Overt Proteinuria Research Articles

The associations between renal disease severity and exposure to organophosphate flame retardants in patients with chronic kidney disease

Organophosphate flame retardants (OPFRs) are emerging and widespread environmental pollutants with potential health hazards, including nephrotoxicity. However, the exposure patterns and nephrotoxic potential of OPFRs are yet to be investigated in patients with chronic kidney disease (CKD). We conducted a cross-sectional study involving 166 patients with CKD stratified by estimated glomerular filtration rate (eGFR) and severity of proteinuria. The urinary concentrations of 10 OPFR compounds were measured to evaluate the exposure patterns. Clinical and urinary OPFR profiles were compared among subgroups to identify whether the OPFR compounds were independently correlated with eGFR and proteinuria. Additionally, lifestyle factors were compared among subgroups stratified by median concentrations of urinary OPFR compounds associated with renal disease severity. This study revealed universal exposure to OPFRs in the CKD population, with an overall urinary detection rate of 98.80 %. Furthermore, after adjusting for covariates, the urinary concentration of bis(2-chloroethyl) phosphate (BCEP) was identified as an independent predictor of lower eGFR (low vs high eGFR, odds ratio (OR) (95 % confidence interval (CI)), 1.761 (1.032–3.005) per log μg/g creatinine, p = 0.038), and the urinary concentration of bis(2-butoxyethyl) phosphate (BBOEP) was independently correlated with overt proteinuria in CKD patients (with vs without overt proteinuria, OR (95 % CI), 1.813 (1.065–3.086) per log μg/g creatinine, p = 0.028). Moreover, frequent seafood consumption was negatively correlated with urinary BCEP concentration (high vs low BCEP, OR (95 % CI), 0.455 (0.228–0.908), p = 0.025), and age was inversely associated with urinary BBOEP concentration (high vs low BBOEP, OR (95 % CI), 0.968 (0.937–0.999) per year, p = 0.048). In conclusion, our investigation highlights the extensive exposure to OPFRs and the independent association between renal disease severity and urinary BCEP/BBOEP concentrations in the CKD population, indicating the nephrotoxic potential of these pollutants.

Diabetic Proteinuria Revisited: Updated Physiologic Perspectives.

Albuminuria, a hallmark of diabetic nephropathy, reflects not only injury and dysfunction of the filtration apparatus, but is also affected by altered glomerular hemodynamics and hyperfiltration, as well as by the inability of renal tubular cells to fully retrieve filtered albumin. Albuminuria further plays a role in the progression of diabetic nephropathy, and the suppression of glomerular albumin leak is a key factor in its prevention. Although microalbuminuria is a classic manifestation of diabetic nephropathy, often progressing to macroalbuminuria or overt proteinuria over time, it does not always precede renal function loss in diabetes. The various components leading to diabetic albuminuria and their associations are herein reviewed, and the physiologic rationale and efficacy of therapeutic interventions that reduce glomerular hyperfiltration and proteinuria are discussed. With these perspectives, we propose that these measures should be initiated early, before microalbuminuria develops, as substantial renal injury may already be present in the absence of proteinuria. We further advocate that the inhibition of the renin–angiotensin axis or of sodium–glucose co-transport likely permits the administration of a normal recommended or even high-protein diet, highly desirable for sarcopenic diabetic patients.

Comparison between outcomes of IgA nephropathy with nephrotic-range proteinuria and nephrotic syndrome: do podocytes play a role?

Background Nephrotic syndrome (NS) and nephrotic-range proteinuria (NRP) are uncommon in IgA nephropathy (IgAN), and their clinicopathology and prognosis have not been discussed. Podocytes may play an important role in both clinical phenotypes. Methods We investigated 119 biopsy-proven IgAN patients with proteinuria over 2 g/d. The patients were divided into three groups according to proteinuria level: the overt proteinuria (OP) group, NS group, and NRP group. In addition, according to the severity of foot process effacement (FPE), the patients were divided into three groups: the segmental FPE (SFPE) group, moderate FPE (MFPE) group, and diffuse FPE (DFPE) group. The outcome was survival from a combined event defined by a doubling of the baseline serum creatinine and a 50% reduction in eGFR or ESRD. Results Compared with the NRP group, patients in the NS group had more severe microscopic hematuria, presented with more severe endocapillary hypercellularity and had a higher percentage of DFPE. The Kaplan–Meier curve showed that MFPE patients had a better outcome in the NRP group <50% of tubular atrophy/interstitial fibrosis. In the multivariate model, the NRP group (HR = 17.098, 95% CI = 3.835–76.224) was associated with an increased risk of the combined event, while MFPE (HR = 0.260, 95% CI = 0.078–0.864; p = 0.028) was associated with a reduced risk of the combined event. After the addition of renin-angiotensin system inhibitors (RASi), the incidence of the combined event in the MFPE group (HR = 0.179, 95% CI = 0.047–0.689; p = 0.012) was further reduced. Conclusions NS presented more active lesions and more severe FPE in IgAN. NRP was an independent risk factor for progression to the renal endpoint, while MFPE indicated a better prognosis in NRP without obvious chronic renal lesions, which may benefit from RASi.

Short- and Long-Term Progression of Kidney Involvement in Systemic Lupus Erythematosus Patients with Low-Grade Proteinuria.

Lupus nephritis remains a common cause of morbidity and mortality in systemic lupus erythematosus (SLE). Current guidelines recommend performing a kidney biopsy at a urine protein-creatinine ratio of ≥0.5 g/g. However, cross-sectional studies reported a high prevalence of active histologic lupus nephritis lesions, and even chronic irreversible scarring, in patients with low-grade proteinuria. This study was initiated to assess disease progression in patients with SLE and low-grade proteinuria to identify risk factors for progression to overt proteinuria suggestive of clinical lupus nephritis. Patients with SLE who had an incident urinary protein-creatinine ratio of ≥0.2 and <0.5 g/g without known lupus nephritis were identified from the Einstein Rheumatic Disease Registry. Patients who developed a random urinary protein-creatinine ratio of ≥0.5 g/g with or without biopsy during the follow-up period were defined as "progressors." Patients who progressed to a urinary protein-creatinine ratio of ≥0.5 g/g within 2 years of developing a urinary protein-creatinine ratio of ≥0.2 and <0.5 g/g were defined as "fast progressors," a subgroup expected to benefit most from early biopsies and therapeutic interventions. Among 151 eligible patients with SLE and low-grade proteinuria at study entry, 76 (50%) progressed to a urinary protein-creatinine ratio of ≥0.5 g/g, of which 44 underwent a clinically indicated biopsy. The median (interquartile range) time from a urinary protein-creatinine ratio of ≥0.2 and <0.5 g/g to progression was 1.2 (0.3-3.0) years. Of the 20 biopsies performed in the first 2 years, 16 specimens showed active, treatable lupus nephritis. Low complement and shorter SLE duration at low-grade proteinuria onset were associated with progression to overt proteinuria across different analyses. Other associated factors included hypertension, diabetes mellitus, younger age, and the presence of hematuria. In this longitudinal cohort of patients with SLE and low-grade proteinuria at study entry, over half progressed to a urinary protein-creatinine ratio of ≥0.5 g/g in a short time period.

Chlorthalidone and Advanced Chronic Kidney Disease.

Chlorthalidone and Advanced Chronic Kidney Disease.

405-P: Glycemic Control Impacts Renal Function Decline among People with Type 1 Diabetes after the Onset of Diabetic Kidney Disease

While poor glycemic control increases the risk of diabetic kidney disease (DKD) , its impact on renal function decline among those with established DKD is unclear. To examine this, we tested the relationship between baseline HbA1c and renal outcomes in the 3-year Preventing Early Renal Loss (PERL) trial (n=530) , which included persons with type 1 diabetes (T1D) and early-to-moderate DKD (eGFR 40-100 ml/min/1.73m2 and persistent albuminuria and/or ongoing GFR decline) . In Cox regression models, baseline HbA1c was associated (p&amp;lt;0.0001) with a higher risk of progression to ESKD or serum creatinine doubling (HR 1.87 per HbA1c unit increment, 95% CI 1.42-2.47) , and in mixed-effects linear regression models, with 0.87 and 0.51 ml/min/1.73m2/year higher rates of estimated glomerular filtration rate (eGFR) and iohexol GFR decline (p&amp;lt;0.00for both) . Baseline albumin excretion rate (AER) was a modifier of the HbA1c-GFR slope relationships (p for interaction &amp;lt;0.05) , such that HbA1c was associated with a higher rate of GFR decline among those with AER≥200 μg/min than among those with AER&amp;lt;20 or 20≤AER&amp;lt;200 (Fig.1) . Thus, worse glycemic control in PERL was a major determinant of GFR decline and ESKD risk after DKD onset, especially in persons with overt proteinuria. Efforts to normalize HbA1c should continue among such persons. Disclosure H.Shah: None. J.B.Mcgill: Advisory Panel; Gilead Sciences, Inc., Lilly Diabetes, MannKind Corporation, Novo Nordisk A/S, Provention Bio, Inc., Salix Pharmaceuticals, Consultant; Bayer AG, Boehringer Ingelheim International GmbH, Research Support; Dexcom, Inc., Novo Nordisk. I.B.Hirsch: Consultant; Abbott Diabetes, Bigfoot Biomedical, Inc., GWave, Roche Diabetes Care, Research Support; Beta Bionics, Inc., Insulet Corporation, Medtronic. C.Wu: None. A.Galecki: None. M.Mauer: None. A.Doria: Research Support; Novo Nordisk Foundation. Perl consortium: n/a. Funding National Institutes of Health UC4DK101108Juvenile Diabetes Research Foundation 17-2012-377The Leona M. and Harry B. Helmsley Charitable Trust 2018PG-T1D014

PCSK9 and Cardiovascular Disease in Individuals with Moderately Decreased Kidney Function.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key regulator of lipid homeostasis. Studies investigating the association between PCSK9 and cardiovascular disease in large cohorts of patients with CKD are limited. The association of PCSK9 concentrations with prevalent and incident cardiovascular disease was investigated in 5138 White participants of the German Chronic Kidney Disease study with a median follow-up of 6.5 years. Inclusion criteria were eGFR of 30-60 or >60 ml/min per 1.73 m2 in the presence of overt proteinuria (urine albumin-creatinine ratio >300 mg/g or equivalent). Prevalent cardiovascular disease was defined as a history of nonfatal myocardial infarction, coronary artery bypass grafting, percutaneous transluminal coronary angioplasty, carotid arteries interventions, and stroke. Incident major adverse cardiovascular disease events included death from cardiovascular causes, acute nonfatal myocardial infarction, and nonfatal stroke. Median PCSK9 concentration in the cohort was 285 ng/ml (interquartile range, 231-346 ng/ml). There was no association between PCSK9 concentrations and baseline eGFR and albuminuria. With each 100-ng/ml increment of PCSK9, the odds for prevalent cardiovascular disease (n=1284) were 1.22-fold (95% confidence interval, 1.12 to 1.34; P<0.001) higher in a model with extended adjustment for major confounders. This association was stronger in nonstatin than statin users (P value for interaction =0.009). During follow-up, 474 individuals experienced a major adverse cardiovascular disease event, and participants in PCSK9 quartiles 2-4 had a 32%-47% higher risk compared with those in quartile 1 (P<0.05). Subgroup analysis revealed that this association was restricted to those participants who already had cardiovascular disease at baseline (all hazard ratios >1.75; P=0.01). In addition, PCSK9 showed a valuable gain in classification accuracy for both prevalent cardiovascular disease (net reclassification index =0.27; 95% confidence interval, 0.20 to 0.33) and incident major adverse cardiovascular disease events during follow-up (net reclassification index =0.10; 95% confidence interval, 0.01 to 0.21) when added to an extended adjustment model. Our findings reveal no relation of PCSK9 with baseline eGFR and albuminuria but a significant association between higher PCSK9 concentrations and risk of cardiovascular disease independent of traditional risk factors, including LDL cholesterol levels.Clinical Trial registry name and registration number: German Chronic Kidney Disease Study (GCKD), DRKS 00003971.

Risk factors for diabetic nephropathy among newly diagnosed type 2 diabetic patients with normal blood pressure

Background: Patients with type 2 diabetes mellitus (T2DM) pass through pre-diabetic stages and during diagnosis, half of them may have different complications including diabetic nephropathy. Hypertension has adverse impacts on diabetic nephropathy. We aimed to evaluate the risk factors for diabetic nephropathy among newly detected T2DM patients with normal blood pressure.&#x0D; Methods: A case-control study was done at a tertiary care hospital in Dhaka, Bangladesh from January 2018 to June 2019. Newly detected (&lt;3 months), adult ( ³18 years), T2DM patients, who underwent tests for urine albumin-to-creatinine ratio (UACR), at least twice, 6-weeks apart, were included in this study. Patients with hypertension, known kidney disease, features of glomerulonephritis, systemic diseases including systemic lupus erythematosus and vasculitis, history of recent fever and exercise, urinary tract infection and pregnancy were excluded. Patients with UACR ³30 mg/g in at least two samples were cases and those with UACR &lt;30 mg/g were controls.&#x0D; Results: Among the total 135 patients, 27 were cases [moderately increased proteinuria (previously, microalbuminuria) (UACR 30–299 mg/g) = 25 and severely increased proteinuria (previously, overt proteinuria) (UACR ³300 mg/g) = 2] and 108 were controls. Multivariate logistic regression revealed that family history of diabetes (OR=2.13; 95% CI, 1.412 to 4.216, p=0.003) and diabetic nephropathy (OR=3.31; 95% CI, 2.145 to 5.249, p=0.001), smoking (OR=3.11; 95% CI, 2.234 to 4.123, p=0.003), dyslipidaemia (OR=2.14; 95% CI, 1.363 to 3.324, p=0.005) and diabetic retinopathy (OR=6.23; 95% CI, 4.197 to 9.464, p=0.004) were significant risk factors.&#x0D; Conclusion: We concluded that, family history of diabetes and diabetic nephropathy, smoking, dyslipidaemia and diabetic retinopathy appeared as significant risk factors for diabetic nephropathy among newly diagnosed T2DM patients with normal blood pressure.&#x0D; BIRDEM Med J 2022; 12(2): 152-157

MO623: Risk Factors of Diabetic Nephropathy Among Newly Detected Type 2 Diabetic Subjects: Preliminary Report from A Tertiary Care Hospital of Bangladesh

Abstract BACKGROUND AND AIMS Patients with type 2 diabetes mellitus may present with different macro- and micro-vascular complications including diabetic nephropathy. This preliminary study was designed to evaluate the risk factors for diabetic nephropathy among type 2 diabetic patients at the time of diabetes diagnosis. METHOD A case-control study was done at a tertiary care hospital in Dhaka, Bangladesh from January to September 2017. Adult (≥18 years), type 2 diabetic patients, who were detected as diabetic for the first time within the previous 3 months and who tested, at least, two urine samples for urine albumin-to-creatinine ratio (UACR), at least 6 weeks apart, within a 6-month period, were consecutively enrolled for the study. Pregnant ladies, patients with diagnosed kidney disease, patients having features of glomerulonephritis and systemic diseases including systemic lupus erythematosus and vasculitis, history of recent fever, urinary tract infection and menstruation were excluded. Patients having UACR ≥30 mg/g in at least two (out of 3, if tested) samples were taken as cases and those with UACR &amp;lt;30 mg/g were taken as controls. Data were analyzed by statistical package for social sciences (SPSS) version 20. RESULTS Total patients were 224 with female predominance (150, 67%). Fifty one (22.8%) patients had diabetic nephropathy (microalbuminuria = 47 and overt proteinuria = 4). Multivariate regression analysis revealed that hypertension {odds ratio (OR) = 3.71 [95% confidence interval (CI) 1.23–4.31], P = 0.003}, smoking [OR = 3.27 (95% CI 2.91–4.79), P = 0.003], family history of diabetes [OR = 2.31 (95% CI 1.84–3.14), P = 0.005] and diabetic nephropathy [OR = 3.34 (95% CI 2.40–4.97), P = 0.001], dyslipidaemia [OR = 2.31 (95% CI 1.98–3.91), P = 0.023], increased body mass index (BMI) [OR = 2.11 (95% CI 1.54–4.87), P = 0.001] and high glycated haemoglobin (HbA1c) [OR 3.21 (95% CI 1.71–5.97), P = 0.034] were significant risk factors for diabetic nephropathy. CONCLUSION Almost 23% of type 2 diabetic patients had diabetic nephropathy during diabetes diagnosis in this study and most patients had microalbuminuria. Presence of hypertension, dyslipidaemia, smoking, family history of diabetes and diabetic nephropathy, increased BMI and high HbA1c were significant risk factors for diabetic nephropathy among patients with type 2 diabetes at diagnosis.

MO209: Baseline Characteristics of Adults Enrolled in the Ongoing Phase 3 Randomized, Double-Blind, Active-Control Trial of Sparsentan For the Treatment of Immunoglobulin A Nephropathy (PROTECT)

Abstract BACKGROUND AND AIMS Immunoglobulin A nephropathy (IgAN) is the most common glomerular disease worldwide. Despite optimized standard of care treatment, up to 40% of individuals with IgAN develop kidney failure requiring dialysis or kidney transplantation, consequently seriously affecting their quality of life and mortality. Treatments that reduce proteinuria and risk of kidney disease progression are urgently needed for IgAN. Sparsentan is a novel Dual Endothelin Angiotensin Receptor Antagonist (DEARA) being investigated for IgAN. The Phase 3 PROTECT study is examining the potential long-term antiproteinuric and nephroprotective potential and safety of sparsentan compared with an active control, angiotensin receptor blocker (ARB) irbesartan, in adults with IgAN. Here we report the baseline characteristics for all patients enrolled in the PROTECT trial. METHOD PROTECT is an ongoing, global, Phase 3, multicenter, randomized, double-blind, parallel-group, active controlled study designed to evaluate the efficacy and safety of sparsentan versus the active control irbesartan in adults with IgAN with overt proteinuria despite receiving maximized treatment with an angiotensin-converting enzyme inhibitor (ACEi) and/or ARB. The study duration is 270 weeks: a double-blind period of 114 weeks followed by an open-label extension period of up to 156 weeks. The primary efficacy endpoint is the change from baseline in urine protein/creatinine ratio (UP/C) based on a 24-h urine sample at Week 36. Key inclusion and exclusion criteria are shown in Table 1. Patients took their last dose of maximized standard-of-care treatment with ACEi and/or ARB therapy the day before randomization. Patients were randomized 1:1 to sparsentan or irbesartan (target dose 400 and 300 mg/day, respectively), stratified by screening eGFR and urine protein excretion values. The blinded and aggregated baseline characteristics of all the patients enrolled in the PROTECT trial are summarized descriptively. RESULTS A total of 406 patients from clinical sites in 18 countries, including sites in North America, Europe and Asia Pacific, were enrolled in PROTECT and 404 patients were included in the primary analysis population. Selected demographic and clinical characteristics are reported in Table 2. CONCLUSION PROTECT is the largest interventional trial testing a novel drug to date in IgAN. Patients with IgAN enrolled in the PROTECT trial display demographic and clinical characteristics consistent with those previously reported in the broader high-risk IgAN patient population. The presentation despite implementation of optimized standard of care treatment demonstrates the burden of IgAN and the unmet need for novel therapies in this patient population.

Augmented Urinary Excretion of Angiotensinogen Precedes Albuminuria in Human Young Adults with Overweight and Mice with High Fat Diet‐Induced Type 2 Diabetes

Obesity is linked to the development of hypertension and type 2 diabetes (T2D) and both causing chronic kidney disease (CKD). Increased body mass index (BMI) and high fat diet (HFD) contribute to activation systemic renin angiotensin system (RAS). In addition, activation of intrarenal and intratubular RAS has been associated with increased pressure (BP), CKD, and augmentation of urinary excretion of angiotensinogen (uAGT) during T2D. However, whether augmentation of uAGT reflect intrarenal/intratububular RAS activation in subjects with overweight, remains unclear. Here, we tested the hypothesis that increases in uAGT precedes renal dysfunction in mice and human subjects with overweight,MethodsC57BL/6 mice (N = 10) were fed either a normal fat diet (NFD) or HFD (45% Kcal from fat) for 28 weeks. During this period, metabolic phenotype along with urinary albumin, creatinine, reactive oxygen species (ROS) and AGT, were measured every 4 weeks. In addition, for evidence in humans (age 19‐22 years‐old), 11 individuals with overweight and 17 individuals with normal weight, were studied. In these subjects, anthropometric parameters, systolic and diastolic BP, fasting blood glucose (FBG), and urinary mRNA levels of AGT and kidney injury markers IL‐18 and connecting tissue growth factor, were determined. Patients with history of cardiac or cerebrovascular events and endocrine diseases, anti‐hypertensive treatment (ACE inhibitors, ARBs) and/or anti‐diabetic drugs, were excludedResultsIn mice with metabolic alterations overtime, systolic BP significantly increased after 18 weeks in HFD but not NFD mice. Intrarenal ROS increased in HFD mice. These changes paralleled the augmentation uAGT excretion, which occurred in the absence of overt albuminuria. In human subjects with overweight, systolic and diastolic BP, urinary transcripts levels of AGT, renin, and injury markers IL‐18 and CTGF were increased as compared to normal weight individuals. However, no significant changes were observed in proteinuria or albuminuria.ConclusionsOur results indicate that augmentation of uAGT precedes albuminuria in young human adults with overweight and mice during the development of HFD‐induced T2D. These findings emphasize the relevance of uAGT and indicator of intrarenal/intratubular RAS activations and its potential as early biomarker of kidney injury during metabolic diseases as obesity and diabetes.

Heart-Type Fatty Acid Binding Protein, Cardiovascular Outcomes, and Death: Findings From the German CKD Cohort Study

Heart-type fatty acid binding protein (H-FABP) is a biomarker that has been shown to provide long-term prognostic information in patients with coronary artery disease independently of high-sensitivity troponin T (hs-TNT). We examined the independent associations of H-FABP with cardiovascular outcomes in patients with chronic kidney disease (CKD). Prospective cohort study. 4,951 patients enrolled in the German Chronic Kidney Disease (GCKD) study with an estimated glomerular filtration rate of 30-60 mL/min/1.73 m2 or overt proteinuria (urinary albumin-creatinine ratio > 300 mg/g or equivalent). Serum levels of H-FABP and hs-TNT were measured at study entry. Noncardiovascular (non-CV) death, CV death, combined major adverse CV events (MACE), and hospitalization for congestive heart failure (CHF). Hazard ratios (HRs) for associations of H-FABP and hs-TNT with outcomes were estimated using Cox regression analyses adjusted for established risk factors. During a maximum follow-up of 6.5 years, 579 non-CV deaths, 190 CV deaths, 522 MACE, and 381 CHF hospitalizations were observed. In Cox regression analyses adjusted for established risk factors, H-FABP was associated with all 4 outcomes, albeit with lower HRs than those found for hs-TNT. After further adjustment for hs-TNT levels, H-FABP was found to be associated with non-CV death (HR, 1.57 [95% CI, 1.14-2.18]) and MACE (HR, 1.40 [95% CI, 1.02-1.92]) but with neither CV death (HR, 1.64 [95% CI, 0.90-2.99]) nor CHF hospitalizations (HR, 1.02 [95% CI, 0.70-1.49]). Single-point measurements of H-FABP and hs-TNT. Uncertain generalizability to non-European populations. In this large cohort of patients with CKD, H-FABP was associated with non-CV death and MACE, even after adjustment for hs-TNT. Whether measurement of H-FABP improves cardiovascular disease risk prediction in these patients warrants further studies.

POS-330 DIABETIC NEPHROPATHY, CLINICAL AND HISTOLOGIC SPECTRUM, A STUDY IN DHAKA

Diabetic nephropathy (DN) is a major complication of diabetes mellitus (DM) and one of the leading causes of end-stage kidney disease. The natural course of DN has traditionally been initial glomerular hyperperfusion followed by microalbuminuria, overt proteinuria, and eventually progressive renal dysfunction. In the present study, we tried to evaluate the histomorphological profiles of DN cases along with associated non-diabetic renal changes and correlation with clinical parameters.

POS-187 PROGNOSTIC ROLES OF URINARY TUBULAR INJURY MARKERS IN DIABETIC NEPHROPATHY

Tubular damage is common in the pathology of diabetic nephropathy (DN) and the severity of interstitial fibrosis and tubular atrophy associates with DN progression. Diabetic patients could have decreased kidney function without overt proteinuria, which highlighted the importance of tubular injury markers in DN management. However, the prognostic roles of urinary tubular injury markers are not well established. This retrospective study sought to correlate current clinically used urinary tubular injury markers with DN pathological features and renal outcomes.

Apolipoprotein A-IV concentrations and clinical outcomes in a large chronic kidney disease cohort: Results from the GCKD study.

BackgroundChronic kidney disease (CKD) represents a chronic proinflammatory state and is associated with very high cardiovascular risk. Apolipoprotein A‐IV (apoA‐IV) has antiatherogenic, antioxidative, anti‐inflammatory and antithrombotic properties and levels increase significantly during the course of CKD.ObjectivesWe aimed to investigate the association between apoA‐IV and all‐cause mortality and cardiovascular outcomes in the German Chronic Kidney Disease study.MethodsThis was a prospective cohort study including 5141 Caucasian patients with available apoA‐IV measurements and CKD. The majority of the patients had an estimated glomerular filtration rate (eGFR) of 30–60 ml/min/1.73m2 or an eGFR >60 ml/min/1.73m2 in the presence of overt proteinuria. Median follow‐up was 6.5 years. The association of apoA‐IV with comorbidities at baseline and endpoints during follow‐up was modelled adjusting for major confounders.ResultsMean apoA‐IV concentrations of the entire cohort were 28.9 ± 9.8 mg/dl. Patients in the highest apoA‐IV quartile had the lowest high‐sensitivity C‐reactive protein values despite the highest prevalence of diabetes, albuminuria and the lowest eGFR. Each 10 mg/dl higher apoA‐IV translated into lower odds of prevalent cardiovascular disease (1289 cases, odds ratio = 0.80, 95% confidence interval [CI] 0.72–0.86, p = 0.0000003). During follow‐up, each 10 mg/dl higher apoA‐IV was significantly associated with a lower risk for all‐cause mortality (600 cases, hazard ratio [HR] = 0.81, 95% CI 0.73–0.89, p = 0.00004), incident major adverse cardiovascular events (506 cases, HR = 0.88, 95% CI 0.79–0.99, p = 0.03) and death or hospitalizations due to heart failure (346 cases, HR = 0.84, 95% CI 0.73–0.96, p = 0.01).ConclusionsThese data support a link between elevated apoA‐IV concentrations and reduced inflammation in moderate CKD. ApoA‐IV appears to be an independent risk marker for reduced all‐cause mortality, cardiovascular events and heart failure in a large cohort of patients with CKD.

Association between Dyslipidemia and Diabetic Nephropathy in Type 2 Diabetic Patients: A Cross-Sectional Study

Introduction: Type 2 diabetes is a severe disease. It contains hormones that produce certain metabolic abnormalities and long-term problems. Urine contains low but abnormal levels of albumin which is the initial stage called “microalbuminuria”. Aim: To examine the association between dyslipidemia and diabetic nephropathy in type 2 diabetic patients. Methodology: Overall, 110 type 2 diabetic patients were involved in this study. Their detailed clinical history was evaluated along with clinical examination, urine albumin creatinine ratio, serum lipid profile. Data was analyzed using the Chi-square test and ANOVA test. It was done by the software EPICAL. A p-value less than 0.05 was considered significant.Study design: A cross-sectional study. Place and duration: This study was conducted at Bilawal Medical College for Boys at LUMHS Jamshoro Pakistan from June 2020 to June 2021. Results: A total of45 patients were having normoalbuminuria, 25 were having overt proteinuria, and the rest 40 patients had microalbuminuria. The most significant lipid abnormalities found in this study was increased LDL and increased triglyceride. Patients having Normoalbuminuria and overt proteinuria were compared and it was found that LDL and triglyceride had a positive correlation. As triglycerides increased, LDL also increased. Both had a p-value &lt;0.001. Conclusion: Lipid abnormalities associated with diabetic nephropathy were increased low-density lipoprotein (LDL) and triglyceride.

Super-Resolution Imaging of the Filtration Barrier Suggests a Role for Podocin R229Q in Genetic Predisposition to Glomerular Disease.

Diseases of the kidney's glomerular filtration barrier are a leading cause of end stage renal failure. Despite a growing understanding of genes involved in glomerular disorders in children, the vast majority of adult patients lack a clear genetic diagnosis. The protein podocin p.R229Q, which results from the most common missense variant in NPHS2, is enriched in cohorts of patients with FSGS. However, p.R229Q has been proposed to cause disease only when transassociated with specific additional genetic alterations, and population-based epidemiologic studies on its association with albuminuria yielded ambiguous results. To test whether podocin p.R229Q may also predispose to the complex disease pathogenesis in adults, we introduced the exact genetic alteration in mice using CRISPR/Cas9-based genome editing (PodR231Q ). We assessed the phenotype using super-resolution microscopy and albuminuria measurements and evaluated the stability of the mutant protein in cell culture experiments. Heterozygous PodR231Q/wild-type mice did not present any overt kidney disease or proteinuria. However, homozygous PodR231Q/R231Q mice developed increased levels of albuminuria with age, and super-resolution microscopy revealed preceding ultrastructural morphologic alterations that were recently linked to disease predisposition. When injected with nephrotoxic serum to induce glomerular injury, heterozygous PodR231Q/wild-type mice showed a more severe course of disease compared with Podwild-type/wild-type mice. Podocin protein levels were decreased in PodR231Q/wild-type and PodR231Q/R231Q mice as well as in human cultured podocytes expressing the podocinR231Q variant. Our in vitro experiments indicate an underlying increased proteasomal degradation. Our findings demonstrate that podocin R231Q exerts a pathogenic effect on its own, supporting the concept of podocin R229Q contributing to genetic predisposition in adult patients.

Biomarkers for early diagnosis of diabetic kidney disease: still a long way to go.

Biomarkers for early diagnosis of diabetic kidney disease: still a long way to go.

Mutation search within monogenic diabetes genes in Polish patients with long-term type 1 diabetes and preserved kidney function.

Some patients with type 1 diabetes (T1DM) are free from advanced complications despite long‑standing disease. These patients may be carriers of gene mutations responsible for maturity‑onset diabetes of the young and may have been misdiagnosed with T1DM. We aimed to determine the clinical characteristics of patients with long‑term T1DM, without advanced microvascular complications, and with well‑preserved kidney function. A search for mutations in monogenic diabetes genes was performed. Patients were recruited at 2 Polish university centers based on the following criteria: T1DM duration of 40 years or longer and absence of advanced complications defined as chronic kidney disease (estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2 ), overt proteinuria, blindness, and diabetic foot syndrome. Mutations in the 7 most frequent monogenic diabetes genes were identified using next‑generation sequencing. We enrolled 45 patients with T1DM (mean [SD] age at examination, 59.2 [8.0] years; mean [SD] age at T1DM diagnosis, 14.6 [6.7] years). Mean (SD) hemoglobin A1c levels were 7.6% (1.4%); daily insulin dose, 0.48 (0.17) U/kg; high‑density lipoprotein (HDL) cholesterol levels, 1.9 (0.6) mmol/l; body mass index (BMI), 26.4 (5.0) kg/m2 ; and eGFR, 82.2 (12.1) ml/min/1.73 m2 . Albuminuria and retinopathy were reported in 7 and 39 patients, respectively. We were not able to assign a causative role to any of 10 genetic variants identified by next‑generation sequencing in this cohort. Patients with long‑term T1DM and preserved kidney function have good glycemic control, elevated HDL cholesterol levels, low insulin requirements, near ‑normal BMI, and a rare occurrence of mutations in monogenic diabetes genes.

Telomere length and chronic kidney disease: cause or consequence?

Telomere length is considered as a clock mirroring aging and is influenced by oxidative stress and inflammation. Both conditions are highly prevalent in patients with chronic kidney disease and other degenerative disorders, such as cardiovascular disease. However, it is discussed controversially whether short telomeres are causally associated with chronic kidney disease or whether chronic kidney disease is contributing to an attrition of telomere length. Park etal., in this issue of Kidney International, use an extended 2-sample Mendelian randomization analysis with large data sets to shed new light on this research question.