A New Modified CKD-EPI Equation for Chinese Patients with Type 2 Diabetes

Objective

To improve the performance of glomerular filtration rate (GFR) estimating equation in Chinese type 2 diabetic patients by modification of the CKD-EPI equation.

Design and patients

A total of 1196 subjects were enrolled. Measured GFR was calibrated to the dual plasma sample ^99mTc-DTPA-GFR. GFRs estimated by the re-expressed 4-variable MDRD equation, the CKD-EPI equation and the Asian modified CKD-EPI equation were compared in 351 diabetic/non-diabetic pairs. And a new modified CKD-EPI equation was reconstructed in a total of 589 type 2 diabetic patients.

Results

In terms of both precision and accuracy, GFR estimating equations all achieved better results in the non-diabetic cohort comparing with those in the type 2 diabetic cohort (30% accuracy, P≤0.01 for all comparisons). In the validation data set, the new modified equation showed less bias (median difference, 2.3 ml/min/1.73 m² for the new modified equation vs. ranged from −3.8 to −7.9 ml/min/1.73 m² for the other 3 equations [P<0.001 for all comparisons]), as was precision (IQR of the difference, 24.5 ml/min/1.73 m² vs. ranged from 27.3 to 30.7 ml/min/1.73 m²), leading to a greater accuracy (30% accuracy, 71.4% vs. 55.2% for the re-expressed 4 variable MDRD equation and 61.0% for the Asian modified CKD-EPI equation [P = 0.001 and P = 0.02]).

Conclusion

A new modified CKD-EPI equation for type 2 diabetic patients was developed and validated. The new modified equation improves the performance of GFR estimation.     

Chronic Kidney Disease and Diabetic Retinopathy in Patients with Type 2 Diabetes

Purpose

To explore the relationship between chronic kidney disease (CKD) and diabetic retinopathy (DR) in a representative population of type 2 diabetes mellitus (DM2) patients in Catalonia (Spain).

Methods

This was a population-based, cross-sectional study. A total of 28,344 patients diagnosed with DM2 who had recorded ophthalmologic and renal functional examinations were evaluated. Data were obtained from a primary healthcare electronic database of medical records. CKD was defined as an estimated glomerular filtration ratio (eGFR) of <60 ml/min/1.73m² and/or urine albumin to creatinine ratio (UACR) ≥30 mg/g. DR was categorized as non-vision threatening diabetic retinopathy and vision threatening diabetic retinopathy.

Results

CKD was associated with a higher rate of DR [OR], 95% confidence interval [CI], 1.5 (1.4–1.7). When we analyzed the association between different levels of UACR and DR prevalence observed that DR prevalence rose with the increase of UACR levels, and this association was significant from UACR values ≥10 mg/g, and increased considerably with UACR values ≥300mg/g (Odds ratio [OR], 95% confidence interval [CI], 2.0 (1.6–2.5). This association was lower in patients with eGFR levels 44 to 30 mL/min/1.73m² [OR], 95% confidence interval [CI], 1.3 (1.1–1.6).

Conclusions

These results show that CKD, high UACR and/or low eGFR, appear to be associated with DR in this DM2 population.     

PCSK9 Plasma Concentrations Are Independent of GFR and Do Not Predict Cardiovascular Events in Patients with Decreased GFR

Background

Impaired renal function causes dyslipidemia that contributes to elevated cardiovascular risk in patients with chronic kidney disease (CKD). The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a regulator of the LDL receptor and plasma cholesterol concentrations. Its relationship to kidney function and cardiovascular events in patients with reduced glomerular filtration rate (GFR) has not been explored.

Methods

Lipid parameters including PCSK9 were measured in two independent cohorts. CARE FOR HOMe (Cardiovascular and Renal Outcome in CKD 2–4 Patients—The Forth Homburg evaluation) enrolled 443 patients with reduced GFR (between 90 and 15 ml/min/1.73 m²) referred for nephrological care that were prospectively followed for the occurrence of a composite cardiovascular endpoint. As a replication cohort, PCSK9 was quantitated in 1450 patients with GFR between 90 and 15 ml/min/1.73 m² enrolled in the Ludwigshafen Risk and Cardiovascular Health Study (LURIC) that were prospectively followed for cardiovascular deaths.

Results

PCSK9 concentrations did not correlate with baseline GFR (CARE FOR HOMe: r = -0.034; p = 0.479; LURIC: r = -0.017; p = 0.512). 91 patients in CARE FOR HOMe and 335 patients in LURIC reached an endpoint during a median follow-up of 3.0 [1.8–4.1] years and 10.0 [7.3–10.6] years, respectively. Kaplan-Meier analyses showed that PCSK9 concentrations did not predict cardiovascular events in either cohort [CARE FOR HOMe (p = 0.622); LURIC (p = 0.729)]. Sensitivity analyses according to statin intake yielded similar results.

Conclusion

In two well characterized independent cohort studies, PCSK9 plasma levels did not correlate with kidney function. Furthermore, PCSK9 plasma concentrations were not associated with cardiovascular events in patients with reduced renal function.     

Mortality Prediction in the Oldest Old with Five Different Equations to Estimate Glomerular Filtration Rate: The Health and Anemia Population-based Study

Background

Kidney function declines considerably with age, but little is known about its clinical significance in the oldest-old.

Objectives

To study the association between reduced glomerular filtration rate (GFR) estimated according to five equations with mortality in the oldest-old.

Design

Prospective population-based study.

Setting

Municipality of Biella, Piedmont, Italy.

Participants

700 subjects aged 85 and older participating in the “Health and Anemia” Study in 2007–2008.

Measurements

GFR was estimated using five creatinine-based equations: the Cockcroft-Gault (C-G), Modification of Diet in Renal Disease (MDRD), MAYO Clinic, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Berlin Initiative Study-1 (BIS-1). Survival analysis was used to study mortality in subjects with reduced eGFR (<60 mL/min/1.73m²) compared to subjects with eGFR ≥60 mL/min/1.73m².

Results

Prevalence of reduced GFR was 90.7% with the C-G, 48.1% with MDRD, 23.3% with MAYO, 53.6% with CKD-EPI and 84.4% with BIS-1. After adjustment for confounders, two-year mortality was significantly increased in subjects with reduced eGFR using BIS-1 and C-G equations (adjusted HRs: 2.88 and 3.30, respectively). Five-year mortality was significantly increased in subjects with eGFR <60 mL/min/1.73m² using MAYO, CKD-EPI and, in a graduated fashion in reduced eGFR categories, MDRD. After 5 years, oldest old with an eGFR <30 mL/min/1.73m² showed a significantly higher risk of death whichever equation was used (adjusted HRs between 2.04 and 2.70).

Conclusion

In the oldest old, prevalence of reduced eGFR varies noticeably depending on the equation used. In this population, risk of mortality was significantly higher for reduced GFR estimated with the BIS-1 and C-G equations over the short term. Though after five years the MDRD appeared on the whole a more consistent predictor, differences in mortality prediction among equations over the long term were less apparent. Noteworthy, subjects with a severely reduced GFR were consistently at higher risk of death regardless of the equation used to estimate GFR.     

Clinical Impact of Kidney Function on Presepsin Levels

Objective

Presepsin is highlighted as a diagnostic and prognostic marker of sepsis. Little information is available regarding the accurate association between presepsin levels and the degree of kidney function. We analyzed presepsin levels in patients with a glomerular filtration rate (GFR) in the categories G1 to G5, evaluated via inulin renal clearance test, and receiving hemodialysis (HD).

Methods

Patients who were not receiving HD were included if they had undergone inulin renal clearance measurements for the accurate measurement of GFR (measured GFR), and patients who were receiving hemodialysis (HD) were included if they had anuria. Exclusion criteria were infection, cancer, liver disease, autoimmune disorders, or steroid or immunosuppressant use. GFR category was defined as follows; G1: GFR ≥ 90 ml/min/1.73m², G2: GFR = 60 to 90 ml/min/1.73m², G3: GFR = 30 to 60 ml/min/1.73m², G4: GFR = 15 to 30 ml/min/1.73m², G5: GFR ≤ 15 ml/min/1.73m².

Results

Seventy-one patients were included. The median (IQR) presepsin values of patients in each GFR category were as follows: G1 + G2: 69.8 (60.8–85.9) pg/ml; G3: 107.0 (68.7–150.0) pg/ml; G4: 171.0 (117.0–200.0) pg/ml; G5: 251.0 (213.0–297.5) pg/ml; and HD: 1160.0 (1070.0–1400.0) pg/ml. The log-transformed presepsin values, excluding patients receiving HD, inversely correlated with the measured GFR (Pearson’s correlation coefficient = -0.687, P < 0.001). The multivariate analysis revealed that measured GFR and hemoglobin levels significantly correlated with elevated presepsin levels.

Conclusion

Presepsin levels were markedly high in patients receiving HD, similar to values seen in patients with severe sepsis or septic shock. In patients who were not receiving HD, presepsin levels increased as GFR decreased. Thus, the evaluation of presepsin levels in patients with chronic kidney disease requires further consideration, and a different cutoff value is needed for diagnosing sepsis in such patients.     

Adherence with Dosing Guideline in Patients with Impaired Renal Function at Hospital Discharge

Objectives

To determine the prevalence, determinants, and potential clinical relevance of adherence with the Dutch dosing guideline in patients with impaired renal function at hospital discharge.

Design

Retrospective cohort study between January 2007 and July 2011.

Setting

Academic teaching hospital in the Netherlands.

Subjects

Patients with an estimated glomerular filtration rate (eGFR) between 10-50 ml/min/1.73m² at discharge and prescribed one or more medicines of which the dose is renal function dependent.

Main Outcome Measures

The prevalence of adherence with the Dutch renal dosing guideline was investigated, and the influence of possible determinants, such as reporting the eGFR and severity of renal impairment (severe: eGFR<30 and moderate: eGFR 30-50 ml/min/1.73m²). Furthermore, the potential clinical relevance of non-adherence was assessed.

Results

1327 patients were included, mean age 67 years, mean eGFR 38 ml/min/1.73m². Adherence with the guideline was present in 53.9% (n=715) of patients. Reporting the eGFR, which was incorporated since April 2009, resulted in more adherence with the guideline: 50.7% vs. 57.0%, RR 1.12 (95% CI 1.02-1.25). Adherence was less in patients with severe renal impairment (46.0%), compared to patients with moderate renal impairment (58.1%, RR 0.79; 95% CI 0.70-0.89). 71.4% of the cases of non-adherence had the potential to cause moderate to severe harm.

Conclusion

Required dosage adjustments in case of impaired renal function are often not performed at hospital discharge, which may cause harm to the majority of patients. Reporting the eGFR can be a small and simple first step to improve adherence with dosing guidelines.     

Long-Term Follow-Up of Proteinuria and Estimated Glomerular Filtration Rate in HIV-Infected Patients with Tubular Proteinuria

Objective

The objective of this prospective observational study was to describe the evolution of tubular proteinuria detected in HIV-infected patients, and to evaluate the impact of tenofovir disoproxil fumarate (TDF) discontinuation.

Methods

Proteinuria and estimated glomerular filtration rate (eGFR) were followed during a median duration of 32 months, in 81 HIV-infected patients with tubular proteinuria and eGFR ≥ 60 ml/min/1.73 m² (determined using the Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration equation). Tubular proteinuria was defined by urine protein to creatinine ratio (uPCR) ≥200 mg/g and albumin to protein ratio (uAPR) <0.4.

Results

Twenty per cent of patients had persistence of tubular proteinuria: TDF continuation was the main factor associated with this persistence [OR 9.0; 95%CI: 1.9–41.4; p = 0.01]. Among the 23 patients who discontinued TDF, uPCR returned below the threshold of 200 mg/g in 11 patients. Overall, eGFR decreased with a mean rate of decline of 3.8 ml/min/1.73m²/year. The decline in eGFR was lesser after discontinuation of TDF (5.8 ml/min/1.73m²/year during TDF exposure versus 3 ml/min/1.73m²/year after TDF discontinuation; p = 0.01).

Conclusions

The continuation of TDF was the main factor associated with the persistence of proteinuria. Moreover, proteinuria was normalized in only half of the patients who discontinued TDF. The clinical significance of TDF-related low level of proteinuria as a factor associated with renal disease progression and bone loss remains poorly understood.     

Low Ankle-Brachial Index Is Associated with Early-Stage Chronic Kidney Disease in Type 2 Diabetic Patients Independent of Albuminuria

Aims

The role of low ankle-brachial index (ABI) in early-stage chronic kidney disease (CKD) is not fully known. This study was designed to investigate the prevalence of low ABI in early-stage CKD defined as an estimated glomerular filtration rate (eGFR) between 60–89 ml/min/1.73 m² of type 2 diabetic patients without albuminuria and to determine the association between the low ABI and mildly decreased eGFR.

Methods

The cross-sectional study enrolled 448 type 2 diabetic patients with normoalbuminuria. The patients were stratified into two groups according to the CKD-EPI eGFR level: the normal group with eGFR level ≥90 mL/min/1.73 m² and the lower group with eGFR of 60–89. ABI was categorized as normal (1.0–1.39), low-normal (0.9–0.99), and low (<0.9). Both stepwise forward multiple linear regression and binary logistic regression analyses were performed to examine the association between ABI categories and eGFR levels and to assess the relation of low ABI and early-stage CKD.

Results

The prevalence of low ABI in early-stage CKD of type 2 diabetic patients without albuminuria was 39.5%. Low ABI was associated with an approximate 3-fold greater risk of early-stage CKD in bivariate logistic regression analysis, and remained significantly associated with a 2.2 fold risk (95% confidence interval: 1.188–4.077; P = 0.012) after adjusting traditional chronic kidney disease risk factors.

Conclusions

There was a high prevalence of low ABI in early-stage CKD patients of type 2 diabetes with normoalbuminuria and a close relation between low ABI and early-stage CKD, suggesting that we should pay much more attention to the patients who have only mildly decreased eGFR and normoalbuminuria but have already had a low ABI in clinic work and consider the preventive therapy in early stage.     

Imaging Features of Pulmonary CT in Type 2 Diabetic Patients with Multidrug-Resistant Tuberculosis

Background

Until now, radiographic manifestations of multidrug-resistant pulmonary tuberculosis (MDR- TB) in patients with diabetes mellitus (DM) have not been reported. We conducted a study to investigate the imaging features of pulmonary computed tomography (CT) for type 2 diabetic (T2DM) patients with MDR-TB.

Methods

The clinical data and pulmonary CT findings of 39 type 2 diabetic patients with MDR-TB, 46 type 2 diabetic patients with drug-susceptible tuberculosis (DS-TB), and 72 pure drug-susceptible TB cases (without T2DM and MDR) treated at Dalian Tuberculosis Hospital from 2012 to 2015 were collected, and the clinical features and imaging differences of the three groups were compared.

Results

The clinical characteristics of the three groups of patients were not significantly different except with respect to age and previous treatment history. However, on imaging, the patients with MDR-TB showed consolidation in and above the pulmonary segments was significantly more extensive than that seen in the DS-TB group with or without T2DM.

Conclusion

Consolidation in or above multiple pulmonary segments with multiple mouth-eaten cavities and bronchial damage on pulmonary CT images in type 2 diabetic patients with tuberculosis suggests the possibility of multi-drug resistance.     

Investigating Sources of Heterogeneity in Randomized Controlled Trials of the Effects of Pharmacist Interventions on Glycemic Control in Type 2 Diabetic Patients: A Systematic Review and Meta-Analysis

Objective

To assess the effect of pharmacist interventions on glycemic control in type 2 diabetic patients and to examine factors that could explain the variation across studies.

Methods

A comprehensive literature search was performed in PubMed, Scopus, and LILACS databases for randomized controlled trials (RCTs) published up to July 2015. The search strategy included the use of MeSH terms or text words related to pharmacist interventions, type 2 diabetes, and randomized controlled trials. RCTs published in English, Portuguese, or Spanish that evaluated the effect of pharmacist intervention on glycemic control in type 2 diabetic outpatients were included. Two independent authors executed study selection, data extraction, and risk of bias assessment. Mean differences in glycosylated hemoglobin (HbA1c) were estimated using random-effect models, and heterogeneity was evaluated by subgroup and meta-regression analyses.

Results

The literature search yielded 963 records of potential interest, of which 30 were included in the systematic review and 22 in the meta-analysis. Most of these RCTs were conducted in the United States in patients in outpatient clinics using face-to-face contact only. All RCTs performed patient education, and most executed the medication review. The appraised sample showed uncertain or high risk of bias in most of the items evaluated, resulting in low-quality studies. In comparison with usual care, pharmacist interventions were associated with significant reductions in HbA1c levels (-8.5% [95% CI: -1.06, -0.65]; P < 0.0001; I² = 67.3%). Subgroup analysis indicated differences of heterogeneity by country, baseline HbA1c levels, setting, intervention frequency, and random allocation. Age and HbA1c levels partly explained the variability across studies by meta-regression.

Conclusions

Our findings confirmed that pharmacist interventions improve glycemic control in patients with type 2 diabetes compared with usual care and suggest that younger patients or with higher baseline HbA1c levels may be the main beneficiaries of pharmacist care.

Protocol PROSPERO Registration Number

CRD42014007457     

Plasma Lipoprotein(a) Levels Are Associated with Mild Renal Impairment in Type 2 Diabetics Independent of Albuminuria

Background

CKD, an independent risk factor for CV disease, increases mortality in T2DM. Treating modifiable CV risk factors decreases mortality in diabetics with microalbuminuria, but the role of early CV prevention in diabetics with mild CKD by GFR criteria alone remains unclear. The purpose of this study was to probe whether T2DM patients with mild GFR impairment have atherogenic lipid profiles compared to diabetic counterparts with normal renal function.

Methods

In the Penn Diabetes Heart Study (PDHS), a single-center observational cohort of T2DM patients without clinical CVD, cross-sectional analyses were performed for directly measured lipid fractions in 1852 subjects with eGFR>60 mL/min/1.73 m² determined by the CKD-EPI equation (n = 1852). Unadjusted and multivariable analyses of eGFR association with log-transformed lipid parameters in incremental linear and logistic regression models (with eGFR 90 mL/min/1.73 m² as a cut-point) were performed.

Results

Mild GFR impairment (eGFR 60–90 mL/min/1.73 m², median urinary ACR 5.25 mg/g) was associated with higher log-transformed Lp(a) values (OR 1.17, p = 0.005) and with clinically atherogenic Lp(a) levels above 30 mg/dL (OR 1.35, p = 0.013) even after full adjustment for demographics, medications, metabolic parameters, and albuminuria. Logistic regression demonstrated a trend towards significance between worse kidney function and apoB (p = 0.17) as well as apoC-III (p = 0.067) in the fully adjusted model.

Conclusions

Elevated Lp(a) levels have a robust association with mild GFR impairment in type 2 diabetics independent of race, insulin resistance, and albuminuria.     

Diabetic Foot Syndrome and Corneal Subbasal Nerve Plexus Changes in Congolese Patients with Type 2 Diabetes

Background

To study the severity of diabetic neuropathy, diabetic retinopathy and grades of diabetic foot syndrome for correlations with corneal subbasal nerve plexus (SBP) changes in Congolese patients with type 2 diabetes.

Methodology/Principal Findings

Twenty-eight type 2 diabetes patients with diabetes-related foot ulceration were recruited in a diabetic care unit in Kinshasa, Democratic Republic of Congo. Corneal SBP was investigated by confocal laser-scanning microscopy to analyse nerve fibre density (NFD) [µm/ µm²], number of branches [n] and number of connectivity points [n]. Foot ulceration was graded using the Wagner ulcer classification. Corneal sensitivity (Cochet-Bonnet), Neuropathy Symptom Score (NSS), Neuropathy Disability Score (NDS), ankle-brachial index (ABI) and ophthalmological status were evaluated. Foot ulceration was ranked as mild (Wagner 0-1: 13 patients/46.4%), moderate (Wagner 2-3: 10 patients/35.7%) and severe (Wagner 4-5: 5 patients/17.9%). The correlation between Wagner Score and NFD (p=0.017, r = - 0,454), NDS and NFD (p=0,039, r = - 0.400) as well as Wagner Score and HbA_1c (p=0,007, r = - 0.477) was stated. Significant differences in confocal SBP parameters were observed between Wagner 0-1 and Wagner 4 5 (number of branches (p=0.012), number of connectivity points (p=0.001), nerve fibre density (p=0.033)) and ABI (p=0.030), and between Wagner 2-3 and Wagner 4-5 (number of branches (p=0.003), number of connectivity points (p=0.005) and nerve fibre density (p=0.014)). Differences in NDS (p=0.001) and corneal sensation (p=0.032) were significant between Wagner 0-1 and Wagner 2-3. Patients with diabetic retinopathy had significantly longer diabetes duration (p=0.03) and higher NDS (p=0.01), but showed no differences in SBP morphology or corneal sensation.

Conclusions/Significance

While confirming the diabetic aetiology of foot ulceration due to medial arterial calcification, this study indicates that the grade of diabetic foot syndrome correlates with corneal SBP changes and corneal sensation in patients in sub-Saharan Africa.     

Drug Transporter Genetic Variants Are Not Associated with TDF-Related Renal Dysfunction in Patients with HIV-1 Infection: A Pharmacogenetic Study

Objective

To investigate whether single nucleotide polymorphisms (SNP) of drug transporter proteins for TDF is a risk factor for TDF-related renal function decrement.

Methods

This study investigated the association between 3 SNPs (ABCC2–24, 1249, and ABCB1 2677), which are shown to be associated with TDF-induced tubulopathy, and clinically important renal outcomes (>10ml/min/1.73m² decrement in eGFR relative to baseline, >25% decrement in eGFR, and eGFR <60ml/min/1.73m²) in 703 HIV-1-infected Japanese patients who initiated TDF-containing antiretroviral therapy (ART). Genotyping was performed by allelic discrimination using TaqMan 5’-nuclease assays.

Results

95% of the study patients were males and 66% were treatment-naïve, with median CD4 count of 249/μl, median baseline eGFR of 96ml/min/1.73m² (IQR 84.6–109.2), and median exposure to TDF of 3.66 years (IQR 1.93–5.59). The frequencies of genotypes at -24, 1249 of ABCC2, and 2677 of ABCB1 were neither different between patients with decrement in eGFR of >10ml/min/1.73m² and those without such decrement (ABCC2: -24, p = 0.53, 1249, p = 0.68; ABCB1: 2677, p = 0.74), nor between those without and with the other two renal outcomes (>25% decrement: ABCC2: -24, p = 0.83, 1249, p = 0.97, ABCB1: 2677, p = 0.40; eGFR <60ml/min/1.73m²: ABCC2: -24, p = 0.51, 1249, p = 0.81, ABCB1: 2677, p = 0.94). Logistic regression analysis showed that the risk genotype of the three SNPs were not associated with any of the three renal outcomes, respectively. Logistic regression model that applied either dominant, recessive, or additive model yielded the same results.

Conclusions

SNPs of the drug transporters for TDF are not associated with clinically important renal outcomes in patients who initiated TDF-containing ART.     

Short and Long-Term Effects of Telaprevir on Kidney Function in Patients with Hepatitis C Virus Infection: A Retrospective Cohort Study

Background

Recent reports suggest that telaprevir, a protease inhibitor used to treat hepatitis C infection, is associated with decline in kidney function during therapy, particularly in patients with baseline renal impairment.

Methods

Patients treated with telaprevir in a single healthcare network were retrospectively reviewed. Kidney function was determined at baseline, during therapy, and twelve weeks and twelve months after telaprevir discontinuation. Significant creatinine rise during therapy was defined as an increase in serum creatinine ≥ 0.3mg/dL from baseline during treatment with telaprevir.

Results

Between July 2011 to January 2013,seventy-eight patients began treatment. The majority completed the prescribed twelve weeks of telaprevir therapy; 32% discontinued due to side effects. The average rise in serum creatinine during therapy was 0.22mg/dL (standard deviation 0.22mg/dL). Thirty-one percent experienced a significant creatinine rise during therapy. Decline in estimated glomerular filtration rate (eGFR) was lower in those with baseline eGFR < 90 mL/min/1.73m² compared to the group with baseline eGFR ≥ 90 mL/min/1.73m² (12 vs. 18 mL/min/1.73m², P = 0.047). Serum creatinine fully normalized by twelve weeks after cessation of telaprevir in 83% of patients, however experiencing a significant creatinine rise during telaprevir use was associated with a 6.6mL/min/1.73m² decrease in estimated glomerular filtration rate at twelve months in an adjusted model.

Conclusions

Decline in kidney function during therapy with telaprevir is common and is not associated with baseline eGFR < 90mL/min/1.73m² as previously reported.     

Effect of Vitamin D Receptor Activators on Glomerular Filtration Rate: A Meta-Analysis and Systematic Review

Background

Vitamin D receptor activators (VDRAs) can protect against mineral bone disease, but they are reported to elevate serum creatinine (SCr) and may also reduce glomerular filtration rate (GFR).

Methods

We conducted a systematic review and meta-analysis of randomized clinical trials (RCTs) to evaluate the effect of VDRAs on kidney function and adverse events. MEDLINE, EMBASE, the Cochrane Controlled Trials Register were searched for RCTs that evaluate vitamin D receptor activators (alfacalcidol, calcitriol, doxercalciferol, falecalcitriol, maxacalcitol and paricalcitol) up to March 2015.

Results

We included 31 studies, all of which were performed between 1976 and 2015, which enrolled 2621 patients. Patients receiving VDRAs had lower eGFR (weighted mean difference WMD -1.29 mL/min /1.73 m², 95% CI -2.42 to -0.17) and elevated serum creatinine (WMD 7.03 μmol/L, 95% CI 0.61 to 13.46) in sensitivity analysis excluding studies with dropout rate more than 30%. Subgroup analysis of the 5 studies that not use SCr-based measures did not indicated lower GFR in the VDRAs group(WMD -0.97 mL/min/1.73 m2, 95% CI -4.85 to 2.92). Compared with control groups, there was no difference in all-cause mortality (relative risk RR 1.41, 95% CI 0.58 to 3.80), cardiovascular disease (RR 0.84, 95% CI 0.42 to 1.71), and severe adverse events (RR 1.15, 95% CI 0.75 to 1.77) for the VDRAs groups. Episodes of hypercalcemia (RR 3.29, 95% CI 2.02 to 5.38) were more common in the VDRAs group than in the control group.

Conclusions

Administration of VDRAs increased serum creatinine levels. Subgroup analysis of studies that did not use SCr-based measures did not indicate a lower GFR in the VDRA group. Future studies with non-SCr-based measures are needed to assess whether the mild elevations of serum creatinine are of clinical significance.     

Effect of Behavior Modification on Outcome in Early- to Moderate-Stage Chronic Kidney Disease: A Cluster-Randomized Trial

Objectives

Owing to recent changes in our understanding of the underlying cause of chronic kidney disease (CKD), the importance of lifestyle modification for preventing the progression of kidney dysfunction and complications has become obvious. In addition, effective cooperation between general physicians (GPs) and nephrologists is essential to ensure a better care system for CKD treatment. In this cluster-randomized study, we studied the effect of behavior modification on the outcome of early- to moderate-stage CKD.

Design

Stratified open cluster-randomized trial.

Setting

A total of 489 GPs belonging to 49 local medical associations (clusters) in Japan.

Participants

A total of 2,379 patients (1,195 in group A (standard intervention) and 1,184 in group B (advanced intervention)) aged between 40 and 74 years, who had CKD and were under consultation with GPs.

Intervention

All patients were managed in accordance with the current CKD guidelines. The group B clusters received three additional interventions: patients received both educational intervention for lifestyle modification and a CKD status letter, attempting to prevent their withdrawal from treatment, and the group B GPs received data sheets to facilitate reducing the gap between target and practice.

Main outcome measure

The primary outcome measures were 1) the non-adherence rate of accepting continuous medical follow-up of the patients, 2) the collaboration rate between GPs and nephrologists, and 3) the progression of CKD.

Results

The rate of discontinuous clinical visits was significantly lower in group B (16.2% in group A vs. 11.5% in group B, p = 0.01). Significantly higher referral and co-treatment rates were observed in group B (p<0.01). The average eGFR deterioration rate tended to be lower in group B (group A: 2.6±5.8 ml/min/1.73 m²/year, group B: 2.4±5.1 ml/min/1.73 m²/year, p = 0.07). A significant difference in eGFR deterioration rate was observed in subjects with Stage 3 CKD (group A: 2.4±5.9 ml/min/1.73 m²/year, group B: 1.9±4.4 ml/min/1.73 m²/year, p = 0.03).

Conclusion

Our care system achieved behavior modification of CKD patients, namely, significantly lower discontinuous clinical visits, and behavior modification of both GPs and nephrologists, namely significantly higher referral and co-treatment rates, resulting in the retardation of CKD progression, especially in patients with proteinuric Stage 3 CKD.

Trial registration

The University Hospital Medical Information Network clinical trials registry UMIN000001159     

Characterization of Early Disease Status in Treatment-Naive Male Paediatric Patients with Fabry Disease Enrolled in a Randomized Clinical Trial

Trial Design

This analysis characterizes the degree of early organ involvement in a cohort of oligo-symptomatic untreated young patients with Fabry disease enrolled in an ongoing randomized, open-label, parallel-group, phase 3B clinical trial.

Methods

Males aged 5–18 years with complete α-galactosidase A deficiency, without symptoms of major organ damage, were enrolled in a phase 3B trial evaluating two doses of agalsidase beta. Baseline disease characteristics of 31 eligible patients (median age 12 years) were studied, including cellular globotriaosylceramide (GL-3) accumulation in skin (n = 31) and kidney biopsy (n = 6; median age 15 years; range 13–17 years), renal function, and glycolipid levels (plasma, urine).

Results

Plasma and urinary GL-3 levels were abnormal in 25 of 30 and 31 of 31 patients, respectively. Plasma lyso-GL-3 was elevated in all patients. GL-3 accumulation was documented in superficial skin capillary endothelial cells (23/31 patients) and deep vessel endothelial cells (23/29 patients). The mean glomerular filtration rate (GFR), measured by plasma disappearance of iohexol, was 118.1 mL/min/1.73 m² (range 90.4–161.0 mL/min/1.73 m²) and the median urinary albumin/creatinine ratio was 10 mg/g (range 4.0–27.0 mg/g). On electron microscopy, renal biopsy revealed GL-3 accumulation in all glomerular cell types (podocytes and parietal, endothelial, and mesangial cells), as well as in peritubular capillary and non-capillary endothelial, interstitial, vascular smooth muscle, and distal tubules/collecting duct cells. Lesions indicative of early Fabry arteriopathy and segmental effacement of podocyte foot processes were found in all 6 patients.

Conclusions

These data reveal that in this small cohort of children with Fabry disease, histological evidence of GL-3 accumulation, and cellular and vascular injury are present in renal tissues at very early stages of the disease, and are noted before onset of microalbuminuria and development of clinically significant renal events (e.g. reduced GFR). These data give additional support to the consideration of early initiation of enzyme replacement therapy, potentially improving long-term outcome.

Trial Registration

ClinicalTrials.gov NCT00701415     

The Association between Chronic Kidney Disease and Diabetic Retinopathy: The Korea National Health and Nutrition Examination Survey 2008-2010

Purpose

To explore the relationship between chronic kidney disease and diabetic retinopathy in a representative population of Korean diabetic adults.

Methods

We analyzed data from the Korea National Health and Nutrition Examination Surveys (2008-2010). A total of 15,409 individuals (weighted frequency, 32,168,636) aged 19 and over who completed ophthalmologic and renal functional examinations were evaluated. Chronic kidney disease (CKD) was defined as an estimated glomerular filtration rate of < 60 ml/min/1.73 m² or proteinuria greater than 1+. Seven standard photographs from the Early Treatment for Diabetic Retinopathy Study were obtained from each eye after pharmacological pupil dilatation. Diabetic retinopathy (DR) was defined as the presence of 1 or more retinal microaneurysms or retinal blot hemorrhages with or without more severe lesions. Vision-threatening diabetic retinopathy (VTDR) was defined as the presence of a clinically significant macular edema (CSME) or proliferative diabetic retinopathy.

Results

CKD was significantly associated with DR and VTDR (odds ratio (OR), 95% confidence interval (CI); 2.49(1.43-4.35) and 3.74(1.56-8.95), respectively) in the diabetic population. After controlling for confounders, however, CKD was significantly associated only with DR [adjusted OR (aOR), 95% CI; 2.34(1.04-5.28)]. In the subgroup analysis for CKD, only proteinuria was significantly associated with DR and VTDR (aOR, 95% CI; 4.56(1.51-13.77) and 5.61(1.06-29.87), respectively) in this population.

Conclusions

Our results show that CKD appears to be associated with DR and VTDR in a Korean diabetic population. In particular, proteinuria, not decreased eGFR, is more significantly associated with DR or VTDR.     

Efficacy and Safety of Tangshen Formula on Patients with Type 2 Diabetic Kidney Disease: A Multicenter Double-Blinded Randomized Placebo-Controlled Trial

Background

Persons with diabetes are at high risk of developing diabetic kidney disease (DKD), which is associated with high morbidity and mortality. Current drug therapies for DKD, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), are not entirely satisfactory. This study aimed to evaluate the additional benefit and safety of the Chinese herbal granule Tangshen Formula (TSF) in treating DKD.

Methods

The study was designed as a six-center randomized, double-blind, placebo-controlled trial. From April 2007 through December 2009, 180 patients with DKD were enrolled. In addition to conventional treatment with ACEIs or ARBs, 122 participants were randomly assigned to receive TSF and 58 participants to receive placebo for 24 weeks. Primary outcome was urinary protein level, measured by urinary albumin excretion rate (UAER) for participants with microalbuminuria, 24-hour urinary protein (24h UP) for participants with macroalbuminuria. Secondary outcomes included renal function, serum lipids, quality of life, symptoms, and adverse events.

Findings

After 24 weeks of treatment, no statistically significant difference in UAER (TSF −19.53 μg/min compared with placebo −7.01 μg/min, with a mean difference of −12.52 μg/min; 95%CI, −68.67 to 43.63, P = 0.696) was found between TSF and placebo groups. However, TSF displayed a statistically significant decrease in 24h UP (TSF−0.21 g compared with placebo 0.36 g, with a mean difference of −0.57g; 95%CI, −1.05 to −0.09, P = 0.024). Estimated glomerular filtration rate (eGFR) was improved in both patients with microalbuminuria and macroalbuminuria, with a mean difference of 15.51 ml/min/1.73 m² (95%CI, 3.71 to 27.31), 9.01 ml/min/1.73 m² (95%CI, −0.10 to 18.13), respectively. Other secondary outcomes showed no statistically significant difference between groups or in the incidence of adverse events.

Conclusions

Based on conventional treatments, TSF appears to provide additional benefits compared with placebo in decreasing proteinuria and improving eGFR in DKD patients with macroalbuminuria. Nevertheless, further study is needed to evaluate TSF treating patients with microalbuminuria.

Trial Registration

Chinese Clinical Trial Registry ChiCTR-TRC-10000843     

Effect of Proteinuria and Glomerular Filtration Rate on Renal Outcome in Patients with Biopsy-Proven Benign Nephrosclerosis

Background

Reduced estimated glomerular filtration rate (eGFR) and proteinuria are risk factors for end-stage renal disease (ESRD), of which benign nephrosclerosis is a common cause. However, few biopsy-based studies have assessed these associations.

Methods

We performed retrospective cohort study of 182 Japanese patients who underwent renal biopsy from June 1985 through March 2014 and who were diagnosed with benign nephrosclerosis. Competing risk regression analyses were used to investigate the effect of eGFR and proteinuria levels at the time of renal biopsy on the risk for renal events (ESRD or a 50% decline in eGFR from baseline).

Results

During a median 5.8-year follow-up, 63 (34.6%) patients experienced renal events. The incidence of renal events increased with lower baseline eGFR and greater baseline proteinuria levels. After adjustment for baseline covariates, lower eGFR levels (subhazard ratios [SHRs], 1.30; 95% confidence interval [CI], 1.01–1.67, per 10 mL/min/1.73 m²) and higher proteinuria levels (SHR, 1.52; 95% CI, 1.23–1.87, per 1.0 g/day) at the time of renal biopsy were associated independently with higher risk for renal events. Lower levels of serum albumin (SHR, 2.07; 95% CI, 1.20–3.55 per 1.0 g/dL) were also associated with renal events. Patients with both eGFR <30 mL/min/1.73 m² and proteinuria ≥0.5 g/day had a 26.7-fold higher risk (95% CI, 3.97–179.4) of renal events than patients with both eGFR ≥60 mL/min/1.73 m² and proteinuria <0.5 g/day.

Conclusions

Reduced eGFR and increased proteinuria as well as lower serum albumin at the time of renal biopsy are independent risk factors for renal events among patients with biopsy-proven benign nephrosclerosis.