Comparative effects of calcitriol and calcimimetic on bone health in renal insufficiency.

Calcitriol and calcimimetics are used to treat hyperparathyroidism secondary to chronic kidney disease (CKD). Calcitriol administration and the subsequent increase in serum calcium concentration decrease parathyroid hormone (PTH) levels, which should reduce bone remodeling. We have previously reported that, when maintaining a given concentration of PTH, the addition of calcimimetics is associated with an increased bone cell activity. Whether calcitriol administration affects bone cell activity while PTH is maintained constant should be evaluated in an animal model of renal osteodystrophy. The aim of the present study was to compare in CKD PTH-clamped rats the bone effects of calcitriol and calcimimetic administration. The results show that the administration of calcitriol and calcimimetic at doses that induced a similar reduction in PTH secretion produced dissimilar effects on osteoblast activity in 5/6 nephrectomized (Nx) rats with secondary hyperparathyroidism and in Nx rats with clamped PTH. Remarkably, in both rat models, the administration of calcitriol decreased osteoblastic activity, whereas calcimimetic increased bone cell activity. In vitro, calcitriol supplementation inhibited nuclear translocation of ß-catenin and reduced proliferation, osteogenesis, and mineralization in mesenchymal stem cells differentiated into osteoblasts. In conclusion, besides the action of calcitriol and calcimimetics at parathyroid level, these treatments have specific effects on bone cells that are independent of the PTH level.

Assessment of Inorganic Phosphate Intake by the Measurement of the Phosphate/Urea Nitrogen Ratio in Urine.

In chronic kidney disease (CKD) patients, it would be desirable to reduce the intake of inorganic phosphate (P) rather than limit the intake of P contained in proteins. Urinary excretion of P should reflect intestinal absorption of P(inorganic plus protein-derived). The aim of the present study is to determine whether the ratio of urinary P to urinary urea nitrogen (P/UUN ratio) helps identify patients with a high intake of inorganic P.A cross-sectional study was performed in 71 patients affected by metabolic syndrome with CKD (stages 2-3) with normal serum P concentration. A 3-day dietary survey was performed to estimate the average daily amount and the source of P ingested. The daily intake ofPwas1086.5 ± 361.3mg/day; 64% contained in animal proteins, 22% in vegetable proteins, and 14% as inorganic P. The total amount of P ingested did not correlate with daily phosphaturia, but it did correlate with the P/UUN ratio (p < 0.018). Patients with the highest tertile of the P/UUN ratio >71.1 mg/g presented more abundant inorganic P intake (p < 0.038).The P/UUN ratio is suggested to be a marker of inorganic P intake. This finding might be useful in clinical practices to identify the source of dietary P and to make personalized dietary recommendations directed to reduce inorganic P intake.

Calcimimetics maintain bone turnover in uremic rats despite the concomitant decrease in parathyroid hormone concentration.

Calcimimetics decrease parathyroid hormone (PTH) secretion in patients with secondary hyperparathyroidism. The decrease in PTH should cause a reduction in bone turnover; however, the direct effect of calcimimetics on bone cells, which express the calcium-sensing receptor (CaSR), has not been defined. In this study, we evaluated the direct bone effects of CaSR activation by a calcimimetic (AMG 641) in vitro and in vivo. To create a PTH "clamp," total parathyroidectomy was performed in rats with and without uremia induced by 5/6 nephrectomy, followed by a continuous subcutaneous infusion of PTH. Animals were then treated with either the calcimimetic or vehicle. Calcimimetic administration increased osteoblast number and osteoid volume in normal rats under a PTH clamp. In uremic rats, the elevated PTH concentration led to reduced bone volume and increased bone turnover, and calcimimetic administration decreased plasma PTH. In uremic rats exposed to PTH at 6-fold the usual replacement dose, calcimimetic administration increased osteoblast number, osteoid surface, and bone formation. A 9-fold higher dose of PTH caused an increase in bone turnover that was not altered by the administration of calcimimetic. In an osteosarcoma cell line, the calcimimetic induced Erk1/2 phosphorylation and the expression of osteoblast genes. The addition of a calcilytic resulted in the opposite effect. Moreover, the calcimimetic promoted the osteogenic differentiation and mineralization of human bone marrow mesenchymal stem cells in vitro. Thus, calcimimetic administration has a direct anabolic effect on bone that counteracts the decrease in PTH levels.

Pathophysiology of Calcium, Phosphorus, and Magnesium Dysregulation in Chronic Kidney Disease.

Calcium, phosphorus, and magnesium homeostasis is altered in chronic kidney disease (CKD). Hypocalcemia, hyperphosphatemia, and hypermagnesemia are not seen until advanced CKD because adaptations develop. Increased parathyroid hormone (PTH) secretion maintains serum calcium normal by increasing calcium efflux from bone, renal calcium reabsorption, and phosphate excretion. Similarly, renal phosphate excretion in CKD is maintained by increased secretion of fibroblast growth factor 23 (FGF23) and PTH. However, the phosphaturic effect of FGF23 is reduced by downregulation of its cofactor Klotho necessary for binding FGF23 to FGF receptors. Intestinal phosphate absorption is diminished in CKD due in part to reduced levels of 1,25 dihydroxyvitamin D. Unlike calcium and phosphorus, magnesium is not regulated by a hormone, but fractional excretion of magnesium increases as CKD progresses. As 60-70% of magnesium is reabsorbed in the thick ascending limb of Henle, activation of the calcium-sensing receptor by magnesium may facilitate magnesium excretion in CKD. Modification of the TRPM6 channel in the distal tubule may also have a role. Besides abnormal bone morphology and vascular calcification, abnormalities in mineral homeostasis are associated with increased cardiovascular risk, increased mortality and progression of CKD.

Calcitonin, the forgotten hormone: does it deserve to be forgotten?

Calcitonin is a 32 amino acid hormone secreted by the C-cells of the thyroid gland. Calcitonin has been preserved during the transition from ocean-based life to land dwellers and is phylogenetically older than parathyroid hormone. Calcitonin secretion is stimulated by increases in the serum calcium concentration and calcitonin protects against the development of hypercalcemia. Calcitonin is also stimulated by gastrointestinal hormones such as gastrin. This has led to the unproven hypothesis that postprandial calcitonin stimulation could play a role in the deposition of calcium and phosphate in bone after feeding. However, no bone or other abnormalities have been described in states of calcitonin deficiency or excess except for diarrhea in a few patients with medullary thyroid carcinoma. Calcitonin is known to stimulate renal 1,25 (OH)2 vitamin D (1,25D) production at a site in the proximal tubule different from parathyroid hormone and hypophosphatemia. During pregnancy and lactation, both calcitonin and 1,25D are increased. The increases in calcitonin and 1,25D may be important in the transfer of maternal calcium to the fetus/infant and in the prevention and recovery of maternal bone loss. Calcitonin has an immediate effect on decreasing osteoclast activity and has been used for treatment of hypercalcemia. Recent studies in the calcitonin gene knockout mouse have shown increases in bone mass and bone formation. This last result together with the presence of calcitonin receptors on the osteocyte suggests that calcitonin could possibly affect osteocyte products which affect bone formation. In summary, a precise role for calcitonin remains elusive more than 50 years after its discovery.

Serum calcium and bone: effect of PTH, phosphate, vitamin D and uremia

Hyperparathyroidism develops in chronic kidney disease (CKD). A decreased calcemic response to parathyroid hormone (PTH) contributes to the development of hyperparathyroidism and is presumed due to reduced calcium efflux from bone. Contributing factors to the decreased calcemic response to PTH in CKD include: 1) hyperphosphatemia; 2) decreased serum calcitriol; 3) downregulation of the PTH1 receptor; 4) large, truncated amino-terminal PTH fragments acting at the carboxy-PTH receptor; and 5) uremic toxins. Also, prolonged high dose calcitriol administration may decrease the exchangeable pool of bone calcium independent of PTH. The goal of the review is to provide a better understanding of how the above cited factors affect calcium efflux from bone in CKD. In conclusion, much remains to be learned about the role of bone in the regulation of serum calcium (AU)

El hiperparatiroidismo se desarrolla en la enfermedad renal crónica (ERC). La disminución de la respuesta calcémica a la hormona paratiroidea (PTH) contribuye al desarrollo de hiperparatiroidismo y es probable que se deba a una reducción de la emisión de calcio de los huesos. Entre los factores que contribuyen a la disminución de la respuesta calcémica a la PTH en la ERC se encuentran: 1) la hiperfosfatemia; 2) la disminución del calcitriol sérico; 3) la desensibilización del receptor PTHR1; 4) la presencia de fragmentos de gran tamaño de los extremos aminoterminales de la hormona paratiroidea que actúan en el receptor carboxi-PTH y 5) las toxinas urémicas. Asimismo, la administración prolongada de una dosis elevada de calcitriol podría disminuir la reserva intercambiable de calcio independiente de la hormona paratiroidea. El objetivo de esta revisión es facilitar la comprensión de cómo afectan los factores mencionados anteriormente a la emisión de calcio procedente del hueso en la ERC. Como conclusión, aún queda mucho por aprender acerca del papel de los huesos en la regulación del calcio sérico (AU)

Serum calcium and bone: effect of PTH, phosphate, vitamin D and uremia.

Hyperparathyroidism develops in chronic kidney disease (CKD). A decreased calcemic response to parathyroid hormone (PTH) contributes to the development of hyperparathyroidism and is presumed due to reduced calcium efflux from bone. Contributing factors to the decreased calcemic response to PTH in CKD include: 1) hyperphosphatemia; 2) decreased serum calcitriol; 3) downregulation of the PTH1 receptor; 4) large, truncated amino-terminal PTH fragments acting at the carboxy-PTH receptor; and 5) uremic toxins. Also, prolonged high dose calcitriol administration may decrease the exchangeable pool of bone calcium independent of PTH. The goal of the review is to provide a better understanding of how the above cited factors affect calcium efflux from bone in CKD. In conclusion, much remains to be learned about the role of bone in the regulation of serum calcium.

Metabolic acidosis-induced hypercalcemia in an azotemic patient with primary hyperparathyroidism.

A 58-year-old man with Stage 3b chronic kidney disease and primary hyperparathyroidism treated with cinacalcet was admitted for acute cholecystitis. A cholecystostomy tube was placed, estimated glomerular filtration rate decreased, metabolic acidosis developed and ionized calcium increased from 1.33 to 1.76 mM despite cinacalcet administration. A sodium bicarbonate infusion corrected the metabolic acidosis restoring ionized calcium to normal despite no improvement in renal function. The correlation between the increase in serum bicarbonate and decrease in ionized calcium was r = -0.93, P < 0.001. In summary, severe hypercalcemia was attributable to metabolic acidosis increasing calcium efflux from bone while renal failure decreased the capacity to excrete calcium.

Approach to treatment of hypophosphatemia.

Hypophosphatemia can be acute or chronic. Acute hypophosphatemia with phosphate depletion is common in the hospital setting and results in significant morbidity and mortality. Chronic hypophosphatemia, often associated with genetic or acquired renal phosphate-wasting disorders, usually produces abnormal growth and rickets in children and osteomalacia in adults. Acute hypophosphatemia may be mild (phosphorus level, 2-2.5 mg/dL), moderate (1-1.9 mg/dL), or severe (<1 mg/dL) and commonly occurs in clinical settings such as refeeding, alcoholism, diabetic ketoacidosis, malnutrition/starvation, and after surgery (particularly after partial hepatectomy) and in the intensive care unit. Phosphate replacement can be given either orally, intravenously, intradialytically, or in total parenteral nutrition solutions. The rate and amount of replacement are empirically determined, and several algorithms are available. Treatment is tailored to symptoms, severity, anticipated duration of illness, and presence of comorbid conditions, such as kidney failure, volume overload, hypo- or hypercalcemia, hypo- or hyperkalemia, and acid-base status. Mild/moderate acute hypophosphatemia usually can be corrected with increased dietary phosphate or oral supplementation, but intravenous replacement generally is needed when significant comorbid conditions or severe hypophosphatemia with phosphate depletion exist. In chronic hypophosphatemia, standard treatment includes oral phosphate supplementation and active vitamin D. Future treatment for specific disorders associated with chronic hypophosphatemia may include cinacalcet, calcitonin, or dypyrimadole.

Development of parathyroid gland hyperplasia without uremia: role of dietary calcium and phosphate.

Background. Many experimental studies have demonstrated that parathyroid cell proliferation is induced by uremia and further aggravated by hypocalcemia, phosphorus retention and vitamin D deficiency. However, these factors may also promote parathyroid growth without uremia. In the present study, we examined the onset and progression of parathyroid hyperplasia regardless of the uremic setting, a situation that might occur soon during the early renal disease. Thus, the novelty of this work resides in the close examination of the time course for the expected changes in proliferation rates and their association with parathyroid hormone (PTH) release in normal rats under the physiological demands of a high-phosphate diet (HPD) or a low-calcium diet (LCD). Methods. We evaluated the functional response of the parathyroid glands in normal rats to different physiological demands an HPD 0.6% Ca, 1.2% P) and LCD 0.2% Ca, 0.6% P) and compared it with that of uremic rats. Furthermore, we also evaluated the time course for the reversal of high-P and low-Ca-induced parathyroid cell growth and PTH upon normalization of dietary Ca and P intake (0.6% Ca, 0.6% P). Proliferation was measured by flow cytometry and calcium receptor (CaR) and vitamin D receptor (VDR) expression were assessed by qRT-PCR. Results. The pattern in the development of parathyroid hyperplasia by the two dietary models was different. The HPD produced a stronger stimulus than the number of proliferating cells doubled after only 1 day, while the LCD required 5 days to induce an increase; the elevated calcitriol might be a mitigating factor. The increase in cell proliferation was accompanied by a transient down-regulation of VDR expression (higher in the HPD); the expression of CaR was not affected by either diet. Cell proliferation and VDR mRNA levels were restored to control values by Day 15; it is as though the gland had attained a sufficient level of hyperplasia to respond to the PTH challenge. Compared to normal rats, the response of uremic rats to the HPD showed sustained and much higher rates of PTH secretion and cell proliferation and sustained down-regulation of both VDR mRNA and CaR mRNA. Finally, the recovery from the HPD or LCD to a control diet resulted in a rapid restoration of PTH values (1 to 2 days), but the reduction in cell proliferation was delayed (3 to 5 days). Conclusions. Regardless of uremia, a physiological demand to increase the PTH secretion driven either by a high P or a low Ca intake is able to induce a different pattern of parathyroid hyperplasia, which might be aggravated by the down-regulation of VDR expression. The recovery from the HPD or LCD to a control diet results in a more rapid reduction in PTH than in cell proliferation.

The journey from vitamin D-resistant rickets to the regulation of renal phosphate transport.

In 1937, Fuller Albright first described two rare genetic disorders: Vitamin D resistant rickets and polyostotic fibrous dysplasia, now respectively known as X-linked hypophosphatemic rickets (XLH) and the McCune-Albright syndrome. Albright carefully characterized and meticulously analyzed one patient, W.M., with vitamin D-resistant rickets. Albright subsequently reported additional carefully performed balance studies on W.M. In this review, which evaluates the journey from the initial description of vitamin D-resistant rickets (XLH) to the regulation of renal phosphate transport, we (1) trace the timeline of important discoveries in unraveling the pathophysiology of XLH, (2) cite the recognized abnormalities in mineral metabolism in XLH, (3) evaluate factors that may affect parathyroid hormone values in XLH, (4) assess the potential interactions between the phosphate-regulating gene with homology to endopeptidase on the X chromosome and fibroblast growth factor 23 (FGF23) and their resultant effects on renal phosphate transport and vitamin D metabolism, (5) analyze the complex interplay between FGF23 and the factors that regulate FGF23, and (6) discuss the genetic and acquired disorders of hypophosphatemia and hyperphosphatemia in which FGF23 plays a role. Although Albright could not measure parathyroid hormone, he concluded on the basis of his studies that showed calcemic resistance to parathyroid extract in W.M. that hyperparathyroidism was present. Using a conceptual approach, we suggest that a defect in the skeletal response to parathyroid hormone contributes to hyperparathyroidism in XLH. Finally, at the end of the review, abnormalities in renal phosphate transport that are sometimes found in patients with polyostotic fibrous dysplasia are discussed.

Dynamics of parathyroid hormone secretion in health and secondary hyperparathyroidism.

This review examines the dynamics of parathyroid hormone secretion in health and in various causes of secondary hyperparathyroidism. Although most studies of parathyroid hormone and calcium have focused on the modification of parathyroid hormone secretion by serum calcium, the relationship between parathyroid hormone and serum calcium is bifunctional because parathyroid hormone also modifies serum calcium. In normal animals and humans, factors such as phosphorus and vitamin D modify the basal parathyroid hormone level and the maximal parathyroid hormone response to hypocalcemia. Certain medications, such as lithium and estrogen, in normal individuals and sustained changes in the serum calcium concentration in hemodialysis patients change the set point of calcium, which reflects the serum calcium concentration at which parathyroid hormone secretion responds. Hypocalcemia increases the basal/maximal parathyroid hormone ratio, a measure of the relative degree of parathyroid hormone stimulation. The phenomenon of hysteresis, defined as a different parathyroid hormone value for the same serum calcium concentration during the induction of and recovery from hypo- and hypercalcemia, is discussed because it provides important insights into factors that affect parathyroid hormone secretion. In three causes of secondary hyperparathyroidism--chronic kidney disease, vitamin D deficiency, and aging--factors that affect the dynamics of parathyroid hormone secretion are evaluated in detail. During recovery from vitamin D deficiency, the maximal parathyroid hormone remains elevated while the basal parathyroid hormone value rapidly becomes normal because of a shift in the set point of calcium. Much remains to be learned about the dynamics of parathyroid hormone secretion in health and secondary hyperparathyroidism.

Effect of changes in ionized calcium concentration in arterial blood and metabolic acidosis on the arterial partial pressure of oxygen in dogs.

OBJECTIVE: To evaluate the effects of metabolic acidosis and changes in ionized calcium (Ca2+) concentration on PaO2 in dogs. ANIMALS: 33 anesthetized dogs receiving assisted ventilation. PROCEDURE: Normal acid-base status was maintained in 8 dogs (group I), and metabolic acidosis was induced in 25 dogs. For 60 minutes, normocalcemia was maintained in group I and 10 other dogs (group II), and 10 dogs were allowed to become hypercalcemic (group III); hypocalcemia was then induced in groups I and II. Groups II and IV (5 dogs) were treated identically except that, at 90 minutes, the latter underwent parathyroidectomy. At intervals, variables including PaO2, Ca2+ concentration, arterial blood pH (pHa), and systolic blood pressure were assessed. RESULTS: In group II, PaO2 increased from baseline value (96 +/- 2 mm Hg) within 10 minutes (pHa, 7.33 +/- 0.001); at 60 minutes (pHa, 7.21 +/- 0.02), PaO2 was 108 +/- 2 mm Hg. For the same pHa decrease, the PaO2 increase was less in group III. In group I, hypocalcemia caused PaO2 to progressively increase (from 95 +/- 2 mm Hg to 104 +/- 3 mm Hg), which correlated (r = -0.66) significantly with a decrease in systolic blood pressure (from 156 +/- 9 mm Hg to 118 +/- 10 mm Hg). Parathyroidectomy did not alter PaO2 values. CONCLUSIONS AND CLINICAL RELEVANCE: Induction of hypocalcemia and metabolic acidosis each increased PaO2 in anesthetized dogs, whereas acidosis-induced hypercalcemia attenuated that increase. In anesthetized dogs, development of metabolic acidosis or hypocalcemia is likely to affect ventilatory control.

Effect of endothelin receptor antagonist on parathyroid gland growth, PTH values and cell proliferation in azotemic rats.

BACKGROUND: A variety of stimuli are involved in the pathogenesis of parathyroid gland hyperplasia in renal failure. Recently, it was shown that blocking the signal from the endothelin-1 (ET-1) receptor (ET(A)R/ET(B)R) by a non-selective receptor antagonist, bosentan, reduced parathyroid cell proliferation, parathyroid gland hyperplasia and parathyroid hormone (PTH) levels in normal rats on a calcium deficient diet. Our goal was to determine whether in 5/6 nephrectomized (NPX) rats with developing or established hyperparathyroidism, the endothelin receptor blocker, bosentan, reduced the increase in parathyroid cell proliferation, parathyroid gland hyperplasia and PTH values. METHODS: High (HPD, 1.2%) or normal phosphorus diets (PD) (NPD, 0.6%) were given to 5/6 NPX rats for 15 days (NPX(15)). In each dietary group, one-half the rats were given bosentan (B) i.p. 100 mg/kg/day. The four groups of rats were: (1) NPX(15)-1.2% P; (2) NPX(15)-1.2% P+B; (3) NPX(15)-0.6% P; and (4) NPX(15)-0.6% P+B. In a second study in which hyperparathyroidism was already established in 5/6 NPX rats fed a HPD for 15 days, rats were divided into two groups in which one group was maintained on a HPD and the other group was changed to very low PD (VLPD, <0.05%) for an additional 15 days. In each dietary group, one-half the rats were given bosentan i.p. 100 mg/kg-day. The four groups of rats were: (1) NPX(30)-1.2% P; (2) NPX(30)-1.2% P+B; (3) NPX(30)-0.05% P and (4) NPX(30)-0.05% P+B. Parathyroid cell proliferation was measured by proliferating cell nuclear antigen (PCNA) staining and ET-1 expression by immunohistochemical techniques. RESULTS: In the study of developing hyperparathyroidism, bosentan reduced ET-1 expression in the parathyroid glands of rats on the NPD and HPD (P<0.05). But only in rats on the NPD did bosentan result in a reduced increase in parathyroid gland weight (P<0.05). In the study of established hyperparathyroidism, in which 5/6 NPX rats were given a HPD for 15 days, bosentan started on day 15 reduced (P<0.05) ET-1 expression in rats maintained for 15 additional days on the HPD or the VLPD. On the VLPD, parathyroid gland weight was less (P<0.05) than that in rats on the HPD sacrificed at 15 or 30 days. Bosentan did not reduce parathyroid cell proliferation or parathyroid gland weight in rats maintained on the HPD or further reduce these parameters beyond that obtained with dietary phosphorus restriction. PTH values were lowest in the VLPD group, intermediate in the NPD group, and highest in the HPD group, but in none of the three groups did bosentan decrease PTH values. CONCLUSIONS: In azotemic rats with developing hyperparathyroidism, bosentan resulted in a reduced increase in parathyroid gland weight when dietary phosphorus content was normal. Despite a reduction in ET-1 expression in rats on a HPD with developing or established hyperparathyroidism, bosentan did not reduce the increase in parathyroid cell proliferation, parathyroid gland growth or PTH values. Thus, ET-1 blockade with bosentan did not prevent parathyroid gland growth in the azotemic rat.

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

BACKGROUND: Both dietary phosphorus restriction and the ingestion of ammonium chloride (NH(4)Cl) 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 NH(4)Cl 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 NH(4)Cl in the drinking water. The six groups were HPD + NH(4)Cl, HPD, NPD + NH(4)Cl, NPD, LPD + NH(4)Cl and LPD. The effect of NH(4)Cl 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 NH(4)Cl. Neither creatinine nor urea clearance was reduced by high dietary phosphorus. Urine calcium excretion was greatest in the LPD group and was increased (P < or = 0.001) in all three groups by NH(4)Cl 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, NH(4)Cl ingestion increased (P < or = 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) NH(4)Cl ingestion increased creatinine and urea clearances, irrespective of dietary phosphorus; (ii) high urine calcium excretion, induced by dietary phosphorus restriction and NH(4)Cl 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 NH(4)Cl 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.

Effect of ammonium chloride and dietary phosphorus in the azotaemic rat. Part II--Kidney hypertrophy and calcium deposition.

BACKGROUND: Kidney hypertrophy is stimulated by both partial nephrectomy and NH(4)Cl 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 NH(4)Cl 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 NH(4)Cl in the drinking water. The six groups of rats were: (i) HPD + NH(4)Cl; (ii) HPD; (iii) NPD + NH(4)Cl; (iv) NPD; (v) LPD + NH(4)Cl and (vi) LPD. In a separate study, PTX was performed to determine whether PTH affected renal hypertrophy in 5/6 nephrectomized rats given NH(4)Cl. RESULTS: Both with and without NH(4)Cl (+/-NH(4)Cl), 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 NH(4)Cl group. In both the +/-NH(4)Cl 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 NH(4)Cl. 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 +/-NH(4)Cl groups, but was greater in the HPD + NH(4)Cl 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 NH(4)Cl. CONCLUSIONS: In azotaemic rats studied for 30 days, NH(4)Cl administration induced kidney hypertrophy. A HPD also induced kidney hypertrophy. The effects on kidney calcium deposition were divergent for which NH(4)Cl 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 NH(4)Cl from inducing kidney hypertrophy and reducing kidney calcium deposition. In conclusion, NH(4)Cl and dietary phosphorus each independently affect kidney growth and calcium deposition in the growing rat with renal failure.