Normoalbuminuric Chronic Kidney Disease Research Articles

Cardiovascular and Kidney Outcomes of Non-Diabetic CKD by Albuminuria Severity: Findings From the CRIC Study

The clinical trajectory of normoalbuminuric chronic kidney disease (CKD), particularly in the absence of diabetes, has not yet been well-studied. This study evaluated the association of kidney and cardiovascular outcomes with levels of albuminuria in a cohort of patients with nondiabetic CKD. Prospective cohort study. 1,463 adults with nondiabetic CKD without known glomerulonephritis and diagnosed with hypertensive nephrosclerosis or unknown cause of CKD participating in the Chronic Renal Insufficiency Cohort (CRIC) Study. Albuminuria stage at study entry. Primary outcome: Composite kidney (halving of estimated glomerular filtration rate [eGFR], kidney transplantation, or dialysis), Secondary outcomes: (1) eGFR slope, (2) composite cardiovascular disease events (hospitalization for heart failure, myocardial infarction, stroke, or all-cause death), (3) all-cause death. Linear mixed effects and Cox proportional hazards regression analyses. Lower levels of albuminuria were associated with female sex and older age. For the primary outcome, compared with normoalbuminuria, those with moderate and severe albuminuria had higher rates of kidney outcomes (adjusted hazard ratio [AHR], 3.3 [95% CI, 2.4-4.6], and AHR, 8.6 [95% CI, 6.0-12.0], respectively) and cardiovascular outcomes (AHR, 1.5 [95% CI, 1.2-1.9], and AHR, 1.5 [95% CI, 1.1-2.0], respectively). Those with normoalbuminuria (<30μg/mg; n=863) had a slower decline in eGFR (-0.46mL/min/1.73m2 per year) compared with those with moderate (30-300μg/mg, n=372; 1.41mL/min/1.73m2 per year) or severe albuminuria (>300μg/mg, n=274; 2.63mL/min/1.73m2 per year). In adjusted analyses, kidney outcomes occurred, on average, sooner among those with moderate (8.6 years) and severe (7.3 years) albuminuria compared with those with normoalbuminuria (9.3 years) whereas the average times to cardiovascular outcomes were similar across albuminuria groups (8.2, 8.1, and 8.6 years, respectively). Self-report of CKD etiology without confirmatory kidney biopsies; residual confounding. Participants with normoalbuminuric nondiabetic CKD experienced substantially slower CKD progression but only modestly lower cardiovascular risk than those with high levels of albuminuria. These findings inform the design of future studies investigating interventions among individuals with lower levels of albuminuria. Diabetes and hypertension are the leading causes of chronic kidney disease (CKD). Urine albumin levels are associated with cardiovascular and kidney disease outcomes among individuals with CKD. However, previous studies of long-term clinical outcomes in CKD largely included patients with diabetes. As well, few studies have evaluated long-term outcomes across different levels of urine albumin among people without diabetes. In this study, we found individuals with nondiabetic CKD and low urine albumin had much slower decline of kidney function but only a modestly lower risk of a cardiovascular events compared with those with high levels of urine albumin. Individuals with low urine albumin were much more likely to have a cardiovascular event than progression of their kidney disease. These findings inform the design of future studies investigating treatments among individuals with lower levels of albuminuria.

Early impact of albuminuria on cardiac function in patients with chronic kidney disease: a prospective study.

Cardiovascular disease (CVD) is the leading cause of end-stage mortality in chronic kidney disease (CKD) patients. However, CVD and CKD are inextricably linked, as microalbuminuria is an independent risk factor for CVD. Herein, we investigated changes in cardiac function and its risk factors in CKD patients who had different urine albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs). We prospectively enrolled 182 CKD patients, classified into three groups based on UACRs and eGFRs. Fifty healthy volunteers were included as controls. Changes in clinical and echocardiographic parameters were assessed in each group, and factors independently associated with strain parameters were further analyzed. Compared with those in the control group, the albuminuria but unimpaired renal function (ALB-CKD G1-2), albuminuria and impaired renal function (ALB-CKD G3), and normoalbuminuric CKD (NACKD) groups had decreased left ventricular (LV), right ventricular (RV), and left atrial (LA) strains, the LA contractile strain being the only statistically comparable parameter. Stepwise multiple linear regression analysis revealed varying factors independently correlating with the LV global longitudinal strain. The LA reservoir and conduit strains independently correlated with LV diastolic function in stage 3 CKD associated with comorbid albuminuria or normoalbuminuria. LV function was a partial determinant of LA and RV function in the ALB-CKD G3 group, whereas ventricular and atrial function were independent of each other in the ALB-CKD G1-2 and NACKD groups. Clinical intervention should focus on specific factors affecting cardiac function in patients to reduce the risk of CVD-related death.

An analysis of DPV and DIVE registry patients with chronic kidney disease according to the finerenone phase III clinical trial selection criteria

BackgroundThe FIDELIO-DKD and FIGARO-DKD randomized clinical trials (RCTs) showed finerenone, a novel non-steroidal mineralocorticoid receptor antagonist (MRA), reduced the risk of renal and cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Using RCT inclusion and exclusion criteria, we analyzed the RCT coverage for patients with T2DM and CKD in routine clinical practice in Germany.MethodsGerman patients from the DPV/DIVE registries who were ≥ 18 years, had T2DM and CKD (an estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2OR eGFR ≥ 60 mL/min/1.73m2 and albuminuria [≥ 30 mg/g]) were included. RCT inclusion and exclusion criteria were then applied, and the characteristics of the two populations compared.ResultsOverall, 65,168 patients with T2DM and CKD were identified from DPV/DIVE. Key findings were (1) Registry patients with CKD were older, less often male, and had a lower eGFR, but more were normoalbuminuric vs the RCTs. Cardiovascular disease burden was higher in the RCTs; diabetic neuropathy, lipid metabolism disorders, and peripheral arterial disease were more frequent in the registry. CKD-specific drugs (e.g., angiotensin-converting enzyme inhibitors [ACEi] and angiotensin receptor blocker [ARBs]) were used less often in clinical practice; (2) Due to the RCT’s albuminuric G1/2 to G4 CKD focus, they did not cover 28,147 (43.2%) normoalbuminuric registry patients, 4,519 (6.9%) albuminuric patients with eGFR < 25, and 6,565 (10.1%) patients with microalbuminuria but normal GFR (≥ 90 ml/min); 3) As RCTs required baseline ACEi or ARB treatment, the number of comparable registry patients was reduced to 28,359. Of these, only 12,322 (43.5%) registry patients fulfilled all trial inclusion and exclusion criteria. Registry patients that would have been eligible for the RCTs were more often male, had higher eGFR values, higher rates of albuminuria, more received metformin, and more SGLT-2 inhibitors than patients that would not be eligible.ConclusionsCertain patient subgroups, especially non-albuminuric CKD-patients, were not included in the RCTs. Although recommended by guidelines, there was an undertreatment of CKD-patients with renin-angiotensin system (RAS) blockers. Further research into patients with normoalbuminuric CKD and a wider prescription of RAS blocking agents for CKD patients in clinical practice appears warranted.

Epidemiological and Metabolic Aspects and Risk Factors of Chronic Kidney Disease in Comorbid Pathology of Type 2 Diabetes Mellitus and Primary Hypothyroidism

INTRODUCTION: The increasing number of patients with diabetes mellitus (DM) and chronic kidney disease (CKD) is one of the most pressing problems of modern medicine. In comorbid pathology a combination of type 2 DM and thyroid hypofunction the negative effect of hypothyroidism on carbohydrate metabolism, lipid metabolism, endothelial function, and glomerular filtration rate (GFR) is a risk factor for the formation and progression of diabetic nephropathy and CKD and requires further study.&#x0D; AIM: To identify risk factors and epidemiological peculiarities of CKD in type 2 DM in combination with thyroid hypofunction and to determine the possibility of using cystatin C levels for the evaluation of the kidney function in this pathology.&#x0D; MATERIALS AND METHODS: The prospective study involved 203 patients with type 2 DM undergoing inpatient treatment in the endocrinology department of the Ryazan Regional Clinical Hospital: group 1 (n = 76), type 2 DM combined with the primary hypothyroidism, and group 2 (n = 127), type 2 DM without thyroid pathology. Carbohydrate, lipid metabolism, albuminuria (AU), thyroid hormone spectrum, adipokines (leptin, plasminogen activator inhibitor-1, interleukin-6, and tumor necrosis factor-) were analyzed. The GFR was calculated using the CKD-EPI formula based on the levels of creatinine and cystatin C. Arterial pressure daily monitoring (APDM) was conducted, and intra-abdominal fat thickness was evaluated by ultrasonography.&#x0D; RESULTS: The incidence of kidney pathology in patients with type 2 DM was 52.22%. In group 1, there was a significant increase in the prevalence of CKD (64.47%, p = 0.006) and of normoalbuminuric CKD (NAU-CKD, 32.89%; p = 0.010). The risk of CKD development in patients with concomitant PH was more than twice that in patients without thyroid pathology with an odds ratio of 2.229 (95% confidence interval (CI) 1.2414.003) and that for NAU-CKD was 2.474 (95% CI 1.2674.833). Significant impairment of several metabolic parameters and individual APDM parameters was revealed in group 1 in comparison with group 2. The dependence of AU and GFR on the body mass index and of AU on the intra-abdominal fat thickness was noted. A negative relationship between GFR and leptin was revealed; in group 1, a correlation of interleukin-6 and thyrotropic hormone was found (r = 0.809, p = 0.001). With concomitant PH, cystatin C values were lower, and the GFR (CKD-EPI-cys) was reliably higher.&#x0D; CONCLUSION: Hypothyroidism is a risk factor for CKD development including NAU-CKD in type 2 DM. Obesity and hormonal activities of the intra-abdominal fatty tissue facilitate AU progression and GFR reduction. The use of cystatin C as a marker of the filtration function of the kidney in patients with hypothyroidism may lead to the underestimation of kidney function; thus, further investigation is required.

Prevalence of normoalbuminuric chronic kidney disease among individuals with type 2 diabetes mellitus from India.

A subset of diabetic individuals are known to develop progressive renal insufficiency without albuminuria, referred to as normoalbuminuric chronic kidney disease (NACKD). There is, however, a paucity of studies regarding this condition in India. So, this study, aimed to find the prevalence of normoalbuminuric renal dysfunction and its clinical associations in diabetic Indian population. Medical record search of patients with type 2 diabetes mellitus at a tertiary care centre was done. Based on the urinary albumin:creatinine ratio (>30 mg/g creatinine) and estimated glomerular filtration rate (e-GFR) (<60 ml/min/1.73m2), individuals were classified as having, (i) no kidney disease (NKD), (ii) chronic kidney disease (CKD), (iii) albuminuria alone (ALB), (iv) normoalbuminuric low e-GFR (NACKD) and (v) albuminuria with low e-GFR albuminuric CKD (ACKD). Furthermore, the clinical and biochemical parameters of these groups were also compared. Data from 3534 diabetes patients with a mean age of 53.8±10.9 yr and mean duration of diabetes of 10.3±7.5 yr were available for the analysis. NACKD constituted 39.1 per cent of the patients with reduced e-GFR, NACKD was found in 2.1 per cent and ACKD in 3.4 per cent of all diabetic patients. Compared to NKD patients, was found an independent association between NACKD and higher age, male sex, lower body weight and statin intake but not with glycated haemoglobin, fasting and postprandial plasma glucose. Patients with NACKD were found to be older than those with ACKD. Retinopathy was found to be more prevalent in the ACKD patients, whereas the rates of macrovascular complications were found to be similar between the groups. The prevalence of NACKD relative to ACKD decreased in CKD stages 3b, 4 and 5. The results of this study suggest that NACKD constituted greater than one third of patients with diabetes and decreased e-GFR, which showed a strong association with age but not with duration or severity of hyperglycaemia or the presence of retinopathy. Both NACKD and ACKD showed similar associations with macrovascular disease.

Clinical and laboratory characteristics of the patterns of chronic kidney disease in patients with type 2 diabetes

BACKGROUND: A growing body of evidence demonstrates increasing prevalence of normoalbuminuric chronic kidney disease (NA-CKD) in subjects with type 2 diabetes (T2D), while proportion of albuminuric pattern is decreasing.&#x0D; AIMS: To determine the clinical and laboratory parameters associated with different patterns of CKD in patients with T2D.&#x0D; METHODS: This observational, single-center, cross-sectional study included 360 patients with T2D duration 10 years. Patients with urinary albumin/creatinine ratio (UACR) 3 mg/mmol and estimated glomerular filtration rate (eGFR) 60 ml/min/1.73 m2 were classified as no-CKD group (n=89). Patients with UACR 3 mg/mmol and eGFR 60 ml/min/1.73 m2 formed NA-CKD group (n=111). Individuals with eGFR 60 ml/min/1.73 m2 and UACR mg/mmol 3 were recorded as albuminuric with preserved renal function (A-CKD, n=87). Patients with eGFR 60 ml/min/1.73 m2 and UACR mg/mmol 3 mg/mmol were considered as albuminuric CKD group (A-CKD+, n=73). Urinary nephrin and podocin, the podocyte injury markers, and whey acidic protein four-disulfide core domain protein 2 (WFDC-2), a marker of tubulointerstitial involvement, was assessed by ELISA and compared to control (20 non-diabetic subjects).&#x0D; RESULTS: Age 65 years (p=0.0001), duration of T2D 15 years (p=0.0009), female sex (p=0.04), and therapy with diuretics (p=0.0005) were found as risk factors for NA-CKD. The risk factors for A-CKD were male sex (p=0.01), smoking (p=0.01), waist-to-hip ratio 1 (p=0.01) and HbA1c levels 8% (p=0.005). The duration of T2D 15 years (p=0.01) and the use of dihydropyridine calcium channel blockers (p=0.01) were associated with A-CKD+. In T2D groups, the urinary excretion of nephrin and podocin was increased (all p0.001), more markedly in albuminuric individuals (p0.01 vs. NA-CKD). WFDC-2 excretion was increased in men from all diabetic groups (p0.05) and in women with decreased eGFR only (p0.05 vs. the control and NA-CKD).&#x0D; CONCLUSIONS: The CKD patterns in T2D are heterogeneous according to their clinical and laboratory characteristics. The changes in the excretion of nephrin and podocin indicate the association of albuminuric patterns with podocyte injury. A decrease in eGFR in women with T2D is associated with an increase in urinary excretion of WFDC-2, tubulointerstitial fibrosis marker.

Synergistic interaction of hypertension and diabetes on chronic kidney disease: Insights from the National Health and Nutrition Examination Survey 1999–2006

BackgroundHypertension and diabetes mellitus are 2 major risk factors for chronic kidney disease (CKD). However, whether hypertension and diabetes have a synergistic interaction towards greater renal damage remains unclear. Our study aimed to investigate whether hypertension and diabetes act synergistically towards CKD. Methods13,693 subjects from the cross-sectional National Health and Nutritional Examination Survey 1999–2006 were included in our analyses. The associations were investigated by multivariate logistic regression models. The interaction was evaluated on both additive and multiplicative scale. ResultsThe prevalence of CKD was 17.62%. After adjustment, subjects with both hypertension and diabetes had a 4.710 (3.652–6.073) times risk of CKD than non-hypertensive non-diabetic subjects, higher than that of subjects with only hypertension or diabetes (1.732, 95% CI: 1.502–1.997 and 2.407, 95% CI: 1.815–3.194, respectively). Furthermore, significant interaction was observed between hypertension and diabetes towards CKD in the additive scale (relative excess risk due to interaction: 1.570, 95% CI: 0.507–2.633; the attributable proportion due to interaction: 0.333, 95% CI: 0.168–0.499; Synergy index: 1.734, 95% CI: 1.239–2.426). Additionally, analyses of the associations with components of the primary endpoint demonstrated that the interaction was also applicable to those with reduced eGFR, albuminuria or normoalbuminuric CKD. ConclusionsThe joint effect of hypertension and diabetes was significantly larger than the sum of their independent impact on CKD. Our findings may provide intuitionistic and straightforward illustrations for the public to understand the danger of combined hypertension and diabetes on the renal injury.

Clinical and biochemical characteristics and the association of angiotensin type 1 receptor with normoalbuminuric chronic kidney disease among South Indian type 2 diabetes population

The aim of the study was to determine the clinical and biochemical characteristics especially cystatin C and the association of angiotensin type I receptor (AT1R) gene polymorphism with normoalbuminuric chronic kidney disease (NACKD) among South Indian type 2 diabetes (T2DM) population. The study comprised of 308 (M:F 190:118) subjects with T2DM categorized into three groups. Group I: T2DM patients without albuminuria (NA) and estimated glomerular filtration rate (eGFR) > 90 ml/min/1.73m2 (n = 110); group II: T2DM patients with albuminuric chronic kidney disease (CKD) with eGFR < 60 ml/min/1.73m2 (n = 98); and group III: T2DM patients with normoalbuminuric CKD (NACKD) and eGFR < 60 ml/min/1.73m2 (n = 100). The eGFR was estimated using the Modification of Diet in Renal Disease (MDRD) formula. Cystatin C was measured by particle-enhanced immunoturbidimetric assay. AT1R gene polymorphism was analyzed using the PCR-RFLP method. The biochemical parameters urea, creatinine, post prandial glucose, HbA1c, triglycerides, cystatin C levels, erythrocyte sedimentation rate (ESR), and diastolic blood pressure were lower and the levels of calcium were higher in normoalbuminuric CKD subjects as compared to albuminuric CKD subjects. The AT1R genotypic distribution of AA, AC, and CC was 80.2%, 19.8%, and 0% in NACKD, and 95.1%, 4.9%, and 0% in CKD subjects. The distribution of allelic frequencies of A and C allele in NACKD was 90.1% and 9.9%, and in CKD, it was 97.6% and 2.4% respectively. The relative risk of AC (p = 0.08) genotype and C (p = 0.01) allele in NACKD was 4 times higher as compared to CKD. The present study highlighted that the clinical and biochemical parameters showed significant differences especially cystatin C whose levels increased in normoalbuminuric CKD subjects as compared to normoalbuminuric subjects. Significant association of AGTR1 A1166C polymorphism was observed in normoalbuminuric CKD subjects as compared to CKD subjects with T2DM.

Normoalbuminuric chronic kidney disease in diabetes

Urinary albumin excretion (UAE) is widely used in clinical practice as indicator of diabetic kidney disease. According to the classical concept of the natural course of diabetic nephropathy, an increase in UAE usually precedes a decline in renal function. Meanwhile, a growing body of evidences indicates a high prevalence of normoalbuminuric chronic kidney disease (NA-CKD) in diabetic subjects, especially among patients with type 2 diabetes. An increase in NA-CKD prevalence can be results of improved glucose, blood pressure, and lipid control, widespread use of renin-angiotensin system blockers, and smoking cessation. It was shown that NA-CKD is more prevalent among women and is associated with arterial hypertension and coronary artery disease. The renal structure in subjects with NA-CKD is more heterogeneous when compared to patients with increased albuminuria, wherein interstitial changes and arteriolosclerosis could be the principal morphological findings, while signs of glomerulopathy may be absent. The prognostic value of NA-CKD needs to be clarified. It was shown that NA-CKD increases the risk of myocardial infarction, stroke and cardiovascular death in patients with diabetes. The search for alternative diagnostic markers for detecting of diabetic kidney disease in the absence of albuminuria, is of practical importance. The evaluations of the markers of tubular damage and interstitial fibrosis, as well as proteomic approaches, are considered as perspective diagnostic and prognostic options in NA-CKD. The study of pathogenesis, pathology, clinical course of NA-CKD in diabetic patients, as well as the development of more specific diagnostic and treatment options is a challenge for future research.

Risk of Progression of Nonalbuminuric CKD to End-Stage Kidney Disease in People With Diabetes: The CRIC (Chronic Renal Insufficiency Cohort) Study

Reduced glomerular filtration rate (GFR) in the absence of albuminuria is a common manifestation of chronic kidney disease (CKD) indiabetes. However, the frequency with which itprogresses to end-stage kidney disease (ESKD) isunknown. Multicenter prospective cohort study. We included 1,908 participants with diabetes and reduced GFR enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study in the United States. Urinary albumin and protein excretion. Incident ESKD, CKD progression (ESKD or≥50% reduction in estimated GFR [eGFR] from baseline), and annual rate of decline in kidney function. ESKD was ascertained by self-report and by linkage to the US Renal Data System. We used Cox proportional hazards modeling to estimate the association of albuminuria and proteinuria with incident ESKD or CKD progression and linear mixed-effects models to assess differences in eGFR slopes among those with and without albuminuria. Mean eGFR at baseline was 41.2mL/min/1.73m2. Normal or mildly increased 24-hour urinary albumin excretion (<30mg/d) at baseline was present in 28% of participants, but in only 5% of those progressing to ESKD. For those with baseline normal or mildly increased albuminuria, moderately increased albuminuria (albumin excretion, 30-299mg/d), and 2 levels of severely increased albuminuria (albumin excretion, 300-999 and≥1,000mg/d): crude rates of ESKD were 7.4, 34.8, 78.7, and 178.7 per 1,000 person-years, respectively; CKD progression rates were 17.0, 61.4, 130.5, and 295.1 per 1,000 person-years, respectively; and annual rates of eGFR decline were-0.17,-1.35,-2.74, and-4.69mL/min/1.73m2, respectively. We were unable to compare the results with healthy controls. In people with diabetes with reduced eGFRs, the absence of albuminuria or proteinuria is common and carries a much lowerrisk for ESKD, CKD progression, or rapid decline in eGFR compared with those with albuminuria or proteinuria. The rate of eGFR decline in normoalbuminuric CKD was similar to that reported for the general diabetic population.

Normoalbuminuric chronic kidney disease in diabetes.

Urinary albumin excretion (UAE) is widely used in clinical practice as indicator of diabetic kidney disease. According to the classical concept of the natural course of diabetic nephropathy, an increase in UAE usually precedes a decline in renal function. Meanwhile, a growing body of evidences indicates a high prevalence of normoalbuminuric chronic kidney disease (NA-CKD) in diabetic subjects, especially among patients with type 2 diabetes. An increase in NA-CKD prevalence can be results of improved glucose, blood pressure, and lipid control, widespread use of renin-angiotensin system blockers, and smoking cessation. It was shown that NA-CKD is more prevalent among women and is associated with arterial hypertension and coronary artery disease. The renal structure in subjects with NA-CKD is more heterogeneous when compared to patients with increased albuminuria, wherein interstitial changes and arteriolosclerosis could be the principal morphological findings, while signs of glomerulopathy may be absent. The prognostic value of NA-CKD needs to be clarified. It was shown that NA-CKD increases the risk of myocardial infarction, stroke and cardiovascular death in patients with diabetes. The search for alternative diagnostic markers for detecting of diabetic kidney disease in the absence of albuminuria, is of practical importance. The evaluations of the markers of tubular damage and interstitial fibrosis, as well as proteomic approaches, are considered as perspective diagnostic and prognostic options in NA-CKD. The study of pathogenesis, pathology, clinical course of NA-CKD in diabetic patients, as well as the development of more specific diagnostic and treatment options is a challenge for future research.