Mean Rate Of Decline In Glomerular Filtration Rate Research Articles

Office and Ambulatory Heart Rate as Predictors of Age-Related Kidney Function Decline.

The decline in glomerular filtration rate (GFR) associated with aging is one of the most important predisposing causes of kidney failure in old age. Identifying persons at risk for accelerated GFR decline is an essential first step in the development of preventive measures to preserve kidney function in the elderly. Heart rate (HR) has not yet been studied as a risk factor for GFR decline in the general population. In the RENIS-T6 (Renal Iohexol-Clearance Survey in Tromsø 6), we measured baseline ambulatory HR and GFR as iohexol clearance in a representative, middle-aged cohort of 1627 persons without self-reported diabetes mellitus, cardiovascular disease, or kidney disease. In the RENIS-FU (RENIS Follow-Up Study), we repeated the GFR measurements and calculated the rate of GFR decline in 81% of the participants after a median follow-up of 5.6 years. The unadjusted mean rate of GFR decline was 0.96 mL/min per year. In multivariable-adjusted linear mixed models, 10 bpm higher ambulatory 24-hour and daytime HRs and office HR were associated with steeper GFR decline rates of 0.20 to 0.21 mL/min per year ( P≤0.01). The odds ratio for predicting a rate of GFR decline twice that of the population mean in a fully adjusted model was 1.24 ( P=0.01) for ambulatory 24-hour HR. Office HR was also an independent predictor of a steeper rate of GFR decline. HR may be a useful biomarker to identify persons at risk of accelerated GFR decline.

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.

Slower Decline of Glomerular Filtration Rate in the Japanese General Population: A Longitudinal 10-Year Follow-Up Study

The prevalence of stage 3 to 5 chronic kidney disease (CKD) in Japan (18.7%) is considerably higher than that in the United States (4.5%). This study investigated in the Japanese general population whether this higher prevalence of CKD might reflect to a progressive decline of renal function, and in turn to the increased risk of end-stage renal disease. A decline in renal function over 10 years was examined in 120,727 individuals aged 40 years or older who participated in the annual health examination program of the two periods over 10 years, 1988-1993 and 1998-2003. Renal function was assessed with estimated glomerular filtration rate (GFR) using the abbreviated Modification of Diet in Renal Disease (MDRD) Study equation modified by a Japanese coefficient. The rate of GFR decline in the participants was 0.36 mL/min/1.73 m2/year on average. In the male population aged 50-79, the mean rate of GFR decline was significantly higher in the presence of hypertension than in its absence. The rate of GFR decline was more than two times higher in participants with proteinuria than in those without proteinuria in both sexes. The rate was significantly higher in participants with an initial GFR<50 mL/min/1.73 m2 among the groups younger than age 70 and in participants with an initial GFR<40 mL/min/1.73 m2 in the group with age 70-79. Based on the slow rate of GFR decline, we concluded that the decline in renal function progresses slowly in the Japanese general population. Hypertension, proteinuria and lower GFR were found to be significant risk factors for a faster decline of GFR.

Elevated vascular endothelial growth factor in type 1 diabetic patients with diabetic nephropathy

Growth factors have been suggested to play a role in the development and progression of diabetic nephropathy. Vascular endothelial growth factor (VEGF) is a potent cytokine family that induces angiogenesis and markedly increases endothelial permeability. The aim of the present study was to investigate plasma levels of VEGF in a large cohort of type 1 diabetic patients with diabetic nephropathy and in long-standing type 1 diabetic patients with persistent normoalbuminuria, and to evaluate VEGF as a predictor of nephropathy progression. We measured VEGF with an enzyme-linked immunosorbent assay (ELISA) technique in 199 type 1 diabetic patients with diabetic nephropathy (122 males, age 41 +/- 10 years, diabetes duration 28 +/- 8 years), glomerular filtration rate (GFR) (median [range]) 75 [10-143] mL/min/1.73 m2, and in 188 long-standing type 1 diabetic patients with persistent normoalbuminuria (115 males, age 43 +/- 10 years, diabetes duration 27 +/- 9 years). One hundred fifty-five of the proteinuric patients were followed for at least 3 years after baseline examination with yearly GFR measurements. Plasma levels of VEGF were significantly increased in patients with nephropathy as compared to the normoalbuminuric group; (median [range]): 45.7 [22.0-410] versus 27.1 [22.0-355] ng/L, respectively, P < 0.001. This difference was ascribed to elevated VEGF levels in nephropathic men: 51.8 [22.0-410] versus 22.0 [22.0-308] ng/L, P < 0. 001. No differences were found between women with and without nephropathy: 37.8 [22.0-325] versus 36.6 [22.0-335] ng/L, NS. In proteinuric patients with GFR above and below the median value, there was no difference in the level of VEGF, NS. Plasma VEGF was below the detection limit (22.0 ng/L) in 60 patients with nephropathy and 93 patients with normoalbuminuria, P < 0.001. The mean rate of GFR decline was 3.5 (SE: 0.4) mL/min/year, and the following baseline variables acted as predictors of progression: albuminuria, mean arterial blood pressure and male gender. Hemoglobin A1c and plasma VEGF did not act as predictors. No significant differences between patients with and without proliferative retinopathy were detected. Our data suggest that VEGF is elevated early in the course of diabetic nephropathy in men with type 1 diabetes mellitus. Baseline albuminuria, arterial blood pressure and male gender was predictors of diabetic nephropathy progression, while plasma VEGF and Hemoglobin A1c did not contribute. The importance of VEGF in the initiation of diabetic nephropathy remains to be established.

Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial

The Ramipril Efficacy In Nephropathy (REIN) study found that in patients with chronic nephropathies and proteinuria of 3 g or more per 24 h, ramipril safely reduced the rate of decline of the glomerular filtration rate (GFR) and halved the combined risk of doubling of serum creatinine or end-stage renal failure (ESRF), as compared with placebo plus conventional antihypertensive drugs at the same level of blood pressure control. At the end of the core study patients continued on or shifted to ramipril and were formally enrolled into the REIN follow-up study. 97 patients entered the follow-up study. Patients originally randomised to ramipril continued with the same daily dose (n=51), whereas those originally on placebo plus conventional antihypertensive drugs switched to ramipril after the first visit of the follow-up study (n=46). Ramipril (1.25 to 5.00 mg/day) and conventional antihypertensive therapy were targeted at achieving diastolic blood pressure under 90 mm Hg. The main efficacy variables were GFR decline and ESRF (need for dialysis). Analysis was by intention to treat. During the follow-up study the mean rate of GFR decline per month decreased from 0.44 (SD 0.54) mL/min per 1.73 m2 in the core study to 0.10 (0.50) mL/min per 1.73 m2 in patients originally randomised to ramipril (p=0.017), and from 0.81 (1.12) to 0.14 (0.87) mL/min per 1.73 m2 in those originally randomised to placebo plus conventional antihypertensive therapy (p=0.017). At the final visit, mean absolute GFR values were 12 mL/min per 1.73 m2 higher (33% better) in patients randomised to ramipril than in those assigned placebo (n=26 and 17, respectively: 35.5 [19.0] vs 23.8 [9.4] mL/min per 1.73 m2, p=0.01). 19 of the patients originally on ramipril versus 35 switched from placebo to ramipril progressed to ESRF (p=0.027) during the whole observation period; of these, six (8%) versus 14 (16%) reached that endpoint during the follow-up study; and the risk ratios were 1.86 (95% CI 1.07-3.26) over the whole observation period and 2.95 (1.13-7.68) during follow-up. Beyond follow-up at month 36, the incidence of ESRF was zero in patients originally randomised to ramipril but 30% in patients on placebo plus conventional antihypertensive therapy. In patients with chronic nephropathy and high risk of rapid progression to ESRF, ramipril reversed the tendency of GFR to decline with time. Moreover, a treatment period of sufficient duration (> or =36 months) eliminated the need for dialysis. Even patients previously treated with antihypertensive drugs other than angiotensin-converting-enzyme inhibitors benefited from shifting to ramipril.

Predictors of the progression of renal disease in the Modification of Diet in Renal Disease Study

The Modification of Diet in Renal Disease (MDRD) Study examined the effects of dietary protein restriction and strict blood pressure control on the decline in glomerular filtration rate (GFR) in 840 patients with diverse renal diseases. We describe a systematic analysis to determine baseline factors that predict the decline in GFR, or which alter the efficacy of the diet or blood pressure interventions. Univariate analysis identified 18 of 41 investigated baseline factors as significant (P < 0.05) predictors of GFR decline. In multivariate analysis, six factors--greater urine protein excretion, diagnosis of polycystic kidney disease (PKD), lower serum transferrin, higher mean arterial pressure, black race, and lower serum HDL cholesterol--independently predicted a faster decline in GFR. Together with the study interventions, these six factors accounted for 34.5% and 33.9% of the variance between patients in GFR slopes in Studies A and B, respectively, with proteinuria and PKD playing the predominant role. The mean rate of GFR decline was not significantly related to baseline GFR, suggesting an approximately linear mean GFR decline as renal disease progresses. The 41 baseline predictors were also assessed for their interactions with the diet and blood pressure interventions. A greater benefit of the low blood pressure intervention was found in patients with higher baseline urine protein. None of the 41 baseline factors were shown to predict a greater or lesser effect of dietary protein restriction.