Angiotensin converting enzyme inhibition improves glomerular size-selectivity in IgA nephropathy

Abstract

Clearances of uncharged dextrans of broad size distribution were used to evaluate the effects of a 30 day course of enalapril on glomerular barrier function in 10 patients with IgA nephropathy and proteinuria (from 1.4 to 5.6 g/day). Dextran clearance experiments were repeated three times: before enalapril therapy, after 30 days of enalapril and again 30 days after enalapril withdrawal. GFR, but not RPF, was significantly reduced by enalapril (basal 38.3 +/- 11.9, enalapril 30.2 +/- 12.6 ml/min/1.73 m2) and returned to basal values after enalapril withdrawal. Urinary protein excretion and fractional clearance of albumin were both significantly reduced by enalapril (basal 2.3 +/- 1.1 g/day and 102 +/- 90 x 10(-5), enalapril 1.2 +/- 0.6 g/day and 51 +/- 23 x 10(-5), respectively) and returned to basal values after enalapril withdrawal. Transglomerular passage of large dextrans (radii 54 to 62 A), but not of lower size (26 to 42 A) were significantly lowered by enalapril. When enalapril was withdrawn the dextran-sieving profile returned comparable to the baseline levels. A theoretical analysis of dextran-sieving profiles indicated that enalapril lowered the radius of largest membrane pores. This effect was independent from glomerular hemodynamic changes. We conclude that angiotensin converting enzyme inhibitors (CEI) in humans with IgA nephropathy reduces urinary protein excretion by a primary action on the intrinsic glomerular membrane properties enhancing barrier size-selective function. The hypofiltration associated with enalapril therapy in these patients, which was eliminated by its withdrawal, has to be taken into account as a possible undesired effect of CEI in long-term treatment.

Role of the deletion of polymorphism of the angiotensin converting enzyme gene in the progression and therapeutic responsiveness of IgA nephropathy.

“…For example, the clinical course of these patients was not uniform, i.e., some patients required chronic dialysis within 5-10 yr after onset, and the renal function of others slowly progressed to renal failure over a period of 20 yr after onset of the first symptoms. Variable histologic findings were also observed in the patients with progressive IgA nephropathy (42,45,46 In many chronic renal diseases, administration of an ACE inhibitor leads to a significant attenuation of proteinuria (16,49,50). Interestingly, it has been recently reported (51) that, in patients with insulin-dependent diabetes with normal renal function, the absence of the D polymorphism decreases the probability of development of microalbuminuria or proteinuria, but a strong correlation was not demonstrated in another study (52).…”

“…Most recently, a multicenter study conducted on patients with diabetic nephropathy in the United States (10) has confirmed the notion suggested earlier by several investigators (11)(12)(13) that ACE inhibitor ameliorates the progressive decline of renal function in diabetic patients. Although results are variable (14, 15), some studies (16,17) also indicate that ACE inhibitor reduces proteinuria and attenuates progressive decline in renal function in IgA nephropathy as well. Of note, the important pathophysiologic role of the renin-angiotensin system has also been implicated in progressive disorders of the heart, notably cardiac hypertrophy and ischemic heart disease.…”

Changes of endothelin in streptozotocin-induced diabetic rats: effects of an angiotensin converting enzyme inhibitor, enalapril maleate

“…ACE inhibitors have specific actions (Heeg et al 1987, Remuzzi et al 1991, Gansevoort et al 1993 in reducing the progression of diabetic nephropathy. The findings in our animal model, namely the increases in kidney weight, urinary albumin and NAG concentrations, mesangial cell proliferation, matrix expansion and enlarged mesangial area, are associated with diabetic nephropathy.…”

Dual Effects of Lisinopril on Puromycin Aminonucleoside Nephrosis in Unilaterally Nephrectomized Rats.

“…Also, ACEI improves the size selectiv ity in humans with IgA nephropathy (13). Therefore, ACEI may have improved both charge and size defects in glomerular permeability.…”