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.     

Glomerular filtration rate and blood pressure monitoring in awake baboons

Minimally invasive techniques were used to collect urine with an external catheter together with automated intermittent monitoring of arterial blood pressure in awake male baboons. Using endogenous creatinine, 24-hour creatinine clearances were measured for 2 to 3 consecutive days in four intact and in four uninephrectomized baboons. Despite large differences in urinary volume and sodium excretion, reproducibility of 24-hour creatinine clearances was within 15% in 15 of 19 studies obtained from 6 of 8 animals. Arterial blood pressure was monitored intermittently at 30 to 60 minute intervals over 24 hours with a Dinamap monitor and recorder. Mean blood pressure averaged 71 +/- 4.4 to 89 +/- 5.5 mm Hg in different animals. Blood pressure tended to be lower at night than during the day. In separate studies using 15 to 60 minute urine collection periods, inulin clearance was compared in awake and in anesthetized animals with endogenous or exogenous creatinine clearance measured simultaneously. The clearance of creatinine systematically exceeded the clearance of inulin, even in intact animals with a normal serum creatinine. The creatinine-to-inulin clearance ratio averaged 1.16 +/- 0.03 at a serum concentration of 0.7 to 0.8 mg/dl; 1.27 +/- 0.03 at a serum creatinine of 1.0 to 1.1 mg/dl and 1.56 +/- 0.04 at a serum creatinine greater than 10 mg/dl. All values exceed unity significantly (p less than 0.001). Thus, renal function, including inulin clearance, can be measured in awake baboons. Duplicate or triplicate 24-hour urine collections are needed to assess the reliability of creatinine excretion. However, creatinine clearance overestimates glomerular filtration rate, as it does in humans.     

Glomerular filtration rate in schoolgirls with covert bacteriuria.

Clearance of technetium-99m-labelled diethylenetriaminepenta-acetic acid was used to measure total and individual kidney glomerular filtration rates in 48 girls with covert bacteriuria. The mean (+/- SD) of the total rates of 18 girls with scarred kidneys (99 +/- 24 ml/min/1.73 m2) was significantly (0.005 greater than p greater than 0.002) lower than that in 30 girls with unscarred kidneys (119 +/- 18 ml/min/1.73 m2). This reduction in glomerular filtration was related to the loss of kidney substance associated with scarring rather than to vesicoureteric reflux. The glomerular filtration rate was unrelated to the duration of bacteriuria. These findings suggest that in girls aged 4 and over neither vesicoureteric reflux nor covert bacteriuria contributes to the progression of kidney damage.     

Glomerular filtration rate determinations in conscious type II diabetic mice

Diabetic nephropathy is a major cause of end-stage renal disease worldwide. The current studies were performed to determine the later stages of the progression of renal disease in type II diabetic mice (BKS; db/db). Methodology was developed for determining glomerular filtration rate (GFR) in conscious, chronically instrumented mice using continuous intravenous infusion of FITC-labeled inulin to achieve a steady-state plasma inulin concentration. Obese diabetic mice exhibited increased GFR compared with control mice. GFR averaged 0.313 ± 0.018 and 0.278 ± 0.007 ml/min in 18-wk-old obese diabetic (n = 11) and control (n = 13) mice, respectively (P < 0.05). In 28-wk-old obese diabetic (n = 10) and control (n = 15) mice, GFR averaged 0.348 ± 0.030 and 0.279 ± 0.009 ml/min, respectively (P < 0.05). GFR expressed per gram BW was significantly reduced in 18- and 28-wk-old obese diabetic compared with control mice (5.9 ± 0.3 vs. 9.0 ± 0.3; 6.6 ± 0.6 vs. 7.8 ± 0.3 μl·min(-1)·g body wt(-1)), respectively (P < 0.05). However, older nonobese type II diabetic mice had significantly reduced GFR (0.179 ± 0.023 ml/min; n = 6) and elevated urinary albumin excretion (811 ± 127 μg/day) compared with obese diabetic and control mice (514 ± 54, 171 ± 18 μg/day), which are consistent with the advanced stages of renal disease. These studies suggest that hyperfiltration contributes to the progression of renal disease in type II diabetic mice.     

Glomerular filtration rate in wild house mice, Mus musculus, acclimated to water scarcity

1. A single injection technique for GFR (14C-methoxyinulin clearance) was adapted for use in small mammals and applied to wild house mice (Mus musculus). 2. GFR in controls was 247 +/- 14(SE) microliter/min while that of mice acclimated to water shortage was reduced some 44%.     

Glomerular filtration and fluid balance in genetically hypertensive mice

The Schlager genetically hypertensive mouse has been shown to be a valuable animal model with which to study human essential hypertension. Previous studies have characterized renal morphology, juxtaglomerular index, hematocrit, prostaglandin levels, brain catecholamines, social behavior, and patterns of inheritance. The present study continues the phenotypic characterization of this animal model. Using desiccation, isotope dilution, and clearance, the total body water, extracellular fluid volume, and glomerular filtration rate (GFR) in hypertensive and normotensive animals during normal postnatal development were measured. Additionally, using an electron microscopic tracer, the relative permeabilities of the glomerular filter in these animals were assessed. The data indicate a volume expansion in the young hypertensive animals along with a reduction in GFR. As the animals mature the volume expansion in the hypertensives subsides and is eventually reversed resulting in a lower than normal fluid volume level. The significance of the reduced GFR in the hypertensives is also diminished with age although not to the same degree as that of the fluid volume. The indication of a reduced glomerular permeability may account for the above in light of Guyton's cascade hypothesis.     

Glomerular filtration barrier in experimental endotoxin shock: a histopathological and physiopathological study

In the present work a morphopathological study is carried out of the glomerular filtration barrier in 20 Large-White pigs weighing 20 kg, subjected to experimental intravenous inoculations of endotoxin from Salmonella enteritidis. The study is completed with the determination of protein plasmatic levels, through urine test with the determination of pH, density, proteins, glucose, ketone body levels and urinary sediment. The histopathological and physiopathological results reveal alterations at the level of the filtration barrier with quantitative differences between the different experimental groups.     

Instantaneous mutation rate in cancer initiation and progression

Background

Cancer is one of the leading causes for the morbidity and mortality worldwide. Although substantial studies have been conducted theoretically and experimentally in recent years, it is still a challenge to explore the mechanisms of cancer initiation and progression. The investigation for these problems is very important for the diagnosis of cancer diseases and development of treatment schemes.

Results

To accurately describe the process of cancer initiation, we propose a new concept of gene initial mutation rate based on our recently designed mathematical model using the non-constant mutation rate. Unlike the widely-used average gene mutation rate that depends on the number of mutations, the gene initial mutation rate can be used to describe the initiation process of a single patient. In addition, we propose the instantaneous tumour doubling time that is a continuous function of time based on the non-constant mutation rate. Our proposed concepts are supported by the clinic data of seven patients with advanced pancreatic cancer. The regression results suggest that, compared with the average mutation rate, the estimated initial mutation rate has a larger value of correlation coefficient with the patient survival time. We also provide the estimated tumour size of these seven patients over time.

Conclusions

The proposed concepts can be used to describe the cancer initiation and progression for different patients more accurately. Since a quantitative understanding of cancer progression is important for clinical treatment, our proposed model and calculated results may provide insights into the development of treatment schemes and also have other clinic implications.

     

Initial filtration rate and initial clogging in the Hemorheometre

The role of different factors contributing to red cell filterability in the Hemorheometre has been investigated. Although the original method uses a small volume of suspension to determine red cell filterability, the present experiments showed that the results obtained are still significantly affected by filter clogging. Consequently a change in filterability could be due to a change in filter clogging possibly by residual leucocytes. An adaptation of filter chamber and filling method is described, resulting in a simpler and faster measuring procedure. The inaccuracy in measuring low haematocrits contributes significantly to experimental errors. Therefore a definition of red cell filterability based on the red cell count (instead of haematocrit) of the suspension is suggested.