Clinical impact of albuminuria and glomerular filtration rate on renal and cardiovascular events,and all-cause mortality in Japanese patients with type 2 diabetes

Background

The number of patients suffering from diabetic nephropathy resulting in end-stage kidney disease is increasing worldwide. In clinical settings, there are limited data regarding the impact of the urinary albumin-to-creatinine ratio (UACR) and reduced estimated glomerular filtration rate (eGFR) on renal and cardiovascular outcomes and all-cause mortality.

Methods

We performed a historical cohort study of 4328 Japanese participants with type 2 diabetes from 10 centers. Risks for renal events (requirement for dialysis or transplantation, or half reduction in eGFR), cardiovascular events (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), and all-cause mortality were assessed according to UACR and eGFR levels.

Results

During follow-up (median 7.0 years, interquartile range 3.0–8.0 years), 419 renal events, 605 cardiovascular events and 236 deaths occurred. The UACR levels increased the risk and the adjusted hazard ratios for these three events. In addition to the effects of UACR levels, eGFR stages significantly increased the adjusted hazard ratios for renal events and all-cause mortality, especially in patients with macroalbuminuria. Diabetic nephropathy score, based on the prognostic factors, well predicted incidence rates per 1000 patient/year for each event.

Conclusions

Increased UACR levels were closely related to the increase in risks for renal, cardiovascular events and all-cause mortality in Japanese patients with type 2 diabetes, whereas the association between high levels of UACR and reduced eGFR was a strong predictor for renal events.     

Incidence of end-stage renal disease and risk factors for progression of renal dysfunction in Japanese patients with type 2 diabetes: the Fukuoka Diabetes Registry

Clinical and Experimental Nephrology - Epidemiological data regarding diabetic kidney disease are accumulated insufficiently in Japan. We prospectively investigated the incidence of end-stage renal...     

Evaluation of plasma cystatin C as a marker for glomerular filtration rate in patients with type 2 diabetes

AIM: To evaluate plasma cystatin C as a marker of the glomerular filtration rate in patients with type 2 diabetes and their age and sex-matched controls. MATERIALS AND METHODS: Forty-seven patients with one decade of type 2 diabetes and 51 non-diabetic control subjects were studied. Plasma cystatin C was measured by particle-enhanced turbidimetric immunoassay in a new application for the Hitachi 704 analyzer. For comparison, plasma creatinine and creatinine clearance were measured. The plasma clearance of 51Cr-EDTA by the single injection method was utilized as reference. RESULTS: In patients with type 2 diabetes the correlation coefficient between plasma cystatin C and the plasma clearance of 51Cr-EDTA was 0.774 (Spearman's coefficient) and that between plasma creatinine and the plasma clearance of 51Cr-EDTA was 0.556 (p = 0.001 for the difference). The correlation between creatinine clearance and the plasma clearance of 51Cr-EDTA was 0.411. In receiver operating characteristic (ROC) curve analysis the diagnostic accuracy of plasma cystatin C was significantly better than that of plasma creatinine (p = 0.047) or creatinine clearance (p = 0.001). The best diagnostic efficiency (98%) for cystatin C was obtained when the cut-off limit was set at 1.32 mg/l. In the control group the correlation coefficients were: between cystatin C and the plasma clearance of 51Cr-EDTA 0.627, between creatinine and the plasma clearance of 51Cr-EDTA 0.466 and between creatinine clearance and the plasma clearance of 51Cr-EDTA 0.416. The area under the ROC plot curve of cystatin C was also greatest in the control group, but the diagnostic accuracy of cystatin C was marginally better than that of either plasma creatinine (p = 0.05) or creatinine clearance (p = 0.08). Among the control subjects various non-renal causes may have interfered with cystatin C concentrations reducing the correlations. CONCLUSIONS: Cystatin C measurement is a more sensitive and specific test for GFR in patients with type 2 diabetes than plasma creatinine or its clearance, when GFR is normal or only slightly reduced. If an elevated cystatin C concentration is found, non-renal factors have to be excluded. The turbidimetric application described here can easily be applied for most clinical chemistry analyzers and is therefore useful in daily clinical practice.     

Estimated glomerular filtration rates are higher when creatinine-based equations are compared with a cystatin C-based equation in coronavirus disease 2019

Objectives

Estimations of glomerular filtration rate (eGFR) are based on analyses of creatinine and cystatin C, respectively. Coronavirus disease 2019 (COVID-19) patients in the intensive care unit (ICU) often have acute kidney injury (AKI) and are at increased risk of drug-induced kidney injury. The aim of this study was to compare creatinine-based eGFR equations to cystatin C-based eGFR in ICU patients with COVID-19.

Methods

After informed consent, we included 370 adult ICU patients with COVID-19. Creatinine and cystatin C were analyzed at admission to the ICU as part of the routine care. Creatinine-based eGFR (ml/min) was calculated using the following equations, developed in chronological order; the Cockcroft–Gault (C-G), Modified Diet in Renal Disease (MDRD)1999, MDRD 2006, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), and Lund–Malmö revised (LMR) equations, which were compared with eGFR calculated using the cystatin C-based Caucasian Asian Pediatric Adult (CAPA) equation.

Results

The median eGFR when determined by C-G was 99 ml/min and interquartile range (IQR: 67 ml/min). Corresponding estimations for MDRD1999 were 90 ml/min (IQR: 54); MDRD2006: 85 ml/min (IQR: 51); CKD-EPI: 91 ml/min (IQR: 47); and for LMR 83 ml/min (IQR: 41). eGFR was calculated using cystatin C and the CAPA equation value was 70 ml/min (IQR: 38). All differences between creatinine-based eGFR versus cystatin C-based eGFR were significant (p < .00001).

Conclusions

Estimation of GFR based on various analyses of creatinine are higher when compared with a cystatin C-based equation. The C-G equation had the worst performance and should not be used in combination with modern creatinine analysis methods for determination of drug dosage in COVID-19 patients.     

Non-invasive fibrosis assessments of non-alcoholic fatty liver disease associated with low estimated glomerular filtration rate among CKD patients: the Fukuoka Kidney disease Registry Study

Clinical and Experimental Nephrology - A growing body of evidence has shown that non-alcoholic fatty liver disease (NAFLD) is associated with chronic kidney disease (CKD). Non-invasive fibrosis...     

Effect of the interaction between estimated glomerular filtration rate and serum uric acid on all-cause and cardiovascular mortality in patients on peritoneal dialysis

Objective To explore the effect of the interaction between estimated glomerular filtration rate (eGFR) and serum uric acid (SUA) on all-cause and cardiovascular mortality in patients on peritoneal dialysis (PD). Methods Patients who performed PD catheterization at the PD center of the First Affiliated Hospital of Sun Yat-sen University and had initiated PD therapy for over 3 months from January 2006 to December 2016 were enrolled and followed up until December 2018. Demographic data, baseline clinical and laboratory examination results of the patients were collected. Kaplan-Meier survival curve and Cox regression analysis were used to explore the correlation between SUA and all-cause mortality, cardiovascular mortality in different eGFR groups of PD patients. Results A total of 2 124 PD patients were enrolled with age of (47.0±15.2) years, among whom 1 269 patients were male and 536 patients had diabetes. The SUA level was (429±96) μmol/L and the median level of eGFR was 6.69(5.17, 8.61) ml?min-1?(1.73 m2)-1. After a median follow-up time of 42 months, 554 patients died, among whom 275 patients were cardiovascular death. The Cox regression analysis revealed that there was a significant interaction between eGFR and SUA on all-cause mortality (P=0.043). The Kaplan-Meier curve showed that the tertile 1 (SUA＜384 μmol/L) and tertile 3 (SUA＞460 μmol/L) group had significantly higher all-cause mortality (P=0.009) than the reference group of tertile 2 (SUA 384-460 μmol/L) in the higher eGFR group [eGFR＞6.69 ml?min-1?(1.73 m2)-1]but not in the lower eGFR. After adjusting for relevant demographic data, complications, biochemical results and other variables, in patients with higher eGFR, the risk of all-cause mortality increased by 0.2% (HR=1.002, 95%CI 1.000-1.003, P=0.019) for every 1 μmol/L increase in SUA. In addition, compared with the tertile 2 reference group, the tertile 3 group was independently correlated with higher risk of all-cause mortality (HR=1.670, 95%CI 1.242-2.245, P=0.001). Conclusions The eGFR and SUA level significantly interacts with all-cause mortality, and the higher SUA level in higher eGFR group is an independent risk factor for all-cause mortality in PD patients.     

Comparison of different equations for estimated glomerular filtration rate in patients with chronic kidney disease

Objective To compare different equations for estimated glomerular filtration rate (eGFR) in patients with chronic kidney disease (CKD). Methods Hospitalized patients with CKD from the nephrology department of the First Affiliated Hospital of Nanjing Medical University (Jiangsu Province Hospital) were recruited between December 2014 and May 2015. The calculations of eGFR and 24 h creatinine clearance rate (Ccr) were accomplished in three days after admission. The eGFRs were calculated separately using the 24 h creatinine clearance rate adjusted by the standard body surface area (Ccr_BSA), Cockcroft-Gault equation adjusted by the standard body surface area (eCcr_BSA), CKD-EPI creatinine equation (EPI_Cr), CKD-EPI cystatin C equation (EPI_CysC), CKD-EPI creatinine-cystatin C equation (EPI_Cr_CysC), simplified MDRD (MDRD) and China MDRD equations. The EPI_Cr_CysC equation was used as the standard and the precision and accuracy of the other six equations were compared and analyzed. Results A total of 403 CKD participants were enrolled in the study, with 228 male patients and a mean age of (54.9±18.4) years. The main primary diseases were chronic glomerulonephritis (43.7%) and diabetic nephropathy (13.2%). The median concentration of serum creatinine and cystatin C were 117.5 (69.7, 242.4) μmol/L and 1.80 (1.13, 3.31) mg/L, respectively. The median values of Ccr_BSA, eCcr_BSA, MDRD, China MDRD, EPI_Cr, EPI_CysC and EPI_Cr_CysC equations were 50.8 (21.1, 96.2), 51.9 (23.3, 93.2), 53.6 (23.0, 97.4), 52.2 (22.4, 94.1), 53.2 (22.1, 97.3), 35.1 (15.4, 67.0) and 49.1 (22.8, 82.3) ml?min-1?(1.73 m2)-1, respectively. There was well agreement among MDRD, China MDRD and EPI_Cr equations, while there were large differences between equations derived from CysC (EPI_Cr_CysC and EPI_CysC) and equations derived only from creatinine (EPI_Cr, MDRD, China MDRD, eCcr_BSA, Ccr_BSA equations). Compared with EPI_Cr_CysC equation (the reference equation), EPI_Cr equation showed the highest accuracy [percentage of other eGFR equation calculations that were ＞30% of the reference equation calculations (1-P30), 30.8%] while Ccr_BSA equation showed the lowest (1-P30, 42.4%). EPI_CysC equation showed the highest precision [inter-quartile range (IQR) of the difference, 11.7 ml?min-1?(1.73 m2)-1] while Ccr_BSA equation showed the lowest [IQR of the difference, 22.8 ml?min-1?(1.73 m2)-1]. Conclusions The agreement among equations derived only from creatinine is better; while it exhibits some differences between equations with cystatin C and equations derived only from creatinine. The accuracy of EPI_Cr equation is second only to EPI_Cr_CysC equation and it is currently the most suitable eGFR equation for clinical popularization of renal glomerular function assessment.     

How to estimate kidney function in kidney transplant recipients with mild to moderate kidney impairment: comparison of estimated glomerular filtration (eGFR) values between creatinine-based GFR equations and cystatin C-based GFR equations for Japanese population

Background

With the recent increase in renal transplantations in Japan, accurate assessment of renal function is required.

Methods

This study included 73 patients who had undergone renal transplantation at Nagoya Daini Red Cross Hospital at least 6 months previously and had stable renal function for >3 months. Glomerular filtration rates (GFRs) were measured by inulin clearance (mGFR) and compared with estimated cystatin C-based GFRs (eGFRcys), estimated creatinine-based GFRs (eGFRcre) and their average values (eGFRave).

Results

mGFR was 43.3 ± 14.1 mL/min/1.73 m², eGFRcre was 39.6 ± 11.7, eGFRcys was 56.0 ± 17.1, and eGFRave was 47.8 ± 13.7 mL/min/1.73 m². Serum cystatin C was 1.39 ± 0.37 mg/L and serum creatinine was 1.58 ± 0.51 mg/dL. The correlation coefficients between mGFR and eGFRcre, eGFRcys, and eGFRave were 0.768, 0.831, and 0.841, respectively (P < 0.001, for all).The intraclass correlation coefficients were 0.754, 0.816, and 0.840, respectively (P < 0.001, for all).The mean differences between measured and estimated GFR values were 3.74 mL/min/1.73 m² with a root-mean square error (RMSE) of 9.06 for eGFRcre, +12.64 with RMSE of 9.48 for eGFRcys, and +4.45 with RMSE of 7.86 for eGFRave. Bland–Altman plots showed that eGFRcys overestimated GFR values compared with mGFR values in most cases and that eGFRave overestimated GFR values in 53 of 73 cases, whereas eGFRcre underestimated the values in 53 of 73 cases.

Conclusion

eGFRave may be the best marker to estimate kidney function in Japanese renal transplant recipients with mildly reduced or normal kidney function.     

Cystatin C,creatinine, estimated glomerular filtration,and long-term mortality in stroke patients

Renal dysfunction is associated with mortality in patients after ischemic stroke. Cystatin C is a potentially superior marker of renal function compared to creatinine and estimated glomerular filtration rate (GFR). In our observational cohort study, 390 Caucasian patients suffered from acute ischemic stroke (mean age 70.9 years; 183 women and 207 men) were included and prospectively followed up to maximal 56 months. Serum creatinine and cystatin C were measured at admission to the hospital; GFR was estimated according to CKD-EPI creatinine and CKD-EPI creatinine/cystatin equations. According to values of serum creatinine, estimated GFR and serum cystatin C patients were divided into quintiles. In the follow-up period, 191 (49%) patients died. For serum cystatin C and estimated GFR based on creatinine and cystatin C, the mortality and the hazard ratios for long-term mortality increased from the first to the fifth quintile nearly linearly. The associations of serum creatinine and estimated GFR categories based on creatinine with long-term mortality were J-shaped. As compared with lowest quintile of serum cystatin C, the fifth quintile was associated with long-term mortality significantly also after multivariate adjustment (age, gender, initial stroke severity, known risk factors for stroke mortality). In contrast, in adjusted analysis serum creatinine and estimated GFR (CKD-EPI creatinine and CKD-EPI creatinine/cystatin) were not associated with long-term mortality. In summary, serum cystatin C was independently and better associated with the risk of long-term mortality in patients suffering from ischemic stroke than were creatinine and estimated GFR using both CKD-EPI equations.     

Lower estimated glomerular filtration rate and higher albuminuria are associated with all-cause and cardiovascular mortality. A collaborative meta-analysis of high-risk population cohorts

Screening for chronic kidney disease is recommended in people at high risk, but data on the independent and combined associations of estimated glomerular filtration rate (eGFR) and albuminuria with all-cause and cardiovascular mortality are limited. To clarify this, we performed a collaborative meta-analysis of 10 cohorts with 266,975 patients selected because of increased risk for chronic kidney disease, defined as a history of hypertension, diabetes, or cardiovascular disease. Risk for all-cause mortality was not associated with eGFR between 60-105 ml/min per 1.73 m2, but increased at lower levels. Hazard ratios at eGFRs of 60, 45, and 15 ml/min per 1.73 m2 were 1.03, 1.38 and 3.11, respectively, compared to an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log risk for all-cause mortality without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 10, 30 and 300 mg/g were 1.08, 1.38, and 2.16, respectively compared to a ratio of five. Albuminuria and eGFR were multiplicatively associated with all-cause mortality, without evidence for interaction. Similar associations were observed for cardiovascular mortality. Findings in cohorts with dipstick data were generally comparable to those in cohorts measuring albumin-to-creatinine ratios. Thus, lower eGFR and higher albuminuria are risk factors for all-cause and cardiovascular mortality in high-risk populations, independent of each other and of cardiovascular risk factors.     

Left ventricular hypertrophy predicts the decline of glomerular filtration rate in patients with type 2 diabetes mellitus

Purpose

The heart and kidney are of utmost importance for the maintenance of cardiovascular (CV) homeostasis. The relationship between cardiac remodeling, especially the left ventricular hypertrophy (LVH) and renal damage reflected by the estimated glomerular filtration rate (eGFR), decline in type 2 diabetes mellitus (T2DM) patients is unclear. And it is also unknown whether cardiac remodeling can be used to assess the eGFR decline in T2DM patients.

Methods

We retrospectively analyzed the relationship between cardiac remodeling especially the LVH and the eGFR decline for 265 patients with T2DM, who were diagnosed between 2011 and 2015 and followed for ≥?3 months. The parameters of cardiac remodeling were determined using Doppler echocardiography.

Results

In the Cox regression model, the parameters of cardiac remodeling were associated with the composite endpoint in different models. These associations were independent of age, body mass index (BMI), history of hypertension, duration of diabetes, the baseline eGFR, 24-h urinary protein, or using angiotensin-converting enzyme inhibitors (ACEI) and (or) angiotensin receptor blockers (ARB). The risk of composite endpoint in patients with T2DM was higher (hazard ratio, 10.832; p?<?0.001 for trend) in the group with the highest number of abnormal echocardiographic parameters, than in the group with no abnormal echocardiographic parameters. In receiver operating characteristics (ROC) curve analyses, the parameter of left ventricular posterior wall (LVPW) thickness was superior to the other parameters of cardiac remodeling as represented by the higher area under the curve (AUC) values generated according to the sensitivity and specificity.

Conclusion

Echocardiographic parameters are strongly correlated with the eGFR decline in patients with T2DM. Moreover, the severity of cardiac remodeling, especially the LVH is closely associated with the eGFR decline in patients with T2DM. Therefore, the recognition of cardiac structural alterations in patients with T2DM may evaluate renal damage at an early stage.

     

Decline in estimated glomerular filtration rate is associated with risk of end-stage renal disease in type 2 diabetes with macroalbuminuria: an observational study from JDNCS

Background

There is increased interest in surrogate endpoints for clinical trials of chronic kidney disease.

Methods

In this nationwide observational study of 456 patients with type 2 diabetes and clinically suspected diabetic nephropathy followed for a median of 4.2 years, we evaluated the association between estimated glomerular filtration rate (eGFR) and albuminuria at baseline or during follow-up and risk of ESRD.

Results

Low eGFR (<60 mL/min/1.73 m²) and macroalbuminuria at enrollment were independently associated with risk of ESRD. In patients with macroalbuminuria, both ≤?50% change and ?50 to ?30% change in eGFR over 1 and 2 years were predictive of ESRD. The higher cut point (≥50% decline in eGFR) was more strongly predictive but less common. Remission of macroalbuminuria to normo-/microalbuminuria at 1 and 2 years was associated with a lower incidence of ESRD than no remission; however, it was not a determinant for ESRD independently of initial eGFR and initial protein-to-creatinine ratio.

Conclusion

These results suggest that a ≥30% decline in eGFR over 1 or 2 years adds prognostic information about risk for ESRD in patients with type 2 diabetes and macroalbuminuria, supporting the consideration of percentage decline in eGFR as a surrogate endpoint among macroalbuminuric cases in type 2 diabetes. On the other hand, our study suggests that additional analyses on the relationship between remission of macroalbuminuria and risk of ESRD are needed in type 2 diabetes.

     

Comparison of the predictability of serum creatinine-based surrogates of skeletal muscle mass for all-cause mortality in patients receiving hemodialysis: creatinine generation rate and creatinine index

Clinical and Experimental Nephrology -