Rapid Loss Of Kidney Function Research Articles

Serum Calcitriol Concentrations and Kidney Function Decline, Heart Failure, and Mortality in Elderly Community-Living Adults: The Health, Aging, and Body Composition Study

Lower 25-hydroxyvitamin D concentrations have been associated with risk for kidney function decline, heart failure, and mortality. However, 25-hydroxyvitamin D requires conversion to its active metabolite, calcitriol, for most biological effects. The associations of calcitriol concentrations with clinical events have not been well explored. Case-cohort study. Well-functioning community-living older adults aged 70 to 79 years at inception who participated in the Health, Aging, and Body Composition (Health ABC) Study. Serum calcitriol measured using positive ion electrospray ionization-tandem mass spectrometry. Major kidney function decline (≥30% decline in estimated glomerular filtration rate from baseline), incident heart failure (HF), and all-cause mortality during 10 years of follow-up. Baseline calcitriol concentrations were measured in a random subcohort of 479 participants and also in cases with major kidney function decline [n=397]) and incident HF (n=207) during 10 years of follow-up. Associations of serum calcitriol concentrations with these end points were evaluated using weighted Cox regression to account for the case-cohort design, while associations with mortality were assessed in the subcohort alone using unweighted Cox regression. During 8.6 years of mean follow-up, 212 (44%) subcohort participants died. In fully adjusted models, each 1-standard deviation lower calcitriol concentration was associated with 30% higher risk for major kidney function decline (95% CI, 1.03-1.65; P=0.03). Calcitriol was not significantly associated with incident HF (HR, 1.16; 95% CI, 0.94-1.47) or mortality (HR, 1.01; 95% CI, 0.81-1.26). We observed no significant interactions between calcitriol concentrations and chronic kidney disease status, baseline intact parathyroid or fibroblast factor 23 concentrations. Observational study design, calcitriol measurements at a single time point, selective study population of older adults only of white or black race. Lower calcitriol concentrations are independently associated with kidney function decline in community-living older adults. Future studies will be needed to clarify whether theseassociations reflect lower calcitriol concentrations resulting from abnormal kidney tubule dysfunction or direct mechanisms relating lower calcitriol concentrations to more rapid loss of kidney function.

Autonomic nervous system in acute kidney injury.

Acute kidney injury (AKI) is a rapid loss of kidney function resulting in accumulation of end metabolic products and associated abnormalities in fluid, electrolyte and acid-base homeostasis. The pathophysiology of AKI is complex and multifactorial involving numerous vascular, tubular and inflammatory pathways. Neurohumoral activation with heightened activity of the sympathetic nervous system and renin-angiotensin-aldosterone system play a critical role in this scenario. Inflammation and/or local renal ischaemia are underlying mechanisms triggering renal tissue hypoxia and resultant renal microcirculation dysfunction; a common feature of AKI occurring in numerous clinical conditions leading to a high morbidity and mortality rate. The contribution of renal nerves to the pathogenesis of AKI has been extensively demonstrated in a series of experimental models over the past decades. While this has led to better knowledge of the pathogenesis of human AKI, therapeutic approaches to improve patient outcomes are scarce. Restoration of autonomic regulatory function with vagal nerve stimulation resulting in anti-inflammatory effects and modulation of centrally-mediated mechanisms could be of clinical relevance. Evidence from experimental studies suggests that a therapeutic splenic ultrasound approach may prevent AKI via activation of the cholinergic anti-inflammatory pathway. This review briefly summarizes renal nerve anatomy, basic insights into neural control of renal function in the physiological state and the involvement of the autonomic nervous system in the pathophysiology of AKI chiefly due to sepsis, cardiopulmonary bypass and ischaemia/reperfusion experimental model. Finally, potentially preventive experimental pre-clinical approaches for the treatment of AKI aimed at sympathetic inhibition and/or parasympathetic stimulation are presented.

Protective effects of sirtuin 3 in a murine model of sepsis-induced acute kidney injury.

Acute kidney injury (AKI) is a rapid loss of kidney function characterized by damage to renal tubular cells driven by mitochondrial dysregulation and oxidative stress. Here, we used a murine caecal ligation and puncture (CLP) model of sepsis-induced AKI to study the role of sirtuin 3 (SIRT3), a NAD+ dependent deacetylase critical for the maintenance of mitochondrial viability, in AKI-related renal tubular cell damage and explored the underlying mechanisms. CLP induced alterations in kidney function and morphology were associated with SIRT3 downregulation, and SIRT3 deletion exacerbated CLP-induced kidney dysfunction, renal tubular cell injury and apoptosis, mitochondrial alterations, and ROS production in a knockout mouse model. SIRT3 deletion increased the CLP-induced upregulation of the NLRP3 inflammasome and apoptosis-associated speck-like protein, resulting in the activation of oxidative stress, increased production of the proinflammatory cytokines interleukin (IL)-1β and IL-18, and the enhancement of apoptosis, and these effects were reversed by antioxidant NAC. Our results suggest that SIRT3 plays a protective role against mitochondrial damage in the kidney by attenuating ROS production, inhibiting the NRLP3 inflammasome, attenuating oxidative stress, and downregulating IL-1β and IL-18.

Inflammation and Progression of CKD: The CRIC Study.

CKD is a global public health problem with significant mortality and morbidity. We examined the multivariable association of plasma levels of IL-1, IL-1 receptor antagonist, IL-6, TNF-α, TGF-β, high-sensitivity C-reactive protein, fibrinogen, and serum albumin with progression of CKD in 3430 Chronic Renal Insufficiency Cohort study participants. Over a median follow-up time of 6.3 years, 899 participants reached the composite end point of ≥50% decline in eGFR from baseline or onset of ESRD. Elevated plasma levels of fibrinogen, IL-6, and TNF-α and lower serum albumin were associated with a greater decline in eGFR over time. After adjusting for demographics, BP, laboratory variables, medication use, and baseline eGFR, hazard ratios for the composite outcome were greater for the patients in the highest quartile of fibrinogen (hazard ratio, 2.05; 95% confidence interval, 1.64 to 2.55; P<0.001), IL-6 (hazard ratio, 1.44; 95% confidence interval, 1.17 to 1.77; P<0.01), and TNF-α (hazard ratio, 1.94; 95% confidence interval, 1.52 to 2.47; P<0.001) compared with those in the respective lowest quartiles. The hazard ratio was 3.48 (95% confidence interval, 2.88 to 4.21; P<0.001) for patients in the lowest serum albumin quartile relative to those in the highest quartile. When also adjusted for albuminuria, the associations of fibrinogen (hazard ratio, 1.49; 95% confidence interval, 1.20 to 1.86; P<0.001), serum albumin (hazard ratio, 1.52; 95% confidence interval, 1.24 to 1.87; P<0.001), and TNF-α (hazard ratio, 1.42; 95% confidence interval, 1.11 to 1.81; P<0.001) with outcome were attenuated but remained significant. Elevated plasma levels of fibrinogen and TNF-α and decreased serum albumin are associated with rapid loss of kidney function in patients with CKD.

The Role of Par‐1a/b Polarity Proteins in Acute Kidney Injury

Acute Kidney Injury (AKI) is defined as the rapid loss of kidney function. Patients with acute kidney injury are unable to filter waste products from their body. The integrity of renal epithelial apico‐basal polarity is critical for many aspects of kidney function, including reabsorption of solutes. Loss of epithelial cell polarity occurs in several kidney disorders, including acute kidney injury. Partitioning defective 1 (Par‐1) is a member of the Par polarity protein family that localizes to the basolateral aspect of cells. Studies of Par‐1a+/−:Par‐1b−/− and Par‐1a−/−:Par‐1b+/− newborn mice determined that Par‐1 contributes to proximal tubular development. Complete loss of Par‐1a/b (Par‐1a−/−: Par‐1b−/−) leads to death early in fetal development of mice. Par‐1a and Par‐1b are expressed in developing nephrons and their expression decreases in adult nephrons. Tubular injury in mice correlates with increased expression of Par‐1a and Par‐1b. In our research, we hypothesized that Par‐1a/b polarity proteins are protective in the setting of acute kidney injury. In order to test this, cisplatin was injected intraperitoneal into Par‐1a/b global knockout mice at 5 weeks and they were sacrificed 3 days after injection. Cisplatin is one of the most widely used chemotherapy drugs that has been recently found to contribute to nephrotoxicity, especially on the signaling pathways leading to renal tubular cell death and inflammation. Hematoxylin and Eosin (H&amp;E) staining was performed to assess tubular injury. Controls were non‐injected Par‐1a−/− and Par‐1b−/− mutants and injected wild type littermates. Ki‐67 staining was performed to identify cell proliferation. The level of tubular injury and cellular proliferation was examined by light microscopy. Our data showed that Par‐1b knockout mice were more susceptible to renal tubular injury than controls. Par‐1b knockout mice also had decreased cellular proliferation after cisplatin injury. Our ongoing experiment is testing the role of Par‐1a in AKI. In conclusion, Par‐1b polarity proteins contribute to renal tubular epithelial response to injury. Either decreased or delayed cellular proliferation may contribute to the increased tubular injury in Par‐1b−/− mice.Support or Funding InformationThis research was supported by American Physiological Society (APS) Short‐Term Research Experience for Underrepresented Persons (STEP‐UP) program, NIH NIDDK K08 5K08DK091507, R03 DK105242, and T32 DK007110. Thank you to Dr. Piwnica‐Worms for the Par‐1b+/− mice.

The Effect of Autophagy on Inflammation Cytokines in Renal Ischemia/Reperfusion Injury.

Acute kidney injury (AKI) is characterized by a rapid loss of kidney function and an antigen-independent inflammatory process that causes tissue damage, which was one of the main manifestations of kidney ischemia/reperfusion (I/R). Recent studies have demonstrated autophagy participated in the pathological process of acute kidney injury. In this study, we discuss how autophagy regulated inflammation response in the kidney I/R. AKI was performed by renal I/R. Autophagy activator rapamycin (Rap) and inhibitor 3-methyladenine (MA) were used to investigate the role of autophagy on kidney function and inflammation response. After the experiment, kidney tissues were obtained for the detection of autophagy-related protein microtubule-associated protein light chain 3(LC3)II, Beclin1, and Rab7 and lysosome-associated membrane protein type (LAMP)2 protein by reverse transcription-polymerase chain reaction (PT-PCR) and Western blotting, and histopathology and tissue injury scores also. The blood was harvested to measure kidney function (creatinine (Cr) and blood urea nitrogen (BUN) levels) after I/R. Cytokines TNF-α, IL-6, HMGB1, and IL-10 were measured after I/R. I/R induced the expression of LC3II, Beclin1, LAMP2, and Rab7. The activation and inhibition of autophagy by rapamycin and 3-MA were promoted and attenuated histological and renal function in renal I/R rats, respectively. Cytokines TNF-α, IL-6, and HMGB1 were decreased, and IL-10 was further increased after activation of autophagy treated in I/R rats, while 3-MA exacerbated the pro-inflammatory cytokines TNF-α, IL-6, HMGB1, and anti-inflammatory cytokine IL-10 in renal I/R. I/R can activated the autophagy, and autophagy increase mitigated the renal injury by decreasing kidney injury score, levels of Cr and BUN after renal I/R, and inflammation response via regulating the balance of pro-inflammation and anti-inflammation cytokines.

Association of age and BMI with kidney function and mortality: a cohort study

Compared with normal weight, obesity might be associated with worse clinical outcomes, including chronic kidney disease. Whether this association is modified by age is not known. We investigated the association of BMI with progressive loss of kidney function and all-cause mortality in US veterans. In a national cohort of 3,376,187 US veterans with an estimated glomerular filtration rate (eGFR) of more than 60 mL/min per 1·73 m(2), we assessed the association of BMI in patients of different ages (<40 years, 40 years to <50 years, 50 years to <60 years, 60 years to <70 years, 70 years to <80 years, and ≥80 years) with loss of kidney function and with all-cause mortality in logistic regression models and Cox proportional hazards models adjusted for ethnic origin, sex, comorbidities, medications, and baseline eGFR. 274,764 (8·1%) of 3,376,187 veterans had a rapid decline in kidney function (decrease in slope of >5 mL/min per 1·73 m(2)). The lowest risk for loss of kidney function was noted in patients with BMI of at least 25 kg/m(2) but less than 30 kg/m(2). A generally consistent U-shaped association was noted between BMI and rapid loss of kidney function that was more prominent with increasing age, except in the patients younger than 40 years, in whom BMI did not seem to be predictive of renal function impairment. 672,341 veterans died (28·7 per 1000 patient-years, 95% CI 28·6-28·7) over a median follow-up of 6·8 years (IQR 6·5-7·7). BMI also showed a U-shaped association with mortality, which was similar in all age groups. A BMI of 30 kg/m(2) or more is associated with rapid loss of kidney function in patients with eGFR of at least 60 mL/min per 1·73 m(2), and this association is accentuated in older patients. A BMI of 35 kg/m(2) or more is also associated with high mortality. A BMI of at least 25 kg/m(2) but less than 30 kg/m(2) is associated with the best clinical outcomes. National Institute of Health, Memphis VA Medical Center, Long Beach VA Healthcare System, Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development, and VA Information Resource Center.

TRPs in the kidney - location, location, location

TRPs in the kidney - location, location, location

DNA methylation profile associated with rapid decline in kidney function: findings from the CRIC Study

Epigenetic mechanisms may be important in the progression of chronic kidney disease (CKD). We studied the genome-wide DNA methylation pattern associated with rapid loss of kidney function using the Infinium HumanMethylation 450 K BeadChip in 40 Chronic Renal Insufficiency (CRIC) study participants (n = 3939) with the highest and lowest rates of decline in estimated glomerular filtration rate. The mean eGFR slope was 2.2 (1.4) and -5.1 (1.2) mL/min/1.73 m(2) in the stable kidney function group and the rapid progression group, respectively. CpG islands in NPHP4, IQSEC1 and TCF3 were hypermethylated to a larger extent in subjects with stable kidney function (P-values of 7.8E-05 to 9.5E-05). These genes are involved in pathways known to promote the epithelial to mesenchymal transition and renal fibrosis. Other CKD-related genes that were differentially methylated are NOS3, NFKBIL2, CLU, NFKBIB, TGFB3 and TGFBI, which are involved in oxidative stress and inflammatory pathways (P-values of 4.5E-03 to 0.046). Pathway analysis using Ingenuity Pathway Analysis showed that gene networks related to cell signaling, carbohydrate metabolism and human behavior are epigenetically regulated in CKD. Epigenetic modifications may be important in determining the rate of loss of kidney function in patients with established CKD.

A novel mechanism of NALP3 inducing ischemia reperfusion injury by activating MAPK pathway in acute renal failure

Acute renal failure (ARF) is a rapid loss of kidney function. The reasons and mechanism by which this occurs has not been clarified so far thus creating obstacles to management of this disease. Presently, the experimental research using the accepted renal ischemia reperfusion injury (I/R injury) model represented for ARF focuses on several possible relevant factors such as reactive oxygen species, no-reflow phenomenon, apoptosis and extensive inflammatory response. The latter is much talked about currently. Some intracellular danger sensing proteins, such as the nucleotide binding domain leucine rich repeats-containing family proteins known as NLRs, adjust the inflammatory response through the formation of a multi-protein complex known as an inflammasome. The most classic family member of this complex is NALP3 confirmed to serve as a contributor to I/R injury. However, how it contributes to the pathology remains obscure. The extensive inflammatory response is considered to be modulated by the mitogen-activated protein kinases (MAPK) signaling pathway. NOD2, another family member of NLR, which shares similar structure with NALP3, indicated that it induced the activation of MAPK in response to a pathogen, thus we assumed that NALP3 performed the harmful process of I/R injury, resulting probably from the activation of the MAPK signaling pathway. If this hypothesis proves to be correct, it might benefit the management of ARF.

Epidemiology and optimal management in patients with renal artery stenosis

Renovascular hypertension (hypertension induced by renal artery stenosis) is a form of secondary hypertension caused by overactivation of the renin-angiotensin system by the ischemic kidney. Prevalence of renal artery stenosis (RAS) is estimated to be between 2% (unselected hypertensives) and 40% (older patients with other atherosclerotic comorbidities). Most cases of RAS are caused by atherosclerosis; other causes, including fibromuscular dysplasia, vasculitis, thromboembolism and aneurysms, are less frequent. The most frequent clinical presentation of RAS is hypertension. Acute kidney injury, rapid loss of kidney function and episodes of flash pulmonary edema are other symptoms of RAS, especially in bilateral disease. In current practice, RAS therapy includes antiplatelet (aspirin) and lipid-lowering (statin) therapy as well as angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors as a first choice of antihypertensive agents. Angiotensin blockade, however, is contraindicated in bilateral RAS and in RAS of the solitary kidney. This review summarizes the current status and perspectives on the epidemiology and management of renovascular hypertension.

Prognostic Indicators of Renal Disease Progression in Adults with Fabry Disease

These analyses were designed to characterize renal disease progression in untreated adults with Fabry disease. Data from the Fabry Registry for 462 untreated adults (121 men and 341 women) who had at least two estimated GFR (eGFR) values over a span of ≥12 months before starting enzyme replacement therapy were included. Most men (86 of 121, 71%) had more rapid loss of kidney function than the normal adult population (loss of eGFR > -1 ml/min per 1.73 m(2) per year), whereas fewer women (133 of 341, 39%) had rapid loss of kidney function. Patients with rapid progression had significantly higher mean averaged urinary protein to urinary creatinine ratios (UP/Cr) than patients with slower progression (1.5 versus 0.2 for men; 1.4 versus 0.5 for women; P < 0.0001). Patients were grouped into quartiles based on averaged UP/Cr; renal function in men declined more rapidly with higher UP/Cr, with the steepest declines observed in men with UP/Cr > 1.5 (mean eGFR slope, -5.6 ml/min per 1.73 m(2) per year; n = 30). eGFR slope declined more slowly in women, with the steepest declines observed in women with UP/Cr > 1.2 (mean eGFR slope, -1.3 ml/min per 1.73 m(2) per year; n = 85). Regression models of eGFR slope indicated that UP/Cr is the most important indicator of renal disease progression in adult Fabry patients. In women, lower baseline eGFR and age were also associated with renal disease progression. Women who had clinical events had more rapid loss of kidney function. Urinary protein excretion is strongly associated with renal disease progression in men and women with Fabry disease.

Is Collapsing C1q Nephropathy Another MYH9-Associated Kidney Disease? A Case Report

C1q nephropathy is a rare kidney disease that can present with nephrotic syndrome and typically has the histologic phenotype of either minimal change disease or focal segmental glomerulosclerosis (FSGS). Disagreement exists about whether it is a distinct immune complex-mediated glomerulopathy or it resides in the spectrum of FSGS-minimal change disease. Two African American patients with C1q nephropathy histologically presenting as the collapsing variant of FSGS (collapsing C1q nephropathy) and rapid loss of kidney function were genotyped for polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9). Both cases were homozygous for the MYH9 E1 risk haplotype, the variant strongly associated with idiopathic FSGS, collapsing FSGS in human immunodeficiency virus-associated nephropathy, and focal global glomerulosclerosis (historically attributed to hypertensive nephrosclerosis). Collapsing C1q nephropathy with rapid progression to end-stage renal disease appears to reside in the MYH9-associated disease spectrum.

It's about Time

It is widely accepted that chronic kidney disease (CKD) associates with accelerated cardiovascular disease and a higher rate of death than would occur otherwise.1 These associations are based on studies of patients who had low renal function identified at a single point in time or, at most, two measurements separated by 3 mo to confirm chronicity. When caring for patients with CKD, we, too, generally estimate risk on the basis of single time point measurements of renal function. For example, a 65-yr-old man with a GFR of 80 ml/min per 1.73 m2 has an estimated risk for death of 12% during the subsequent 5 yr; however, if his GFR is 40 ml/min per 1.73 m2, then this risk is at least doubled.1 In this issue of JASN, Shlipak et al.2 determined whether changes in kidney function during the first 7 yr of the Cardiovascular Health Study associated with increased cardiovascular risk during the subsequent 8 yr. The authors compared 1083 community-dwelling, ambulatory older adults with rapid declines in kidney function to 3295 adults without rapid decline. At baseline, participants were an average age of 72 yr, and 14% had diabetes. The incidence of cardiovascular disease was significantly higher in individuals with rapid declines in kidney function (defined as an annual decline in cystatin C–based eGFR >3 ml/min per 1.73 m2), even after multivariable adjustment for demographics, average kidney function, and established cardiovascular disease risk factors. Specifically, the hazard for heart failure increased by 24% for rapid decliners, whereas for myocardial infarction and peripheral arterial disease, the hazard was 42 and 67% higher, respectively. Nephrologists naturally appreciate that a more rapid loss of kidney function over time associates with a greater risk for kidney failure. With these results, Shlipak et al.2 advance the concept that patterns of kidney function over time can also be used to appreciate cardiovascular risk better: A more rapid loss of kidney function associates with greater risk for cardiovascular disease. Whether this is a causal relationship is still a matter of ongoing debate. Of note, patients enrolled in the Cardiovascular Health Study are those typically followed by primary care physicians and not nephrologists, because the average eGFR at the start of follow-up was 79 ml/min per 1.73 m2. Evaluating changes in an exposure, such as kidney function over time, also represents a change in modern epidemiology. Traditionally, exposures have been modeled as static conditions, assessed at a single point in time. In the case of CKD, people with declining kidney function are classified in the same risk group as those with diminished but stable renal function. However, exposures of interest to epidemiologists are, in truth, seldom constant.3 Some studies have characterized exposure–response relationships as dynamic entities, changing in time.4,5 Such studies typically require larger amounts of data over a longer period of time, which is increasingly possible with larger clinical studies and electronic medical records. There is also a growing sophistication to statistical analysis. Shlipak et al.2 used traditional survival analysis methods, accounting for changes in renal function over time with fixed-covariate values. Others have used time-dependent covariates,6 which can now be modeled for proportional hazards regression in most statistical software packages.7 Certainly, there are additional efforts required to characterize an exposure over time, yet the payoff for such efforts can be an improvement in our interpretation of evidence around exposure–disease relationships. With their study, Shilpak et al.2 extend our mechanistic understanding of the kidney–cardiovascular relationship by acknowledging the importance of time and trajectory of kidney function decline. From an epidemiologic perspective, the Greek leader Pericles (perhaps, unknowingly) said it best: “Time may be the wisest counselor of all.” Disclosures A.Y. was supported by a Doctoral Research Award from the Canadian Institutes of Health Research. A.X.G. was supported by a Clinician Scientist Award from the Canadian Institutes of Health Research.

Crescentic Glomerulonephritis With Ribbon-like Immunofluorescence Pattern

Crescentic glomerulonephritis (GN) is characterized by extensive glomerular crescents (>50% glomeruli) and rapid loss of kidney function, often described as rapidly progressive GN. Crescentic GN can be categorized as pauci-immune type, anti–glomerular basement membrane (anti-GBM) nephritis, and immune complex–mediated process, primarily based on immunofluorescence microscopy (IF) and electron microscopy (EM). Although both pauci-immune and anti-GBM nephritis lack electron-dense deposits, the latter is characterized by linear IF staining with immunoglobulin G (IgG).

Oral estrogen therapy in postmenopausal women is associated with loss of kidney function

Women are generally protected against progressive loss of kidney function; however, this advantage seems to diminish with menopause. Because of conflicting reports on the association between use of hormone therapy and kidney function we studied 5845 women (1459 on hormone therapy and 4386 non-users) who were over 66 years of age and had at least 2 serum creatinine measurements during the 2 year study period. After adjustment for covariates, hormone use (estrogen-only, progestin-only, or both) was associated with a significant loss of estimated GFR as the primary outcome along with an increased risk of rapid loss of kidney function as the secondary outcome compared to non-users. This increased rate of loss was associated with oral but not transvaginal estrogen use. An increased cumulative dose of estrogen was also associated with a greater decline in estimated GFR. Our study shows an independent association in a dose-dependent manner of estrogen use and loss of kidney function in this elderly population.

Prevalence of Chronic Kidney Disease and Survival among Aboriginal People

Globally, it is known that the incidence of end-stage renal disease is higher among Aboriginals, but it is unknown whether this is due to an increased prevalence of chronic kidney disease or other unidentified factors. We studied 658,664 people of non-First Nations and 14,989 people of First Nations and found that the age- and sex-adjusted prevalence of chronic kidney disease was significantly higher among those of non-First Nations compared to those of First Nations (67.5 versus 59.5 per 1000 population; P < 0.0001). However, severe chronic kidney disease (estimated glomerular filtration rate <30 ml/min per 1.73 m2) was almost two-fold higher among people of First Nations (P < 0.0001). Cox proportional hazards models suggested that compared to people of non-First Nations, those of First Nations with chronic kidney disease had a 77% increased risk of death after adjusting for age, gender, diabetes and baseline eGFR. In conclusion, whether the higher incidence of end-stage renal disease among people of First Nations is due to suboptimal management of chronic kidney disease and its associated comorbidities, more rapid loss of kidney function, or other unidentified factors remains to be determined.