Early urinary markers of diabetic kidney disease: a nested case-control study from the Diabetes Control and Complications Trial (DCCT).

BACKGROUND: Urinary markers were tested as predictors of macroalbuminuria or microalbuminuria in patients with type 1 diabetes. STUDY DESIGN: Nested case-control of participants in the Diabetes Control and Complications Trial (DCCT). SETTING & PARTICIPANTS: 87 cases of microalbuminuria were matched to 174 controls in a 1:2 ratio, while 4 cases were matched to 4 controls in a 1:1 ratio, resulting in 91 cases and 178 controls for microalbuminuria. 55 cases of macroalbuminuria were matched to 110 controls in a 1:2 ratio. Controls were free of micro-/macroalbuminuria when their matching case first developed micro-/macroalbuminuria. PREDICTORS: Urinary N-acetyl-beta-d-glucosaminidase (NAG), pentosidine, advanced glycation end product (AGE) fluorescence, and albumin excretion rate (AER). OUTCOMES: Incident microalbuminuria (2 consecutive annual AERs > 40 but < or = 300 mg/d) or macroalbuminuria (AER > 300 mg/d). MEASUREMENTS: Stored urine samples from DCCT entry and 1-9 years later when macro- or microalbuminuria occurred were measured for the lysosomal enzyme NAG and the AGE pentosidine and AGE fluorescence. AER and adjustor variables were obtained from the DCCT. RESULTS: Submicroalbuminuric AER levels at baseline independently predicted microalbuminuria (adjusted OR, 1.83; P < 0.001) and macroalbuminuria (adjusted OR, 1.82; P < 0.001). Baseline NAG excretion independently predicted macroalbuminuria (adjusted OR, 2.26; P < 0.001) and microalbuminuria (adjusted OR, 1.86; P < 0.001). Baseline pentosidine excretion predicted macroalbuminuria (adjusted OR, 6.89; P = 0.002). Baseline AGE fluorescence predicted microalbuminuria (adjusted OR, 1.68; P = 0.02). However, adjusted for NAG excretion, pentosidine excretion and AGE fluorescence lost the predictive association with macroalbuminuria and microalbuminuria, respectively. LIMITATIONS: Use of angiotensin-converting enzyme inhibitors was not directly ascertained, although their use was proscribed during the DCCT. CONCLUSIONS: Early in type 1 diabetes, repeated measurements of AER and urinary NAG excretion may identify individuals susceptible to future diabetic nephropathy. Combining the 2 markers may yield a better predictive model than either one alone. Renal tubule stress may be more severe, reflecting abnormal renal tubule processing of AGE-modified proteins, in individuals susceptible to diabetic nephropathy.

Survival benefit of nephrologic care in patients with diabetes mellitus and chronic kidney disease.

BACKGROUND: The association of nephrologic care and survival in patients with diabetes mellitus and chronic kidney disease is unknown. METHODS: Using data from 1997 to 2000, we conducted a retrospective cohort study of Veterans Health Administration clinic users having diabetes mellitus and stage 3 or 4 chronic kidney disease. The baseline period was 12 months and median follow-up was 19.3 months. Degree of consistency of visits to a nephrologist, defined as the number of calendar quarters in which there was 1 visit or more (range, 0-4 quarters), and covariates were calculated from the baseline period. The outcome measure was dialysis-free death. RESULTS: Of 39,031 patients, 70.0%, 22.4%, and 7.6% had early stage 3, late stage 3, and stage 4 chronic kidney disease, respectively, and 3.1%, 9.5%, and 28.2%, respectively, visited a nephrologist. Dialysis-free mortality rates were 9.6, 14.1, and 19.4, respectively, per 100 person-years. More calendar quarters with visits to a nephrologist were associated with lower mortality: adjusted hazard ratios were 0.80 (95% confidence interval, 0.67-0.97), 0.68 (95% confidence interval, 0.55-0.86), and 0.45 (95% confidence interval, 0.32-0.63), respectively, when the groups having 2, 3, and 4 visits were compared with those who had no visits. One visit only was not associated with a difference in mortality when compared with no visits (adjusted hazard ratio,1.02; 95% confidence interval, 0.89-1.16). CONCLUSIONS: The consistency of outpatient nephrologic care was independently associated in a graded fashion with lower risk of deaths in patients with diabetes and moderately severe to severe chronic kidney disease. However, only a minority of patients had any visits to a nephrologist.

Bleomycin-induced pulmonary fibrosis is attenuated by a monoclonal antibody targeting HER2.

The importance of HER2/HER3 signaling in decreasing the effects of lung injury was recently demonstrated. Transgenic mice unable to signal through HER2/HER3 had significantly less bleomycin-induced pulmonary fibrosis and showed a survival benefit. Based on these data, we hypothesized that pharmacological blockade of HER2/HER3 in vivo in wild-type mice would have the same beneficial effects. We tested this hypothesis in a bleomycin lung injury model using 2C4, a monoclonal antibody directed against HER2 that blocks HER2/HER3 signaling. The administration of 2C4 before injury decreased the effects of bleomycin at days 15 and 21 after injury. HER2/HER3 blockade resulted in less collagen deposition (362.8 +/- 37.9 compared with 610.5 +/- 27.1 microg/mg; P = 0.03) and less lung morphological changes (injury score of 1.99 +/- 1.55 vs. 3.90 +/- 0.76; P < 0.04). In addition, HER2/HER3 blockade resulted in a significant survival advantage with 50% vs. 25% survival at 30 days (P = 0.04). These results confirm that HER2 signaling can be pharmacologically targeted to reduce lung fibrosis and remodeling after injury.

Facility variation in utilization of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in patients with diabetes mellitus and chronic kidney disease.

OBJECTIVE: To evaluate facility-level variation in prescription rates of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) medications for patients with diabetes mellitus (DM) and chronic kidney disease (CKD). STUDY DESIGN: Retrospective database analysis from 143 Veterans Health Administration facilities. METHODS: Subjects with DM aged 18 to 75 years were identified as having stage 2-4 CKD using estimated glomerular filtration rate (eGFR) based on an index eGFR in 1999 and a subsequent eGFR 90-365 days later. Whether ACEI/ARB medications were prescribed within 1 year after the index eGFR was determined. Variation in facility-level rates was evaluated separately for subjects age <65 years and 65 to 75 years from facilities with more than 50 subjects per age group. RESULTS: A total of 103 853 subjects had stage 2 CKD; 51 728, stage 3; and 3233, stage 4. However, 25% of facilities had fewer than 50 patients age <65 years with either stage 3 or 4 CKD. The median (range) facility-level prescription rates of ACEI/ARB for stage 2 and combined stage 3-4 CKD were 58.5% (44.3%-71.2%) and 73.3% (51.7%-84.6%), respectively, for subjects age <65 years; and 56.5% (38.1%-71.4%) and 68.4% (51.6%-80.1%), respectively, for subjects aged 65 to 75 years. Spearman rank correlation between facility rankings by age group was 0.72 for stage 2 (139 facilities) and 0.49 for stage 3-4 (111 facilities) (P < .001). CONCLUSION: Although ascertainment of prescription rates of ACEI/ARB to CKD patients is feasible using electronic health records, small sample size at the healthcare-system level preclude their utility for public reporting.

Failure of ICD-9-CM codes to identify patients with comorbid chronic kidney disease in diabetes.

OBJECTIVE: To determine prevalence of chronic kidney disease (CKD) in patients with diabetes, and accuracy of International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes to identify such patients. DATA SOURCES/STUDY SETTING: Secondary data from 1999 to 2000. We linked all inpatient and outpatient administrative and clinical records of U.S. veterans with diabetes dually enrolled in Medicare and the Veterans Administration (VA) health care systems. STUDY DESIGN: We used a cross-sectional, observational design to determine the sensitivity and specificity of renal-related ICD-9-CM diagnosis codes in identifying individuals with chronic kidney disease. DATA COLLECTION/EXTRACTION METHODS: We estimated glomerular filtration rate (eGFR) from serum creatinine and defined CKD as Stage 3, 4, or 5 CKD by eGFR criterion according to the Kidney Disease Outcomes Quality Initiative guidelines. Renal-related ICD-9-CM codes were grouped by algorithm. PRINCIPAL FINDINGS: Prevalence of CKD was 31.6 percent in the veteran sample with diabetes. Depending on the detail of the algorithm, only 20.2 to 42.4 percent of individuals with CKD received a renal-related diagnosis code in either VA or Medicare records over 1 year. Specificity of renal codes for CKD ranged from 93.2 to 99.4 percent. Patients hospitalized in VA facilities were slightly more likely to be correctly coded for CKD than patients hospitalized in facilities reimbursed by Medicare (OR 5.4 versus 4.1, p=.0330) CONCLUSIONS: CKD is a common comorbidity for patients with diabetes in the VA system. Diagnosis codes in administrative records from Medicare and VA systems are insensitive, but specific markers for patients with CKD.