Estimating glomerular filtration rate in diabetes using serum cystatin C

Chronic kidney disease (CKD) is a major public health problem, especially for people with diabetes. Not only is it a risk factor for end-stage renal disease (ESRD) but it is also a major cardiovascular disease (CVD) risk factor. Methods that accurately and simply estimate glomerular filtration rate (GFR) are therefore needed to optimise the detection and management of CKD in people with diabetes. One of the main failures of commonly used creatinine-based methods for estimating renal function is that they lack applicability across the full range of GFR values and underestimate GFR levels >60 mL/min/1.73m(2). Methods for accurately estimating an early pathological decline in GFR (i.e. ΔGFR >3.3 mL/min/year before reaching a GFR <60 mL/min/1.73m(2)) are especially needed as appropriate interventions have been shown to retard progression to ESRD and reduce CVD risk in people with diabetes. In contrast, recent studies have suggested that estimates of GFR based on serum cystatin C concentration might provide a simple and accurate method for detecting and monitoring an early decline in renal function.     

胱蛋白酶抑制剂C与肌酐评价儿童肾小球滤过功能中的作用比较

用胱蛋白酶抑制剂C与肌酐、内生肌酐清除率评价儿童肾小球滤过功能,并将其作用进行比较,确定胱蛋白酶抑制剂C在儿童中的正常参考范围。采用颗粒增强散射免疫比浊法检测150例出生后2d～13岁正常儿童及90例1～16岁患不同程度肾脏疾病的儿童血清中胱蛋白酶抑制剂C和血肌酐的浓度,并比较胱蛋白酶抑制剂C与血肌酐的相关性。结果发现胱蛋白酶抑制剂C在出生后四个月内水平明显高于成人,但在出生5个月以后下降至接近成人参考范围。血清胱蛋白酶抑制剂浓度C与尿素清除率之间有显著相关性(P<0.01)。此外,在内生肌酐清除率CCr>80(属于正常参考范围)的肾脏疾病的患儿中有56%胱蛋白酶抑制剂C异常,说明胱蛋白酶抑制剂C比血肌酐更能够敏感地反应儿童肾小球滤过功能的损伤,建议用胱蛋白酶抑制剂C作为儿童肾脏疾病的患者肾小球滤过功能的损伤指标。     

Assessment of serum beta-trace protein (BTP) measurement in the prediction of glomerular filtration rate. Comparison with serum cystatin C

Serum BTP measurement is sometimes believed to be an alternative marker of glomerular filtration rate (GFR) assessment. The aim of the present work was to investigate the correlation between creatinine, cystatin C, and BTP values in sera and to compare the diagnostic efficacy for serum BTP and cystatin C with the glomerular filtration rate estimate. 25 individuals were tested. GFR was estimated from creatinine clearance, serum cystatin C and BTP and urine alpha-1 microglobulin, albumin, GMT and creatinine were measured. BTP values correlated with cystatin C (r = 0.75; p < 0.01), creatinine (r = 0.73, p < 0.01), GFR (r = -0.46; p = 0.02), urine alpha-1-microglobulin (r = 0.66; p < 0.01). The diagnostic efficacy of BTP for reduced GFR was insufficient and the calculation of GFR with BTP was not included in the regression model.     

Mechanisms of neonatal increase in glomerular filtration rate

To investigate the mechanisms responsible for the neonatal increase in glomerular filtration rate (GFR), renal function studies (whole kidney and micropuncture) were carried out in anesthesized fetal sheep (133-140 days gestation; term = 150 days) and lambs (12-18 days). Fetuses were delivered and placed in a water bath (39.5 degrees C), keeping the umbilical cord moist and intact. Lambs were studied on a thermostatically controlled heating pad. Animals were prepared for either blood flow studies or micropuncture measurements. Expected differences in blood composition and cardiovascular and renal function were observed between fetuses and lambs, and values obtained for most variables were similar to those measured in chronically catheterized unanesthetized animals. Fetal GFR was much lower than that of lambs (0.20 vs. 0.62 ml.min(-1).g kidney(-1), P < 0.001). Free-flow, stop-flow, and net filtration pressures (NFP) were lower in the fetuses than the lambs (NFP 20.8 vs. 23.8 mmHg, P < 0.001), as was the calculated ultrafiltration coefficient (0.014 vs. 0.022 ml.min(-1).g(-1).mmHg(-1), P < 0.001). Thus, we conclude that rises in both net filtration pressure and the ultrafiltration coefficient contribute to the large increase in GFR between fetal life and approximately 2 wk after birth.     

Rapid determination of glomerular filtration rate by single-bolus inulin: a comparison of estimation analyses

Rapid measurement of glomerular filtration rate(GFR) by an inulin single-bolus technique would be useful, but itsaccuracy has been questioned. We hypothesized that reportedinaccuracies reflect the use of inappropriate mathematical models. GFRwas measured in 14 intact and 5 unilaterally nephrectomized conscious male Sprague-Dawley rats (mean weight 368 ± 12 g) by bothsingle-bolus (25 mg/kg) and constant-infusion techniques (0.693 mg · kg¹ · min¹).The temporal decline in plasma inulin concentration was analyzed through biexponential curve fitting, which accounted for renal inulinloss before complete vascular and interstitial mixing. We compared ourmathematical model based on empirical rationale with those of otherinvestigators whose studies suggest inaccuracy of single-bolus methods.Our mathematical model yielded GFR values by single bolus that agreedwith those obtained by constant infusion [slope = 0.94 ± 0.16 (SE); y intercept = 0.23 ± 0.64; r = 0.82]. Incomparison to the data obtained by constant inulin infusion, thismethod yielded a very small bias of 0.0041 ± 0.19 ml/min. Two previously reported models yielded unsatisfactory values (slope = 1.46 ± 0.34, y intercept = 0.47 ± 1.5, r = 0.72; and slope = 0.17 ± 1.26, y intercept = 17.15 ± 5.14, r = 0.03). The biases obtained byusing these methods were 2.21 ± 0.42 and 13.90 ± 1.44 ml/min, respectively. The data indicate that when appropriate mathematical models are used, inulin clearance after single-bolus delivery can be used to measure GFR equivalent to that obtained byconstant infusion of inulin. Attempts to use methods of analysis forsimplicity or expediency can result in unacceptable measurements relative to the clinical range of values seen.

     

Regulation of glomerular filtration rate and sodium excretion by angiotensin II

In addition to its extrarenal functions, including the control of arterial pressure and aldosterone secretion, the renin-angiotensin system (RAS) also has multiple intrarenal actions in controlling glomerular filtration rate (GFR) and sodium excretion. Angiotensin II (AngII) helps to prevent excessive decreases in GFR in different physiological and pathophysiological conditions by preferentially constricting the efferent arterioles, an action that can be mediated by either intrarenally formed or circulating AngII. Circulating AngII and intrarenally formed AngII do not appear to directly constrict preglomerular vessels, including the afferent arterioles, when the RAS is activated physiologically. The sodium-retaining action of AngII may be due, in part, to constriction of efferent arterioles and to subsequent changes in peritubular capillary physical forces. However, AngII may also directly stimulate sodium reabsorption in proximal and distal tubules, although the exact site at which AngII increases distal tubular transport is still uncertain. Considerable evidence indicates that the direct intrarenal effects of AngII on tubular reabsorption, including those caused by changes in peritubular capillary physical forces or a direct action on tubular transport, are quantitatively more important than those mediated by changes in aldosterone secretion. Thus, the intrarenal effects of AngII provide a mechanism for stabilizing the GFR and excretion of metabolic waste products while causing sodium and water retention, thereby helping to regulate body fluid volumes and arterial pressure.     

Effect of prostaglandin inhibition on glomerular filtration rate in normal and uremic rabbits

Studies were performed to assess the effect of alterations in prostaglandin biosynthesis on glomerular filtration rate in rabbits with normal renal function and after surgical reduction of renal mass. In normal animals, the administration of either of two cyclo-oxygenase inhibitors resulted in a 53% reduction in urine prostaglandin E excretion, but no change in creatinine clearance. Creatinine clearance rates were almost 71% lower in the uremic animals when compared to the animals with normal renal function. Despite the reduction in renal mass, urine prostaglandin E excretion rates in the uremic animals were over twice that seen in normal rabbits. When factored by either glomerular filtration rate or remaining renal mass, urine prostaglandin E excretion rates in uremic rabbits when compared to normal animals were increased more than 9-times and 4-times respectively. Administration of cyclo-oxygenase inhibitors in the uremic animals resulted in a 71% decrease in urine prostaglandin E excretion and, unlike the non-uremic animals, a 53% fall in creatinine clearance. These findings suggest that intact renal prostaglandin biosynthesis is a necessary factor in the homeostatic adaptive mechanisms which maintain the glomerular filtration rate in animals with decreased renal mass.     

Insulin induces the correlation between renal blood flow and glomerular filtration rate in diabetes: implications for mechanisms causing hyperfiltration

Glomerular filtration rate (GFR) and renal blood flow (RBF) are normally kept constant via renal autoregulation. However, early diabetes results in increased GFR and the potential mechanisms are debated. Tubuloglomerular feedback (TGF) inactivation, with concomitantly increased RBF, is proposed but challenged by the finding of glomerular hyperfiltration in diabetic adenosine A(1) receptor-deficient mice, which lack TGF. Furthermore, we consistently find elevated GFR in diabetes with only minor changes in RBF. This may relate to the use of a lower streptozotocin dose, which produces a degree of hyperglycemia, which is manageable without supplemental suboptimal insulin administration, as has been used by other investigators. Therefore, we examined the relationship between RBF and GFR in diabetic rats with (diabetes + insulin) and without suboptimal insulin administration (untreated diabetes). As insulin can affect nitric oxide (NO) release, the role of NO was also investigated. GFR, RBF, and glomerular filtration pressures were measured. Dynamic RBF autoregulation was examined by transfer function analysis between arterial pressure and RBF. Both diabetic groups had increased GFR (+60-67%) and RBF (+20-23%) compared with controls. However, only the diabetes + insulin group displayed a correlation between GFR and RBF (R(2) = 0.81, P < 0.0001). Net filtration pressure was increased in untreated diabetes compared with both other groups. The difference between untreated and insulin-treated diabetic rats disappeared after administering N(ω)-nitro-l-arginine methyl ester to inhibit NO synthase and subsequent NO release. In conclusion, mechanisms causing diabetes-induced glomerular hyperfiltration are animal model-dependent. Supplemental insulin administration results in a RBF-dependent mechanism, whereas elevated GFR in untreated diabetes is mediated primarily by a tubular event. Insulin-induced NO release partially contributes to these differences.     

Association between estimated glomerular filtration rate at initiation of dialysis and mortality

Background

Recent studies have reported a trend toward earlier initiation of dialysis (i.e., at higher levels of glomerular filtration rate) and an association between early initiation and increased risk of death. We examined trends in initiation of hemodialysis within Canada and compared the risk of death between patients with early and late initiation of dialysis.

Methods

The analytic cohort consisted of 25 910 patients at least 18 years of age who initiated hemodialysis, as identified from the Canadian Organ Replacement Register (2001–2007). We defined the initiation of dialysis as early if the estimated glomerular filtration rate was greater than 10.5 mL/min per 1.73 m². We fitted time-dependent proportional-hazards Cox models to compare the risk of death between patients with early and late initiation of dialysis.

Results

Between 2001 and 2007, mean estimated glomerular filtration rate at initiation of dialysis increased from 9.3 (standard deviation [SD] 5.2) to 10.2 (SD 7.1) (p < 0.001), and the proportion of early starts rose from 28% (95% confidence interval [CI] 27%–30%) to 36% (95% CI 34%–37%). Mean glomerular filtration rate was 15.5 (SD 7.7) mL/min per 1.73 m² among those with early initiation and 7.1 (SD 2.0) mL/min per 1.73 m² among those with late initiation. The unadjusted hazard ratio (HR) for mortality with early relative to late initiation was 1.48 (95% CI 1.43–1.54). The HR decreased to 1.18 (95% CI 1.13–1.23) after adjustment for demographic characteristics, serum albumin, primary cause of end-stage renal disease, vascular access type, comorbidities, late referral and transplant status. The mortality differential between early and late initiation per 1000 patient-years narrowed after one year of follow-up, but never crossed and began widening again after 24 months of follow-up. The differences were significant at 6, 12, 30 and 36 months.

Interpretation

In Canada, dialysis is being initiated at increasingly higher levels of glomerular filtration rate. A higher glomerular filtration rate at initiation of dialysis is associated with an increased risk of death that is not fully explained by differences in baseline characteristics.Examination of dialysis registry data, both in the United States and Europe, has shown that this procedure is being initiated for patients with increasingly higher levels of estimated glomerular filtration rate.^1–4 Although the indications for dialysis are often not recorded or not accessible for data-gathering, a large international survey of physicians in 2000 revealed that the two leading determinants of early initiation were uremic signs and symptoms (38%) and residual kidney function (32%), with 90% of respondents indicating that initiating dialysis earlier (by 6–12 months) would give some major advantage in terms of outcomes.⁵ The timing of initiation of dialysis is based on clinical judgment and the interpretation of signs, symptoms and laboratory test results, with possibly greater emphasis recently on estimated glomerular filtration rate following the introduction of national guidelines.^6,7 These guidelines were influenced by studies conducted in the 1980s and 1990s, which suggested that late initiation was potentially harmful.^8,9 In 2006, the US National Kidney Foundation suggested that initiation of dialysis be considered before stage 5 chronic kidney disease (estimated glomerular filtration rate < 15 mL/min per 1.73 m²) if symptoms were related to both comorbidities and level of residual kidney function.¹⁰ The guidelines were based on existing observational information and never advocated initiating dialysis at a specific value of estimated glomerular filtration rate. However, studies conducted since 2001 have shown no survival benefit with initiation of hemodialysis at higher values of estimated glomerular filtration rate.^4,11–14Using data from the Canadian Organ Replacement Register, we examined trends in the timing of hemodialysis initiation between 2001 and 2007, characterized patients with early and late initiation of dialysis and compared the risk of death between these groups over time while controlling for baseline imbalances. In this article, we discuss the confounding effects of selection, survivor, misclassification, lead-time and indication bias.