimated at 1.8 in diabetes and 19.5 in hypertension. Among those with ACR

Aims/hypothesis This prospective, observational study examines associations between 51 urinary metabolites and risk of progression of diabetic nephropathy in individuals with type 1 diabetes by employing an automated NMR metabolomics technique suitable for large-scale urine sample collections. Methods We collected 24-h urine samples for 2670 individuals with type 1 diabetes from the Finnish Diabetic Nephropathy study and measured metabolite concentrations by NMR. Individuals were followed up for 9.0 ± 5.0 years until their first sign of progression of diabetic nephropathy, end-stage kidney disease or study end. Cox regressions were performed on the entire study population (overall progression), on 1999 individuals with normoalbuminuria and 347 individuals with macroalbuminuria at baseline. Results Seven urinary metabolites were associated with overall progression after adjustment for baseline albuminuria and chronic kidney disease stage (p −4): leucine (HR 1.47 [95% CI 1.30, 1.66] per 1-SD creatinine-scaled metabolite concentration), valine (1.38 [1.22, 1.56]), isoleucine (1.33 [1.18, 1.50]), pseudouridine (1.25 [1.11, 1.42]), threonine (1.27 [1.11, 1.46]) and citrate (0.84 [0.75, 0.93]). 2-Hydroxyisobutyrate was associated with overall progression (1.30 [1.16, 1.45]) and also progression from normoalbuminuria (1.56 [1.25, 1.95]). Six amino acids and pyroglutamate were associated with progression from macroalbuminuria. Conclusions/interpretation Branched-chain amino acids and other urinary metabolites were associated with the progression of diabetic nephropathy on top of baseline albuminuria and chronic kidney disease. We found differences in associations for overall progression and progression from normo- and macroalbuminuria. These novel discoveries illustrate the utility of analysing urinary metabolites in entire population cohorts. Graphical abstract

Background. Diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM) is associated with a risk of developing chronic heart failure (CHF). The degree of albuminuria is a marker of DN and is associated with an increased risk of chronic heart failure (CHF).Aim. To evaluate fibrosis biomarkers and echocardiographic parameters in patients with T2DM without CHF, depending on urinary albumin excretion.Materials and methods. The study included 42 patients with T2DM without verified CHF. The patients were divided into two groups: 1) a group with normoalbuminuria and 2) a group with a moderate increase in albuminuria (albumin / creatinine ratio of 30–300 mg / g). Echocardiography was performed and galectin-3, ST-2, PIСP, MMP-9, and TIMP-1 concentrations were measured.Results. The groups did not differ by age, sex, body mass index (BMI), glycated hemoglobin (HbA1c), and glomerular filtration rate (GFR). Galectin-3 concentrations were significantly higher in the group with a moderate increase in albuminuria than in the group of patients without albuminuria – 13.6 (11.2; 15.1) ng / ml and 7.4 (6.7; 7.9) ng / ml, respectively, p = 0.002. The groups also did not differ in the values of biomarkers, such as P1CP, TIMP-1, and MMP-9. Besides, the group with normoalbuminuria had lower E/e’ values than the group with a moderate increase in albuminuria – 8 (7; 9) and 10 (9; 12.5), p = 0.02.Conclusion. The patients with type 2 diabetes and a moderate increase in albuminuria have higher values of galectin-3 and a more pronounced diastolic dysfunction. The identified changes may reflect a higher risk of chronic heart failure in this group of patients.

Chronic kidney disease (CKD) is an important sequela of hematopoietic stem cell transplantation (HSCT), but data regarding CKD after pediatric HSCT are limited. In this single center cohort study, we evaluated the estimated glomerular filtration rate (eGFR) dynamics, proteinuria and hypertension in the first decade after HSCT and assessed risk factors for CKD in 216 pediatric HSCT survivors, transplanted 2002-2012. The eGFR decreased from a median of 148 to 116 ml/min/1.73 m2 between pre-HSCT to ten years post-HSCT. CKD (KDIGO stages G2 or A2 or more; eGFR under 90 ml/min/1.73m2 and/or albuminuria) occurred in 17% of patients. In multivariate analysis, severe prolonged stage 2 or more acute kidney injury (AKI), with an eGFR under 60ml/min/1.73m2 and duration of 28 days or more, was the main risk factor for CKD (hazard ratio 9.5, 95% confidence interval 3.4-27). Stage 2 or more AKI with an eGFR of 60ml/min/1.73m2 or more and KDIGO stage 2 or more AKI with eGFR under 60ml/min/1.73m2 but recovery within 28 days were not associated with CKD. Furthermore, hematological malignancy as HSCT indication was an independent risk factor for CKD. One third of patients had both CKD criteria, one third had isolated eGFR reduction and one third only had albuminuria. Hypertension occurred in 27% of patients with CKD compared to 4.4% of patients without. Tubular proteinuria was present in 7% of a subgroup of 71 patients with available β2-microglobulinuria. Thus, a significant proportion of pediatric HSCT recipients developed CKD within ten years. Our data stress the importance of structural long-term monitoring of eGFR, urine and blood pressure after HSCT to identify patients with incipient CKD who can benefit from nephroprotective interventions.