Effect of ACE and AT-2 inhibitors on mortality and progression to microalbuminuria in a nested case-control study of diabetic nephropathy in diabetes mellitus type 2: results from the GENDIAN study.
BACKGROUND
There is an established role of clinical risk factors such as arterial hypertension and smoking in causing cardiovascular morbidity and diabetic nephropathy (DNP). Genetic factors increase the risk for DNP. To examine the genetic risk, we initiated a case-control study with predefined follow-up examinations. We describe the study design and baseline characteristics under special consideration of comedication, and give preliminary results of the 4-year follow-up.


METHODS
We enrolled all 477 patients with DNP receiving maintenance hemodialysis in 30 centers in Southern Germany between August 1999 and January 2000. As controls, we enrolled all 482 diabetes mellitus type 2 patients without urinary microalbuminuria in two examinations on consecutive days and without other signs of renal disease in a large diabetes clinic from September 2000 to September 2001. Follow-up examinations are performed 4 and 6 years after inclusion by questionnaire and telephone interview to determine mortality and new morbidity. Controls progressing to novel DNP at follow-up, as defined by semiquantitative dipstick urinary albumin/creatinine ratio > 30 mg/g, are defined as cases in the study's nested case control component.


RESULTS
At study inclusion in cases and controls, respectively, mean age was 67.3 +/- 8.2 and 58.1 +/- 11.2 years and duration of diabetes mellitus was 15.6 +/- 9.6 (at dialysis initiation) and 11.0 +/- 8.6 years. 328 controls (of which 25 had died and 14 did not perform urinalysis) were subjected to follow-up at 4 years, at a mean of 3.5 +/- 0.8 years after inclusion. 51.2% (n = 148) of living controls remained normalbuminuric, 33.9% (n = 98) had microor macroalbuminuria, and in 14.9% (n = 43) the dipstick test was inconclusive. There was no significant difference in progression to micro- or macroalbuminuria between controls treated with ACE or AT-2 inhibitors at baseline or not. Renal function as estimated by the abbreviated MDRD formula declined from 86.8 +/- 21.0 to 82.5 +/- 22.3 ml/min/1.73 m2 (p < 0.001). The decline was significant in patients on ACE or AT-2 inhibitors at baseline and not in patients without such medication at baseline.


CONCLUSIONS
GENDIAN is a large case-control study designed to evaluate clinical and genetic determinants of DNP and other complications of long-standing diabetes mellitus type 2. We observed an association of ACE or AT-2 inhibitor therapy with cardiovascular comorbidity and a significant decline in renal function after a 4-year follow-up.
Böger
C A
CA
Klinik und Poliklinik für Innere Medizin II, University of Regensburg, Regensburg, Germany. carsten.boeger@klinik.uni-regensburg.de
Haak
T
T
Götz
A K
AK
Christ
J
J
Ruff
E
E
Hoffmann
U
U
Riegger
G A J
GA
Krämer
B K
BK
D000367:Age Factors; D000368:Aged; D000419:Albuminuria / Q000453:epidemiology / Q000401:mortality / Q000517:prevention & control*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016022:Case-Control Studies; D015897:Comorbidity; D003404:Creatinine / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics; D003928:Diabetic Nephropathies / Q000453:epidemiology / Q000235:genetics / Q000628:therapy*; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005858:Germany / Q000453:epidemiology; D006801:Humans; D008297:Male; D006435:Renal Dialysis; D012737:Sex Factors; D011795:Surveys and Questionnaires; D015996:Survival Rate
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D003404:Creatinine