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American Journal of Kidney Diseases

Risk of Progression of Nonalbuminuric CKD to End-Stage Kidney Disease in People With Diabetes: The CRIC (Chronic Renal Insufficiency Cohort) Study

  • Digsu N. Koye
    Correspondence
    Address for Correspondence: Digsu N. Koye, MPH, Baker Heart and Diabetes Institute, 99 Commercial Road, Melbourne, VIC 3004, Australia.
    Affiliations
    Department of Clinical Diabetes and Epidemiology, Baker Heart and Diabetes Institute, Melbourne, Australia

    Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
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  • Dianna J. Magliano
    Affiliations
    Department of Clinical Diabetes and Epidemiology, Baker Heart and Diabetes Institute, Melbourne, Australia

    Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
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  • Christopher M. Reid
    Affiliations
    Department of Clinical Diabetes and Epidemiology, Baker Heart and Diabetes Institute, Melbourne, Australia

    School of Public Health, Curtin University, Perth, Australia
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  • Christopher Jepson
    Affiliations
    Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA
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  • Harold I. Feldman
    Affiliations
    Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, PA
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  • William H. Herman
    Affiliations
    Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI

    Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI
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  • Jonathan E. Shaw
    Affiliations
    Department of Clinical Diabetes and Epidemiology, Baker Heart and Diabetes Institute, Melbourne, Australia

    Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
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      Background

      Reduced glomerular filtration rate (GFR) in the absence of albuminuria is a common manifestation of chronic kidney disease (CKD) in diabetes. However, the frequency with which it progresses to end-stage kidney disease (ESKD) is unknown.

      Study Design

      Multicenter prospective cohort study.

      Setting & Participants

      We included 1,908 participants with diabetes and reduced GFR enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study in the United States.

      Predictors

      Urinary albumin and protein excretion.

      Outcomes

      Incident ESKD, CKD progression (ESKD or ≥50% reduction in estimated GFR [eGFR] from baseline), and annual rate of decline in kidney function.

      Measurements

      ESKD was ascertained by self-report and by linkage to the US Renal Data System. We used Cox proportional hazards modeling to estimate the association of albuminuria and proteinuria with incident ESKD or CKD progression and linear mixed-effects models to assess differences in eGFR slopes among those with and without albuminuria.

      Results

      Mean eGFR at baseline was 41.2 mL/min/1.73 m2. Normal or mildly increased 24-hour urinary albumin excretion (<30 mg/d) at baseline was present in 28% of participants, but in only 5% of those progressing to ESKD. For those with baseline normal or mildly increased albuminuria, moderately increased albuminuria (albumin excretion, 30-299 mg/d), and 2 levels of severely increased albuminuria (albumin excretion, 300-999 and ≥1,000 mg/d): crude rates of ESKD were 7.4, 34.8, 78.7, and 178.7 per 1,000 person-years, respectively; CKD progression rates were 17.0, 61.4, 130.5, and 295.1 per 1,000 person-years, respectively; and annual rates of eGFR decline were −0.17, −1.35, −2.74, and −4.69 mL/min/1.73 m2, respectively.

      Limitations

      We were unable to compare the results with healthy controls.

      Conclusions

      In people with diabetes with reduced eGFRs, the absence of albuminuria or proteinuria is common and carries a much lower risk for ESKD, CKD progression, or rapid decline in eGFR compared with those with albuminuria or proteinuria. The rate of eGFR decline in normoalbuminuric CKD was similar to that reported for the general diabetic population.

      Index Words

      Editorial, p. 631
      Diabetic kidney disease is one of the most frequent complications of diabetes. It occurs in 20% to 30% of patients with type 1 or type 2 diabetes
      American Diabetes Association
      Nephropathy in diabetes.
      and is the leading cause of end-stage kidney disease (ESKD) in the general population.
      American Diabetes Association
      Nephropathy in diabetes.
      • Tuttle K.R.
      • Bakris G.L.
      • Bilous R.W.
      • et al.
      Diabetic kidney disease: a report from an ADA Consensus Conference.
      • White S.
      • Chadban S.
      KinD Report (Kidneys in Diabetes) Temporal Trends in the Epidemiology of Diabetic Kidney Disease and the Associated Health Care Burden in Australia.
      Traditionally, the natural history of diabetic kidney disease has been conceptualized as starting with the development of moderately increased albuminuria and progressing to severely increased albuminuria and loss of glomerular filtration rate (GFR).
      • Mogensen C.E.
      • Christensen C.K.
      • Vittinghus E.
      The stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy.
      Albuminuria is generally considered a hallmark of diabetic kidney disease.
      • Robles N.R.
      • Villa J.
      • Gallego R.H.
      Non-proteinuric diabetic nephropathy.
      • Chawla V.
      • Roshan B.
      Non-proteinuric diabetic nephropathy.
      However, this classic concept has been challenged in the last decade. Several studies have reported substantial kidney function decline (estimated GFR [eGFR] < 60 mL/min/1.73 m2) in patients with diabetes without albuminuria or proteinuria. Kramer et al
      • Kramer H.J.
      • Nguyen Q.D.
      • Curhan G.
      • Hsu C.-Y.
      Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus.
      reported that more than one-third (36%) of patients with type 2 diabetes and kidney function decline in the Third National Health and Nutrition Examination Survey had normal to mildly increased albuminuria. Using the same study, Garg et al
      • Garg A.X.
      • Kiberd B.A.
      • Clark W.F.
      • Haynes R.B.
      • Clase C.M.
      Albuminuria and renal insufficiency prevalence guides population screening: results from the NHANES III.
      reported that 37% of participants with eGFRs < 30 mL/min/1.73 m2 demonstrated no albuminuria. MacIsaac et al
      • MacIsaac R.J.
      • Tsalamandris C.
      • Panagiotopoulos S.
      • Smith T.J.
      • McNeil K.J.
      • Jerums G.
      Nonalbuminuric renal insufficiency in type 2 diabetes.
      reported that 39% of patients with type 2 diabetes had significant kidney function decline without albuminuria or proteinuria. After excluding patients whose normoalbuminuric status was possibly related to the initiation of treatment with a renin-angiotensin-aldosterone system (RAAS) inhibitor, they reported that the prevalence of GFR < 60 mL/min/1.73 m2 and normoalbuminuria was 23%.
      • MacIsaac R.J.
      • Tsalamandris C.
      • Panagiotopoulos S.
      • Smith T.J.
      • McNeil K.J.
      • Jerums G.
      Nonalbuminuric renal insufficiency in type 2 diabetes.
      The UK Prospective Diabetes Study (UKPDS) also reported that 51% of patients with type 2 diabetes and incident decreased kidney function (Cockcroft-Gault estimated creatinine clearance < 60 mL/min or doubling of plasma creatinine) were found not to have preceding albuminuria.
      • Retnakaran R.
      • Cull C.A.
      • Thorne K.I.
      • Adler A.I.
      • Holman R.R.
      Risk factors for renal dysfunction in type 2 diabetes: U.K. Prospective Diabetes Study 74.
      Similarly, in the Renal Insufficiency And Cardiovascular Events (RIACE) Study, 56.6% of patients with type 2 diabetes and kidney function decline had normal or mildly increased albuminuria.
      • Penno G.
      • Solini A.
      • Bonora E.
      • et al.
      Clinical significance of nonalbuminuric renal impairment in type 2 diabetes.
      These data suggest that nonalbuminuric kidney disease is an important component of kidney disease in people with diabetes. However, little is known about the risk that this form of kidney disease will progress to more severe forms of kidney disease such as ESKD. Thus, its clinical significance remains uncertain. While it may represent an alternative, but important, pathway to ESKD that needs to be managed aggressively and the mechanisms of which need to be elucidated, it may also represent age-related decline in kidney function in persons with diabetes and may have a minimal risk of progression to ESKD. Using the Chronic Renal Insufficiency Cohort (CRIC) Study, a cohort of patients with chronic kidney disease (CKD), many of whom have diabetes, we aimed to evaluate the progression of nonalbuminuric kidney disease to ESKD in people with diabetes.

      Methods

      Study Design and Participants

      The CRIC Study methods have been previously reported.
      • Feldman H.I.
      • Appel L.J.
      • Chertow G.M.
      • et al.
      The Chronic Renal Insufficiency Cohort (CRIC) Study: design and methods.
      • Lash J.P.
      • Go A.S.
      • Appel L.J.
      • et al.
      Chronic Renal Insufficiency Cohort (CRIC) Study: baseline characteristics and associations with kidney function.
      Briefly, it is a multicenter prospective study of patients with CKD in the United States. Its primary goals are to identify risk factors for progression of CKD and cardiovascular disease among adults aged 21 to 74 years at baseline with mild to moderate CKD. CRIC participants were enrolled through 7 clinical centers. Details of the inclusion and exclusion criteria are described elsewhere.
      • Lash J.P.
      • Go A.S.
      • Appel L.J.
      • et al.
      Chronic Renal Insufficiency Cohort (CRIC) Study: baseline characteristics and associations with kidney function.
      Most clinical centers had access to at least one large database to identify individuals with elevated serum creatinine levels. However, recruitment strategies varied from center to center and included computerized searches of laboratory databases and hand searches of medical records and referrals from health care providers. From 2003 to 2008, each clinical center enrolled 405 to 848 individuals during a 5-year period to establish a cohort of 3,939 ethnically/racially diverse participants, of whom 48% had diabetes (the target percentage defined at the outset of enrollment was 40%-60%).
      At recruitment, all participants had eGFRs ≥ 20 mL/min/1.73 m2. The upper limit for baseline eGFR differed by age (70 mL/min/1.73 m2 for participants aged 21-44 years, 60 mL/min/1.73 m2 for participants aged 45-64 years, and 50 mL/min/1.73 m2 for participants aged 65-74 years) to minimize inclusion of participants with age-related declines in eGFR.
      Sociodemographic characteristics, anthropometrics, medical history, lifestyle behaviors, and current medications were recorded at the baseline visit. Blood pressure measurements were obtained using standard protocols. Diabetes was defined as fasting plasma glucose level ≥ 126 mg/dL, nonfasting plasma glucose level ≥ 200 mg/dL, or self-report of glucose-lowering medication use. Type of diabetes was not ascertained in the study, but we believe that the vast majority of CRIC Study participants had type 2 diabetes because only 12.1% of participants had both diabetes onset before age 30 years and insulin use (insulin only or insulin plus other antidiabetic medications) at the baseline visit. (This subgroup was examined as a distinct category in sensitivity analyses.)
      Participants were followed up until the development of ESKD, death, loss to follow-up or withdrawal from the study, or March 31, 2013, whichever came first. Participants returned annually for in-person follow-up visits. Follow-up included clinic visits incorporating measures of kidney function (eGFR and proteinuria). They were also contacted by telephone at the 6-month timepoint between clinic visits and queried about clinical events (kidney transplantation, dialysis, treatment for diabetes, and cardiovascular events) and updates on general health and contact information. The National Death Index was searched periodically for all participants lost to follow-up to ensure complete vital status information.

      Main Predictors of ESKD or CKD Progression

      Twenty-four–hour urinary total protein excretion was measured at baseline and then annually. Twenty-four–hour urinary albumin excretion was measured at the baseline visit only. Participants were grouped into the following 4 categories according to baseline 24-hour urinary albumin excretion: normal or mildly increased albuminuria (albumin excretion < 30 mg/24 h), moderately increased albuminuria (30-299 mg/24 h), and 2 levels of severely increased albuminuria (300-999 and ≥1,000 mg/24 h). Similarly, 24-hour urinary protein excretion rate was grouped into 4 categories: <0.1, 0.1 to <0.5, 0.5 to <1.5, and ≥1.5 g/24 h.
      • Yang W.
      • Xie D.
      • Anderson A.H.
      • et al.
      Association of kidney disease outcomes with risk factors for CKD: findings from the Chronic Renal Insufficiency Cohort (CRIC) study.
      • Sandsmark D.K.
      • Messé S.R.
      • Zhang X.
      • et al.
      Proteinuria, but not eGFR, predicts stroke risk in chronic kidney disease: Chronic Renal Insufficiency Cohort Study.

      Outcome Assessment

      Incident ESKD was defined as initiation of maintenance dialysis therapy or kidney transplantation. This was self-reported by participants during the biannual surveillance by CRIC Study personnel. Subsequent linkage to the US Renal Data System (USRDS) showed that 93% of cases of ESKD defined by CRIC were also present on the USRDS. GFR was estimated annually based on an equation developed and validated in a subgroup of 1,433 CRIC participants who had an iothalamate GFR measurement.
      • Anderson A.H.
      • Yang W.
      • Hsu C-y
      • et al.
      Estimating GFR among participants in the Chronic Renal Insufficiency Cohort (CRIC) Study.
      The equation uses serum creatinine and cystatin C levels, age, sex, and race and has been demonstrated to have superior accuracy in this cohort compared with other eGFR equations.
      • Anderson A.H.
      • Yang W.
      • Hsu C-y
      • et al.
      Estimating GFR among participants in the Chronic Renal Insufficiency Cohort (CRIC) Study.
      The CRIC Study equation was not developed to replace other published equations such as the CKD Epidemiology Collaboration (CKD-EPI) equation in the clinical setting. Its performance was most accurate among subgroups of younger participants, men, nonblacks, non-Hispanics, those without diabetes, those with body mass index < 30 kg/m2, those with higher 24-hour urine creatinine excretion, those with lower high-sensitivity C-reactive protein levels, and those with higher measured GFRs. However, the CRIC GFR estimating equation has not been externally validated.
      CKD progression was defined as incident ESKD or ≥50% reduction in eGFR from baseline. Because serum creatinine values for eGFR calculation were obtained annually, the exact time until 50% reduction in eGFR was imputed assuming a linear decline between in-person annual study visits, as described previously.
      • Yang W.
      • Xie D.
      • Anderson A.H.
      • et al.
      Association of kidney disease outcomes with risk factors for CKD: findings from the Chronic Renal Insufficiency Cohort (CRIC) study.
      Mean annual rate of decline in kidney function (slope of eGFR over time) was calculated as an additional measure of CKD progression.

      Statistical Analyses

      Differences in the mean or proportion of risk factors across albuminuria groups were compared using analysis of variance or χ2 tests when appropriate. Kaplan-Meier curves were used to estimate the proportion of participants at different levels of albuminuria surviving without a kidney end point for specified durations. Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals (CIs) for time to ESKD or CKD progression after study enrollment associated with the presence versus absence of baseline albuminuria or proteinuria. The association of baseline albuminuria with eGFR decline during the follow-up period was assessed using a linear mixed-effects model with both random intercept and slope terms. The final analyses (in both Cox regression and linear mixed-effects models) were adjusted for age, sex, race/ethnicity, education, smoking, health insurance status, baseline eGFR, level of nephrology care, systolic blood pressure, serum uric acid level, use of angiotensin-converting enzyme (ACE) inhibitors/angiotensin II-receptor blockers (ARBs), body mass index, and hemoglobin A1c level. In sensitivity analyses, we considered death before incident ESKD as a competing risk using the method described by Fine and Gray.
      • Fine J.P.
      • Gray R.J.
      A proportional hazards model for the subdistribution of a competing risk.
      In a separate analysis, we used a time-updated proteinuria variable as predictor of ESKD and CKD progression in standard Cox proportional hazards models. In the fully adjusted model, nephrology care, systolic blood pressure, ACE inhibitor/ARB use, body mass index, and hemoglobin A1c level were included as time-updated covariates. All statistical analyses were performed using STATA, version 14.1 (StataCorp).
      We received a deidentified data set from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) central repository after institutional review board approval from the human research ethics committees of the Alfred Hospital (Project No: 467/16) and Monash University, Melbourne. All study participants provided written informed consent before the baseline visit.

      Results

      Baseline Participant Characteristics

      There were 1,908 participants who had diabetes at baseline. At baseline, 95 (5.0%) participants had missing values for albuminuria; analyses were carried out on the remaining 1,813 participants. Among these participants, 515 (28.0%) had normal or mildly increased 24-hour urinary albumin excretion at baseline. As shown in Table 1, compared with other participants, those with normal or mildly increased urinary albumin excretion at baseline had an older mean age and were more likely to be women, non-Hispanic white, and highly educated. In addition, they had higher baseline mean eGFRs and lower serum uric acid levels and systolic and diastolic blood pressures and were more likely to be using ACE inhibitors/ARBs. At baseline, 110 (5.8%) participants had missing values for proteinuria; analyses regarding proteinuria were carried out on the remaining 1,798 participants. Among these participants, 26.5%, 28.6%, 17.8%, and 27.1% had proteinuria with protein excretion <0.1, 0.1 to <0.5, 0.5 to <1.5 and ≥1.5 g/24 h at baseline, respectively.
      Table 1Baseline Demographic and Clinical Characteristics of Participants Stratified by Albuminuria
      VariableAlbuminuria Status, mg/24 hTotalP
      <3030-299300-999≥1,000
      No. of participants5154983354651,831
      Age, y61.4 ± 9.161.7 ± 8.358.9 ± 9.455.5 ± 10.759.5 ± 9.7<0.001
      Male sex212 (41.2%)292 (58.6%)210 (62.7%)303 (65.2%)1,017 (56.1%)<0.001
      Race/ethnicity<0.001
       Non-Hispanic white224 (43.5%)195 (39.2%)107 (31.9%)106 (22.8%)632 (34.9%)
       Non-Hispanic black218 (42.3%)219 (44.0%)169 (50.5%)197 (42.4%)803 (44.3%)
       Hispanic53 (10.3%)59 (11.9%)49 (14.6%)144 (31.0%)305 (16.8%)
       Others20 (3.9%)25 (5.0%)10 (3.0%)18 (3.9%)73 (4.0%)
      Education<0.001
       <High school105 (20.4%)127 (25.5%)87 (26.0%)164 (35.3%)483 (27.6%)
       High school graduate98 (19.0%)96 (19.3%)76 (22.7%)90 (19.4%)360 (19.9%)
       Some college165 (32.0%)149 (29.9%)87 (26.0%)126 (27.1%)527 (29.1%)
       ≥College graduate147 (28.5%)126 (25.3%)85 (25.4%)85 (18.3%)443 (24.4%)
      BMI category0.4
       Normal weight38 (7.4%)51 (10.3%)38 (11.4%)52 (11.2%)179 (9.9%)
       Overweight119 (23.2%)122 (24.7%)77 (23.1%)115 (24.8%)433 (24.0%)
       Obese357 (69.5%)322 (65.1%)219 (65.6%)297 (64.0%)1,195 (66.1%)
      Current smoker50 (9.7%)52 (10.4%)47 (14.0%)64 (13.8%)213 (11.7%)0.09
      Hypertensive165 (32.0%)246 (49.4%)212 (63.3%)359 (77.4%)982 (54.2%)<0.001
      Systolic BP, mm Hg121.5 ± 18.4130.7 ± 20.0137.2 ± 21.3146.1 ± 22.8133.2 ± 22.6<0.001
      Diastolic BP, mm Hg65.1 ± 11.267.6 ± 12.171.0 ± 12.375.7 ± 12.769.6 ± 12.7<0.001
      Type 2 diabetes479 (93.0%)441 (88.6%)287 (85.7%)386 (83.0%)1,593 (87.9%)<0.001
      HbA1c, %7.2 ± 1.47.6 ± 1.68.0 ± 1.87.8 ± 1.77.6 ± 1.6<0.001
      Uric acid, mg/dL7.3 ± 2.07.8 ± 2.07.8 ± 1.97.6 ± 1.77.6 ± 1.9<0.001
      Has health insurance453 (96.2%)394 (92.1%)263 (90.7%)338 (86.5%)1,448 (91.7%)<0.001
      Visited a nephrologist264 (51.3%)343 (68.9%)233 (69.6%)343 (73.8%)1,183 (65.3%)<0.001
      ACE inhibitors/ARB use425 (82.9%)391 (79.3%)272 (81.4%)346 (74.7%)1,434 (79.5%)0.01
      eGFR, mL/min/1.73 m247.9 ± 16.241.0 ± 13.739.8 ± 13.234.9 ± 11.841.2 ± 14.8<0.001
      Note: Categorical data are presented as count (percentage); continuous data, as mean ± standard deviation. P values are for analyses of variance and χ2 tests.
      Abbreviations: ACE, angiotensin-converting enzyme; ARB, aldosterone receptor blockers; BMI, body mass index; BP, blood pressure; eGFR, estimated glomerular filtration rate (calculated using the Chronic Renal Insufficiency Cohort [CRIC] Study equation); HbA1c, glycated hemoglobin.

      Incidence of ESKD and CKD Progression

      During a median follow-up of 6.3 (interquartile range, 3.3-7.8) years, 583 (32.2%) participants developed ESKD, 323 (17.8%) died before reaching ESKD, 72 (4.0%) withdrew from the study or were lost to follow-up, and 835 (46.0%) were censored at the end of follow-up without having experienced an event. During follow-up, participants contributed to a total of 10,141 person-years and the incidence of ESKD among people with diabetes was 57.5 (95% CI, 53.0-62.3) per 1,000 person-years. The rate of CKD progression was 93.1 (95% CI, 86.6-100.1) per 1,000 person-years of follow-up (1,688 people at risk, 7,914 person-years of follow-up, and 737 events during a median follow-up of 4.6 years).

      Risk for ESKD and CKD Progression by Baseline Albuminuria and Proteinuria Status

      Among 515 participants with normal/mildly increased 24-hour urinary albumin excretion at baseline, only 26 (5%) progressed to ESKD and only 5% of ESKD events occurred in people with normoalbuminuric decreased kidney function at baseline. Among those with baseline moderately increased (n = 498) and severely increased albuminuria (n = 800), 21.7% and 56.1% progressed to ESKD, respectively. Baseline albumin excretion was strongly and positively associated with crude incidence rates of ESKD and CKD progression (Figs 1 and 2; Table 2). Similarly, in adjusted models, compared with baseline normal or mildly increased albuminuria, those with albuminuria had higher risk for ESKD and CKD progression (Table 3). The same pattern was observed for baseline 24-hour urinary protein excretion (Table 2, Table 3).
      Figure thumbnail gr1
      Figure 1Kaplan-Meier plots of the cumulative hazard of end-stage kidney disease (ESKD) by baseline 24-hour urinary albumin excretion.
      Figure thumbnail gr2
      Figure 2Kaplan-Meier plots of the cumulative hazard of chronic kidney disease (CKD) progression by baseline 24-hour urinary albumin excretion.
      Table 2Unadjusted Risk for ESKD by Baseline Albuminuria and Proteinuria Status
      No. of ESKD EventsNo. of Person-yIncidence rate (95% CI) per 1,000 person-yHR (95% CI)P
      Albuminuria category
       <30 mg/24 h263,526.37.4 (5.0-10.8)1.00 (reference)
       30-299 mg/24 h1083,100.434.8 (28.9-42.1)4.78 (3.12-7.34)<0.001
       300-999 mg/24 h1411,791.378.7 (66.7-92.8)11.18 (7.35-16.99)<0.001
       ≥1,000 mg/24 h3081,723.2178.7 (159.9-199.9)27.43 (18.35-41.03)<0.001
      Urine protein category
       <0.1 g/24 h273,275.98.2 (5.7-12.0)1.00 (reference)
       0.10-<0.50 g/24 h933,264.528.5 (23.3-34.9)3.49 (2.28-5.36)<0.001
       0.50-<1.50 g/24 h1371,708.280.2 (67.8-94.8)10.23 (6.77-15.46)<0.001
       ≥1.50 g/24 h3201,843.3173.6 (155.6-193.7)23.77 (16.02-35.27)<0.001
      Abbreviations: CI, confidence interval; ESKD, end-stage kidney disease; HR, hazard ratio.
      Table 3Adjusted Risk for End-Stage Kidney Disease and CKD Progression According to Baseline 24-Hour Albuminuria and Proteinuria Status
      ModelESKDESKD, Death as a Competing RiskESKD or 50% eGFR Loss
      Albuminuria, mg/24 h
      Reference group is <30mg/24h.
      nAlbuminuria, mg/24 h
      Reference group is <30mg/24h.
      nAlbuminuria, mg/24 h
      Reference group is <30mg/24h.
      n
      30-299300-999≥1,00030-299300-999≥1,00030-299300-999≥1,000
      14.92 (3.20-7.55)11.59 (7.60-17.67)28.55 (18.97-42.95)1,8134.77 (3.10-7.32)10.81 (7.10-16.48)23.53 (15.61-35.46)1,8133.83 (2.78-5.29)8.83 (6.42-12.13)22.38 (16.47-30.40)1,688
      23.10 (2.01-4.78)7.02 (4.58-10.75)14.97 (9.88-22.69)1,8133.25 (2.10-5.01)7.02 (4.58-10.77)12.41 (8.13-18.92)1,8132.77 (2.00-3.84)6.16 (4.45-8.52)12.97 (9.46-17.78)1,688
      32.78 (1.78-4.36)6.19 (3.99-9.62)14.08 (9.18-21.59)1,5802.88 (1.84-4.52)5.92 (3.78-9.26)12.77 (8.25-19.76)1,5802.50 (1.79-3.49)5.81 (4.16-8.10)12.81 (9.28-17.68)1,570
      42.32 (1.48-3.65)4.61 (2.95-7.22)9.92 (6.38-15.44)1,5462.42 (1.53-3.82)4.45 (2.80-7.08)9.08 (5.72-14.42)1,5462.05 (1.46-2.89)4.31 (3.06-6.08)9.19 (6.55-12.90)1,536
      ModelESKDESKD, Death as a Competing RiskESKD or 50% eGFR Loss
      Proteinuria, g/24 h
      Reference group is <0.1g/24h.
      nProteinuria, g/24 h
      Reference group is <0.1g/24h.
      nProteinuria, g/24 h
      Reference group is <0.1g/24h.
      n
      0.10-<0.500.50-<1.50>1.500.10-<0.500.50-<1.50>1.500.10-<0.500.50-<1.50>1.50
      13.58 (2.33-5.50)10.78 (7.11-16.36)25.37 (16.97-37.92)1,7983.48 (2.27-5.34)9.95 (6.56-15.07)20.64 (13.80-30.87)1,7983.05 (2.20-4.22)7.91 (5.73-10.91)21.25 (15.63-28.90)1,675
      22.75 (1.79-4.23)6.83 (4.49-10.39)15.0 (9.98-22.62)1,7982.69 (1.76-4.11)6.48 (4.27-9.82)11.75 (7.80-17.69)1,7982.54 (1.83-3.52)5.71 (4.12-7.90)13.53 (9.88-18.54)1,675
      32.41 (1.54-3.77)5.83 (3.78-9.01)14.26 (9.36-21.70)1,5672.39 (1.54-3.71)5.50 (3.56-8.49)12.57 (8.22-19.23)1,5672.30 (1.64-3.22)5.22 (3.73-7.30)13.57 (9.83-18.72)1,557
      42.15 (1.37-3.38)4.48 (2.88-6.98)10.57 (6.85-16.31)1,5342.13 (1.36-3.35)4.24 (2.68-6.70)9.25 (5.85-14.63)1,5342.02 (1.43-2.84)4.02 (2.85-5.68)10.15 (7.25-14.21)1,524
      Note: Data are hazard ratio (95% confidence interval). Model 1: adjusted for age and sex. Model 2: adjusted for age, sex, baseline eGFR, clinical site, and race. Model 3: model 2 + education, health insurance, nephrology care, and smoking. Model 4: model 3 + systolic blood pressure, serum uric acid level, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, body mass index, and glycated hemoglobin level.
      Abbreviations: CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate (calculated using the Chronic Renal Insufficiency Cohort [CRIC] Study equation); ESKD, end-stage kidney disease.
      a Reference group is <30 mg/24 h.
      b Reference group is <0.1 g/24 h.
      As shown in Table S1, the much lower rates of ESKD in those without albuminuria compared with those with albuminuria were consistent across a range of important subgroups (defined according to type of diabetes, age, sex, race/ethnicity, eGFR, and use of RAAS blockade). In sensitivity analyses, the findings were not significantly different when we considered the competing risk for death for the risk for ESKD (Table 3).

      Risk for ESKD and CKD Progression by Time-Updated Proteinuria Levels

      In a separate analysis, we compared the risk for ESKD and CKD progression according to proteinuria levels that were updated annually over time. The pattern of association was similar to that of the baseline proteinuria (Table S2).

      Changes in eGFR per Year by Baseline Albuminuria Status

      During follow-up, those with baseline normal or mildly increased albuminuria had a decline in eGFR of 0.17 mL/min/1.73 m2 per year, which was significantly lower than for those with albuminuria (Table 4). Adjustment for baseline eGFR and other relevant factors had only a minimal effect on the differences in rates of eGFR decline across albuminuria groups.
      Table 4Changes in eGFR per Year by Baseline Albuminuria Status
      Albuminuria, mg/24 hnUnadjusted eGFR Change, mL/min/1.73 m2 per yAdjusted eGFR Change, mL/min/1.73 m2 per y
      Adjusted for age, sex, baseline eGFR, and clinical site.
      Difference in eGFR Change, mL/min/1.73 m2 per y
      Adjusted for age, sex, baseline eGFR, clinical site, race, education, health insurance, nephrology care, smoking, systolic blood pressure, serum uric acid level, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, body mass index, and glycated hemoglobin level.
      <30515−0.17 (0.11)−0.19 (0.11)Reference
      30-299498−1.35 (0.10)−1.38 (0.11)−1.17 (0.16)
      300-999335−2.74 (0.17)−2.78 (0.19)−2.44 (0.19)
      ≥1,000465−4.69 (0.17)−5.25 (0.20)−4.34 (0.20)
      Note: Values in parentheses are standard errors.
      Abbreviation: eGFR, estimated glomerular filtration rate.
      a Adjusted for age, sex, baseline eGFR, and clinical site.
      b Adjusted for age, sex, baseline eGFR, clinical site, race, education, health insurance, nephrology care, smoking, systolic blood pressure, serum uric acid level, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use, body mass index, and glycated hemoglobin level.

      Discussion

      This prospective study of patients with diabetes and CKD demonstrated that those with normoalbuminuric CKD have a much lower risk for ESKD, CKD progression, or rapid decline in eGFR compared with those in whom albuminuria or proteinuria are present.
      There is ample evidence showing that high urinary albumin excretion levels predict incident ESKD in patients with diabetes; however, the rate of progression of normoalbuminuric kidney disease in people with diabetes has not been well investigated. Nonalbuminuric reduced GFR in type 2 diabetes has been considered as an important clinical entity,
      • Kramer H.J.
      • Nguyen Q.D.
      • Curhan G.
      • Hsu C.-Y.
      Renal insufficiency in the absence of albuminuria and retinopathy among adults with type 2 diabetes mellitus.
      • MacIsaac R.J.
      • Tsalamandris C.
      • Panagiotopoulos S.
      • Smith T.J.
      • McNeil K.J.
      • Jerums G.
      Nonalbuminuric renal insufficiency in type 2 diabetes.
      • Penno G.
      • Solini A.
      • Bonora E.
      • et al.
      Clinical significance of nonalbuminuric renal impairment in type 2 diabetes.
      • Dwyer J.P.
      • Parving H.-H.
      • Hunsicker L.G.
      • Ravid M.
      • Remuzzi G.
      • Lewis J.B.
      Renal dysfunction in the presence of normoalbuminuria in type 2 diabetes: results from the DEMAND Study.
      • Mottl A.K.
      • Kwon K.-S.
      • Mauer M.
      • Mayer-Davis E.J.
      • Hogan S.L.
      • Kshirsagar A.V.
      Normoalbuminuric diabetic kidney disease in the U.S. population.
      • So W.Y.
      • Kong A.P.S.
      • Ma R.C.W.
      • et al.
      Glomerular filtration rate, cardiorenal end points, and all-cause mortality in type 2 diabetic patients.
      • Thomas M.C.
      • Macisaac R.J.
      • Jerums G.
      • et al.
      Nonalbuminuric renal impairment in type 2 diabetic patients and in the general population (National Evaluation of the Frequency of Renal Impairment Co-existing With NIDDM [NEFRON] 11).
      • Yokoyama H.
      • Sone H.
      • Oishi M.
      • et al.
      Prevalence of albuminuria and renal insufficiency and associated clinical factors in type 2 diabetes: the Japan Diabetes Clinical Data Management study (JDDM15).
      • Porrini E.
      • Ruggenenti P.
      • Mogensen C.E.
      • et al.
      Non-proteinuric pathways in loss of renal function in patients with type 2 diabetes.
      with the implication that it carries a significant risk for ESKD. However, in the setting of widespread use of RAAS blockade (80% of participants were using ACE inhibitors/ARBs at baseline), our analyses suggest that those with nonalbuminuric reduced GFR are at low risk for progressing to serious kidney disease. Although more than a quarter of diabetic participants had nonalbuminuric kidney disease at baseline, it accounted for only 5% of ESKD, and the mean annual decline in eGFR appears to be no worse than that reported elsewhere in the general diabetic population.
      • Hobeika L.
      • Hunt K.J.
      • Neely B.A.
      • Arthur J.M.
      Comparison of the rate of renal function decline in nonproteinuric patients with and without diabetes.
      • Kim S.S.
      • Song S.H.
      • Kim I.J.
      • et al.
      Urinary cystatin C and tubular proteinuria predict progression of diabetic nephropathy.
      • Zoppini G.
      • Targher G.
      • Chonchol M.
      • et al.
      Predictors of estimated GFR decline in patients with type 2 diabetes and preserved kidney function.
      Our results are not without support. Rigalleau et al
      • Rigalleau V.
      • Lasseur C.
      • Raffaitin C.
      • et al.
      Normoalbuminuric renal-insufficient diabetic patients: a lower-risk group.
      studied 89 patients with diabetes and decreased kidney function. After a mean follow-up of 38 months, 12 of the albuminuric patients required dialysis therapy (2/36 of those with moderately increased albuminuria and 10/38 of those with severely increased albuminuria group), but none of the patients with nonalbuminuric reduced GFR died or required dialysis therapy during follow-up. Similarly, in a study by Amin et al,
      • Amin A.P.
      • Whaley-Connell A.T.
      • Li S.
      • et al.
      The synergistic relationship between estimated GFR and microalbuminuria in predicting long-term progression to ESRD or death in patients with diabetes: results from the Kidney Early Evaluation Program (KEEP).
      low rates of progression to incident ESKD in patients with diabetes and either no albuminuria or normal kidney function were documented in the Kidney Early Evaluation Program (KEEP). The investigators reported that participants with eGFRs < 30 mL/min/1.73 m2 and severely increased albuminuria were at extremely high risk for developing ESKD during the median 4 years of follow-up compared with participants with eGFRs > 60 mL/min/1.73 m2 and no albuminuria. Moreover, in a study of Pima Indians, the incidence of ESKD was 4.9, 11.5, and 60.2 per 1,000 person-years among those with type 2 diabetes and normal or mildly increased, moderately increased, and severely increased albuminuria, respectively.
      • Berhane A.M.
      • Weil E.J.
      • Knowler W.C.
      • Nelson R.G.
      • Hanson R.L.
      Albuminuria and estimated glomerular filtration rate as predictors of diabetic end-stage renal disease and death.
      However, it should be noted that in this study, there were too few individuals with normoalbuminuric reduced GFR to determine the rate of ESKD in this group.
      We used the annual rate of decline in eGFR as an additional measure of CKD progression. Results in this study suggest that those with nonalbuminuric reduced eGFRs had very slow rates of eGFR decline. Similarly, Leehey et al
      • Leehey D.J.
      • Kramer H.J.
      • Daoud T.M.
      • Chatha M.P.
      • Isreb M.A.
      Progression of kidney disease in type 2 diabetes - beyond blood pressure control: an observational study.
      reported that greater degrees of proteinuria were associated with higher rates of eGFR decline among patients with clinical evidence of CKD, type 2 diabetes, and controlled hypertension. Consistent with this, Hoefield et al
      • Hoefield R.A.
      • Kalra P.A.
      • Baker P.G.
      • et al.
      The use of eGFR and ACR to predict decline in renal function in people with diabetes.
      demonstrated eGFR decline at a rate of 0.3% per year among individuals with normal or mildly increased albuminuria, 1.5% per year in people with moderately increased albuminuria, and 5.7% per year in people with severely increased albuminuria. In contrast to our findings, MacIsaac et al
      • MacIsaac R.J.
      • Tsalamandris C.
      • Panagiotopoulos S.
      • Smith T.J.
      • McNeil K.J.
      • Jerums G.
      Nonalbuminuric renal insufficiency in type 2 diabetes.
      reported no significant difference in rates of eGFR decline between nonalbuminuric and albuminuric groups with type 2 diabetes. However, it should be noted that this study was conducted in a small group of patients and the nonsignificant finding may be due to lack of statistical power. In addition, there was potential selection bias because eGFR decline was calculated only among patients who had already reached a low eGFR, and the eGFR trajectory was determined retrospectively from earlier values, biasing toward higher rates of decline in all groups.
      Patients with decreased kidney function have a high risk for overall and cardiovascular mortality,
      • Penno G.
      • Solini A.
      • Bonora E.
      • et al.
      Clinical significance of nonalbuminuric renal impairment in type 2 diabetes.
      • So W.Y.
      • Kong A.P.S.
      • Ma R.C.W.
      • et al.
      Glomerular filtration rate, cardiorenal end points, and all-cause mortality in type 2 diabetic patients.
      and thus it is important to consider competing risk in these kinds of analyses. When we accounted for a competing risk for death, we observed no material differences in hazard ratios across levels of albuminuria. Although risk for progression to ESKD is very low in this group of patients, the low GFR could be an important marker for mortality and cardiovascular events.
      The major strengths of the current study are large sample size, longer follow-up, and adequate event rates for analysis. Moreover, the CRIC Study included a diverse group of participants.
      However, there are some limitations to note. In this study, we were unable to compare results with healthy controls (without diabetes and with normal eGFRs at baseline). The CRIC Study is a cohort of individuals with CKD who were therefore all at high risk for CKD progression. Thus, the incidence of ESKD that we reported (7.4 per 1,000 person-years) among nonalbuminuric diabetic patients with CKD is higher than in healthy nondiabetic controls and nonalbuminuric diabetic patients with normal eGFR. Chang et al
      • Chang T.I.
      • Li S.
      • Chen S.-C.
      • et al.
      Risk factors for ESRD in individuals with preserved estimated GFR with and without albuminuria: results from the Kidney Early Evaluation Program (KEEP).
      reported an incidence rate of ESKD of 0.04 per 1,000 person-years among those without diabetes, eGFRs > 60 mL/min/1.73 m2, and no albuminuria, and 3.0 per 1,000 person-years among those with diabetes, eGFRs > 60 mL/ min/1.73 m2, and no albuminuria.
      The CRIC Study sample included participants with both type 1 and type 2 diabetes, and our inability to distinguish which participants had which type represents a limitation. However, we identified those who were likely to have type 1 diabetes as being those who both had diabetes onset before age 30 years and were taking insulin at the baseline visit, and because this group constituted only 12% of the overall sample, we strongly believe that the vast majority of CRIC Study participants had type 2 diabetes. Furthermore, nonalbuminuric kidney disease is more common in type 2 diabetes compared to type 1 diabetes.
      • Tsalamandris C.
      • Allen T.J.
      • Gilbert R.E.
      • et al.
      Progressive decline in renal function in diabetic patients with and without albuminuria.
      A further limitation was the lack of information about the primary kidney disease. Thus, some diabetic participants may have had causes other than diabetes for their CKD and/or ESKD. Because it would be expected that this would be more common among those with normal or mildly increased albuminuria at baseline than in those with moderately or severely increased albuminuria, knowledge of the primary kidney disease would likely have led to an even lower progression rate to diabetes-related ESKD in the normoalbuminuric group than we have reported. Hypertensive nephrosclerosis may be the renal pathology in some of those with normal or mildly increased albuminuria. However, for some people, the reduced eGFR may simply be age-related.
      It is possible that the normoalbuminuric group was enriched with patients who responded well to interventions that protect kidney function and may have normalized albumin excretion. However, we believe that this is unlikely to have been a major factor because as shown in the supplementary material, the relatively low risk for disease progression associated with normal or mildly increased albuminuria was at least as strong among those who were not on RAAS blockade at baseline as among those who were on RAAS blockade. The results of the time-updated analysis should be interpreted with caution because the analysis did not account for the possibility of time-dependent confounding.
      This study demonstrated that in people with diabetes, risk for ESKD, CKD progression, or rapid decline in eGFR is very low among patients with CKD who do not have baseline moderately increased albuminuria or proteinuria compared with those with albuminuria or proteinuria. Nonalbuminuric reduced eGFR, while being common, can be expected to run a less malignant clinical course in the setting of RAAS blockade and ongoing medical care. The classic albuminuric diabetic kidney disease appears to be the main route to ESKD in diabetes.

      Supplementary Material

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      Linked Article

      • Diabetic Kidney Disease: The Tiger May Have New Stripes
        American Journal of Kidney DiseasesVol. 72Issue 5
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          Diabetic kidney disease is a common complication of diabetes mellitus (DM) and is the leading cause of end-stage kidney disease (ESKD) in the United States. A natural history study done in the 1970s in patients with type 1 DM by Kussman et al1 provided the data that underpin the classic understanding regarding the development and progression of diabetic nephropathy (DN). Patients with type 2 DM have been shown historically to have a similar natural history,2,3 although it is more difficult to precisely document because in patients with type 2 DM, the time of onset of DM is often unknown and the time course is censored by cardiovascular death.
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