Rapid Glomerular Filtration Rate Research Articles

Cardiovascular Autonomic Neuropathy and Risk of Kidney Function Decline in Type 1 and Type 2 Diabetes: Findings From the PERL and ACCORD Cohorts.

Previous studies have suggested that cardiovascular autonomic neuropathy (CAN) may predict rapid kidney function decline among persons with diabetes. We analyzed the association between baseline CAN and subsequent glomerular filtration rate (GFR) decline among individuals with type 1 diabetes (T1D) from the Preventing Early Renal Loss in Diabetes (PERL) study (N=469) and with type 2 diabetes (T2D) from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study (N=7,973). Baseline CAN was ascertained using ECG-derived heart rate variability indices. Its association with GFR slopes, rapid kidney function decline (GFR loss ≥-5 ml/min/1.73 m2/year), and ≥40% GFR loss was evaluated by linear mixed effect, logistic, and Cox regression, respectively. Participants with CAN experienced more rapid GFR decline, by an excess 1.15 (95%CI [-1.93, -0.37], P= 4.0x10-3) ml/min/1.73m2/year in PERL and 0.34 (95%CI [-0.49, -0.19], P= 6.3x10-6) ml/min/1.73m2/year in ACCORD. This translated in 2.11 (95% CI [1.23-3.63], P=6.9x10-3) and 1.39 (95% CI [1.20-1.61], P=1.1x10-5) odds ratios of rapid kidney function decline in PERL and ACCORD, respectively. Baseline CAN was also associated with a greater risk of ≥40% GFR loss events during follow-up (HR=2.60, 95%CI [1.15-5.45], p=0.02 in PERL and HR=1.54, 95%CI [1.28-1.84], P=3.8×10-6 in ACCORD). These associations remained significant after adjustment for potential confounders, including baseline GFR and albuminuria. Our findings indicate that CAN is a strong, independent predictor of rapid kidney function decline in both T1D and T2D. Further studies of the link between these two complications may help develop new therapies to prevent kidney function decline in patients with diabetes.

Independent risk factors of rapid glomerular filtration rate decline in patients with type 2 diabetes with preserved kidney function and normoalbuminuria: A multicenter cohort study.

Research on the incidence and underlying mechanisms of rapid renal function decline in patients with type 2 diabetes mellitus with preserved renal function and normoalbuminuria is limited. This study aimed to investigate the involvement of hemoglobin level as a risk factor for rapid decliners among patients with type 2 diabetes with preserved renal function and normoalbuminuria. This was a retrospective observational study of 242 patients with type 2 diabetes with a baseline estimated glomerular filtration rate of ≥60 mL/min/1.73 m2 and normoalbuminuria (<30 mg/gCr), followed up for >1 year. The annual rate of estimated glomerular filtration rate decline during the follow-up period was calculated using least square regression analysis; rapid decliners defined at ≥3.3%/year. Risk factors associated with rapid decliners were identified using a logistic regression analysis of variables previously identified as risk factors of rapid decliners. The median follow-up period was 6.7 years, and 34 patients showed rapid decliners. On multivariate analysis, lower baseline hemoglobin level was a risk factor of rapid decliners (odds ratio 0.69, 95% confidence interval 0.47-0.99; P = 0.045). Furthermore, the baseline hemoglobin levels were correlated positively with iron and ferritin levels, implying that an impaired iron metabolism might cause lower hemoglobin levels in rapid decliners. In patients with type 2 diabetes with preserved renal function and normoalbuminuria, lower hemoglobin levels were a risk factor for rapid decliners, where disturbed iron metabolism might precede the development of diabetic kidney disease.

Salt loading with unilateral nephrectomy accelerates decline in glomerular filtration rate in the hypertensive, obese, type 2 diabetic SDT fatty rat model of diabetic kidney disease.

For the evaluation of novel therapeutic agents for diabetic kidney disease (DKD), it is desirable to examine their efficacy in animal models by using the glomerular filtration rate (GFR) as an index. For this purpose, animal models that demonstrate a short-term GFR decline because of disease progression are required. Therefore, we aimed to develop such an animal model of DKD by using obese type 2 diabetic spontaneously diabetic Torii (SDT) fatty rats treated with salt loading by drinking water containing sodium chloride with or without unilateral nephrectomy. As a result, we have found that 0.3% salt loading with unilateral nephrectomy or 0.8% salt loading alone caused a rapid GFR decline, hypertension and rapid development of tubulointerstitial fibrosis. Moreover, the addition of losartan to a mixed diet suppressed the GFR decline in SDT fatty rats treated with 0.3% salt loading with unilateral nephrectomy. These results suggest that the model of SDT fatty rats treated with 0.3% salt loading and unilateral nephrectomy could be used as a hypertensive DKD model for evaluating therapeutic agents based on suppression of GFR decline.

401-P: Decline of Hemoglobin A1c in One Year Is Associated with Rapid GFR Decline in Patients with Type 2 Diabetes at Stage G1

Objective: Rapid glomerular filtration rate (GFR) decline, increased hemoglobin A1c (HbA1c) and hyperfiltration were risk factors for renal function decline. We aimed to explore the effect of HbA1c decline on short-term GFR decline in patients with type 2 diabetes (T2D).Methods: A total of 3920 patients were enrolled if they had 2-3 times HbA1c and eGFR test in 12 months. Of them, 16.7%, 29.4%, 12.5%, 14.1% and 27.3 had relatively stable (RS:- 3.49~3.49), rapid decline (RD:> - 10.00), modest decline (MD:- 10.00~3.50), modest increase (3.50~10.00) and rapidly increase (>10.00) of eGFR (mL/min/1.73 m2) respectively. The final analysis comprised 2295 patients in group RS, RD and MD.Results: Multinomial logistic regression analysis showed HbA1c decline of ≥-3.10% [OR:2.251 (95%CI: 1.316~3.850)], -3.00~-2.10% [OR: 1.962 (95%CI: 1.160~3.316)], -2.00~-1.10% [OR:1.592 (95%CI: 1.089~2.329)], stage G1 (eGFR≥90) [OR: 4.111 (95%CI: 3.043~5.552)] and stage A3 UACR [OR: 1.819 (95%CI: 1.070~3.093)] were major risk factors for GFR RD. No significant risk factors were found to be related with GFR MD (Table).Conclusions: High proportion of patients with T2D experienced short term eGFR RD or RI. Decline of HbA1c (≥-1.10%) and being at stage G1 or A3 were risk factors for eGFR RD. The eGFR accompanied by HbA1c decline may indicate the real renal function.View largeDownload slideView largeDownload slide DisclosureL. An: None. L. Ji: None.

Association of High-Density Lipoprotein Cholesterol With GFR Decline in a General Nondiabetic Population

IntroductionAlthough lower high-density lipoprotein cholesterol (HDL-C) levels are considered a risk factor for cardiovascular disease (CVD), experimental evidence suggest that aging, inflammation, and oxidative stress may remodel HDL-C, leading to dysfunctional HDL-C. Population studies on HDL-C and loss of the glomerular filtration rate (GFR) reported inconsistent results, but they used inaccurate estimates of the GFR and may have been confounded by comorbidity.MethodsWe investigated the association of HDL-C levels with risk of GFR loss in a general population cohort; the participants were aged 50–62 years and did not have diabetes, CVD, or chronic kidney disease (CKD) at baseline. The GFR was measured using iohexol-clearance at baseline (n=1627) and at the follow-up (n=1324) after a median of 5.6 years. We also investigated any possible effect modification by low-grade inflammation, physical activity, and sex.ResultsHigher HDL-C levels were associated with steeper GFR decline rates and increased risk of rapid GFR decline (>3 ml/min per 1.73 m2 per year) in multivariable adjusted linear mixed models and logistic regression (–0.64 ml/min per 1.73 m2 per year [95% CI –0.99, –0.29; P < 0.001] and odds ratio 2.7 [95% CI 1.4, 5.2; P < 0.001] per doubling in HDL-C). Effect modifications indicated a stronger association between high HDL-C and GFR loss in physically inactive persons, those with low-grade inflammation, and men.ConclusionHigher HDL-C levels were independently associated with accelerated GFR loss in a general middle-aged nondiabetic population.

Polycystic Renal Disease Presented by Anuria and Nephrolithiasis Associated Progressive Kidney Damage: A Case Report

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disease. Kidney stones develop in 20-30% of patients with ADPKD.Hydronephrosis, which is the most valuable radiological finding in the diagnosis of stone-related postrenal insufficiency, may be difficult to differentiate from common cysts in ADPKD patients. When kidney dysfunction develops in ADPKD patients, Glomerular Filtration Rate (GFR) loss reaches an average of 4.4 to 5.9 mL / min per year. Faster deterioration in these patients requires investigation for prerenal factors such as dehydration that triggers acute kidney damage or stone-related postrenal factors. In ADPKD, stone-related postrenal obstruction should be considered in rapid GFR losses despite negative ultrasound report for hydronephrosis as there is frequent occurrence of kidney stones and the difficulty in detecting hydronephrosis with ultrasonography (US) in these patients. Here, we present a case with ADPKD whose renal functions rapidly deteriorated while under chronic follow-up and renal function markers returned to the basal levels with the treatment of the underlying cause.

Estimated GFR Slope in Kidney Transplant Patients: When the Error Is Random.

The evaluation of renal function changes over time is crucial in day-to-day renal transplant care, and the slope of renal function is a major outcome in clinical trials. Little is known about the reliability of estimated glomerular filtration rate (eGFR) in reflecting real glomerular filtration rate (GFR) changes. We analyzed the variability of eGFR slope by 63 equations in estimating measured GFR (mGFR) changes in 110 renal transplant patients. The agreement between eGFR and mGFR slopes was evaluated by the concordance correlation coefficient and the limits of agreement. Patients were grouped based on mGFR slope in rapid GFR loss: faster than -3 mL/min/y; stable renal function: -3 to +3 mL/min/y; and improvement in GFR: higher than +3 mL/min/y. Concordance correlation coefficient averaged 0.36 and limits of agreement ±10 mL/min/y, indicating very poor agreement between eGFR and mGFR slopes. The eGFR slope classified patients into the same group of mGFR slope only in 25% of the cases. In about two-thirds of patients, the eGFR slope was either markedly faster or slower than the mGFR slope. In half of these cases, the discrepancy between mGFR and eGFR slopes was ≥50%. Formulas are neither accurate nor precise in reflecting real GFR decline in renal transplant patients, making them unreliable for clinical practice and trials.

Arteriolar hyalinosis is related to rapid GFR decline and long-standing GFR changes observed on renal biopsies in normo-microalbuminuric type 2 diabetic patients

Whether or not renal structural changes, especially arteriolar hyalinosis, are related to the rate of renal functional decline and increase in urinary albumin excretion (UAE) at the early stage of diabetic nephropathy in patients with type 2 diabetes is still unknown. Our previous study determined that arteriolar hyalinosis is an independent risk factor for low GFR. We sought to determine whether arteriolar hyalinosis is also a risk factor for rapidly progressive decline in GFR. We evaluated 22 type 2 diabetic patients with normo- or microalbuminuria who took part in the previous study, to clarify which renal histological factors were associated with changes in UAE and the glomerular filtration rate (GFR) during 11.0 ± 3.0 years of follow-up. Light and electron microscopy-based morphometric analyses were performed to quantitatively evaluate the glomerular and interstitial structural changes. In all 22 patients, the GFR was significantly decreased from baseline to follow-up, while the UAE did not change markedly between the 2 periods. After 11 ± 3 years of follow-up, the GFR was significantly lower in the rapid decliner group (annual rate of GFR decline ≥3.0%) than in the non-rapid decliner group (p = 0.017). The index of arteriolar hyalinosis (IAH) at baseline in the rapid decliners was significantly larger than in the non-rapid decliners (p = 0.015). The IAH showed a significant negative correlation with the GFR at follow-up (r = 0.50, p = 0.018) and the annual rate in the GFR decline (r = 0.47, p = 0.027) and significant positive correlations with UAE at follow-up (r = 0.46, p = 0.034) and the annual rate in the UAE increase (r = 0.57, p = 0.005). The GFR at follow-up in patients with IAH ≥2.0 was significantly decreased from baseline (p = 0.042) and significantly lower than that of the patients with IAH <2.0 (p = 0.026), which did not decrease significantly from baseline. The frequency of rapid decliners was larger in the IAH ≥2.0 than in the IAH <2.0 patients (p = 0.037). Aggravated arteriolar hyalinosis was a risk factor for a rapid GFR decline. This finding might reflect initial changes in early diabetic nephropathy.

Urinary excretion of epidermal growth factor and rapid loss of kidney function.

Lower urinary excretion of the kidney tubule-specific biomarker epidermal growth factor (uEGF) is associated with increased risk of renal function [glomerular filtration rate (GFR)] loss in diabetes and in patients with established chronic kidney disease (CKD). We investigated whether uEGF is associated with rapid GFR decline or incident CKD in the general population. Subjects without CKD or diabetes were recruited from the general population in Tromso, Norway [Renal Iohexol Clearance Survey (RENIS); N = 1249] and Groningen, the Netherlands [Prevention of REnal and Vascular END-stage disease (PREVEND); N = 4534], with a median follow-up of 5.6 and 7.4 years, respectively. GFR was measured by iohexol clearance in the RENIS and estimated using the CKD Epidemiology Collaboration creatinine-cystatin C equation in the PREVEND study. Rapid GFR decline was defined as an annual GFR loss >3.0 mL/min/1.73 m2 and in sensitivity analyses as subjects with the 10% steepest GFR slope within each cohort. Lower baseline uEGF excretion was associated with rapid GFR loss in both cohorts {RENIS, odds ratio [OR] per 1 μg/mmol lower uEGF 1.42 [95% confidence interval (CI) 1.06-1.91], P = 0.02; PREVEND, OR 1.29 [95% CI 1.10-1.53], P < 0.01}, adjusted for baseline GFR, albumin:creatinine ratio and conventional CKD risk factors. Similar results were obtained using the outcome of the 10% steepest GFR slope in each cohort. Lower uEGF levels were associated with incident CKD in the combined analysis of both cohorts. Lower uEGF levels are associated with increased risk of rapid GFR loss and incident CKD in the general population. This finding, together with previous findings in CKD and high-risk populations, supports that uEGF may serve as a broadly applicable biomarker representing the tubular component of the current glomerulus-centric clinical risk assessment system.

Different alterations of glomerular filtration rate and their association with uric acid in children and adolescents with type 1 diabetes or with overweight/obesity.

Hyperfiltration (HF) occurs early in diabetes or obesity (OB)-associated renal disease. Alterations of glomerular filtration rate (GFR) in childhood OB remain unclear. To compare the prevalence of GFR alterations and its association with uric acid in children and adolescents with type 1 diabetes (T1D) vs overweight (OW)/OB. Cross-sectional study of 29 youths (aged: 13 ± 2 years) with T1D (disease duration: 7 ± 3 years) and 165 with OW/OB (aged: 11 ± 3 years). Patients with an albumin-creatinine ratio >3.39 mg/mmol were excluded. GFR was estimated with creatinine-cystatin C Zappitelli equation. HF and low GFR were defined by a GFR > 135 and <90 mL/min.1.73 m2 , respectively. HF was higher in children with T1D vs OW/OB (28% vs 10%, P < .005). Children with OW/OB also showed a 10% of low GFR. In patients with T1D, HbA1c (β = .8, P < .001), and systolic blood pressure (β = 11.4, P < .005) were independent predictors of GFR (R2 = .65). In OW/OB, HF cases were almost limited to prepubertal children and low GFR to pubertal ones. GFR in OW/OB was associated with age (β = -2.2, P < .001), male sex (β = -11.6, P < .001), and uric acid (β = -.05, P < .001) in adjusted models (R2 = .33). GFR alterations were different between youths with T1D and with OW/OB. Higher uric acid, older age, and puberty were related to lower GFR values in OW/OB children. Longitudinal studies will determine if low GFR is consequence of a rapid GFR decline in pediatric patients with OW/OB.

MicroRNAs 1915–3p, 2861, and 4532 Are Associated with Long-Term Renal Function Decline in Type 1 Diabetes

To the Editor: Diabetic kidney disease (DKD)1 is the leading cause of end-stage renal disease worldwide (1). Microalbuminuria is the earliest indicator of DKD in diabetes mellitus (DM). Microalbuminuria is clinically sensitive but not specific to this disease, which in some patients progresses with rapid glomerular filtration rate (GFR) decline (2). Research on new urinary biomarkers had demonstrated the ability of microRNAs (miRNAs) to discriminate between individuals with DKD and either healthy or non-DKD individuals (3). In an article published in Clinical Chemistry , Cardenas-Gonzalez et al. identified miRNAs miR-1915-3p, miR-2861, and miR-4532 as novel urinary miRNA biomarkers in DKD (3). Despite validating the results in different DM cohorts, the study's cross-sectional design was unable to address causality or prediction of subsequent outcomes. To further evaluate the prognostic potential of these new biomarkers, we tested the correlation between the expression of the 3 miRNAs and long-term estimated GFR (eGFR) decline in a cohort of 113 individuals with type 1 diabetes (T1D) who were recruited from 2013 to 2017 at the Diabetes Outpatient Clinic, Hospital das Clinicas. At the time of recruitment, spot urine samples were collected in sterile RNase-free flasks, centrifuged for 10 min, 3000 g at 4 °C, and frozen at −80 °C without additives or protease inhibitors within 4 h from collection. Clinical and demographic data [sex, age, T1D duration, use of angiotensin-converting …

Arterial Stiffness Predicts Rapid Decline in Glomerular Filtration Rate Among Patients with High Cardiovascular Risks.

Aims: Arterial stiffness is known to be an important surrogate marker for atherosclerosis and predictor of peripheral vascular and cardiovascular (CV) disease. Whether high cardio-ankle vascular index (CAVI) is associated with the development of rapid glomerular filtration rate (GFR) decline remains uncertain. The study aimed to determine the relationship between CAVI and renal function progression among patients with high CV risk.Methods: This study employed a prospective cohort design with 1-year follow-up among patients with high CV risk. Arterial stiffness was measured using CAVI method. GFR was estimated using the chronic kidney disease (CKD) epidemiology collaboration equation, and rapid decline in GFR was defined with decrease in GFR ≥ 5 mL/min/1.73 m2 yearly.Results: Of 352 patients with mean age 67.8 ± 10.1 years, 224 patients (63.6%) were suspected to have arteriosclerosis (CAVI ≥ 9), and 208 patients (59.1%) had CKD (GFR < 60 mL/min/1.73 m2). Annual decline of GFR was −0.75 [interquartile range (IQR), −1.16 to 6.08] mL/min/1.73 m2/year, and 30.1% of patients experienced a rapid decline in GFR. Compared with normal CAVI (CAVI < 8), high CAVI (CAVI ≥ 9) and borderline CAVI (CAVI 8–8.9) in all subjects and subgroup of baseline GFR > 60 mL/min/1.73 m2 were associated with rapid GFR decline. Multivariable analysis showed that high CAVI and borderline CAVI were associated with 2.47-fold (95% CI, 0.89–6.84; P = 0.082) and 4.04-fold (95% CI, 1.46–11.18; P = 0.007) increased odds ratio of rapid GFR decline, respectively.Conclusion: Among patients with high risk of CV with or without CKD, high CAVI (cut point of ≥ 9) was independently associated with a rapid decline in GFR, suggesting that systemic vascular stiffness predicted a decrease in renal function in this population.

Preventing Early Renal Loss in Diabetes (PERL) Study: A Randomized Double-Blinded Trial of Allopurinol-Rationale, Design, and Baseline Data.

Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics. This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40-99.9 mL/min/1.73 m2, SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m2/year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period. Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m2, and historical eGFR slope -3.5 mL/min/1.73 m2/year. Compared with participants with albuminuria (n = 419), those with NDKF (n = 94) were significantly older (56 vs. 52 years), had lower HbA1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m2) and historical eGFR loss (-4.7 vs. -2.5 mL/min/1.73 m2/year). These differences persisted when comparing groups with similar rates of historical eGFR loss. PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity.

Urinary biomarkers of tubular injury to predict renal progression and end stage renal disease in type 2 diabetes mellitus with advanced nephropathy: A prospective cohort study

BackgroundNovel potential tubular biomarkers in diabetic nephropathy could improve risk stratification and prediction. The study aimed to evaluate the association of tubular damage markers with rapid renal progression and incidence of end stage renal disease (ESRD) in type 2 diabetes (T2DM). MethodsA prospective cohort study, involving a total of 257 patients with T2DM, was included. The baseline values of urine albumin, cystatin-C, angiotensinogen, kidney injury molecule-1 (KIM-1) and neutrophil-gelatinase associated lipocalin (NGAL) were measured. The composite outcomes included a rapid glomerular filtration rate (GFR) decline or incident of ESRD at 3-year follow-up. Main findingsThe composite outcomes were noted in 26.1%. Using univariate followed by multivariate COX proportional hazard regression analysis, the patients with highest quartiles of urine cystatin-C (HR 2.96, 95% CI, 1.38–6.35), urine angiotensinogen (HR 2.93, 95% CI, 1.40– 6.13) urine KIM-1 (HR 2.77, 95% CI, 1.27-6.05) and urine NGAL (HR 2.53, 95% CI, 1.11-5.76) were significantly associated with rapid renal progression when compared with the patients with the lowest quartiles of all tubular biomarkers. ConclusionsPatients with T2DM with high levels of baseline urine tubular biomarkers (cystatin-C, angiotensinogen, KIM-1 and NGAL) had a greater incidence of ESRD and rapid GFR decline.

Urinary epidermal growth factor, monocyte chemoattractant protein-1 or their ratio as predictors for rapid loss of renal function in type 2 diabetic patients with diabetic kidney disease

BackgroundIncreased monocyte chemoattractant protein-1 (MCP-1) and decreased epidermal growth factor (EGF) are promising biomarkers to predict progressive decline in kidney function in non-diabetic kidney diseases. We aimed to evaluate the performance of urinary EGF, MCP-1 or their ratio in predicting rapid decline of GFR in a cohort of Type 2 diabetic patients (T2DM) with diabetic kidney disease (DKD).MethodsT2DM patients (n = 83) with DKD at high risk for renal progression were followed up prospectively. The baseline urine values of MCP-1 to creatinine ratio (UMCP-1), EGF to creatinine ratio (UEGF), EGF to MCP-1 ratio (UEGF/MCP-1) and albumin to creatinine ratio (UACR) were measured. The primary outcome was a decline in estimated glomerular filtration rate (GFR) of ≥25% yearly from baseline.ResultsDuring follow-up time of 23 months, patients with rapid decline in estimated GFR of ≥25% yearly from baseline had significantly higher baseline levels of UMCP-1, and UACR and lower UEGF and UEGF/MCP-1 ratio. All renal biomarkers predicted primary outcomes with ROC (95%CI) for UMCP-1=0.73 (0.62-0.84), UEGF=0.68 (0.57-0.80), UEGF/MCP-1=0.74 (0.63-0.85), and UACR =0.84 (0.75-0.93). By univariate analysis, blood pressure, GFR, UACR, UMCP-1, UEGF, and UEGF/MCP-1 were associated with rapid decline GFR. By multivariate analysis, UACR, systolic blood pressure, and UMCP-1 or UEGF/MCP-1 were independently associated with rapid GFR decline.ConclusionsUMCP-1 or UEGF/MCP-1 ratio were associated with rapid renal progression independent from conventional risk factors in DKD.

Long-term prospective observation suggests that glomerular hyperfiltration is associated with rapid decline in renal filtration function: A multiethnic study.

Glomerular hyperfiltration usually occurs early in development of kidney complications in diabetes. To understand hyperfiltration as a marker of renal disease progression in type 2 diabetes mellitus, we aimed to examine association between glomerular hyperfiltration (estimated glomerular filtration rate ⩾ 120 mL/min/1.73 m2) and rapid renal decline (annual estimated glomerular filtration rate loss ⩾ 3 mL/min/1.73 m2). This was a prospective cohort comprising 1014 patients with type 2 diabetes mellitus attending a Diabetes Centre of a regional hospital in 2002-2014. A separate prospective cohort, comprising 491 patients who attended Diabetes Centre or primary-care polyclinics, was used for validation. We performed binary mediation analysis to examine role of hyperfiltration on relationship between baseline haemoglobin A1c and rapid renal decline. Among patients in discovery cohort, 5.2% had baseline hyperfiltration. Over mean follow-up of 6 years, 22.9% had rapid glomerular filtration rate decline. Baseline hyperfiltration was significantly associated with greater odds of rapid renal decline after adjusting for demographics, diabetes duration and clinical covariates (odds ratio: 2.57; 95% confidence interval: 1.21-5.46; p = 0.014). Similar finding was found in validation cohort (odds ratio: 2.98; 95% confidence interval: 1.06-8.42; p = 0.034). Hyperfiltration significantly accounted for 35.3% of association between increasing baseline haemoglobin A1c and rapid renal decline. Glomerular hyperfiltration is an independent risk factor of rapid renal decline. It mediates the association between increasing haemoglobin A1c and rapid renal decline.

Insulin Sensitivity and Diabetic Kidney Disease in Children and Adolescents With Type 2 Diabetes: An Observational Analysis of Data From the TODAY Clinical Trial

Diabetic kidney disease is a major cause of premature mortality in type 2 diabetes mellitus (T2DM). Worsening insulin sensitivity independent of glycemic control may contribute to the development of diabetic kidney disease. We investigated the longitudinal association of insulin sensitivity with hyperfiltration and increased albumin excretion in adolescents with T2DM. Observational prospective cohort study. 532 TODAY (Treatment Options for Type 2 Diabetes in Adolescents and Youth) participants aged 12 to 17 years with T2DM duration less than 2 years at baseline. The TODAY Study was a multicenter randomized clinical trial that examined the efficacy of 3 treatment regimens (metformin monotherapy, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention program) to achieve durable glycemic control. Natural log-transformed estimated insulin sensitivity (reciprocal of fasting insulin), hemoglobin A1c concentration, age, race-ethnicity, treatment group, body mass index, loss of glycemic control, and hypertension. Hyperfiltration was defined as 99th percentile or higher of estimated glomerular filtration rate (≥140mL/min/1.73m2) when referenced to healthy adolescents (NHANES 1999-2002) and albumin-creatinine ratio≥ 30μg/mg at 3 consecutive annual visits. Hyperfiltration was observed in 7.0% of participants at baseline and in 13.3% by 5 years, with a cumulative incidence of 5.0% over 5 years. The prevalence of increased albumin excretion was 6% at baseline and 18% by 5 years, with a cumulative incidence of 13.4%. There was an 8% increase in risk for hyperfiltration per 10% lower estimated insulin sensitivity in unadjusted and adjusted models (P=0.01). Increased albumin excretion was associated with hemoglobin A1c concentration, but not estimated insulin sensitivity. Longer follow-up is needed to capture the transition from hyperfiltration to rapid glomerular filtration rate decline in youth-onset T2DM. Lower estimated insulin sensitivity was associated with risk for hyperfiltration over time, whereas increased albumin excretion was associated with hyperglycemia in youth-onset T2DM.

Factors Related to the Progression of Sickle Cell Disease Nephropathy

BACKGROUNDAs life expectancy in sickle cell disease (SCD) has continued to increase, chronic diseases are playing a bigger role in morbidity and mortality in this population. SCD nephropathy is a known risk factor for early mortality, and risk of death increases with worsening glomerular filtration rate (GFR) (Elmariah et al. 2014; Platt et al. 1994). Glomerular ischemia, hyperfiltration, and hyposthenuria characterize the renal dysfunction found in SCD, but the natural history of and risk factors contributing to progression of disease remain unclear. Potential markers of SCD nephropathy, such as anemia severity, hemolytic rate, blood pressure (BP), and albuminuria, have been studied with varied conclusions (Aoki and Saad 1995; Asnani et al. 2016; Elmariah et al. 2014; Falk et al. 1992; Guasch et al. 2006; Gurkan et al. 2010). Our recent work also identified two variant alleles (“G1” and “G2”) of the APOL1 gene as risk factors for SCD nephropathy (Ashley-Koch et al. 2011). We sought to evaluate clinical, laboratory, and genetic predictors of SCD nephropathy progression in a longitudinal SCD cohort. METHODSWe performed a chart review of 280 adults (age ≥18 at enrollment) with SCD followed regularly at the Duke University Medical Center and enrolled in a previously well-described study (Elmariah et al. 2014). All outpatient laboratory data were collected using the data extraction tool DEDUCE (Duke Enterprise Data Unified Content Explorer), and descriptive data were collected at time of enrollment and at most recent outpatient follow-up. APOL1 variants were genotyped as previously described (Ashley-Koch et al. 2011). Estimated GFR was calculated using both the extended MDRD and the CKD-EPI equations (Levey et al. 1999; Levey et al. 2009). CKD and hyperfiltration were defined as GFR <60 and >130 mL/min/1.73 m2, respectively. Statistical analysis was performed using SAS (SAS Systems, Cary, NC). RESULTSMean age at enrollment was 33.3 years, and mean baseline GFR was 148.6 mL/min/1.73 m2 by MDRD and 127 mL/min/1.73 m2 by CKD-EPI (see Table 1 for baseline characteristics). Results from the two equations correlated well for GFRs in the low to normal range but diverged for GFRs over ~150 mL/min/1.73 m2, with MDRD producing a wider range (Fig. 1). Given the high prevalence of hyperfiltration in our cohort, we chose to perform further analyses using CKD-EPI. Baseline GFR was associated with baseline proteinuria (p<0.0001), hemoglobinuria (p<0.0001), Hb level (p=0.03), platelet count (p<0.0001), reticulocyte count (p=0.03), bilirubin (p<0.0001), systolic BP (p=0.0003), diastolic BP (p<0.0001), and the APOL1 G1 allele (p=0.02). To characterize the pattern of progression of SCD nephropathy, we then identified 183 subjects with at least 5 years of follow-up and ≥3 outpatient GFR measurements in order to calculate a rate of GFR decline. There were no statistically significant differences in baseline characteristics for the two cohorts (Table 1). The mean rate of GFR decline was 2.5 ± 5.6 mL/min/1.73 m2 per year, higher than the 1.27 mL/min/1.73 m2 estimated annual GFR decline in African Americans in the general population (Young et al. 2016).We then defined a composite outcome of SCD nephropathy as either rapid rate of GFR decline (>3 mL/min/1.73 m2 per year, (Peralta et al. 2013; Young et al. 2016)), or incident CKD during the follow-up period. Seventy-three subjects (40%) developed nephropathy as thus defined. Using multivariable logistic regression modeling, with baseline GFR as a covariate, we found that lower baseline Hb (p=0.008), baseline proteinuria (p=0.01), higher reticulocyte count (p=0.03), and higher LDH (p=0.02) were all positive predictors of nephropathy. Baseline hemoglobinuria, white blood cell count, platelet count, bilirubin, BP, BMI, and APOL1 variants did not predict nephropathy. Subjects with hyperfiltration physiology at baseline also did not have a higher incidence of nephropathy over 5 years of follow up. DISCUSSIONOur results highlight the rapid rate of GFR decline and the high prevalence of hyperfiltration in adults with SCD, while not showing a correlation between the two. Proteinuria and markers of a higher hemolytic rate, among other measures, were most predictive of a rapid GFR decline. Additional investigation into the longitudinal trajectory of SCD nephropathy and potential interventions targeted to slowing the rate of GFR decline may improve outcomes in SCD. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Adiponectin is associated with early diabetic kidney disease in adults with type 1 diabetes: A Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study

ObjectiveThe associations between elevated adiponectin and end-stage renal disease are well recognized and thought to be at least partially explained by reduced renal clearance. Conversely, the relationship between adiponectin and early diabetic kidney disease (DKD) with preserved glomerular filtration rate (GFR), including rapid GFR decline and incident chronic kidney disease (CKD) is unclear. We hypothesized that elevated adiponectin would be associated with early DKD in adults with type 1 diabetes. MethodsAdults with type 1 diabetes (n=646 at baseline, n=525 at 6years) had adiponectin and renal function by estimated GFR (eGFR) by CKD-EPI creatinine and albumin-excretion rate (AER) evaluated at baseline and 6years. Linear and logistic models evaluated the associations of baseline adiponectin with AER, macroalbuminuria (AER ≥200μg/min), eGFR, CKD (<60mL/min/1.73m2) and rapid GFR decline (>3mL/min/1.73m2/year). Models adjusted for age, sex, duration, HbA1c, SBP, LDL-C and current smoking. ResultsCompared to non-diabetics, adults with type 1 diabetes had significantly higher adiponectin, and the difference remained significant after adjusting for AER and/or eGFR (p<0.0001). Adiponectin at baseline was positively associated with rapid GFR decline (OR: 1.24, 95% CI 1.00–1.53), incident CKD (OR: 1.75, 1.14–2.70), and persistent macroalbuminuria and CKD (OR: 1.61, 1.10–2.36) over 6years in adjusted models. The associations also remained significant after further adjustments for CRP, estimated insulin sensitivity and ACEi/ARB therapy. ConclusionsAdults with type 1 diabetes have higher adiponectin than their non-diabetic peers, and elevated adiponectin at baseline is independently associated with greater odds of developing early DKD over 6years.

Rapid GFR decline is associated with renal hyperfiltration and impaired GFR in adults with Type 1 diabetes.

Rapid glomerular filtration rate (GFR) decline (>3 mL/min/1.73 m(2)) is an increasingly recognized high-risk diabetic nephropathy (DN) phenotype in Type 1 diabetes. Rapid GFR decline is a recognized predictor of impaired GFR (<60 mL/min/1.73 m(2)). However, the association between rapid GFR decline and renal hyperfiltration is not well described in Type 1 diabetes. We hypothesized that renal hyperfiltration (estimated glomerular filtration rate, eGFR ≥ 120 mL/min/1.73 m(2)) would predict rapid GFR decline over 6 years and that rapid GFR decline would predict impaired GFR at 6 years in adults with Type 1 diabetes. GFR was calculated by chronic kidney disease epidemiology (CKD-EPI) creatinine in 646 adults with Type 1 diabetes in the coronary artery calcification in Type 1 diabetes study. Logistic multivariable models were employed to investigate the relationships between renal hyperfiltration and rapid GFR decline, and rapid GFR decline and incident impaired GFR over 6 years. Renal hyperfiltration predicted greater odds of rapid GFR decline over 6 years [odds ratio (OR): 5.00, 95% confidence interval (CI): 3.03-8.25, P < 0.0001] adjusting for hemoglobin A1c (HbA1c), systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), sex, duration, log of albumin/creatinine ratio and estimated insulin sensitivity. Furthermore, rapid GFR decline predicted greater odds of incident impaired eGFR (OR: 15.99, 95% CI 2.34-114.37, P = 0.006) in a similarly adjusted model. Sensitivity analyses with GFR calculated by CKD-EPI combined creatinine and cystatin C, and renal hyperfiltration defined as ≥135 mL/min/1.73 m(2) yielded similar results. In adults with Type 1 diabetes, rapid GFR decline over 6 years was associated with baseline renal hyperfiltration and incident GFR impairment. These observations may suggest an intermediate and predictive role of rapid GFR decline in the progression of DN.