03234705428Kidney IntKidney Int.Kidney international0085-25381523-175525272234438242010.1038/ki.2014.330NIHMS624902ArticleElevation of circulating TNF receptors 1 and 2 increases the risk of
end-stage renal disease in American Indians with type 2 diabetesPAVKOVMEDA E.MD, PHD1NELSONROBERT G.MD, PHD2KNOWLERWILLIAM C.MD, DRPH2CHENGYILINGMD1KROLEWSKIANDRZEJ S.MD, PHD34NIEWCZASMONIKA A.MD, PHD34Division of Diabetes Translation, Centers for Disease Control and
Prevention, Atlanta, GADiabetes Epidemiology and Clinical Research Section, National Institute of
Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZResearch Division, Joslin Diabetes Center, Boston, MADepartment of Medicine, Harvard Medical School, Boston, MACorresponding author: Dr. Robert G. Nelson, National Institutes of Health,
1550 East Indian School Road, Phoenix, AZ 85014-4972 USA., rnelson@nih.gov,
Telephone: (602) 200-5205, Facsimile: (602) 200-52251792014011020144201501102015874812819
In Caucasians with type 2 diabetes, circulating TNF receptors 1 (TNFR1) and 2
(TNFR2) predict end-stage renal disease (ESRD). Here we examined this relationship in a
longitudinal cohort study of American Indians with type 2 diabetes with measured
glomerular filtration rate (mGFR, iothalamate) and urinary albumin-to-creatinine ratio.
ESRD was defined as dialysis, kidney transplant, or death attributed to diabetic kidney
disease. Age-gender-adjusted incidence rates and incidence rate ratios of ESRD were
computed by Mantel-Haenszel stratification. The hazard ratio of ESRD was assessed per
interquartile range increase in the distribution of each TNFR after adjusting for baseline
age, gender, mean blood pressure, HbA1c, albumin-to-creatinine ratio, and mGFR. Among the
193 participants, 62 developed ESRD and 25 died without ESRD during a median follow-up of
9.5 years. The age-gender-adjusted incidence rate ratio of ESRD was higher among
participants in the highest vs. lowest quartile for TNFR1 (6.6, 95% CI
3.3–13.3) or TNFR2 (8.8, 95% CI 4.3–18.0). In the fully adjusted
model, the risk of ESRD per interquartile range increase was 1.6 times (95% CI
1.1–2.2) as high for TNFR1 and 1.7 times (95% CI 1.2–2.3) as high
for TNFR2. Thus, elevated serum concentrations of TNFR1 or TNFR2 are associated with
increased risk of ESRD in American Indians with type 2 diabetes after accounting for
traditional risk factors including albumin-to-creatinine ratio and mGFR
Inflammatory processes play an important role in the pathophysiology of diabetic
kidney disease. Inflammatory cells have been observed in kidney tissue biopsies from
streptozocin-treated diabetic rats1 and
patients with various degrees of diabetic glomerulosclerosis.2 Moreover, inflammatory markers, including tumor necrosis
factor (TNFα) and its receptors TNFR1 and TNFR2, are associated with progression of
diabetic kidney disease. TNFα is the main ligand for both TNFR1 and TNFR2. Depending
on a number of local factors and the activation of the two receptors, TNFα induces
different and sometimes contrasting effects.3
These effects have been observed mostly in vitro and may not be specific to a particular cause
of renal disease. Activated TNFR1 is the primary receptor mediating tissue injury through
proinflammatory signals and/or cell death, whereas TNFR2 may promote cell migration,
regeneration and proliferation and regulates TNFR1 induced apoptosis.4 In addition, TNFR2 may have a synergistic effect with TNFR1
by ligand passing, a process in which TNFR2-bound TNFα increases the local
TNFα concentration in the vicinity of TNFR1.5 TNFR1 and TNF-related apoptosis-inducing ligand (TRAIL) have been
implicated in pancreatic β-cell destruction associated with type 1 diabetes;6,7 TRAIL
correlates positively with body fat and serum LDL cholesterol in elderly subjects,8 and was shown to induce insulin
resistance.9,10 TRAIL gene deletion in ApoE−/− mice fed a high-fat diet
resulted in increased systemic inflammation, diabetes, accelerated atherosclerosis,11 suggesting that TRAIL may play a role in the
development of diabetes and its macro- and micro-vascular complications.
Circulating levels of TNFRs have recently emerged as very robust and independent
predictors of the progression of diabetic kidney disease in the Joslin Kidney Study.
12–14 In that study, elevated concentrations of circulating TNFR1 and 2 were
strongly associated with subsequent end-stage renal disease (ESRD) in predominantly Caucasian
subjects with type 2 diabetes after accounting for several risk factors for kidney disease
present at baseline, including HbA1c, albuminuria, glomerular filtration rate (GFR), free and
bound TNFα, markers of endothelial dysfunction and markers of systemic
inflammation.13
To evaluate the role of circulating TNFRs in a population at high risk of renal
function decline, we examined the relationship between serum concentrations of TNFR1 and TNFR2
and progression to ESRD in American Indians with type 2 diabetes.
RESULTS
The study included 193 subjects with type 2 diabetes, followed for a median of 9.5
years (interquartile range 7.1–11.6 years). During follow-up, 62 (32%) of
the participants developed ESRD and 25 (13%) died from natural causes other than
diabetic kidney disease without progressing to ESRD. Baseline characteristics of the cohort
are summarized in Table 1. At baseline, 127 subjects
(65.8%) were receiving glucose lowering medicines and 12 (6.2%) were
receiving antihypertensive medicines. 61 participants (32%) had normal ACR, 72
(37%) had moderate albuminuria, and 60 (31%) had severe albuminuria; mGFR
was ≥60 ml/min in 171 participants (89%). The frequency distributions of
serum concentrations of TNFR1 and TNFR2 at baseline are shown in Figure 1. Median serum concentrations of the receptors were 2833
pg/ml and 4835 pg/ml, respectively, and both distributions were skewed.
Serum concentrations of TNFR1 and TNFR2 correlated strongly with each other
(r=0.78) and moderately with mGFR, cystatin C, ACR, age, MAP, and duration of
diabetes; they did not correlate significantly with HbA1c, BMI (Table 2). The correlations between the serum concentrations of the
receptors and ACR are shown in Figure 2
(r=0.37, P<0.001 for TNFR1, r=0.42,
P<0.001 for TNFR2).
Unadjusted and age-sex-adjusted incidence rates of ESRD are shown in Table 3 by quartiles of TNFR1 and TNFR2. Compared with the lowest
quartile of TNFR1, the age-sex-adjusted incidence rate of ESRD was significantly higher
among subjects in the third and fourth quartiles of TNFR1 (IRR for third quartile
=2.4, 95% CI 1.01–5.7; IRR for fourth quartile =6.6,
95% CI 3.3–13.3). The age-sex-adjusted incidence of ESRD was significantly
higher among subjects in the third and fourth quartiles of TNFR2 versus the lowest quartile
(IRR for third quartile= 2.8, 95% CI 1.2–6.4; IRR for fourth
quartile=8.8, 95% CI 4.3–18.0).
Figure 3 shows the cumulative incidence of
ESRD at 10 years of follow-up, when 48 of the 62 cases of ESRD had occurred, according to
the level of albuminuria and TNFRs. The highest quartile of each TNFR is compared with the
lowest three quartiles combined. Among participants with severe albuminuria, the cumulative
incidence of ESRD at 10 years of follow-up was 96.2% in those in the highest TNFR1
quartile at baseline and 44.6% in those in lower TNFR1 quartiles (p<0.001).
Similarly, for TNFR2 the cumulative incidence of ESRD was 88.7% and 47.3%,
respectively (p<0.001). Among participants without severe albuminuria, the 10-year
cumulative incidence of ESRD was 14.4% and 6.1% in the highest and lower
TNFR1 quartiles, respectively (p=0.51), and 26.9% and 4.7% in the
highest and lower TNFR2 quartiles, respectively (p=0.049).
In the Cox regression analysis, 26 participants were censored at the time of death
(25 deaths due to natural causes and 1 death due to injury of external cause) and 105 were
administratively censored at the end of follow-up (December 31, 2013). Unadjusted hazard
ratio for ESRD per interquartile range increase of TNFR1 was 2.5 (95% CI
2.1–3.1) and for TNFR2 was 2.5 (95% CI 2.1–3.0). Adjusted for age,
sex, HbA1c, MAP, ACR and mGFR, the incidence of ESRD was 1.6 times (95% CI
1.1–2.2) as high per interquartile range increase in the distribution of TNFR1 and
1.7 times (95% CI 1.2–2.3) as high per interquartile range increase in the
distribution of TNFR2. The univariate and multivariate models are shown in Table 4.
For the Cox regression model that included baseline clinical covariates alone
(i.e., age, sex, HbA1c, MAP, and ACR), the C-index for predicting ESRD was 0.858. The
C-index for clinical covariates plus mGFR was 0.880; for clinical covariates plus TNFR1
0.873; and for clinical covariates plus TNFR2 0.879; each of these markers significantly
increased the C-index for predicting ESRD (P<0.001). After additional
adjustment for mGFR, the C-index for predicting ESRD increased from 0.880 to 0.887 for TNFR1
(P=0.006) and to 0.888 for TNFR2
(P=0.002, Table 5).
DISCUSSION
Circulating TNFR1 and TNFR2 were strongly associated with risk of progression to
ESRD in American Indians with type 2 diabetes and mostly preserved kidney function. These
associations were present after accounting for the effects of clinically recognized risk
factors, including HbA1c, blood pressure, ACR, and mGFR. In Cox regression models adjusting
for the traditional clinical covariates, the hazard ratio for ESRD increased nearly 2 times
per interquartile range increase in the distribution of TNFR1 or TNFR2. Both receptors
enhanced the discrimination of the survival models for ESRD beyond that achievable by the
clinically recognized risk factors when examined using the C-index. These findings suggest
that either receptor may be used as an early predictor of ESRD.
Our findings confirm the important role of circulating levels of TNFRs as
predictors of risk of ESRD as previously reported in 410 predominantly Caucasian subjects
with type 2 diabetes participating in the Joslin Kidney Study.13 There were some differences, however, between the
results obtained in these two studies. First, the 10-year cumulative risk of ESRD among
participants in the 4th (highest) quartiles of TNFR1 and TNFR2 was higher in Pima Indians
than in Caucasians with type 2 diabetes and severe albuminuria (96% and 89%
in Pima Indians and 75% and 73% in Caucasians, respectively). This risk was
also different in subjects in quartiles 1–3 combined (45% and 47% in
Pima Indians and 16% and 20% in Caucasians, respectively). Second, in
subjects without severe albuminuria, although the 10-year cumulative risk of ESRD according
to quartiles of serum TNFRs was very similar in both populations and was higher in the 4th
quartile than in quartiles 1–3 combined, at 12-years follow-up the cumulative risk
in the Pima Indians converged for the highest and lower quartiles of TNFR1.
The absolute concentrations of circulating TNFRs in the Pima Indians were almost
twice as high as those in the Joslin Kidney Study participants. Previous studies show that
obesity is associated with macrophage accumulation and increased TNF mRNA expression in
adipose tissue15,16 and severely obese individuals (BMI~40kg/m2) have much
higher TNFR concentrations than those who are lean.17 These observations suggest that a higher degree of obesity among the
Pima Indians may be responsible for their higher TNFR concentrations, although other factors
might also be involved. Serum concentrations of TNFRs were not correlated with BMI or HbA1c,
because these variables were narrowly distributed, with most participants having high BMI
and high HbA1c. The differences in the distribution of circulating TNFRs in Pima Indians and
Caucasians indicate that the risk of ESRD is not associated with a specific threshold of
circulating TNFRs that is consistent across populations. Factors unrelated to risk of kidney
disease may also influence the concentrations of circulating TNFRs, suggesting that
population-specific risk assessment may be needed to identify subjects at high or low risk
of ESRD in type 2 diabetes. Such a requirement could diminish the clinical value of these
measures as biomarkers of diabetic kidney disease.
Circulating TNFR1 and TNFR2 were highly correlated with each other in the present
study, as in the Joslin Study. Moreover, the associations of both receptors with diabetic
kidney disease progression were equivalent. Similarities in the generation of the soluble
forms of these receptors may explain the tight correlation. It remains to be elucidated
whether alterations of the soluble form generation may be responsible for increase in TNFRs
in circulation and whether this increase contributes to kidney injury. The 55-kDa TNFR1 and
75-kDa TNFR2 are cell membrane bound receptors involved in key aspects of the immune
response. TNFR1 and TNFR2 are released into the extracellular space via inducible cleavage
of TNFR ectodomain by ADAM17.18 An
additional mechanism of the soluble form generation, the constitutive release of TNFR1
within exosome-like vesicles, was described by Levine et al. 19 The presence of circulating TNFR1 in the exosomal
fraction was confirmed in the Joslin Kidney Study subjects with diabetic kidney disease, and
the presence of TNFR2 in the exosomes and correlation of exosomal TNFRs with their
respective protein expression in leukocytes was also demonstrated.14,20 Exposure of
kidney organ culture to TNFRs increases tubular apoptosis,21 and development of fibrosis is delayed in TNFR-deficient
murine models of tubulointerstitial injury.22 Nevertheless, a particular role of TNFRs in diabetic kidney disease has
not yet been established, but the strong association between circulating TNFRs and risk of
ESRD argue for development of a diagnostic test to identify subjects at risk of ESRD in
diabetes.
Since Hasegawa et al. first demonstrated the role of TNFα pathway in the
experimental model of diabetic nephropathy,1 a number of reports have pointed to potential involvement of the
TNFα pathway in diabetic kidney disease.23,24 Experimental studies
demonstrated that TNFα-mediated mechanisms may result in vasoconstriction leading to
GFR decline, in the disruption of the glomerular barrier resulting in increased permeability
to albumin, and in the recruitment of inflammatory cells into the kidney.25 TNFα is assumed to mediate these
actions via its two TNF receptors; nevertheless most of those experimental studies did not
investigate in greater detail whether TNFRs mediated actually those biological effects of
TNFα. In humans, TNFα level is associated with diabetic
nephropathy,25,26 but these associations are weaker than for
TNFRs.12–14
We are uncertain whether TNFRs are associated with progression to ESRD in a
non-diabetic population. Circulating TNFRs were previously shown to associate with renal
function and albuminuria in subjects without diabetes, but those studies were mainly
cross-sectional or focused on more advanced stages of chronic kidney disease.27–30 In addition, TNFR1 and TNFR2 were also implicated in the development of
specific non-diabetic kidney diseases such as kidney allograft rejection, immune-complex
mediated glomerulonephritis, lupus nephritis, hepatitis C virus-associated
glomerulonephritis, obstructive renal injury, and ANCA-associated vasculitis.31–36 Whether TNFRs are also implicated in the progression of these kidney
diseases to ESRD, however, is not known.
Strengths of the study include measurement of GFR to account for differences in
baseline kidney function. In addition, the study has excellent follow-up and was conducted
in a population with a high baseline GFR. Indeed, 67 (34.7 %) subjects had
hyperfiltration, defined by an mGFR ≥154 ml/min, a value two standard deviations
above the mean mGFR for Pima Indians with normal glucose tolerance. Limitations include the
small study size, and the arbitrary distribution of circulating TNFRs into quartiles, with
the most significant differences in risk of ESRD observed between the 4th
quartile and quartiles 1–3 combined. This dose-response relationship needs to be
investigated further to identify the best diagnostic criteria to predict risk of ESRD. The
potential impact of TNFα on ESRD was not explored in this study due to insufficient
serum sample volume for measuring free and total TNFα, and the effect of TNFRs on
cardiovascular mortality was not evaluated due to the small number of cardiovascular deaths
in this study population. Moderate associations of circulating TNFRs with cardiovascular
mortality (but weaker than for progression to ESRD) were suggested elsewhere.13,37
In conclusion, elevated serum concentrations of TNFR1 or TNFR2 are associated with
an increased risk of ESRD in American Indians with type 2 diabetes after accounting for
traditional risk factors including ACR and GFR. Absolute concentrations of these receptors
in the serum are substantially higher than in a Caucasian type 2 diabetes population,
suggesting that population-specific risk assessment may be needed to identify subjects with
type 2 diabetes who are at high or low risk of ESRD.
MATERIALS AND METHODSStudy participants
Between 1965 and 2007, American Indians from the Gila River Indian Community
participated in a longitudinal study of diabetes and its complications. Each member of
this community who was at least 5 years old was invited to have a research examination
approximately every 2 years. Diabetes was diagnosed by a 2-hour post-load plasma glucose
concentration ≥200 mg/dl (11.1 mmol/l) at these biennial examinations, or when the
diagnosis was documented in the medical record. For the present study, we selected
participants from this longitudinal population-based study who had type 2 diabetes and
also participated in longitudinal studies of kidney function that included measurements of
glomerular filtration rate (mGFR) by the urinary clearance of iothalamate.38,39
Laboratory measurements
All urine and serum samples were stored at −80°C until assay.
Urinary albumin was measured by nephelometric immunoassay, and concentrations below the
threshold detected by the assay (6.8 mg/l) were set to this value in the analyses. Urinary
albumin excretion was estimated by computing the urinary albumin-to-creatinine ratio (ACR)
in units of mg/g. ACR was considered normal if <30 mg/g, moderate if ≥30 mg/g
but <300 mg/g, and severe if ≥300 mg/g.40
Urinary clearance of non-radioactive iothalamate was estimated by the average of
four timed urine collections, bracketed by the collection of blood samples, made at 20-min
intervals after a water load and a 60-minute equilibration period. A high performance
liquid chromatography system with a sensitive ultraviolet light detector was used to assay
iothalamate at 236 nm (Instrumentation Shimadzu #6A, www.shimadzu.com).41 Serum levels of TNFRs were measured in samples
collected from the eligible participants between July 1989 and December 2001. Measurements
were performed by ELISA in Dr. A. Krolewski’s laboratory, Joslin Diabetes Center,
Boston, MA, according to the same protocol used in the Joslin Kidney Study.13 Intra-assay coefficient of variation (CV)
for mGFR was 1.1%, and for TNFR1 and TNFR2 were <5%; the inter-assay
CVs were 2.9%, 16%, and 5%, respectively. Reproducibility of the
TNFR assays was assessed by intra-class correlation of measurements from 21 duplicate
samples blinded to the performance laboratory. The intra-class correlation for TNFR1 was
0.80 and for TNFR2 was 0.97, reflecting good agreement.
Body mass index (BMI) was defined as weight divided by the square of height
(kg/m2). Mean arterial pressure was calculated as MAP = 2/3 diastolic
arterial pressure + 1/3 systolic arterial pressure.
The study was approved by the Institutional Review Board of the National
Institute of Diabetes and Digestive and Kidney Diseases. Each subject gave informed
consent at each renal clearance study.
Statistical analyses
Baseline clinical and demographic features are presented as medians
(interquartile range). Participants were followed from their first examination with TNFR
measurement until December 31, 2013, onset of ESRD, or death, whichever came first. ESRD
was defined as initiation of dialysis, kidney transplant, or death from diabetic kidney
disease if dialysis or transplantation was refused. Cause of kidney disease was determined
by review of medical records and review of available biopsy findings. The concentrations
of TNFR1 and TNFR2 were divided into quartiles for the incidence-density and Kaplan-Meier
analyses, with the divisions occurring at the 25th, 50th, and
75th percentiles. The incidence rate of diabetic ESRD was computed as the
number of new cases of ESRD per 1,000 person-years (pyrs) at risk according to these
quartiles.42 Age- and sex-adjusted
incidence rate ratios (IRR) relative to the lowest quartile of each TNFR were computed by
an incidence-density adaptation of Mantel-Haenszel stratification which stratifies events
and person-years in a time-dependent fashion according to decades of age. This method is
robust to sparse data within strata. When the values for age changed during follow-up,
person-years for each subject were apportioned to the appropriate new strata. Tests for
general association were computed by the Mantel-Haenszel test43 adapted for person-year denominators44 and for linear association by the Mantel
extension test.45 The trend test for
unadjusted incidence rates across quartiles of TNFRs is based on a weighted regression
analysis that changes estimates across the strata.46 Relationships between baseline characteristics and measures of TNFRs
were examined by Spearman’s correlations.
Unadjusted cumulative incidence of ESRD as a function of follow-up time,
stratified by quartiles of TNFR1 and TNFR2 and by the level of ACR, was estimated by the
Kaplan-Meier product-limit method. Differences in cumulative incidence were assessed by
the log-rank test. Cox regression analysis was used to estimate the hazard ratio for
development of ESRD associated with an interquartile range increase in the distribution of
each TNFR after adjusting for known risk factors for ESRD, including baseline age, sex,
MAP, HbA1c, ACR, and mGFR. Additional adjustment of the Cox models for diabetes duration,
BMI, anti-hypertensive treatment, and glucose-lowering treatment did not change the
conclusions of the study, and these variables were therefore not included in the final
model. The models assessed the risk of outcome for the difference between the upper
75th and lower 25th percentile as unit of change in the continuous
distribution of each TNFR. Adequacy of the fit of each model to individual observations
was assessed by inspection of deviance residuals. Product terms of predictor variables did
not significantly improve the regression models and were not included.
C-indexes and the differences in C-indexes were calculated for each predictive
model and the 95% CI for the difference in C-indexes was computed based on 1,000
bootstrap samples. Hypothesis testing for the difference between C-indexes was performed
by likelihood ratio tests.47–48 Calculations were performed using SAS
software version 9.3 (SAS Institute, Cary, NC). All analyses used only baseline
measurements because our primary interest was the clinically-relevant predictive value of
TNFRs at a single time point for subsequent development of ESRD.
This study was supported in part by the Intramural Research Program of the National
Institute of Diabetes and Digestive and Kidney Diseases and by grants from the National
Institutes of Health (NIH): DRC P30DK036836 to M. A. Niewczas; DK41526 and DK67638 to A.S.
Krolewski. M.E.P., M.A.N, and R.G.N. wrote the manuscript and researched data. A.S.K.,
R.G.N., and W.C.K. reviewed/edited the manuscript. Y.C. researched data and contributed to
discussion.
DISCLOSURE
A.S.K. and M.A.N are co-inventors in a patent application on TNFRs, which is assigned to
Joslin Diabetes Center, and is licensed to Argutus Medical/EKF Diagnostics.
DISCLAIMER
The findings and conclusions in this report are those of the authors and do not
necessarily represent the official position of the Centers for Disease Control and
Prevention.
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Frequency distributions of the baseline serum levels of TNFR1 and TNFR2 in Pima Indians
with type 2 diabetes.
Relationships of serum concentrations of TNFR1 and TNFR2 with ACR at baseline on
logarithmic scales. Spearman’s correlations and their corresponding
P-values are shown on the figure.
Cumulative incidence of diabetic end-stage renal disease during 10 years of follow-up,
when 48 of the 62 events occurred, according to quartiles of TNFR1 and TNFR2 at baseline
and albuminuria status. Cut-points for the 25th, 50th, and
75th percentiles of TNFRs distributions are presented in Table 3. Numbers of participants at risk at the end of each
2-year interval are indicated along the x-axes. ACR=albumin/creatinine ratio,
Qt=quartile, TNFR=tumor necrosis factor receptor.
Baseline characteristics of Pima Indians with type 2 diabetes.
Baseline characteristic
Median (interquartile range)
n (% male)
193 (29)
Age (years)
46 (39–53)
Diabetes duration (years)
14 (11–19)
BMI (kg/m2)
33 (29–39)
HbA1c (%)*
9.6 (7.7–11.1)
MAP (mmHg)
93 (87–99)
mGFR (ml/min)
133 (100–171)
mGFR (ml/min/1.73 m2)
120 (88–149)
Cystatin C (mg/l)
0.97 (0.87–1.10)
Serum creatinine (μmol/l)
57 (48–74)
ACR (mg/g)
72 (19–493)
TNFR1 (pg/ml)
2833 (2081–4092)
TNFR2 (pg/ml)
4835 (3875–6997)
Glucose-lowering treatment (%)
66
Hypertension treatment (%)
6
HbA1c in IFCC units (mmol/mol)=81.4 (60.7–97.8).
TNFR=tumor necrosis factor receptor, mGFR=iothalamate glomerular
filtration rate, ACR=urinary albumin-to-creatinine ratio, BMI=body mass
index, MAP=mean arterial pressure. Cystatin C values are IFCC standardized.
Serum creatinine values are IDMS standardized.
Spearman’s correlations for comparisons between TNFRs and baseline measurements.
For each comparison, the P-values are shown below the correlation
coefficients.
TNFR1
TNFR2
Age
DM Duration
mGFR
Cystatin C
ACR
HbA1c
BMI
MAP
TNFR1
1
0.78
0.29
0.27
−0.48
0.52
0.36
−0.13
0.06
0.27
<.001
<.001
0.001
<.001
<.001
<.001
0.08
0.41
0.0002
TNFR2
0.78
1
0.33
0.29
−0.49
0.63
0.42
−0.11
0.05
0.33
<.001
<.001
<.001
<.001
<.001
<.001
0.15
0.48
<.001
TNFR=Tumor necrosis factor receptor, DM=diabetes, mGFR=
measured glomerular filtration rate, ACR=urinary albumin-to-creatinine ratio,
BMI= body mass index, MAP=mean arterial pressure.
Unadjusted, and age-sex-adjusted incidence rate ratio of end-stage renal disease (ESRD)
by quartiles of TNFR1 and TNFR2 distribution. TNFR=tumor necrosis factor
receptor.
Quartile1
Quartile2
Quartile3
Quartile4
Unadjusted incidence of ESRD (cases/100
pyrs)**
Cases/pyrs
Rate
Cases/pyrs
Rate
Cases/pyrs
Rate
Cases/pyrs
Rate
TNFR1*
8/5754
1.4
10/555
1.8
16/479
3.3
28/287
9.8
TNFR2*
7/590
1.2
9/549
1.6
17/500
3.4
29/257
11.3
Age-sex-adjusted incidence rate ratio for
ESRD (95% CI)
TNFR1*
Ref
1.2 (0.5, 3.1)
2.4 (1.01, 5.7)
6.6 (3.3, 13.3)
TNFR2*
Ref
1.3 (0.5, 3.3)
2.8 (1.2, 6.4)
8.8 (4.3, 18.0)
Quartile boundaries for TNFR1 are: 25th percentile - 2081pg/ml,
50th percentile - 2833pg/ml and 75th percentile – 4092pg/ml
and for TNFR2: 25th percentile - 3875pg/ml, 50th percentile - 4835pg/ml
and 75th percentile – 6997pg/ml, respectively.
P <0.001 for trend test of incidence rates.
Univariate and multivariate adjusted Cox proportional hazard models (HR and 95%
CI) for the risk of ESRD associated with TNFR1 and TNFR2 in Pima Indians with type 2
diabetes. The unit of change is the difference between the 75th and
25th percentiles in the distribution of each TNFR as continuous variable.
ACR and mGFR are expressed as the logarithm base 2 (log2) to reflect the association
with ESRD corresponding to a two-fold increase in ACR and decrease in mGFR,
respectively. Effect measures are expressed as the HRs for an increase per specified
unit in the distribution of each covariate except for mGFR.
C-indices, differences in C-indices, and P-values for the likelihood
ratio tests for the differences in the Cox proportional hazards models with and without
the biomarker information.