Renal Failure, 12(2), 113-119 (1990)

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Calcium Channel Blocker Nisoldipine in Chronic Renal Failure A. Blau, MB, BS, D. Herzog, MD, P. Shechter, MD, D. Sachs, MD, and H. E. Eliahou, MD Deparmtent of Nephrology Chaim Sheba Medical Center Tel-Hashomer, 52621, Israel


Patients with a stable progression of chronic renal failure with a creatinine clearance of 1 5 4 mL/min were randomly assigned to two groups of antihypertensive therapy: 1-nisoldipine as the only antihypertensive agent and 2-antihypertensive drugs without calcium channel blockers and a placebo tablet instead of nisoldpine. The patients were already on a low-protein diet and some form of antihypertensive therapy but without calcium channel blockers. There were 18patients in the placebo group and 2Opatients in the nisoldipine group. Thefollowup period averaged 23.7 f 10.6 (SO)months in the placebo group and 23 f 11.3 months in the nisoldipine group. Ihe slopes of the reciprocal of serum creatinine were calculated for the period prior to and following our intervention. The number of patients whose slopes improved following intervention was 6/18 in the placebo group and 15/20 in the nisoldipine group @ < .02). The patients whose slopes improved had a signijcant fall in systolic and diastolic BP, as well as in the MAP. Those whose slopes did not improve had a sign@cant decrease in systolic BP, but no change in diastolic BP and no sign@cant difference in the MAP. When all 38 patients are analyzed together, regardless of their grouping, the correlation between the differencepercent in the slope, and the differencepercent in the MAP, was sign$cant. Furthermore, punch biopsies of the skin showed a markedly different calcium content in the two groups, which was sign@cantly less in the nisoldipine-treatedpatients as compared with the patients not receiving calcium blockers. It is reasonable to conclude that the calcium channel blocker nisouipine is able to decrease the slope of progression of l/serum creatinine sign$cantly in the majority of patients. It is also reasonable to suppose that there is a defnite correlation between the decrease in BP, especially the diastolic or the MAP, and the slope of progression. We 113 Copyright 0 1990 by Marcel Defier, Inc.


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hypothesize that the benejicial action of the calcium blocker was not through changes in the intraglomerular hemodynam'cs, but rather through 2 possible mechanismsm: (a) the decrease in systemic BP which is transmitted unhindered to the glomerular capillaries; (b) by preventing calcium deposition in the renal cortex.

Many attempts have been made to elucidate the causes of the progression of chronic renal failure to its end stage. The intraglomerular hyperfiltration in remnant kidneys in rats found by Hostetter et al. (1) and its application by Brenner et al. (2) seems to give a reasonable explanation. The essence of this hypothesis is that with the loss of some glomeruli, those remaining enter a state of hyperfiltration with an increase in glomerular capillary pressure, leading to glomerular sclerosis. This' is supported by the fact that improvement in the remnant kidney function is directly due to a decrease in intraglomerular capillary pressure which is usually obtained by converting enzyme inhibitors (3, 4). Nevertheless, it has always been known that systemic hypertension is important in causing renal damage, and indeed it is known thal the majority of patients with CRF suffer from systemic hypertension. The importance of hypertension in1 the remnant kidney model in rats (5) as well as in rats widh glomerulonephritis and clip hypertension (6) was reconfirmed in the experimental animal. Bidani et al. gave further (7) support to these findings by their observation that there was no progressive morphological injury to the glomeruli in normotensive Wistar-Kyoto rats with 80% ablation of kidney tissue. It has been shown that the failing kidney contains a high concentration of tissue elemental calcium, and that the calcium content of these kidneys has a correlation to the serum creatinine level, as well as to dne serum phosphorus and to the [Ca]*[P] product (8, 9). Furthermore, it was found that verapamil protected rats from nephrocalcinosis when given for 3 weeks after partial nephrectomy (8). Verapamil also protected against renal dysfunction, renal histological damage, nephrocalcinosis, and myocardial calcification, and improved survival in the remnant kidney model in the rat, independently of lblood pressure (10). Thus it seems that calcium deposition in the cortex of the failing kidney may be another contributing factor to the progression of renal failure. Our preliminary data (1 1) in man showed that when the calcium channel blocker nisoldipine was used in small doses for a prolonged period of time (i.e., over 1 year), there was a definite improvement in the slope of progression of renal failure, as measured by l/serum

creatinine. A reassessment was subsequently performed when the observation period neared 2 years.

MATERIALS AND METHODS Patients with a stable progression of chronic renal failure without other systemic diseases or overt cardiovascular disease were included in the study, provided they satisfied the following criteria: 24-h creatinine clearance of 15-45 mL/min. A sufficient number of serum creatinine determinations for at least a year prior to the entry to the study to plot a significant line of regression of Userum creatinine against time. Patients were already on a low-protein diet. Patients were already being treated for their hypertension. Patients signed an informed consent.

The patients were randomized to the placebo (PL) group or to the nisoldipine (Nis) group in a single blinded manner. The patients came for a monthly visit for the duration of the study. The blood pressure was examined in the sitting position as well as in the upright position. Urinalyses and routine blood chemistry were carried out. Thus Userum creatinine values were determined every month. Skin punch biopsies were performed on the patients who agreed to undergo the procedure. The biopsies were performed at an average of 34.4 months after the initiation of nisoldipine therapy, range 2 4 4 2 months. In the placebo group the biopsies were done after a mean of 29 months, range 19-41 months, after entering the study. Punch biopsies weighing 2.6 to 29.8 mg were hydrolyzed overnight with 0.5 mL of 32% HCl. Then 0.4 mL of 50%NaOH was slowly added to the hydrolsate. After mixing and centrifugation, calcium was measured by a colorimetric method, using methyl-thymol blue as indicator (BioMerieux Ca kit). A 1/10dilution of the 10 mg/dL calcium standard was done in a mixture of 5 p 32% HC1 to 4 p 50%NaOH. This mixture was also used as the zero standard. A 1 : l O sample-to-reagent ratio was used. Protein intake was assessed by the formula of Cottini et al. (12):

Nisoldipine in Chronic Renal Failure

Urine urea (g/day) = -4.40 intake (glday)]



[2.08 x Nitrogen


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Patients (Table 1) There were 18 patients in the group receiving placebo plus regular antihypertensive therapy without calcium channel blockers, the PL group; and 20 in the group receiving nisoldipine as the only antihypertensivetherapy, the Nis group. Female-to-male ratios were 6/12 in the PL group and 6/14 in the Nis group. Their ages averaged 48.3 f 13.3 in the PL group and 47.1 f 12.7 years in the Nis group. The follow-up averaged 23.7 f 10.6 months in the placebo group and 23 f 11.3 months in the nisoldipine group. The daily dose of nisoldipine averaged 27.5 f 19.6 mg/day, the range being 10-60 mglday.

The Slope of l/Serum Creatinine Versus Time The pre- and postintervention slopes of Userum creatinine were compared. Only those with significant linear regression lines were included in this study. Improved Versus Nonimproved Slopes (Table 1). The number of patients whose slope of l/senun creatinine was improved was 6/18 in the PL group and 15/20 in the Nis group, the difference being highly significant; the x2 = 6.65 and p < .02. The Difference in the Slopes @resented as x 1 Oa,for convenience). The differences in the absolute values of the slopes (i.e., before - after intervention) averaged -1.32 f 2.56inthePLgroupand +1.86 f 5.13inthe Nis group, the difference being significant; t test showing a 2-sided p = .022. The differences percent was also significant, being -29.8% f 48.3 in the PL and +32.2% f 54.3 in the Nis group, 2-sided p C .001. The absolute values of these slopes are shown in Table 1. It can be seen that when the absolute values in each group are averaged, there is no difference in the slopes of each group following intervention. This is because not all the patients had similar responses; that is, there were patients in the PL group who improved, and there were patients in the Nis group whose slopes became steeper. However, if the groups are divided into 2 subgroups,

those who improved and those who stayed the same or did not improve, then the differences become highly significant. Those who improved had a significant decrease in slope. Those who did not improve had an increase in their slope, indicating an accelerationin the progression of their slope (Table 2).

Correlation of Slopes with Arterial Blood Pressure The average blood pressures before and after intervention are shown in Table 2. There is a definite decrease in systolic blood pressure in both the placebo-treated and the nisoldipine-treated groups. The diastolic pressures decreased only in patients whose slopes improved. The mean arterial pressure also decreased significantly only in the patients whose slopes improved. In the patients whose slopes did not improve, the mean arterial pressure did not change significantly. Thus, the change in slope is associated with change in both systolic and diastolic pressures simultaneously. Changes Measured as Diferences Percent (Table 3). If all the 38 patients in the study are taken together, the difference percent in the slopes correlates significantly with the difference percent in the mean arterial pressure. However, if the difference percent in the slopes in the placebo group and that in the nisoldipine group are correlated separately with the differencepercent in the mean arterial pressure, there is no significant correlation (r = .239 in the placebo group and 0.415 in the nisoldipine group, both p > .05).

Protein Intake The daily protein intake of the patients, in grams per kilogram body weight, was 0.83 f 0.21 prior to and 0.89 f 0.23 during intervention, in the PL group. In the nisoldipine-treated group, it was 0.84 f 0.2 and 0.85 f 0.17, respectively. The differences between any of these figures were not significant. The number of months the patients were on a low-protein diet prior to their entrance to the study varied considerably and ranged between 0 and 48 months, averaging 13.1 f 16 in the placebo group; and between 0 and 30 months, averaging 10.5 f 11.5 months in the group receiving the nisoldipine. Calcium Content in Skin Punch Biopsies. The calcium content in the skin biopsies was 6.8 f 3.4 nmollmg wet tissue in the nisoldipine-treated patients (n = 6) and 16.7 f 6.0 nmol/mg wet tissue (n = 5 ) in the placebo-treated group, 2-sided p c .02.

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Blau et al.

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Nisoldipine in Chronic Renal Failure


Table 3 Differences Percent in Slopes of l/Serum Creatinine and Mean Arterial Pressure

All patients combined Placebo group Nisoldipine group


A% Map

A% slopes

Correlation coefficient r

38 18 20

4.32 f 7.45 3.05 f 7.63 5.46 f 7.1

-1.01 f 60.6 -29.8 f 48.3 24.9 f 58.9

0.367 (p < .0125)

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DISCUSSION This long-term clinical observation shows that the majority of patients in the nisoldipine-treated group had a decrease in the slope of Userum creatinine. In the group receiving placebo plus standard antihypertensivetherapy without calcium channel blockers, most of the patients did not have a decrease in their slopes, and in many of them there was an acceleration of the progression as evidenced by a steeper slope. Our experiments in the remnant kidney model of chronic renal failure have shown that there is a direct correlation between BP and serum creatinine 5/6th nephrectomized rats (5). Neugarten et al. (13) did sequential dextran sieving 2 weeks after the induction of nephrotoxic serum nephritis (NSN) and uninephrectomy. This hypertensive model gave a MAP of 154 f 3 mm Hg. The perfusion BP was lowered artifically to a level of about 110 mm Hg by putting a ligature around the abdominal aorta. GFR decreased from 1.35 i-0.24 to 0.95 f 0.19 mL/min (p < . 0 2 ) and proteinuria decreased from 0.69 f 0.2 to 0.39 f 0.1 mg/mL GFR (p < .W). The glomerular transcapillary hydraulic pressure (delta-P) declined from 43 to 33 mm Hg (p < .001). The fractional clearance of dextrans (molec. radii > 40A),which is elevated in NSN rats, declined towards normal and remained elevated only at molecular radii > 55A. These studies demonstratethat glomerular size-selective barrier dysfunction in hypertensive NSN can be promptly corrected upon reduction of glomerular hypertension and perfusion. Thus, systemic hypertension does, in fact, directly impair glomerular size-selectivebarrier function in NSN. Its control results in the correction of this abnormality (14). The possible mechanism by which systemic hypertension influences the progression of CRF was described by Raij et al. (15). They used two types of rats: 1-the SHR; in which wholekidney GFR and SNGFR are normal.

0.239 (NS) 0.4 (0.05 < p < .lo)

There is marked preglomerular vasoconstriction,protecting the kidney by keeping the glomerular capillary pressure normal. 2-Dahl salt-sensitive rats, in which there is a congenital decrease in the number of glomeruli of about 15 % , with normal whole-kidney GFR but with compensatory increase in SNGFR. In these rats, there is a decrease in preglomerular resistance. Producing immune complex nephritis in both of these types of rats, at similar levels of systemic BP, resulted in severe glomerular injury in the Dahl rats, but only a mild injury in the SHR type of rat. Uninephrectomy in the S H R with nephritis resulted in a decrease in preglomerular vasoconstriction. This resulted in glomerular injury similar to that obtained in the Dahl rats. These findings indicate that systemic hypertension accelerates progression in renal damage, primarily when accompanied by glomerular hypertension, probably secondary to glomerular capillary dilatation. Using the slopes of the reciprocal of serum creatinine, Bray et al. (16) found that patients with chronic renal failure who had higher levels of diastolic BP were associated with a more rapid rate of progression to end stage failure. In 19 patients diastolicBP > 90 mm Hg was associated with a faster rate of decline of renal function (expressed as the slope of the reciprocal of serum creatinine) as compared with periods where the diastolic BP was controlled to levels < 90 mm Hg (16). Shimamatsu et al. (17) made the interesting observation that there was no correlation between the systolic BP and the progression rate, but the correlation between the progression rate and the diastolic BP was significant (r = 0.410, p < .02). The mean of the progression rate in patients with diastolic BP > 90 mm Hg was significantly higher than in patients with a diastolic BP < 90 mm Hg. In our earlier assessment of the results (1l), the decrease in the diastolic BP, though small, was indeed significant in the Nis group, in which there was a definite improvement in the slope of progression. There are observations

Blau et al.

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which indicate that the changes in BP do not have to be large (i.e., less than 10 mm Hg) to influence the slope of progression (18). In the observations of Shimamatsu et al. (17) as well as in the experimental work of Garcia et al. (18) in rats, it was found thiit mild changes in systemicBP (i.e., changes of around 7 % in diastolic BP) have significant influence on the slope of progression of renal failure. In the present study, the decrease in the slope was indeed associated with a decrease in both systolic and diastolic blood pressure. Patients whose slopes did not improve, despite a decrease in systoflicblood pressure, showed no change in their diastolic pressure. It seems, therefore, that a decrease in diastolic BP is necessary for an association with an improvement in the slope of progression. The changes in the mean arterial pressure correlated significantly with the changes in slope of Userum creatinine. The mean arterial pressure decreased significantly in the patients with improved slopes but showed no significant change in the patients whose slopes did not improve. Nevertheless, when the change percent in the slope of l/serum creatinine in each of the two groups, placebo and nisoldipine, was correlated wparately with the change percent in mean arterial pressure, it was found that there was no significant correlation between these two parameters in either group. Thus, it can be assumed that the association of the decrease in BP with the decrease in the slope of l/serum creatinine, though real, is not unique, because other contributing factors may play a role in the ameliorating effect of nisoldipine. !Skin punch biopsies showed a marked difference between the patients on nisoldipine and those who did not bike calcium channel blockers. It can be assumed that, being a potent calcium channel blocker, nisoldipine could prevent the deposition of calcium in soft tissues including the renal tissue, thus protecting the kidney from parenchymal damage which is known to occur with this phenomenon. This was clearly demonstrated in the study of Gimitiez et al. (19), who observed that renal calcium content correlated significantly with serum cmtinine and thus with renal impairment. It seems unlikely that this improvement is brought about by a parallel decrease in intraglomerular capillary pressure, because of the observations;of Pelayo et al. (20) in the remnant kidney in rats. Here, verapamil did not affect the glomerular capillary pressure, which remained the same as in the saline-treated group of rats. Yet, it is in this same model that verapamil bad a significant protective effect (10). Loutzenhiser and Epstein (21) found that in the isolated

rat kidney, calcium channel blockers do not dilate further the already dilated capillaries. Calcium blockers were found to dilate glomerular capillaries only if they have been constricted by a stimulus such as KC1 or norepinephrine, Thus, the calcium blocker in this study could not have achieved its beneficial effect through changes in the tone of the glomerular capillaries. These findings support the assumption that the dilated intraglomerular capillaries of the failing kidney allow the changes in systemic blood pressure to be transmitted unhindered down to the glomerulus. Thus, a decrease in systemic blood pressure would cause a parallel decrease in the glomerular capillary pressure resulting in decrease in the rate of progression. It is also possible that calcium deposition in the renal cortex, which can be prevented by nisoldipine, is another contributory factor. Whatever the mechanismsmay be, it is clear that there is a correlation of the decrease in blood pressure, especially the diastolic, and the mean arterial pressure with the slope of progression of renal failure.

ACKNOWLEDGMENTS We would like to express our thanks to BAYER AG for their support and supply of nisoldipine tablets. Our thanks go to Ms. Clarissa Shahar for editing and typing the manuscript.

REFERENCES 1. Hostetter TH, Olson JL, Rennke HG, VenkatachalamMA, Brenner BM: Hypertiltrationin remnant nephrons: a potentially adverse response to renal ablation. Am J Physiol241:F85-F93, 1981. 2. Brenner BM, Meyer TW,Hostetter TH:Dietary protein intake and the pmgmsive nature of kidney disease: the role of hemodynamically mediated glomerular injury in the pathogenesis of progressive glomerular sclerosis in aging, renal ablation and intrinsic renal disease. N Engl J Med 307:652-659, 1982. 3. Anderson S, Rennke HG, Brenner BM: In arresting progressive renal disease all antihypertensive drugs are not created equal. Abstract. Roceedings 18th Annual Meeting of the American Society of Nephrology. New Orleans, Dec 1985, p 54. 4. Anderson S, Meyer TW,Rennke HG, Brenner BM: Control of gladhypertension limits glom& injury in rats with reduced renal mass. J Clin Invest 76:612-619, 1985. 5. Eliahou HE, Cohen D, Henog D, Shechter P, Serban I, Kapular S, Schiby G,Gavendo S: The control of hypertension and its effect on renal function in rat remnant kidney. Nephrobgy, Dialysis, Transplantation 3:38-44, 1988. 6. Blantz RC, Gabbai F, Gushwa LC, Wilson CB: The influence of concomitant experimental hypertension and glomerulnephritis. Kidney International 32:652-663, 1987. 7. Bidani A, Mitchell K, Schwartz MM, Navar LG,Lewis El:"Hyperfiltration injury- does not occur in a normotensive rat remnant

Nisoldipine in Chronic Renal Failure


9. 10. 11.

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kidney model. 20th Annual Meeting of the American Society of Nephrology. Washington DC,Dec 13-16,1987,Abstract, p 224A. Goligorsky M,Chaimovitz C, Rapoport J, Goldstein J, Kol R: Calcium metabolism in uremic nephrosclerosis: preventive effect of verapamil. Kidney International 27:774-779, 1985. Ibels L, Alfrey A, Huffer W, Craswell P, Weil R Calcification in end-stage kidneys. Am J Med 71:33-37, 1980. Harris DCH, Hammond WS, Burke TJ, Schrier RW: Verapamil protects against progression of experimentalchronic renal failure. Kidney International 31:41-46, 1987. Eliahou HE, &hen D, Hellberg B, Ben-David A, Herzog D, Shechter P, Kapuler S, Kogan N: Effect of the calcium channel blocker nisoldipine on the progression of chronic renal failure in man. Am J Nephrology 8:285-290,1988. Cottini EP, Gallina DL, Dominguez JM: Urea excretion in adult humans with varying degrees of kidney malfunction fed milk, eggs or amino acid mixture: assessment of nitrogen balance. J Nutr

103:11-19, 1973. 13. Neugarten J, Alfino P, Langs C, Schacht RG, Baldwin DS: Nephrotoxic serum neplnitis with hypertension: perfusion pressure and permselectivity. Kidney International 33:53-57,1988. 14. Neugarten J, Kaminetsky B, Feiner H, Schacht RG, Liu DT, Baldwin DS: Nephrotoxic serum nephritis with hypertension

119 ameliorated by antihypertensive therapy. Kidney International

28~135-139,1985. 15. Raij L, Azar S, Keane WF: Role of hypertension in progressive glomerular immune injury. Hypertension 7:398-404,1985. 16. B r a y PC, Stead WW, Fitzwilliams JF. Progression of renal insufficiency: role of blood pressure. Kidney International

35~670-674,1989. 17. Shimamatsu K, Onoyama K, Harada A, Kumagai H, Hirakata H, Miishima C,Inenaga T, Fujimi S, Fujishima M, Omea T Effect of blood pressure on the progression rate of renal impairment in chronic glomerulonephritis. J Clin Hypertem'on 3:239-244,1985. 18. Garcia DL, Rennke HG, Brenner BM, Anderson S: Chronic glucocortiwidtherapy amplifies glomerutar injury in rats with renal ablation. J Clin Invest 802367-874, 1987. 19. Giminez LF, Solez K, Gordon Walker W: Relation between renal calcium content and renal impairment in 246 human renal biopsies, Kidney International 31:93-99, 1987. 20. Pelayo JC, Harris DCH, Shanley PF, Miller GJ, Schrier RW: Glomerular hemodynamic adaptations in remnant nephrons: effects of verapamil. Am J Physiol 254(23):F425-F431, 1988. 21. Loutzenhiser R, Epstein M: Modification of the hemodynamic response to vasoconstrictors by calcium antagonists. Am J Nephrol 7:Suppl 1 , 7-16, 1987.

Calcium channel blocker nisoldipine in chronic renal failure.

Patients with a stable progression of chronic renal failure with a creatinine clearance of 15-45 mL/min were randomly assigned to two groups of antihy...
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