Effect of ammonium chloride and dietary phosphorus in the azotaemic rat. I. Renal function and biochemical changes

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, California, 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



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Both dietary phosphorus restriction and the ingestion of ammonium chloride (NH4Cl) given to rats on a high-phosphorus diet have been shown to preserve renal function in the azotaemic rat. Parathyroidectomy also has been reported to preserve renal function and, in addition, to prevent kidney hypertrophy in the remnant kidney model. Our goals were (i) to evaluate in azotaemic rats the effect of dietary phosphorus on renal function in a shorter time frame than previously studied and (ii) to determine whether NH4Cl administration (a) enhances the renoprotective effect of dietary phosphorus restriction and (b) improves renal function in the absence of parathyroid hormone (PTH).

Methods. High (H; 1.2%), normal (N; 0.6%) and low (L; <0.05%) phosphorus diets (PD) were given for 30 days to 5/6 nephrectomized rats. In each dietary group, one-half of the rats were given NH4Cl in the drinking water. The six groups were HPD + NH4Cl, HPD, NPD + NH4Cl, NPD, LPD + NH4Cl and LPD. The effect of NH4Cl administration was also evaluated in 5/6 nephrectomized, parathyroidectomized (PTX) rats on NPD.

Results. In each of the three dietary phosphorus groups, creatinine and urea clearances were greater (P<0.01) in rats receiving NH4Cl. Neither creatinine nor urea clearance was reduced by high dietary phosphorus. Urine calcium excretion was greatest in the LPD group and was increased (P ≤ 0.001) in all three groups by NH4Cl ingestion. An inverse correlation was present between plasma calcium and phosphorus in the parathyroid intact (r = –0.79, P<0.001) and PTX groups (r = –0.46, P = 0.02). In PTX rats, NH4Cl ingestion increased (P ≤ 0.01) creatinine and urea clearances and both an increasing plasma calcium concentration (r = 0.67, P<0.001) and urine calcium excretion (r = 0.73, P<0.001) increased urine phosphorus excretion.

Conclusions. At 30 days of renal failure (i) NH4Cl ingestion increased creatinine and urea clearances, irrespective of dietary phosphorus; (ii) high urine calcium excretion, induced by dietary phosphorus restriction and NH4Cl ingestion, did not adversely affect renal function; (iii) high dietary phosphorus did not decrease renal function; (iv) the absence of PTH did not preserve renal function or prevent NH4Cl from improving renal function; and (v) both an increasing plasma calcium concentration and urine calcium excretion resulted in an increase in urine phosphorus excretion in PTX rats.

Keywords: ammonium chloride; calcium; dietary phosphorus; phosphorus; renal failure



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Studies performed 2 decades ago showed that long-term dietary phosphorus restriction slowed the progression of renal failure in azotaemic rats [1–3]. Recent studies have shown that the use of the phosphorus binder, sevelamer, has a similar renoprotective effect in azotaemic rats [4,5]. Recently, we showed that ammonium chloride (NH4Cl) administration protected against the progression of renal failure in 5/6 nephrectomized rats given a high-phosphorus diet (HPD) for 30 days [6]. Both a low-phosphorus diet (LPD) and NH4Cl administration increase renal calcium excretion [6–8]. NH4Cl administration also has been shown to facilitate renal excretion of phosphorus [9]. While NH4Cl administration was renoprotective with a HPD, it is not known whether NH4Cl administration improves renal function in azotaemic rats on LPD or normal-phosphorus diet (NPD). Moreover, it is also possible that NH4Cl-induced potentiation of the hypercalcaemic and hypercalciuric effects seen with dietary phosphorus restriction could result in renal damage.

More than a decade ago, Lau [10] advanced a precipitation–calcification hypothesis, in which he proposed that phosphate absorbed in excess of excretory capacity is precipitated and deposited as calcium phosphate microcrystals in the tubular lumen, peritubular space, capillaries and interstitium and, thus, contributes to renal failure. Others have reported that parathyroidectomy (PTX) or a drug-induced reduction in parathyroid hormone values retards the progression of renal failure in the azotaemic rat [11,12].

In the first part of our study, our goal was: (i) to evaluate in azotaemic rats the effect of dietary phosphorus on renal function in a shorter time frame than previously studied and (ii) to determine whether NH4Cl administration (a) enhances the renoprotective effect of dietary phosphorus restriction and (b) improves renal function in the absence of parathyroid hormone (PTH).



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Male Sprague–Dawley rats weighing 180–200 g were studied. Renal failure was induced by arterial ligation of two of the three hilar branches of the left main artery and 1 week later, a right nephrectomy was performed [6,13]. During surgical procedures, rats were anaesthetized with intraperitoneally administered ketamine 7.5 mg/100 g (Ketaset; Fort Dodge Laboratories, Fort Dodge, IA, USA) and xylazine 0.5 mg/100 g (AnaSed; Lloyd Laboratories, Shenandoah, IA, USA). Rats were housed in individual cages, given 14 g food daily and allowed free access to water. Rats were removed from the study if they did not consume >90% of their diet.

After the right nephrectomy, rats were divided into three different groups of dietary phosphorus and in half of each group, NH4Cl was added to the drinking water to form a 0.75% solution of NH4Cl. The three different contents of dietary phosphorus were 1.2% (HPD), 0.6% (NPD) and <0.05% (LPD). Dietary calcium was 0.6% and dietary protein content was 20% for each of the three phosphorus diets (ICN, Cleveland, OH, USA). There were six groups: HPD + NH4Cl, HPD, NPD + NH4Cl, NPD, LPD + NH4Cl and LPD. In a separate study, a selective PTX was performed in rats before the 5/6 nephrectomy. These rats were given a 0.6% phosphorus, 0.6% calcium diet and in one half, NH4Cl was added to the drinking water. Because these rats were unable to tolerate a 0.75% NH4Cl solution as drinking water, it was reduced to 0.375% NH4Cl.

Two days before sacrifice, rats were placed in a metabolic cage and 24 h urine was collected during the second day. Thirty days after the right nephrectomy, rats were sacrificed after an overnight fast. After rats were anaesthetized, the abdomen was opened and blood was obtained from the aorta for blood gas and chemistry measurements. The rats were then sacrificed.

Plasma calcium, phosphorus and urea nitrogen were measured with specific kits (Sigma, St Louis, MO, USA). Plasma and urinary creatinine were measured with a creatinine analyser (Beckman, Fullerton, CA, USA). Other urinary measurements were calcium, phosphorus and urea nitrogen (Sigma, St Louis, MO, USA). PTH was measured with an immunoradiometric assay specific for intact PTH in the rat (Nichols, San Juan Capistrano, CA, USA). The intra-assay coefficient of variation was 4%. Arterial pH and pCO2 were directly measured on a blood gas analyser (Ciba Corning, Medfield, MA, USA). The bicarbonate concentration was calculated from the Henderson–Hasselbach equation. The creatinine and urea clearances were calculated from the clearance formula of UV/P x 1/1440 min, where U represents the urine concentration, V the urine volume and P the plasma concentration. The results were then corrected for the weight of the rat. Finally, because we and others have shown in rats on a phosphorus-depleted diet (<0.05% P) that the plasma phosphorus values are inappropriately increased when rats are fasted overnight and these values fall dramatically after feeding [8,14], the plasma phosphorus value was adjusted downwards from the high plasma phosphorus value of 8.41±0.47 mg/dl present in this group. The amount adjusted represented the difference observed in our previous study between rats fasted overnight and those given a morning feed [8].

Statistics
Statistical analysis was performed using the software program NCSS (Kaysville, UT, USA). The unpaired t-test was used for the comparison between two groups. When the comparison consisted of three groups, one-way analysis of variance (ANOVA) was used to determine differences. If the P-value was ≤0.05 for the ANOVA, the Newman–Keuls test was used for intergroup comparisons. When the result of the ANOVA had P-values between 0.05 and 0.10, these values are shown in the tables for informational purposes, but intergroup comparisons were not performed. Results are shown as means±SE.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In Tables 1–3GoGo, the data are stratified for both intergroup and intragroup comparisons. The intergroup comparison is among the three dietary groups (LPD, NPD and HPD) with and without NH4Cl (+/–NH4Cl) in the drinking water. The intragroup comparison is between the +/–NH4Cl rats in each dietary group (LPD, NPD and HPD).


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Table 1. Plasma chemistries

 

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Table 2. Urine chemistries

 

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Table 3. Pre- and post-study weights and weight gain (delta weight)

 
In the intergroup analysis, the plasma calcium value in both groups (+/–NH4Cl) was greatest in the LPD group (Table 1). In the intragroup analysis, the plasma calcium value was greater in the –NH4Cl group in the LPD group, but in the HPD groups was greater in the +NH4Cl group. In the intergroup analysis, the phosphorus value was greatest in the HPD group for both the +NH4Cl and –NH4Cl groups. In the intragroup analysis, the phosphorus value for the HPD groups was less in the +NH4Cl group. As shown in Figure 1A, a strong inverse correlation was present between plasma calcium and phosphorus values.



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Fig. 1. Correlation between plasma calcium and phosphorus in parathyroid-intact (A) and PTX (B) rats. A significant inverse correlation was present between plasma calcium and plasma phosphorus in both parathyroid-intact (A) and PTX (B) rats.

 
Intergroup analysis showed that among the +NH4Cl groups, arterial pH was lowest in the HPD group (Table 1). Arterial pH was not different among the –NH4Cl groups. In the intragroup analysis, arterial pH was less in +NH4Cl groups in the NPD and HPD groups. Intergroup and intragroup comparisons for plasma bicarbonate were similar to those of pH, except that the bicarbonate value in the NPD group was less than in the LPD group. Blood urea nitrogen (BUN) values were not different for intergroup or intragroup comparisons. Creatinine values were similar among the +NH4Cl groups (intergroup), but were greater in the HPD group among the –NH4Cl groups. For the intragroup comparison, creatinine values were greater in the –NH4Cl group for all three groups (LPD, NPD and HPD). The correlation between plasma creatinine and BUN was r = 0.81 (P<0.001). Finally, PTH values were greater in the HPD groups for both +/–NH4Cl intergroup comparisons. For the intragroup comparisons, the PTH value was greater in the –NH4Cl group in the NPD and HPD groups.

As shown in Figure 2, urinary calcium excretion was greatest in the LPD group and it was increased by NH4Cl administration in each of the three groups. Both creatinine and urea clearances were greater in each of the groups receiving NH4Cl (Figure 3).



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Fig. 2. Urine calcium excretion during 24 h in +NH4Cl and –NH4Cl groups. In the parathyroid-intact rats, 24 h urine calcium excretion for the +NH4Cl groups (dark grey bars) was greatest in the LPD group and similar in the NPD and HPD groups. This is shown in the comparison of the three dark grey bars (+NH4Cl) in which a and b are different (P<0.05) from each other. Among the –NH4Cl groups (light grey bars), urine calcium excretion was greatest in the LPD group and not different between the NPD and HPD groups. This is shown in the comparison of the three light grey bars (–NH4Cl) in which y is different (P<0.05) from x. In the LPD, NPD and HPD groups, urine calcium excretion was greater (P<0.05) in the +NH4Cl group than in the –NH4Cl group (*).

 


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Fig. 3. Creatinine (A) and urea (B) clearances in +NH4Cl and –NH4Cl groups. In the parathyroid-intact rats, creatinine and urea clearances were greater (P<0.05) in the +NH4Cl groups (dark grey bars) in each of the HPD, NPD and LPD groups. The –NH4Cl groups are shown by light grey bars.

 
Urine phosphorus excretion reflected the differences in dietary phosphorus intake (Table 2). Urine creatinine excretion was not different among groups (intergroup) or between groups (intragroup). Urea nitrogen excretion was greater in the HPD group among +NH4Cl groups and similar among –NH4Cl groups (intergroup). Urea nitrogen excretion was greater in +NH4Cl groups (intragroup) in all three groups (LPD, NPD and HPD). Urine volume was greater in the HPD groups for both the +NH4Cl and –NH4Cl intergroup comparisons.

Pre-study weights were not different (Table 3). The sacrifice weight (post-study) was lowest in the HPD groups for both +NH4Cl and NH4Cl groups (intergroup). The only intragroup difference was in the NPD group. The increase in weight (delta weight) during the study was less in the HPD group in both +NH4Cl and –NH4Cl groups.

To determine whether PTH modified the changes observed with NH4Cl, azotaemic rats on a NPD were studied after PTX. In the PTX groups, differences in plasma values were observed only for phosphorus and creatinine, both of which were less with NH4Cl (Table 4). As with parathyroid intact rats, an inverse correlation was present between plasma calcium and phosphorus (Figure 1B). Urine chemistries were remarkable for greater calcium and urea nitrogen excretion and higher creatinine and urea clearances in the +NH4Cl group.


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Table 4. Plasma and urine chemistries and weights in PTX rats

 
Some interesting relationships were observed in the PTX rats. As expected, the higher the plasma calcium concentration, the greater the urine calcium excretion (Table 5). Significant correlations were present between plasma calcium and urine phosphorus and between urine calcium and urine phosphorus. These correlations suggest that urine calcium excretion may act to enhance urine phosphorus excretion. Finally, the inverse correlation between plasma phosphorus and urine phosphorus showed that a high plasma phosphorus concentration did not increase urine phosphorus excretion.


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Table 5. Relationships among plasma calcium and phosphorus and urine calcium and phosphorus in PTX rats

 


   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Studies performed 2 decades ago showed that dietary phosphorus restriction preserved renal function in azotaemic rats [1–3]. Several recent studies in azotaemic rats have shown that the use of the phosphorus binder, sevelamer, preserved renal function and also reduced kidney calcium deposition [4,5]. Our interest in the preservation of renal function in azotaemic rats came from a different direction. In a study, which was originally designed to evaluate whether NH4Cl-induced acidosis increased PTH secretion, we unexpectedly found that NH4Cl administration preserved renal function in azotaemic rats on a HPD [6]. Our original study, which had a shorter duration than the cited studies on dietary phosphorus restriction and sevelamer use [1–5], has now been expanded to determine whether NH4Cl administration preserves renal function in azotaemic rats on NPD and LPD. We show that NH4Cl administration increases the creatinine and urea clearances in azotaemic rats on HPD, NPD and LPD. In results to be presented in the second part of our study, we show that the kidney hypertrophy, induced by both NH4Cl and high dietary phosphorus, was responsible for the enhanced renal function.

In groups not receiving NH4Cl, the failure to find a higher creatinine clearance in the low compared with the high dietary phosphorus group might seem to be against the accepted concept that dietary phosphorus restriction preserves renal function. However, we do not believe that our results are at variance with previous studies, because in those studies the duration of renal failure was much longer than 30 days [1–5]. We selected a 30 day study period, because it was the duration used in our previous study in which NH4Cl administration unexpectedly preserved renal function. In addition, an evaluation for a shorter period of time provides a perspective on how differences in dietary phosphorus act to affect long-term changes in renal function. As is often the case, short-term benefits are not always translated into long-term gains. Also, as will be shown in the second part of our study, kidney hypertrophy appeared to be the reason that the creatinine clearance was maintained in the high-phosphorus group. Thus, we believe that our biochemical and histological results serve to better define the evolution of progressive renal failure in the azotaemic rat.

The magnitude of acidosis was greater in rats on a HPD. Because urine volume was greatest in this group, it is probably correct to assume that the intake of water containing NH4Cl was also greater during the study. As such, the HPD group would be ingesting more than twice the amount of NH4Cl as the other two groups. The urine volume was also greater in the HPD group not given NH4Cl. Thus, the effect of the HPD was probably not only due to acidosis. A greater urine volume in HPD groups was observed, even though the LPD groups had factors such as hypercalcaemia and marked hypercalciuria, which should have increased urine volume. It is likely that the increased urine volume in the HPD groups resulted from the tubulointerstitial injury that is seen with a HPD [4,15]. Nephrocalcinosis was probably the initiating factor for the tubulointerstitial injury, which primarily affects the corticomedullary junction and reduces the renal concentrating capacity [7].

Our results are in agreement with previous studies that have shown that both dietary phosphorus restriction and NH4Cl administration increase urinary calcium excretion [6–8]. Of interest, we also showed that NH4Cl ingestion further increased calcium excretion in the LPD group with an already high calcium excretion. It is possible that the increased calcium excretion in the LPD group receiving NH4Cl contributed to the lower plasma calcium value in this group (LPD vs LPD + NH4Cl). At a time when calcium mobilization from bone was increased by phosphorus deprivation and then, probably, further enhanced by NH4Cl ingestion, whether an increase in the plasma calcium concentration is seen depends on the capacity of the remnant kidney to increase calcium excretion. Finally, despite the increased urinary calcium excretion in the +NH4Cl groups (LPD, NPD and HPD), renal function was not compromised.

The similar urea nitrogen excretion in the groups not receiving NH4Cl supports the supplier's statement that dietary protein was the same for the three diets. The daily amount of excreted urea nitrogen was greater in the rats given NH4Cl and, also, there was a tendency for weight gain to be less in the groups receiving NH4Cl. Thus, the increased excretion of urea nitrogen in the groups given NH4Cl was probably from acidosis-induced tissue catabolism. Such a conclusion is supported from previous studies in rats in which the ubiquitin pathway was shown to be activated by acidosis [16]. However, exogenously administered NH4Cl also enters the urea cycle and could have contributed to the increase in urinary urea nitrogen excretion in the +NH4Cl groups [17].

An inverse correlation was observed between plasma calcium and phosphorus. Previous studies in azotaemic rats have shown that high dietary phosphorus together with normal dietary calcium results in hypocalcaemia and hyperphosphataemia, despite high PTH values [13]. Conversely, dietary phosphorus deprivation, despite low PTH values, results in hypercalcaemia and hypophosphataemia [8]. Because of the inverse relationship between plasma calcium and phosphorus, the calcium–phosphorus product was little different among the groups with only a small increase in the two HPD groups (data not shown). Our results also show that to maintain a normal plasma calcium concentration in the azotaemic rat on a HPD, it is necessary to supply an exogenous source of calcium, such as high dietary calcium.

Even though only a normal phosphorus diet was used in the PTX groups, a similar inverse correlation was observed between plasma calcium and phosphorus. Moreover, the correlations among plasma and urine calcium and phosphorus suggest the possibility of an interesting cause and effect relationship. The correlation between plasma and urine calcium was as expected, because in the absence of PTH, urine calcium excretion increases rapidly once a threshold, which is below a normal plasma calcium value, is reached [18]. Both an increase in plasma calcium concentration and in urine calcium excretion were shown to be associated with an increase in urine phosphorus excretion. Such a result was previously shown in humans with hypoparathyroidism by Eisenberg in the 1960s [19]. Recent studies have shown that the calcium-sensing receptor on the luminal surface of the proximal tubule is involved in phosphorus excretion as a result of its interaction with the NaPi-2 transporter [20]. Thus, it is possible that an increasing calcium concentration in the glomerular filtrate activates the calcium-sensing receptor in the proximal tubule resulting in increased phosphorus excretion. Finally, the inverse correlation between plasma phosphorus and urine phosphorus shows that high plasma phosphorus failed to increase urine phosphorus excretion.

Azotaemic rats were subjected to PTX to determine whether an increase in creatinine clearance would develop with NH4Cl ingestion in the absence of PTH. Previous studies have shown that PTX or a drug-induced reduction in PTH not only preserved renal function in the remnant kidney model, but also prevented kidney hypertrophy [11,12]. In our PTX rats, NH4Cl ingestion resulted in an increase in creatinine and urea clearances and, as will be shown in the second part of our study, did not prevent kidney hypertrophy.

In summary, in our 30 day study in azotaemic rats, NH4Cl ingestion improved the creatinine clearance, increased urinary calcium excretion and, probably, increased protein catabolism in all three dietary phosphorus groups and in PTX rats. High dietary phosphorus reduced urine calcium excretion, but did not reduce the creatinine clearance. The latter result was probably because of the shorter duration of our study in contrast to previous studies, which have shown that dietary phosphorus restriction was renoprotective. The absence of PTH in PTX rats did not prevent NH4Cl from increasing the creatinine clearance. Moreover, in PTX rats, an increase in the plasma calcium concentration and in urine calcium excretion resulted in an increase in urine phosphorus excretion. In conclusion, both NH4Cl administration and dietary phosphorus content result in complex interactions that affect renal function and metabolism in the growing rat with renal failure.



   Acknowledgments
 
The authors would like to thank Drs Mariano Rodriguez and Barton Levine for helpful suggestions about the manuscript. This study was supported by grant no. 1000560 from FONDECYT (Fondo Nacional de Ciencia y Tecnologia de Chile).

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 25. 3.04
Accepted in revised form: 16. 4.04





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