Antihypertensive treatment of patients with clinical manifestations of diabetic nephropathy, and especially, renin-angiotensin system (RAS) inhibition, slows, but may not fully arrest progression towards end-stage renal disease. Studies using `hard' endpoints such as doubling of serum creatinine, dialysis, or death that are initiated before emergence of any renal functional abnormalities in diabetes, would be of impractical length and size. We therefore undertook a primary prevention study (The Renin-Angiotensin System Study or RASS) to determine if inhibition of the RAS could slow the development of a key diabetic glomerulopathy structural endpoint, increase in mesangial fractional volume (Vv[Mes/glom]).
Methods
This is a parallel group, double-blind, placebo-controlled trial with 285 patients with Type 1 diabetes mellitus (95 per group) randomised to receive the angiotensin-converting enzyme inhibitor, enalapril, the angiotensin II receptor blocker, losartan, or placebo. All patients are normotensive, normoalbuminuric and have normal or increased glomerular filtration rates at study entry. The study is based on primary endpoint of change in Vv(Mes/glom) from baseline to the five-year renal biopsy, with baseline and interval measures of albumin excretion rate, glomerular filtration rate, blood pressure, and glycaemia. Baseline, mid-point, and five-year retinal fundus photography are also performed.
Results
One thousand and sixty-five patients were interviewed, 707 refused participation and 73 were excluded. The target of 285 subjects were randomised and their clinical and demographic characteristics are described. Biopsy complications occurred in 17 (6%), only one of which required hospitalisation. There were no permanent biopsy-related sequelae.
Conclusions
Renal structural variables are reasonable surrogate endpoints for studies of progression of early diabetic nephropathy. Although requiring substantial recruitment effort, diabetic nephropathy primary prevention trials based on change in renal structure are feasible.
Mauer M., Fioretto P., Woredekal Y., Friedman EADiabetic Nephropathy. In, Diseases of the Kidney. Schrier and Gottschalk (eds.), pp. 2083-128, 2001.
2.
USRDS 1999 Annual Data Report.The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Bethesda, MD, 1999 .
3.
Mauer SM, Steffes MW, Ellis EN, Sutherland DER, Brown DM, Goetz FCStructural-functional relationships in diabetic nephropathy. J Clin Invest1984;74:1143-55.
4.
sterby R.Glomerular structural changes in Type 1 (insulin-dependent) diabetes mellitus: causes, consequences, and prevention. Diabetologia1992;35:803-12.
5.
Fioretto P., Steffes MW, Mauer M.Glomerular structure in nonproteinuric IDDM patients with various levels of albuminuria. Diabetes1994;43:1358-64.
6.
Caramori ML, Kim Y., Huang C. et al. Cellular basis of diabetic nephropathy: 1. Study design and renal structural-functional relationships in patients with long-standing diabetes . Diabetes2002;51:506-13.
7.
The Diabetes Control and Complications Trial Research Group.The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med1993;329: 877-86.
8.
Fioretto P., Steffes MW, Sutherland DER, Goetz FC, Mauer M.Reversal of lesions of diabetic nephropathy after pancreas transplantation .NEnglJMed1998;339:69-75.
9.
The Diabetes Control and Complications Trial/ Epidemiology of Diabetes Interventions and Complications Research Group.Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med2000;342(6):381-9.
10.
Zatz R., Dunn BR, Meyer TW, Anderson S., Rennke HG, Brenner BMPrevention of diabetic glomerulopathy by pharmacological amelioration of glomerular capillary hypertension. J Clin Invest1986 ;77:1925-30.
11.
Kanai H., Centrella M., Noble NA, Border WAAngiotensin II upregulates the expression of TGF-β Type I and type II receptors [Abstract].JAm Soc Nephrol1997;8:518A.
12.
Wolf G., Ziyadeh FNThe role of angiotensin II in diabetic nephropathy: emphasis on nonhemodynamic mechanisms.Am J Kidney Dis1997;29:153-63.
13.
Kagami S., Border WA, Miller DE, Noble NAAngiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells. J Clin Invest1994;93:2431-7.
14.
Lewis EJ, Hunsicker LG, Bain RP, Rohde RDThe effect of angiotensin converting enzyme inhibition on diabetic nephropathy . N Engl J Med1993;329:1456-62.
15.
Lewis EJ, Hunsicker LG, Clarke WR et al., for the Collaborative Study Group.Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med2001; 345(12):851-60.
16.
Brenner BM, Cooper ME, de Zeeuw D. et al., for the RENAAL Study Investigators. N Engl J Med2001;345(12):861-9.
17.
Mathiesen ER , Hommel E., Giese J., Parving H-H .Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria . BMJ1991 ;303:210-16.
18.
Parving H-H. , Lehnert H., Bröchner-Mortensen J., Gomis R., Andersen S., Arner P., for the Irbesartan in patients with Type 2 Diabetes and Microalbuminuria Study Group. N Engl J Med2001;345(12):870-8.
19.
Brenner BM, Chertow GMCongenital oligonephropathy and the etiology of adult hypertension and progressive renal injury. Am J Kidney Dis1994;23:171-5.
20.
FDA NDA No. 20-757/S-021. Supplement to NDA 20-757, Dec. 2001.
21.
Andersen S. , Tarnow L., Rossing P., Hansen BV, Parving H-H.Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Kidney Int2000;57(2):601-06.
22.
Warram JH, Gearin G., Laffel L., Krolewski ASEffect of duration of type I diabetes on the prevalence of stages of diabetic nephropathy defined by urinary albumin/creatinine ratio. JAm Soc Nephrol1996;7:930-7.
23.
Caramori ML , Fioretto P., Mauer M.The need for early predictors of diabetic nephropathy risk: Is albumin excretion rate sufficient?Diabetes2000;49:1399-408.
24.
Mauer M., Drummond K., for the International Diabetic Nephropathy Study Group (IDNSG).The early natural history of nephropathy in type 1 diabetes. I. Study design and baseline characteristics of the study participants . Diabetes2002;51: 1572-9.
25.
Drummond K. , Mauer M., for the International Diabetic Nephropathy Study Group (IDNSG).The early natural history of nephropathy in type 1 diabetes. II. Early renal structural changes in type 1 diabetes. Diabetes2002;51:1580-7.
26.
The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med1997;157:2413-46.
27.
Gaspari F., Perico N., Matalone M. et al. Precision of plasma clearance of iohexol for estimation of GFR in patients with renal disease. J Am Soc Nephrol1998;9(2):310-13.
28.
Gaspari F., Perico N., Remuzzi G.Application of newer clearance techniques for the determination of glomerular filtration rate. Curr Opin Nephrol Hypertens1998;7(6):675-80.
29.
Brochner-Mortensen J., Giese J., Rossing N.Renal inulin clearance versus total plasma clearance of 51Cr-EDTA. Scand J Clin Lab Invest1969;23(4):301-05.
30.
Chavers BM, Simonson J., Michael AFA solid phase immunoassay for albumin. Kidney Int1984;25:576-8.
31.
Kim Y., Kleppel MM, Butkowski R., Mauer SM,Wieslander J., Michael AFDifferential expression of basement membrane collagen chains in diabetic nephropathy . Am J Pathol1991; 138(2):413-20.
32.
Zhu D., Kim Y.,Steffes MW, Groppoli TJ,Butkowski RJ, Mauer SMGlomerular distribution of type IV collagen in diabetes by high resolution quantitative immunochemistry. Kidney Int1994 ;45:425-33.
33.
Diabetic Retinopathy Study Research Group: Report 7.A modification of the Airlie House classification of diabetic retinopathy. Invest Ophthalmol Vis Sci1981;21:210-26.
34.
Klein R., Klein BEK, Magli YL et al. An alternative method of grading diabetic retinopathy. Invent Ophthalmol Vis Sci1986;93:1183-6.
35.
Early Treatment Diabetic Retinopathy Study Research Group.Grading diabetic retinopathy from stereoscopic color fundus photographs: an extension of the modified Airlie House Classifications. ETDRS Report No. 10. Ophthalmology1991; 98:786-806.
36.
Early Treatment Diabetic Retinopathy Study Research Group.Photographic risk factors for progression of diabetic retinopathy: ETDRS Report Number 12. Ophthalmology1991;98:823-33.
37.
Mauer M., Fioretto P.Diabetic nephropathy as a model for the use of renal structural endpoints in clinical trials. Kidney Int1997;52(suppl 63):S155-S158.
38.
Hayashi H., Suzuki Y., Ogino S. et al.An electron microscopic study of glomeruli in Japanese patients with non-insulin dependent diabetes mellitus. Kidney Int1992;41:749-57.
39.
sterby R., Gall MA, Schmitz A., Nielsen FS, Nyberg G., Parving H-H.Glomerular structure and function in proteinuric type II (non-insulin-dependent) diabetic patients. Diabetologia1993;32:1064-70.
40.
Nosadini R. ,Velussi M., Brocco E. et al. Course of renal function in type 2 diabetic patients with abnormalities of albumin excretion rate. Diabetes2000;49(3):476-84.
41.
Fioretto P. , Steffes MW, Sutherland DER, Mauer M.Sequential renal biopsies in insulin-dependent diabetic patients: Structural factors associated with clinical progression . Kidney Int1995 ;48:1929-35.
42.
sterby R., Parving H-H., Hommel E., Jørgensen HE, Løkkegaard H.Glomerular structure and function in diabetic nephropathy. Early to advanced stages. Diabetes1990;39:1057-63.
43.
Lane PH, Steffes MW, Fioretto P., Mauer SMRenal interstitial expansion in insulin-dependent diabetes mellitus . Kidney Int1993;43:661-7.
44.
Bader R., Bader H., Grud KE, Mackensen-Haen S., Christ H., Bohle A.Structure and function of the kidney in diabetic glomerulosclerosis. Correlations between morphological and functional parameters. Path Res Pract1980;167:204-16.
45.
Böhle A., Wehrmann M., Bogenschütz O., Batz C., Müller CA, Müller GAThe pathogenesis of chronic renal failure in diabetic nephropathy. Investigation of glomerulosclerosis. Pathol Res Pract1991 ;187(2-3):251-9.
46.
Taft JL, Nolan CJ, Yeung SP, Hewitson TD, Martin FIR.Clinical and histological correlations of decline in renal function in diabetic patients with proteinuria. Diabetes1994;43: 1046-51.
Marcussen N.Atubular glomeruli and the structural basis for chronic renal failure. Lab Invest1992 ;66(3):265-84.
49.
Daneman D., Crompton CH, Balfe JW et al. Plasma prorenin as an early marker of nephropathy in diabetic (IDDM) adolescents. Kidney Int1994;46:1154-9.
50.
Wilson DM, Luetscher JAPlasma prorenin activity and complications in children with insulin-dependent diabetes mellitus. N Engl JMed1990;323:1101-06.
51.
Sharma K., Ziyadeh FNHyperglycemia and diabetic kidney disease. The case for transforming growth factor-beta as a key mediator. Diabetes1995 ;44:1139-46.
52.
Zhang SL, Filep JG, Hohman TC, Tang SS, Ingelfinger JR, Chan JSMolecular mechanisms of glucose action on angiotensinogen gene expression in rat proximal tubular cells. Kidney Int1999;55:454-64.
53.
Tang SS, Diamant D., Rhoads DB, Ingelfinger JRAngiotensin II regulates glucose uptake in immortalized rat proximal tubular cells [Abstract].JAm Soc Nephrol1995 ;6:748.
54.
Liu FY, Cogan MGRole of protein kinase C in proximal bicarbonate absorption and angiotensin signaling. Am J Physiol1990;258:F927.
55.
Singh R.,Alavi N., Singh AK, Leehey DJRole of angiotensin II in glucose-induced inhibition of mesangial matrix degradation . Diabetes1999;48:2066-73.
56.
Hutchison FN , Cui X., Paul RV, Olivero M., Coffman TMIncrease in renal transforming growth factor β in diabetes is angiotensin II dependent [Abstract] . J Am Soc Nephrol1996; 7:1872-3.
Gruden G., Zonca S., Hayward A. et al. Mechanical stretch-induced fibronectin and transforming growth factor-β1 production in human mesangial cells is p38 mitogen-activated protein kinase-dependent. Diabetes2000;49(4):655-61.
