Treatments of Hemodynamic Maladjustment and Oxidative Stress Prevent Renal Disease Progression in Chronically Severe Glomerulonephritides

Abstract

Hemodynamic maladjustment is a unique observation in chronically severe glomerulonephritides. It is characterized by a markedly elevated efferent arteriolar resistance (RE), an elevated intraglomerular hydrostatic pressure (PG) and a markedly decreased renal plasma flow (RPF), and peritubular capillary flow (PTCF). A correction of such hemodynamic maladjustment can be accomplished by administering a combination of vasodilators (angiotensin receptor antagonist, angiotensin converting enzyme inhibitor, and calcium channel blocker) in 14 chronic glomerulonephritides with severe renal function impairment (mean serum creatinine 3.6 + 1.3 mg/dL). Doses titration aim for maximal renal perfusion effect (increased RPF, PTCF) or maximal renal function improvement (increased CCr, reduced FE Mg) usually higher than needed for maximal blood pressure reduction. Evidence of oxidative stress is also corrected with high doses of vitamins C and E. After a mean period of treatment for 13.5 months, improvements in CCr (pre R_x 22 ± 10 vs. post R_x 32 ± 13 mL/min/1.73 m²), and FE Mg (pre R_x 11.9 ± 4% vs. post R_x 10 ± 3%) were observed in conjunction with the improvement in intrarenal hemodynamics namely RPF (pre R_x 201 ± 71 vs. post R_x 288 ± 99 mL/min/1.73 m²), PTCF (pre R_x 161 ± 57 vs. post R_x 242 ± 90 mL/min/1.73 m²), PG (pre R_x 56.7 ± 0.5 vs. post R_x 51 ± 0.1 mm Hg), and RE (pre R_x 12085 ± 6503 vs. post R_x 6550 ± 1872 dyne.s.cm⁻⁵).

• Hemodynamic
• Oxidative stress
• Vasodilators
• Chronic glomerulo-nephritides
• Pathogenesis

Introduction

Human glomerulonephritides remain one of the most important causes of end-stage renal disease worldwide.[[1]] It is a general consensus that involvement of the tubulointerstitial compartment reflects a severity and chronicity of the disease. In this regard, activation of humoral as well as cellular immunity would result in releases of proinflammatory and profibrotic cytokines, which insult the tubulointerstitial structure. Angiotensin II that is also generated through the activation of inflammatory pathway can itself modulate cell growth-related events and synthesis of matrix proteins in renal interstitial fibroblasts.[[2]] In addition, an enhanced production of angiotensin II as well as other vasoconstrictors namely endothelin, thromboxane A₂ is also observed as a reflection of endothelial dysfunction in the renal microcirculation.[[3]] Indeed, glomerular endothelial dysfunction has been substantiated in a variety of glomerulonephritides and nephrotic syndrome. It is reflected by the defective release of vasodilator from the glomerular endothelium, which can be demonstrated as renal perfusion deficit by intrarenal hemodynamic study.[[4]]

It is the purpose of this study to propose through the intrarenal hemodynamic demonstration that a hemodynamic maladjustment as a consequence of glomerular endothelial dysfunction is likely to be central to the pathogenesis of nephronal damage namely tubulointerstitial fibrosis. That correction of such hemodynamic maladjustment can restore the remaining nephronal function and prevent the renal disease progression in chronic glomerulonephritides with severely impaired renal function.

Material and Method

Sixteen patients associated with severe renal function impairment consisted of 5 patients associated with nephrosis FSGS, 5 patients with atherosclerotic disease, 2 patients with diabetic nephropathy, 2 patients with chronic glomerulonephritis, 1 patient with IgA nephropathy, and 1 patient with SLE. Two of these 16 patients (1 patient with SLE and 1 patient with chronic glomerulonephritis) were excluded from the study due to a rapidly progressive renal failure, which required renal replacement therapy. Of the remaining 14 patients whose mean ages were 43.7 years, the initial renal function studies were performed which included creatinine clearance (CCr), fractional excretion of filtered magnesium (FE Mg), total urinary protein excretion, and intrarenal hemodynamic study by the previously described method.[[5]]

Mode of Therapy

All patients were subject to a low protein, low sugar, and low fat diet. They were encouraged to have adequate hydration and avoidance of any use of diuretic. Acidosis if present is treated accordingly. The main therapeutic regimen consisted of (i) Losartan 50–100 mg/day, (ii) Enalapril 5–20 mg/day, (iii) Isradipine or Felodipine 5–20 mg/day, (iv) Vitamin C 1000–1500 mg/day, (v) Vitamin E 400–800 IU/day (vi) Folic acid 5 mg/day. The dose titration depended mainly upon the degree of renal function impairment and/or magnitude of renal perfusion deficit by which it is aimed for maximal renal function effect and maximal renal perfusion effect respectively. In addition, five patients also received statin due to hypercholesterolemia (lipidemia) in conjunction with isosorbide–5-mononitrate. Three patients also received beta-blocker and dipyridamole.

Statistical Analysis

Values in text are expressed as mean ± SEM. The difference between pre- and post-treatment values was performed by Student's paired t-test. The difference was statistically significant when the p value was less than 0.05.

Results

The initial mean systolic blood pressure was 159 ± 14 mm Hg and the initial mean diastolic blood pressure was 117 ± 12 mmHg. The initial renal function studies were as follow: serum creatinine mean 3.66 ± 1.2 mg/dL, CCr mean 22 ± 10 mL/min/1.73 m², FE Mg 11.9 ± 4%, and 24 h urinary protein 1.6 ± 0.6 g. The initial intrarenal hemodynamic study revealed: renal plasma flow (RPF) 201 ± 71 vs. normal 600 mL/min/1.73 m², peritubular capillary flow, PTCF 161 ± 57 vs. normal 480 mL/min/1.73 m², GFR 40 ± 17 vs. normal 120 mL/min/1.73 m², ultrafiltration coefficient of glomerulus, KFG 0.01 vs. normal 0.05 mL/s/mm Hg, intraglomerular hydrostatic pressure (PG) 56.7 ± 0.5 vs. normal 52 mm Hg, afferent arteriolar resistance (RA) 13563 ± 5958 vs. normal 3000 dyne.s.cm⁻⁵, and efferent arteriolar resistance (RE) 12085 ± 6503 vs. normal 3000 dyne.s.cm⁻⁵. Following the treatment, the mean systolic blood pressure was 117 ± 12 mm Hg and the mean diastolic blood pressure was 72 ± 9 mm Hg. The serum Cr was 3.1 ± 1 mg/dL; p<.01, CCr 32 ± 13 mL/min/1.73 m²; p<.001, FE Mg 10 ± 3%; p<.05, urinary protein 0.7 ± 0.2 g; p>.05. The intrarenal hemodynamic study revealed: RPF 288 ± 99 mL/min/1.73 m², PTCF 242 ± 90 mL/min/1.73 m², GFR 45 ± 10 mL/min/1.73 m², KFG 0.02 mL/s/mm Hg, PG 51 ± 0.1 mm Hg, RA 6108 ± 1999 dyne.s.cm⁻⁵, and RE 6550 ± 1827 dyne.s.cm⁻⁵.

Discussion

An attempt to prevent the renal disease progression in chronic glomerulonephritides with severe renal function impairment (serum creatinine greater than 3 mg/dL) has generally been unsuccessful. Although inhibitors of the renin-angiotensin system and control of hypertension has recently been able to reduce the rate of GFR decline and end-stage renal disease in patients with severe renal insufficiency, the treatment as such has never been clearly established to improve or restore the renal function.[[6]], [[7]] Such observation is quite contrast to our therapeutic approach. It appears that our therapeutic goal is to maximize the enhancing renal perfusion effect or maximize the renal function effect. The therapeutic dose in such approach is titrated by the magnitude of renal perfusion deficit or of renal arteriolar resistance rather than by the level of blood pressure since there is dissociation between systemic blood pressure and renal arteriolar resistance. A very high renal arteriolar resistance is usually observed in renal patient with impaired renal function or reduced renal perfusion despite the blood pressure recording is normal. Therefore, the therapeutic regimen has been continued or titrated for the maximal enhancing renal perfusion effect or for the maximal renal function improvement. In this regard, doses of vasodilators for hemodynamic maladjustment correction is higher than needed for maximal blood pressure reduction. This approach is quite contrast to the general concept which is mainly dependent upon the blood pressure control.

In respect to the pathogenetic concept of renal disease progression, a hemodynamic maladjustment with preferential constriction at the efferent arteriole has generally been observed in chronic glomerulonephritides regardless of the underlying histopathology. A preferential constriction at the efferent arteriole exerts three significant hemodynamic impacts. Proximal to the efferent arteriolar constriction, it induces (1) and overestimation of glomerular filtration rate due to hyperfiltration. It induces (2) intraglomerular hypertension (PG) due to the higher blood-inflow and the lesser blood-outflow in the presence of reduced ultrafiltration coefficient of the glomerulus (KFG). Distal to the efferent arteriolar constriction, it exaggeratedly reduces (3) the peritubular capillary flow, which supplies the tubulointerstitial structure. A sustained ischemic injury would activate the proinflammatory and profibrotic pathways and thereby induce tubulointerstitial fibrosis.[[8]], [[9]] In this regard, it has recently been noted that a sustained reduction in peritubular capillary flow and renal plasma flow inversely correlates with the degree of tubulointerstitial fibrosis and glomerulosclerosis respectively.[[10]], [[11]] Therefore, the correction of hemodynamic maladjustment with vasodilators would improve the renal perfusion by which it is likely to prevent the renal disease progression. Correction of defective quality of blood such as hypercholesterolemia, hypercoagulability, and hyperaggregability of platelet if present, would improve the altered hemorheology. Antioxidant therapy, which corrects the oxidative stress encountered in chronic renal patients, would also likely preserve the glomerular endothelial function.[[12]] A sustained improvement in renal perfusion under this circumstance would assist in recovery of nephronal structure and function. Improvement in CCr and FE Mg is delineated in this study along with the enhancement of RPF and PTCF. Inasmuch as FE Mg correlates with the tubulointerstitial fibrosis[[13]] and inversely correlates with the PTCF,[[14]] the improvement in FE Mg following the treatment implies that there is likely a regression of tubulointerstitial injury. This view is further supported by the observation that suppression of angiotensin II formation in the kidney can be achieved by the combination of angiotensin II receptor antagonist and angiotensin converting enzyme inhibitor.[[15]] A suppression of angiotensin II in the kidney would likely reduce the inflammatory and profibrotic process as well as minimize the infiltration of inflammatory cells.[[16]]