Therapeutic strategy for progressive renal disease

Renal disease constitutes an important determinant of cardiovascular disease. Although the mechanisms for the progression of renal impairment remain fully undetermined, available evidence indicate that renal glomerular hypertension is responsible in part for the development of renal injury. In renal disease, afferent arteriolar tone is reported to be reduced, while the augmented intrarenal angiotensin II serves to act as an efferent arteriolar constrictor, both of which result in an increase in glomerular capillary pressure. Angiotensin converting enzyme inhibitors (ACE-I) are established as the agent possessing both antihypertensive and renoprotective actions, which exert vasodilator action on efferent arterioles. Calcium antagonists are also reported to have salutary effect on renal disease, although their beneficial action varies depending on the antagonists used and the underlying disease. The use of calcium antagonists, however, is mandatory particularly under the circumstance where renal failure moderately to severely progresses and the ACE-I cannot be used.     

Renal protection with calcium antagonism in essential hypertension

The natural history of uncontrolled essential hypertension, with respect to renal function, is characterized by a progressive rise in renal vascular resistance, a progressive fall in effective renal plasma flow, and a progressive fall in glomerular filtration rate. Sustained effective antihypertensive therapy may reverse this pathophysiological sequence, preventing the development of arteriolar nephrosclerosis. It is unknown whether such a therapeutic benefit is a nonspecific response to controlling systemic hypertension, or is dependent on controlling both systemic and glomerular hypertension. Recent experimental evidence indicates that the control of systemic blood pressure may not necessarily be associated with control of glomerular capillary hypertension. The renal effects of calcium antagonists in essential hypertensive patients are only now being characterized. We have demonstrated that diltiazem, amlodipine, and nifedipine monotherapies enhance glomerular filtration rate and effective renal plasma flow, and lower renal vascular resistance. Although calcium antagonists attenuate the intrarenal effects of norepinephrine and angiotensin II, the precise mechanism(s) by which these drugs reverse the functional renal abnormalities in the essential hypertensive state, and by which they may attenuate the progression of hypertensive renal disease, are unknown. It is our hypothesis that renal protection requires normalization of both systemic and glomerular capillary pressure. Calcium antagonists have the ability to control systemic hypertension. If they can be demonstrated experimentally to reduce both pre- and post-glomerular capillary resistances (i.e. maintain a normal glomerular capillary pressure), they can be expected to provide long-term renal protection.     

Can progression of renal disease be prevented?

Renal disease from a variety of causes often progresses to end-stage renal failure. The progression may be caused by factors accompanying, but not initiating, renal injury. These factors include glomerular hyperfiltration, glomerular hypertension, systemic hypertension, and hyperlipidemia. Studies, primarily in animals, indicate that causative factors may be altered by control of systemic hypertension, dietary protein restriction, administration of angiotensin-converting enzyme inhibitors or calcium channel blockers, and plasma lipid control. Whether such interventions will significantly alter progressive renal disease in humans is, as yet, uncertain.     

Calcium antagonists and the kidney.

Recently, attention has focused on the effects of calcium antagonists on renal function. When administered in vitro to the isolated perfused kidney, calcium antagonist exhibit consistent actions permitting characterization of their renal effects. Calcium antagonists do not affect the vasodilated isolated perfused kidney, but they do dramatically alter the response of the kidney to vasoconstrictor agents. In the presence of norepinephrine, calcium antagonists markedly augment glomerular filtration rate but produce only a modest improvement in renal perfusion. Utilizing the isolated perfused hydronephrotic rat kidney model that permits direct visualization of afferent and efferent arterioles, we have demonstrated that this preferential augmentation of glomerular filtration rate is primarily attributable to a selective vasodilation of pre-glomerular vessels. Although the clinical implications of such observations are not yet clear, preliminary studies in experimental animal models indicate that calcium antagonists may exert salutary effects on renal function in clinical settings that are characterized by impaired renal hemodynamics. The possible benefits of calcium antagonists in ameliorating the development of renal dysfunction in patients in whom there is increased risk for the development of acute renal insufficiency remain to be evaluated.     

Cyclosporine-induced synthesis of endothelin by cultured human endothelial cells.

Endothelin (ET), a peptide synthesized by endothelial cells (EC), causes a decreased renal blood flow and glomerular filtration rate and an increased mean arterial pressure when infused in animals. In tissue culture, ET causes smooth muscle cell (SMC) proliferation and contraction by influx of extracellular calcium, which is inhibited by calcium channel antagonists. Infusion of cyclosporine (CSA) hemodynamically parallels ET action, and knowing that CSA effects EC, we hypothesize that the vasoconstrictive effects of CSA are a result of ET synthesis by EC. Varying concentrations of CSA were incubated with EC resulting in ET present in the supernatants in a dose-dependent manner peaking at 75% above basal activity. Coincubation of either cremophor alone or cycloheximide with CSA resulted in minimal ET present in the EC supernatants (P less than 0.01 each). Incubation of conditioned media from CSA-treated EC with SMC caused proliferation at 114% above basal activity, which did not occur in the presence of CSA alone (P less than 0.01). This activity is specifically inhibited in the presence of an anti-ET antibody or nonspecifically in the presence of calcium channel antagonists (P less than 0.01 each). Therefore, CSA stimulates EC synthesis of ET which in turn causes SMC proliferation. This action is inhibited by the coincubation of a specific antibody to ET or a calcium channel antagonist. These findings may help in the understanding of CSA-induced hypertension and vasculopathy.     

Dietary protein restriction in established renal injury in the rat. Selective role of glomerular capillary pressure in progressive glomerular dysfunction.

Dietary protein restriction imposed before renal injury is established in the remnant kidney model in the rat reduces glomerular hypertension and hyperperfusion and renal injury. We demonstrate that dietary protein restriction (6% vs. 20%) imposed on a background of established renal injury in the remnant model leads to a greater preservation of renal function as measured by glomerular filtration rate and fractional clearances of albumin and IgG, despite the persistence of systemic hypertension. In similarly prepared rats, dietary protein restriction (6% vs. 20%) led to a lower glomerular capillary hydraulic pressure, a higher ultrafiltration coefficient, and similar single nephron filtration rates. In addition, less impairment of glomerular permselectivity was demonstrable after protein restriction. Our data demonstrate that the preservation of renal function with dietary protein restriction after established glomerular injury follows upon reduction of glomerular capillary hydraulic pressure, despite constancy of single nephron filtration rate and plasma flow and persistence of arterial hypertension.     

Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass.

Micropuncture and morphologic studies were performed in four groups of male Munich-Wistar rats after removal of the right kidney and segmental infarction of two-thirds of the left kidney. Groups 1 and 3 received no specific therapy. Groups 2 and 4 were treated with the angiotensin I converting enzyme inhibitor, enalapril, 50 mg/liter of which was put in their drinking water. All rats were fed standard chow. Groups 1 and 2 underwent micropuncture study 4 wk after renal ablation. Untreated group 1 rats exhibited systemic hypertension and elevation of the single nephron glomerular filtration rate (SNGFR) due to high average values for the mean glomerular transcapillary hydraulic pressure difference and glomerular plasma flow rate. In group 2 rats, treatment with enalapril prevented systemic hypertension and maintained the mean glomerular transcapillary hydraulic pressure gradient at near-normal levels without significantly compromising SNGFR and the glomerular capillary plasma flow rate, as compared with untreated group 1 rats. Groups 3 and 4 were studied 8 wk after renal ablation. Untreated group 3 rats demonstrated persistent systemic hypertension, progressive proteinuria, and glomerular structural lesions, including mesangial expansion and segmental sclerosis. In group 4 rats, treatment with enalapril maintained systemic blood pressure at normal levels over the 8-wk period and significantly limited the development of proteinuria and glomerular lesions. These studies suggest that control of glomerular hypertension effectively limits glomerular injury in rats with renal ablation, and further support the view that glomerular hemodynamic changes mediate progressive renal injury when nephron number is reduced.     

University of Miami Division of Clinical Pharmacology Therapeutic Rounds: managing hypertension in patients with kidney disease-implications for preservation of renal function

Renal parenchymal hypertension is defined as hypertension caused by disease of the kidneys. Impaired renal sodium excretion leading to extracellular fluid volume (ECFV) expansion is the most clinically important mechanism leading to hypertension in patients with kidney disease. Most patients with renal parenchymal hypertension have sodium-sensitive hypertension, and, consequently, sodium restriction and loop diuretics constitute the initial steps in effective antihypertensive therapy in patients with renal disease. The loop diuretics (furosemide, ethacrynic acid, bumetanide, torasemide) are used for the management of ECFV and hypertension in patients with renal disease because thiazide diuretics are generally not effective in patients with serum creatinine values above 2.0 mg/dL or creatinine clearances below 30 mL/min. The Joint National Committee VI recommends the use of angiotensin-converting enzyme (ACE) inhibitors in patients with hypertension and chronic renal disease to control hypertension and to slow progressive renal failure. Antihypertensive treatment with ACE inhibitors may favorably alter renal hemodynamics, thereby slowing the progression of renal dysfunction. ACE inhibitors have been found to be useful agents in preventing the progression of renal disease in the settings of established insulin-dependent diabetes mellitus (IDDM) nephropathy, non-insulin-dependent diabetes mellitus (NIDDM) nephropathy, IDDM patients with normal blood pressures and microalbuminuria, NIDDM patients with microalbuminuria and normal renal function, and a variety of non-diabetic renal diseases, especially in the setting of significant proteinuria. Calcium antagonists are effective for treating hypertensive patients with chronic renal impairment, and the initial results for calcium antagonists and for combination calcium antagonist-ACE inhibitor therapy have been encouraging. Although promising, the calcium antagonists and the new angiotensin II antagonists have not been studied as intensively as ACE inhibitors in regard to their ability to slow the progression of renal insufficiency.     

Mechanisms of tubulo-interstitiaI injury in progressive renal diseases

Abstract. A vast amount of evidence, based upon human renal biopsy material, indicates that the presence of tubular atrophy and interstitial fibrosis is a better indicator of outcome of renal function than is the extent of glomerular sclerosis. The pathophysiological basis for this surprising fact has not been adequately addressed. In this review we point out that the systemic hypertension which accompanies most forms of chronic renal disease could impact adversely upon the vasodilated interstitial vascular compartment which, together with a component of primary capillary injury related to the disease process, could cause progressive obliteration of particular capillaries. This would initiate a process of chronic tubular ischaemia ultimately leading to tubular atrophy. Since tubular cells have been shown to produce an array of cytokines and growth factors which modulate fibroblast proliferation, extracellular matrix production and chemo-attracts for infiltrating cells, it is further proposed that it is the tubular injury which initiates the deleterious cascade of events. Tubular injury may be aggravated by the filtration of potentially 'noxious' molecules through the diseased glomerulus and by infiltrating cells. As the vascular bed into which glomerular blood flow empties is progressively obliterated, glomerular function declines and renal failure advances in relation to the degree of tubulo-interstitial fibrosis.     

Calcium ions, drug action and the heart--with special reference to calcium antagonist drugs

Calcium antagonists, of which the best known are verapamil, nifedipine and diltiazem, are a powerful group of cardioactive agents with a clinical spectrum of indications rather similar to those of beta-adrenoceptor blockade, including angina of effort, angina at rest, hypertension and supraventricular tachycardias (nifedipine is ineffective for the latter). In angina caused by coronary spasm, calcium antagonists are preferred to beta-blockade. Calcium antagonists have a basically different mode of action from beta-adrenoceptor blockade, although both ultimately act on the free cytoplasmic calcium ion concentration. Critical differences between the calcium antagonists are dependent on the individual properties of the calcium antagonists concerned. Different binding sites on the sarcolemma have been identified for nifedipine-like agents and verapamil, but with a different interaction with the nifedipine site. None of these sites might be relevant to the binding of calcium antagonists to the tissue of their therapeutic site of action (arterial smooth muscle for all; atrioventricular node for verapamil and diltiazem). As a group, calcium antagonists cause vascular dilation and do not cause bronchial constriction, in contrast to the beta-adrenoceptor blocking agents. In many patients, these diverse properties allow safe combination of calcium antagonists and beta-adrenoceptor blockers if due care is observed, especially in the case of nifedipine. The clinical differences between the effects of various calcium antagonists reflect: (i) the greater vasodilator capacity of nifedipine, so that at a given concentration the afterload effect dominates over possible effects on the nodal or myocardial tissue; (ii) the greater inhibition of vagal tone by nifedipine than by verapamil or diltiazem; and (iii) the greater inhibition of the atrioventricular node by verapamil and diltiazem. In angina of effort, calcium antagonists are now becoming the agents of first choice in some centers. Experimental use of calcium antagonists include the possible prevention of ventricular fibrillation, the inhibition of ischemic injury, the prevention of catecholamine mediated injury to the myocardium and decreased arterial calcinosis.     

Supportive medical management of patients with chronic renal failure

Progressive renal failure occurs in a large number of patients even in the absence of the original cause of injury. It is suggested that the initial reduction in nephron number progressively damages the remaining ones. Various mechanisms underlie the pathogenesis of progressive glomerular injury. Several studies have extensively shown that both dietary protein restriction and pharmacologic intervention with ACE-inhibitiors and angiotensin receptor antagonists effectively slow the progression of chronic renal diseases. This article will present treatment recommendations designed to delay the progression of chronic renal disease, to optimize its medical management and to reduce complications induced by renal insufficiency including hypertension, renal osteodystrophy and anemia. Ten steps in the management of patients with chronic renal failure recommended by an international panel of experts based on existing guidelines are presented.     

Nephroprotective effect of treatment with calcium channel blockers in spontaneously hypertensive rats

The influence of hypertension and of treatment with some dihydropyridine-type Ca(2+) channel blockers and with the nondihydropyridine-type vasodilator hydralazine on the morphology of kidney was investigated in 26-week-old spontaneously hypertensive rats (SHR) and in age-matched Wistar-Kyoto rats. Fourteen-week-old SHR were treated for 12 weeks with a nonhypotensive dose of lercanidipine or with equihypotensive doses of lercanidipine, manidipine, nicardipine, and hydralazine. In control SHR, systolic pressure values were significantly higher in comparison with Wistar-Kyoto rats. Treatment with the low dose of lercanidipine did not reduce systolic blood pressure in SHR, whereas the higher dose of lercanidipine or other compounds tested significantly decreased systolic pressure values. Glomerular hypertrophy accompanied by signs of glomerulosclerosis, increase of mesangial cells, and convoluted tubules degeneration were observed in control SHR. Hypotensive doses of Ca(2+) antagonists countered glomerular injury, the increase of mesangial cells, the reduction of capsular space, and tubular degeneration. Hydralazine, in spite of its hypotensive activity, displayed a slight nephroprotective action. The nonhypotensive dose of lercanidipine countered in part glomerular injury, narrowing of capsular space, and tubular degeneration, and decreased mesangial cell augmentation in SHR. These results suggest that treatment with dihydropyridine-type Ca(+2) antagonists counters hypertensive glomerular and tubular changes occurring in SHR. The demonstration of nephroprotection by the nonhypotensive dose of lercanidipine suggests that the renal effects of the compound may be in part unrelated to its hemodynamic activity.     

Effects of genetic obesity on renal structure and function in the Zucker rat

Although hyperphagia and obesity in the Zucker rat strain have been reported to be associated with spontaneous focal glomerulosclerosis (FGS), little is known about the age of onset and the natural history of hypertension, albuminuria, renal function, and glomerular injury in this model. We systematically investigated renal structure and function in obese male Zucker rats. Lean male littermates were used as controls. Obese rats developed glomerular mesangial matrix expansion and albuminuria by 14 weeks of age. These changes occurred despite normal inulin clearance (2.2 +/- 0.6 ml/min obese vs. 2.0 +/- 0.4 ml/min lean, P greater than 0.1) and filtration fraction (0.32 +/- 0.08 obese vs. 0.34 +/- 0.06 lean, P greater than 0.1), suggesting that increased glomerular filtration and renal plasma flow were not a prerequisite for the development of FGS. By 28 weeks of age, FGS was evident in seven of eight obese rats, and at 68 weeks of age all obese rats had marked FGS. Mean systolic blood pressure was elevated by 11 to 25 mm Hg in obese rats at all ages. Although the pathogenesis of glomerular injury is unknown, our data demonstrate that microalbuminuria, mild hypertension, and mesangial matrix expansion precede the development of progressive FGS in obese Zucker rats.     

Diabetes mellitus and hypertension: a mandate for intense treatment according to new guidelines

Diabetics without a prior myocardial infarction have the same risk of a future myocardial infarction as nondiabetics with a prior myocardial infarction; however, epidemiologic studies suggest that lower blood pressure treatment goals may have potential benefit for diabetics with hypertension. Low-dose diuretics, beta-blockers, angiotensin-converting enzyme inhibitors, and dihydropyridine calcium antagonists have reduced cardiovascular events in patients with diabetes. Angiotensin receptor blockers with diabetic renal disease have reduced the rate of end-stage renal disease, whereas dihydropyridine calcium antagonists show no benefit. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers reduce overall mortality, cardiovascular events, and the development of the overt nephropathy in high-risk patients with diabetes without advanced renal disease. The blood pressure treatment goal for patients with diabetes without macroalbuminuria is less than 130/80 mm Hg and less than 125/75 mm Hg for patients with diabetes and nephrotic syndrome. To achieve these goals, multiple antihypertensive drugs are required.     

Calcium antagonists and renal hemodynamics: implications for renal protection.

Recently, attention has focussed on the effects of calcium antagonists on renal function. When administered in vitro to the isolated perfused kidney, calcium antagonists exhibit consistent actions permitting characterization of their renal hemodynamic effects. Calcium antagonists do not affect the vascular tone of the vasodilated isolated perfused kidney, but they do dramatically reverse the response of this preparation to vasoconstrictor agents. Studies using the isolated hydronephrotic rat kidney model, which permits direct visualization of afferent and efferent arterioles, have demonstrated that calcium antagonists selectively vasodilate preglomerular vessels. The clinical implications of such observations are still being delineated. Nevertheless, the results of preliminary studies in experimental animal models and in human transplant recipients suggest that calcium antagonists exert salutary effects on renal function in clinical settings characterized by impaired renal hemodynamics. Furthermore, a case can be made that these salutary renal hemodynamic effects of calcium antagonists commend their use in the management of essential hypertension.     

Chronic glucocorticoid therapy amplifies glomerular injury in rats with renal ablation.

Functional and/or structural measurements were performed in eight groups of Munich-Wistar rats after five-sixths nephrectomy. Groups 1 and 5 received no therapy. Groups 2 and 6 received daily doses of methylprednisolone (MP). Groups 3 and 7 received MP plus the angiotensin I converting enzyme inhibitor (CEI), benzazepril. Groups 4 and 8 received CEI alone. Groups 1 through 4 underwent micropuncture study 2 wk after renal ablation. Untreated group 1 rats exhibited systemic hypertension and elevation of the single nephron glomerular filtration rate due to glomerular capillary hyperperfusion and hypertension. Administration of MP in group 2 resulted in comparable systemic hypertension, with further elevation of the single nephron glomerular filtration rate due to even higher values for glomerular perfusion and hydraulic pressure. Concurrent treatment with CEI in groups 3 and 4 controlled systemic and glomerular hypertension despite equivalent renal ablation and, in group 3, comparable doses of MP. Groups 5 through 8 were followed for 12 wk. Untreated group 1 rats demonstrated continued systemic hypertension, progressive proteinuria, and eventual glomerular sclerosis. Addition of MP in group 6 dramatically accelerated the development of proteinuria and glomerular sclerosis, while CEI (groups 7 and 8) afforded striking protection against disease progression. Thus, potent vasodilator glucocorticoids may amplify hemodynamically mediated glomerular injury, whereas control of systemic and glomerular hypertension prevents this undesirable consequence of chronic steroid therapy.     

ARTERIAL BARORECEPTOR REFLEX AND CALCIUM ANTAGONISTS

Summary— The tachycardia elicited by decreases in aortic pressure produced by various calcium antagonists, regardless of their chemical structures, is not always simply related to the reduction in pressure. Several experimental and clinical experiments have clearly demonstrated that some of these compounds interfer with the baroreceptor reflex control of heart rate. The voltage-dependent calcium channel blockade induced by these antagonists is probably not involved in the baroreceptor mechanotransduction, but central modulation of the baroreceptor reflex is probably an important site for action of these drugs at therapeutic levels. During chronic treatment of hypertension with calcium antagonists, a resetting of the reflex occurred with parallel shift of the set-point and of the baroreceptor reflex-response curve towards lower pressures, thus explaining the lack of change in heart rate despite a permanent reduction in blood pressure under these conditions. However, these effects of calcium antagonists on the baroreceptor reflex do not provide evidence that such interactions could play a role in their antihypertensive action during chronic therapy.     

Calciuretic renal function in patients with essential hypertension

Under the conditions of standard and customary calcium use, patients suffering from essential hypertension (EH) do not manifest any changes in calciuresis either at the expense of the glomerular or tubular mechanisms. After intravenous hypercalcemic injections EH patients demonstrate well-defined disorders in calciuretic renal function, caused by inadequate suppression of tubular reabsorption of calcium by parathyroid hormone (PTH). The hormonal-renal correlations in EH patients differ from those in normals. More pronounced alterations in the concentration of radioimmune PTH and calcitonin under acute hypercalcemia are not associated with an adequate increment of fractional excretion of calcium whereas the calciuretic effect of exogenous calcium-regulating hormones (CRH) realized at the tubular level is less remarkable. Therefore EH patients manifest changes not only in CRH secretion but also in the sensitivity to them of the renal tubules. White changing parathyroid regulation of calcium metabolism prolonged administration of calcium to EH patients enhances body capabilities of resisting acute alterations in calcemia because of normalization of calciuretic renal function, especially tubular calcium transport. In addition, it lowers arterial pressure and enables reduction of the dose of calcium antagonists used in the treatment of EH.     

Glomerular injury in uninephrectomized spontaneously hypertensive rats. A consequence of glomerular capillary hypertension.

Micropuncture and/or morphologic studies were performed in intact Wistar-Kyoto rats (WKY) (group 0), intact spontaneously hypertensive rats (SHR) (groups 1 and 5), uninephrectomized (UNX) WKY (groups 2 and 6), and UNX SHR (groups 3 and 4, 7 and 8). UNX was performed when rats were 5 wk of age. Groups 0-4 were observed for 34 wk after which whole kidney clearance and morphologic studies were performed. Groups 5-8 underwent micropuncture study at 10 wk of age. Groups 4 and 8 were fed a diet containing 6% protein. All other rats ingested standard laboratory diet. 5 wk after UNX, normotensive group 6 had higher single nephron glomerular filtration rate (SNGFR) and initial glomerular plasma flow rate (QA) than intact, hypertensive group 5. Glomerular transcapillary hydraulic pressure difference (delta P) was similar in these two groups. Hypertensive group 7 exhibited less elevation in SNGFR and QA than group 6, but delta P was significantly increased. The presence of glomerular capillary hypertension in UNX SHR at 10 wk was associated with the development of significant proteinuria and an increased incidence of mesangial expansion and glomerular sclerosis at 7 mo (group 3) as compared with groups 0, 1, and 2. Protein restriction prevented the development of increased delta P in UNX SHR (group 8) and also conferred long-term protection from increased urinary protein excretion and glomerular injury (group 4). These studies suggest that glomerular capillary hypertension predisposes to glomerular injury in this model of hypertension with reduced renal mass.     

Succinate receptor GPR91 provides a direct link between high glucose levels and renin release in murine and rabbit kidney

Diabetes mellitus is the most common and rapidly growing cause of end-stage renal disease in developed countries. A classic hallmark of early diabetes mellitus includes activation of the renin-angiotensin system (RAS), which may lead to hypertension and renal tissue injury, but the mechanism of RAS activation is elusive. Here we identified a paracrine signaling pathway in the kidney in which high levels of glucose directly triggered the release of the prohypertensive hormone renin. The signaling cascade involved the local accumulation of succinate and activation of the kidney-specific G protein-coupled metabolic receptor, GPR91, in the glomerular endothelium as observed in rat, mouse, and rabbit kidney sections. Elements of signal transduction included endothelial Ca2+, the production of NO and prostaglandin (PGE2), and their paracrine actions on adjacent renin-producing cells. This GPR91 signaling cascade may serve to modulate kidney function and help remove metabolic waste products through renal hyperfiltration, and it could also link metabolic diseases, such as diabetes, or metabolic syndrome with RAS overactivation, systemic hypertension, and organ injury.