How To Fully Protect the Kidney in a Severe Model of Progressive Nephropathy

Abstract

Abstract. The current therapy for chronic proteinuric nephropathies is angiotensin-converting enzyme inhibitors (ACEi), which slow, but may not halt, the progression of disease, and which may be not effective to the same degree in all patients. In accelerated passive Heymann nephritis (PHN), this study assessed the effect of combining ACEi with angiotensin II receptor antagonist (AIIRA) and with statin that, besides lowering cholesterol, influences inflammatory and fibrogenic processes. Uninephrectomized PHN rats were divided into four groups (n ϭ 10 each) and daily given oral doses of the following: vehicle; 40 mg/L lisinopril; 100 mg/L lisinopril plus L-158,809; 0.3 mg/kg lisinopril plus L-158,809 plus cerivastatin. Treatments started at 2 mo when rats had massive proteinuria and signs of renal injury and lasted until 10 mo. Increases in BP were equally lowered by treatments. ACEi kept proteinuria at levels comparable to pretreatment and numerically lower than vehicle. The addition of AIIRA to lisinopril was more effective, being proteinuria reduced below pretreatment values and significantly lower than vehicle. When cerivastatin was added on top of ACE inhibition and AIIR blockade, urinary protein regressed to normal values and renal failure was prevented. Renal ACE activity was increased threefold in PHN, it was inhibited by more than 60% after ACEi, and decreased below control values with triple therapy. Cerivastatin inhibited ACE activity by 30%. Glomerulosclerosis, tubular damage and interstitial inflammation were ameliorated by ACEi alone or combined with AIIRA, and prevented by addition of statin. TGF-␤ 1 mRNA upregulation in PHN kidney was partially reduced after ACEi or combined with AIIRA and almost normalized after adding statin. Cerivastatin inhibited TGF-␤ 1 gene upregulation by 25%. These data suggest a possible future strategy to induce remission of proteinuria, lessen renal injury, and protect from loss of function in those patients who do not fully respond to ACEi therapy.

Combined Blockade of the Renin-Angiotensin System With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Antagonists

“…In addition to the systemic BP-lowering effect, the intrarenal hemodynamic changes induced by dual RAS blockade are certainly one of the mechanisms for its increased efficacy. 61 Many other explanations can be offered: more complete neutralization of the Ang II autocrine effects on intrarenal hemodynamics, 64 glomerular size permeability 65 or structure, 66 decreased transforming growth factor-␤1 production, 58,67 and glomerular nephrin expression. 68, 69 The downregulation in both gene and protein expression of the transmembrane protein nephrin, a major component of the slit diaphragm of the glomerular podocyte that plays a key role in the function of the glomerular filtration barrier, which accompanies the development of albuminuria in experimental models of hypertension and diabetes, has been shown to be reversed by an AT1R antagonist or an ACE inhibitor.…”

Blood Pressure, Proteinuria, and Phosphate as Risk Factors for Progressive Kidney Disease: A Hypothesis

“…This was demonstrated effectively by a multimodal intervention strategy, the Remission Clinic program, that used all available lifestyle recommendations and pharmacologic tools to further reduce proteinuria in patients with CKD and severe proteinuria already treated with RAAS-blocking agents. [46][47] We recently confirmed the beneficial effects of this strategy in patients with Alport syndrome. 48…”

Increased Capillary Branching Contributes to Angiotensin Type 1 Receptor Blocker (ARB)–Induced Regression of Sclerosis

“…Some previous studies have focused on a decreased area of sclerosis and decreased matrix accumulation as key mechanisms affecting regression. 4,8,11 More recently, changes in glomerular cellular composition have also been investigated. In the studies by Adamczak et al, glomerular volume and podocyte number were not affected, but regression was associated with fewer cells within the mesangium.…”

“…4 PAI-1 is the major inhibitor of the plasmin/plasminogen activator system and inhibits both fibrinolysis and proteolysis. 11 PAI-1 also has plasmin-independent effects on matrix and cell migration. PAI-1 is induced by many profibrotic stimuli, including angiotensin type 2 through the angiotensin type 1 receptor and transforming growth factor-␤.…”

“…4 -10 Additional benefit to ameliorate or even regress sclerosis or progressive CKD clinically in experimental models and in human CKD has been achieved with combination of angiotensin blockade and a statin, pointing to the complexity of the mechanisms involved. 11 Currently, the mechanisms through which regression could occur are not well understood. New glomeruli cannot be generated after term birth in humans, but segmentally scarred glomeruli could potentially undergo regression of existing sclerosis by resorption of areas with matrix accumulation and enhanced growth of the remaining capillary loops.…”