Effect of ammonium chloride and dietary phosphorus in the azotaemic rat. Part IIkidney hypertrophy and calcium deposition
Aquiles Jara1,
Cecilia Chacón1,
Magdalena Ibaceta1,
Andres Valdivieso1 and
Arnold J. Felsenfeld2
1 Department of Nephrology, Pontificia Universidad Católica de Chile, Santiago, Chile and 2 Department of Medicine, West Los Angeles VA Medical Center and UCLA, Los Angeles, CA, USA
Correspondence and offprint requests to: Aquiles Jara, MD, Department of Nephrology, Pontificia Universidad Católica de Chile, Lira 85, Santiago, Chile. Email: ajara{at}med.puc.cl
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Abstract
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Background. Kidney hypertrophy is stimulated by both partial nephrectomy and NH4Cl administration. Also, parathyroidectomy (PTX) has been reported to prevent kidney hypertrophy induced by a high protein diet. Our goal was to determine in the azotaemic rat: (i) the combined effects of NH4Cl administration and dietary phosphorus on the development of kidney hypertrophy and calcium deposition in the kidney and (ii) whether the absence of parathyroid hormone (PTH) affected the development of kidney hypertrophy and calcium deposition.
Methods. High (HPD, 1.2%), normal (NPD, 0.6%) or low (LPD, <0.05%) phosphorus diets were given to 5/6 nephrectomized rats for 30 days. In each dietary group, one-half of the rats were given NH4Cl in the drinking water. The six groups of rats were: (i) HPD + NH4Cl; (ii) HPD; (iii) NPD + NH4Cl; (iv) NPD; (v) LPD + NH4Cl and (vi) LPD. In a separate study, PTX was performed to determine whether PTH affected renal hypertrophy in 5/6 nephrectomized rats given NH4Cl.
Results. Both with and without NH4Cl (+/NH4Cl), kidney weight was greatest (P<0.05) in the HPD groups. In each dietary phosphorus group, kidney weight was greater (P<0.05) in the NH4Cl group. In both the +/NH4Cl groups, kidney calcium content was greatest (P<0.05) in the HPD group, but was less (P<0.05) in the NPD and HPD groups given NH4Cl. An inverse correlation was present between creatinine clearance and kidney calcium content (r = 0.51, P<0.001). When factored for kidney weight, creatinine clearance was less (P<0.05) in the HPD group in both the +/NH4Cl groups, but was greater in the HPD + NH4Cl than in the HPD group. In PTX rats, kidney weight was greater (P<0.05) and kidney calcium deposition was less (P<0.05) in rats given NH4Cl.
Conclusions. In azotaemic rats studied for 30 days, NH4Cl administration induced kidney hypertrophy. A HPD also induced kidney hypertrophy. The effects on kidney calcium deposition were divergent for which NH4Cl administration decreased and a HPD increased calcium deposition. The inverse correlation between kidney calcium content and creatinine clearance suggests that kidney calcium deposition is harmful to renal function. When factored for kidney weight, the lower creatinine clearance in the high phosphorus group suggests that kidney hypertrophy does not completely compensate for the harmful effects of a HPD. This result also suggests that a longer study would probably result in more rapid deterioration in the high phosphorus group. In PTX rats, the absence of PTH did not prevent NH4Cl from inducing kidney hypertrophy and reducing kidney calcium deposition. In conclusion, NH4Cl and dietary phosphorus each independently affect kidney growth and calcium deposition in the growing rat with renal failure.
Keywords: ammonium chloride; dietary phosphorus; kidney hypertrophy; nephrocalcinosis
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Introduction
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Kidney hypertrophy is stimulated by both NH4Cl administration and partial nephrectomy. NH4Cl administration results in kidney hypertrophy [1,2] by inducing an imbalance between protein synthesis and degradation [3,4]. In partial nephrectomy, the cause of kidney hypertrophy has been attributed to a TGF-ß mediated cell cycle arrest in the G1 phase [3,4]. High dietary protein is another cause of kidney hypertrophy, which may be prevented by parathyroidectomy (PTX) in the remnant kidney model [5]. Finally, it has been suggested that high dietary phosphorus may also favour the development of kidney hypertrophy [68].
Results from several studies in azotaemic rats have suggested that calcium deposition in the kidney is a major factor in the progression of renal failure [6,9]. In recent studies in azotaemic rats, treatment with the phosphorus binder sevelamer has reduced kidney calcium deposition, tubulointerstitial fibrosis and parathyroid hormone (PTH) values [10,11]. Moreover, the extent of kidney calcium deposition was shown to inversely correlate with the creatinine clearance [12]. Finally, PTX as well as a reduction in PTH values by the drug WR-2721 have been reported to retard the progression of renal failure and reduce kidney deposition of calcium and in the azotaemic rat [5,1315].
The purpose of our study was to determine in the azotemic rat: (i) the combined effects of NH4Cl administration and dietary phosphorus on the development of kidney hypertrophy and calcium deposition in the kidney and (ii) whether the absence of PTH modifies kidney hypertrophy and calcium deposition.
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Subjects and methods
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Male SpragueDawley rats weighing 180200 g were studied. Details on the induction of renal failure and handling of the rats are provided in Part I. Dietary calcium was 0.6% and dietary protein was 20% for each of the three phosphorus diets (ICN, Cleveland, OH). There were a total of six groups, three different dietary phosphorus contents [high (HPD), 1.2%; normal (NPD), 0.6% and low (LPD), <0.05%]. In each dietary phosphorus group, one-half the rats received NH4Cl in the drinking water (0.75% solution). The six groups were: (i) HPD (1.2% P) + NH4Cl; (ii) HPD; (iii) NPD (0.6% P) + NH4Cl; (iv) NPD; (v) LPD (<0.05% P) + NH4Cl and (vi) LPD. A group of sham-operated rats on a 0.6% P, 0.6% calcium diet was used to compare kidney weight and calcium content. These rats had surgeries at the same time as the 5/6 nephrectomized rats, but were not subjected to arterial ligation or nephrectomy. In the sham-operated rat, the kidney weight given is the left kidney, the same as in the remnant kidney rat. Finally, a separate group of PTX rats receiving a 0.6% P, 0.6% calcium diet was also studied. One-half of these rats received NH4Cl in the drinking water (0.375% solution). Thirty days after the induction of renal failure, rats were killed after an overnight fast.
The methodology and results of the biochemical measurements are shown in Part 1. Measurements included plasma and urinary calcium, phosphorus, creatinine and urea nitrogen, PTH and plasma bicarbonate. The kidney weight was recorded as wet weight and kidney calcium content was measured by the method described by Tew et al. [16].
Statistics
Statistical analysis was performed using the software program NCSS (Kaysville, UT). The unpaired t test was used for the comparison between two groups. When the comparison consisted of three groups, one-way ANOVA was used to determine the presence of differences. If the P value was
0.05 for the ANOVA, the NewmanKeuls test was used for inter-group comparisons. Because the degree of acidosis varied among the NH4Cl groups, analysis of covariance (ANCOVA) was used to factor for differences in the degree of acidosis and to determine whether dietary phosphorus content (low, normal or high) independently affected the response variable (kidney weight). Covariates were evaluated for interactions and were included in the model if the P value for the covariate was <0.15. Because dietary phosphorus was a significant (P<0.05) factor in the ANCOVA, the NewmanKeuls test was used to test comparisons among the group. Results are shown as the mean value±standard error (SE).
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Results
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The weight of the remnant kidney, corrected for body weight, is shown in Figure 1. Among the +NH4Cl groups, kidney weight was greatest in the HPD group and least in the LPD group with the NPD group intermediate. Among the NH4Cl groups, kidney weight was greatest in the HPD group. In all three groups (LPD, NPD and HPD), kidney weight was greater in the groups receiving NH4Cl. The results were similar when the kidney weight was not corrected for the body weight (data not shown).

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Fig. 1. Kidney weight in +NH4Cl and NH4Cl groups. Among the +NH4Cl groups (dark grey bars), kidney weight was greatest in the HPD group (n = 12) and greater in the NPD group (n = 13) than in the LPD group (n = 14). In this comparison +NH4Cl, a, b and c are different (P<0.05) from each other. Among the NH4Cl groups (light grey bars), kidney weight was greatest in the HPD group (n = 12) and not different between the LPD (n = 15) and NPD (n = 12) groups. In this comparison NH4Cl, y is different (P<0.05) from x. In the LPD, NPD and HPD groups, kidney weight was greater (P<0.05) in the +NH4Cl group than in the NH4Cl group; this is shown by *. Finally, kidney weight was greater (P<0.05) in the NPD group with renal failure (NH4Cl) than in the sham-operated NPD group with normal renal function (n = 12); this is shown by +.
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Because the degree of acidosis varied in the groups receiving NH4Cl, ANCOVA was performed to determine whether dietary phosphorus affected the development of kidney hypertrophy. Covariates in the model included plasma calcium, phosphorus, bicarbonate and PTH and kidney calcium content. As shown in Table 1, after differences in the degree of acidosis were factored, high dietary phosphorus increased kidney hypertrophy.
In both +NH4Cl and NH4Cl groups, kidney calcium content was greatest in the HPD group (Figure 2). In the NPD and HPD groups, kidney calcium content was less in the groups receiving NH4Cl. It is also shown that kidney calcium content in all azotaemic groups was much greater than in normal rats.

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Fig. 2. Kidney calcium content in +NH4Cl and NH4Cl groups. Among the +NH4Cl groups (dark grey bars), kidney calcium content (µmol/g) was greater in the HPD (n = 9) than in the NPD (n = 11) and LPD (n = 10) groups. In this comparison (+NH4Cl), b is different (P<0.05) from a. Among the NH4Cl groups (light grey bars), kidney calcium content was greater in the HPD (n = 8) than in the LPD (n = 9) group. The NPD group (n = 7) was not different from the LPD and HPD groups. In this comparison (NH4Cl), y is different (P<0.05) from x and # is not different from x or y. Kidney calcium content in the NPD and HPD groups was greater (P<0.05) in the NH4Cl group than in the +NH4Cl group; this is shown by *. Finally, kidney calcium content in the NPD group with renal failure (NH4Cl) was greater (P<0.05) than in the sham-operated NPD group (n = 8); this is shown by +.
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In Figure 3, the correlation between the creatinine clearance and kidney calcium content is shown. When all groups were combined, an inverse correlation was present, r = 0.51, P<0.001 (Figure 3). Similarly, when the same correlation was evaluated in each of the individual groups, it was significant in the LPD (r = 0.59, P = 0.01), NPD (r = 0.52, P = 0.04) and HPD (r = 0.56, P = 0.02) groups. Moreover, the inverse correlation also approached significance in the PTX group (r = 0.42, P = 0.08).

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Fig. 3. Correlation between creatinine clearance and kidney calcium content. A significant inverse correlation was present between creatinine clearance and kidney calcium content in the overall group. Not shown in the figure is that significant inverse correlations were also present in each of the individual groups, LPD (r = 0.59, P = 0.01), NPD (r = 0.52, P = 0.04) and HPD (r = 0.56, P = 0.02) groups.
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To determine whether kidney hypertrophy was the primary reason for the increase in creatinine clearance, the creatinine clearance was evaluated per kidney weight. As shown in Figure 4, the creatinine clearance corrected for kidney weight was lowest in the HPD groups in both the +NH4Cl and NH4Cl groups. For the comparison between the +NH4Cl and NH4Cl groups, only in the high dietary phosphorus group was the creatinine clearance factored for kidney weight greater in the +NH4Cl group. The correlation between the creatinine clearance factored for kidney weight and kidney calcium content was r = 0.57, P<0.001.

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Fig. 4. Creatinine clearance factored for kidney weight. In both the +NH4Cl (dark grey bar) and the NH4Cl (light grey bar) groups, the lowest value for the creatinine clearance factored for kidney weight was in the high phosphorus group. Among the +NH4Cl groups, b was less (P<0.05) than a. Among the NH4Cl groups, y was less (P<0.05) than x. Also in the HPD group, the creatinine clearance factor for kidney weight was greater (*, P<0.05) in the +NH4Cl group. The number of rats in each group is the same as that shown in Figure 1.
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In the PTX groups, the kidney weight was greater and the kidney calcium content was less in the +NH4Cl group (Figure 5). Moreover, in the PTX and the NPD groups not given NH4Cl, both of which were on the same 0.6% P, 0.6% calcium diet, kidney weight and kidney calcium deposition were not different. Between the PTX and NPD groups given NH4Cl, the kidney weight was greater (P = 0.03) and the kidney calcium deposition tended to be less (P = 0.06) in the NPD group. But these differences may have been attributable to the lesser amount of NH4Cl in the drinking water of PTX rats.

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Fig. 5. Kidney weight and kidney calcium content in PTX rats. The kidney weight was greater and kidney calcium content was less in the +NH4Cl group (n = 15 and n = 10, respectively) than in the NH4Cl group (n = 11 and n = 9, respectively) in PTX rats.
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Discussion
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In the present study, NH4Cl administration and differences in dietary phosphorus content were used to evaluate their combined effects on the progression of renal failure, kidney hypertrophy and kidney calcium deposition in the azotaemic rat. Our study showed that both NH4Cl and high dietary phosphorus induced hypertrophy of the remnant kidney and their effects were additive. The effect of dietary phosphorus was particularly complex because high dietary phosphorus did not decrease the creatinine clearance. But when factored for kidney weight, the creatinine clearance was actually lower with the HPD. Also, the creatinine clearance inversely correlated with the amount of calcium deposition in the kidney, which was reduced with NH4Cl ingestion and increased with high dietary phosphorus. Finally, studies in azotaemic rats subjected to PTX showed that NH4Cl increased the creatinine clearance and resulted in kidney hypertrophy even in the absence of PTH. Moreover, PTX did not protect against the deposition of calcium in the kidney.
Previous studies have shown that both partial nephrectomy and NH4Cl induce kidney hypertrophy [1,4] and our study confirms these results (for validation of partial nephrectomy results, see Figure 1, NPD vs sham-NPD). Recent studies have suggested that the mechanism of kidney hypertrophy is different between partial nephrectomy and NH4Cl. Partial nephrectomy-induced kidney hypertrophy is characterized by TGF-ß induced cell cycle arrest after progression to the early G1 phase, while that of NH4Cl appears to be from an imbalance between protein synthesis and degradation [3,4]. In the present study, high dietary phosphorus was also shown to independently contribute to kidney hypertrophy. It could be argued that the increase in kidney weight associated with increasing dietary phosphorus might have been related to the increasing calcium deposition seen with high dietary phosphorus. However, each µmol of calcium is equal to only 0.04 mg. Thus, even 100 µmol of calcium is equal to only 0.4 mg and the mean uncorrected weight of the remnant kidney for all groups was much greater at 1.45±0.05 g. Another possible reason for the greater kidney hypertrophy with the higher dietary phosphorus intake might be that a HPD is associated with an increased protein intake, a known cause of kidney hypertrophy [1,5]. But besides the same dietary protein content of 20% stated for the three diets, this information was confirmed by the similar urea nitrogen excretion among the NH4Cl groups. Thus, the evidence indicates that high dietary phosphorus independently induced kidney hypertrophy. Whether the kidney hypertrophy induced by high dietary phosphorus is a specific effect of phosphorus or is a response to ongoing injury induced by continuous calcium deposition in the kidney will need to be addressed in future studies.
In the remnant kidney model, dietary phosphorus restriction has been shown to reduce renal growth [17]. It also reduced the increased oxygen consumption, the high intracellular pH and the hypermetabolism present in the remnant kidney [8]. Thus, it would seem possible that high dietary phosphorus further increases oxygen consumption and the hypermetabolism in the remnant kidney, thus producing an increased metabolic demand, which results in kidney hypertrophy. Our study is not the first to show that high dietary phosphorus induces kidney hypertrophy [6,7]. Besides confirming these earlier findings, our results show that the effect of dietary phosphorus is progressive from low to high dietary phosphorus and also acts to enhance the hypertrophic effect of NH4Cl.
ANCOVA was performed because the degree of acidosis varied among the NH4Cl groups. ANCOVA showed that high dietary phosphorus independently contributed to the development of kidney hypertrophy. Thus, even when differences in bicarbonate and PTH were accounted for, high dietary phosphorus had a major effect on kidney hypertrophy.
Recent studies in azotaemic rats on a HPD have shown that sevelamer added to the diet reduces nephrocalcinosis [1012,18]. Clinical studies have shown that sevelamer use in dialysis patients results in a decrease in serum bicarbonate levels [1921]. Moreover, based on body weight, the dose of sevelamer used in the rat studies was more than 20 times greater than that given to patients. Of the four cited studies of sevelamer in rats [1012,18], only two measured blood pH or serum bicarbonate values [10,18]. These two studies did not find a reduction in values at death (presumably after an overnight fast) as compared with other similarly treated groups. But such results do not preclude that sevelamer may have induced a mild metabolic acidosis in the rats during the study. Moreover, it has been suggested that sevelamer use in rats increased urinary ammonium excretion [21]. Thus, besides the renoprotective effect gained from phosphorus lowering, it is possible that metabolic acidosis could have contributed to this beneficial effect.
An important finding of our study was the relationship between overall renal function and renal function factored for kidney weight. In each dietary group, creatinine clearance was greater in the NH4Cl group (see Part I). Among the three dietary phosphorus groups, it was similar in +NH4Cl and in NH4Cl groups. But when creatinine clearance was factored for kidney weight, it was lowest in the high dietary phosphorus group. Thus, it would seem that the greater kidney mass in the high dietary phosphorus group was responsible for maintaining the similar creatinine clearance in the HPD groups. Because renal function per kidney mass was decreased in the HPD groups, our results would also suggest that with time, renal function would likely deteriorate more in these HPD groups.
In a previous study, we showed that NH4Cl administration retarded the progression of renal failure in 5/6 nephrectomized rats on a HPD [22]. At that time we suggested that the protective effect of NH4Cl administration on renal function might be because of reduced kidney calcium deposition. In the present study, support for such a hypothesis includes: (i) NH4Cl administration reduced kidney calcium deposition; (ii) the inverse correlation between creatinine clearance and kidney calcium content and (iii) in the HPD groups, the reduction in calcium deposition in the +NH4Cl group was associated with a greater creatinine clearance when factored for kidney weight. Our hypothesis regarding the deleterious effect of kidney calcium deposition is also in agreement with recent studies in which the use of sevelamer in azotaemic rats reduced kidney calcium deposition and preserved renal function [10,12].
Kidney calcium deposition was much less in sham operated than in azotaemic rats, even in those on a LPD. In human studies, chronic renal failure has been shown to be associated with greater kidney calcium deposition [23]. In the present study, in addition to the renal failure, the hypercalcaemia seen with the LPD and the increased phosphorus burden in the other two dietary groups probably contributed to the increased calcium deposition in the remnant kidney.
In previous studies, both PTX and WR-2721, an inhibitor of PTH secretion, have been shown to reduce kidney calcium deposition [5,1315,24]. Moreover, in azotaemic rats, these same interventions preserved renal function and reduced kidney hypertrophy [5,15]. In these latter studies, the stimuli for kidney hypertrophy were partial nephrectomy or the combination of high protein diet and partial nephrectomy [5,15]. It has been suggested that the absence of PTH is the factor by which PTX retards the development of kidney hypertrophy [7,25]. In our study, one goal was to determine if NH4Cl-induced kidney hypertrophy was modified by PTX. Even though the amount of NH4Cl ingested was less in PTX rats than in the other +NH4Cl groups, kidney hypertrophy along with an increase in creatinine clearance and a reduction in kidney calcium deposition were still observed in the PTX group. In PTX rats not given NH4Cl, kidney weight and calcium deposition were not different from its parathyroid-intact counterpart receiving the same diet (NPD group). Others have reported in non-azotaemic rats that PTX reduces nephrocalcinosis by preventing PTH-induced stimulation of cellular calcium metabolism and transport [23]. But in our study in azotaemic rats, PTX did not retard kidney calcium deposition or preserve renal function as measured by the creatinine and urea clearances. However, all variables were not controlled for as values of plasma calcium and phosphorus were different in the PTX group.
In summary, in our 30-day study of azotaemic rats, NH4Cl administration induced kidney hypertrophy and decreased kidney calcium deposition. A HPD induced kidney hypertrophy and increased kidney calcium deposition. In the high dietary phosphorus group, kidney hypertrophy played an important role in maintaining the creatinine clearance. In PTX rats, the absence of PTH did not prevent NH4Cl from inducing kidney hypertrophy and reducing kidney calcium deposition. In conclusion, NH4Cl and dietary phosphorus content each result in complex interactions, which affect kidney growth and calcium deposition in the growing rat with renal failure. It is also likely that based on the results of kidney calcium deposition that a prolongation of the study would show that high dietary phosphorus would result in progressive kidney damage while NH4Cl administration would act to preserve renal function.
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Acknowledgments
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The authors would like to thank Drs Mariano Rodriguez and Barton Levine for helpful suggestions about the manuscript and Drs Armando Torres and Alejandro Jimenez for their advice on the ANCOVA. This study was supported by grant #1000560 from FONDECYT (Fondo Nacional de Ciencia y Technologia de Chile).
Conflict of interest statement. None declared.
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Received for publication: 23. 3.04
Accepted in revised form: 7. 4.04