Effect of parathyroid hormone on energy metabolism of skeletal muscle

Clinical states with primary or secondary hyperparathyroidism are associated with muscle dysfunction, suggesting that parathyroid hormone (PTH) may affect muscle metabolism. The present study examined the effect of 1-84 PTH and its amino-terminal fragment (1-34 PTH) on energy production, transfer, and utilization by skeletal muscle. Rats weighing 150 to 200 g were injected intraperitoneally with 1-84 or 1-34 PTH, 200 U/day, for 4 days, and control animals received vehicle only. The effect of the simultaneous administration of a calcium channel blocker, verapamil, was examined also. The muscle content of inorganic phosphorus, creatine phosphate, and adenine nucleotides were significantly (P less than 0.01) lower in the PTH-treated rats than in control animals. The hormone significantly reduced mitochondrial oxygen consumption without altering ADP:0 ratio, indicating reduced phosphorylation. Both 1-84 and 1-34 PTH produced significant (P less than 0.01) reduction in the activities of mitochondrial and myofibrillar CPK, and mitochondrial MgATPase. 1-84 PTH reduced the activity of myofibrillar CaATPase as well. There was a significant (P less than 0.01) increment in muscle uptake of 45Ca in the 1-84 PTH-treated rats. Verapamil abolished all the effects of PTH. Our data demonstrate that both 1-84 and 1-34 PTH impair energy production, transfer, and utilization. These biochemical derangements may, at least in part, underlie the myopathy observed in conditions associated with excess PTH.     

Effect of chronic renal failure on heart. Role of secondary hyperparathyroidism

This study examined the effects of chronic renal failure in rats with and without parathyroid glands on myocardial energy production, transfer and utilization as well as on cardiac index. Chronic renal failure was produced by 7/8 nephrectomy in rats weighing between 240 and 350 g with intact parathyroid glands (CRF-control) and in parathyroidectomized (CRF-PTX) rats maintained normocalcemic. The data were compared to results obtained in intact rats and in normocalcemic parathyroidectomized rats with normal renal function. There were significant (p less than 0.01) decrements in myocardial content of ATP and creatine phosphate, mitochondrial oxygen consumption, and in the activity of both mitochondrial and myofibrillar creatine phosphokinase in CRF-control rats as compared to normal animals. The myocardial calcium content and the 45Ca uptake in CRF-control rats were significantly (p less than 0.01) higher than in normal rats. In CRF-PTX animals, the myocardial content of ATP, mitochondrial oxygen consumption, 45Ca uptake and calcium content were normal, but PTX did not normalize the activity of mitochondrial and myofibrillar creatine phosphokinase. Parathyroidectomy in rats with normal renal function was associated with a significant reduction in the activity of creatine phosphokinase of myocardial mitochondria and myofibrils. There was a significant (p less than 0.01) decrease in cardiac index in CRF-control rats as compared to normal animals, and cardiac index did not return to normal in CRF-PTX rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes in organic matrix of bone and of bone and blood ATP in rats fed rachitogenic diets

Summary Vitamin D deficient and phosphate deficient states were produced in young rats by the use of synthetic diets. Whole blood ATP, serum calcium and phosphorus and the ash, phospholipid, hexosamine and hydroxyproline contents of metaphyseal bones of control and rachitic rats were measured after 4 weeks on the diets.There was a decrease in whole blood ATP and serum phosphorus of the rachitic rats, and in the contents of ash, phospholipid and hexosamine of the rachitic metaphyses, while the hydroxyproline contents of the rachitic bones were higher than those of the controls. Subcutaneous injection of ATP or inorganic phosphate in rats, fed a low phosphate diet deficient in vitamin D, caused an increase in serum phosphorus and blood ATP levels and in metaphyseal ash contents. It is suggested that some of the metabolic disturbances in rickets are due to alteration in ATP production.     

Elevated creatine phosphokinase in patients with ureteral calculi Cause for unwarranted concern of coronary occlusion

Although slight to markedly elevated serum creatine phosphokinase activity in patients with ureteral stone colic is a common finding, it is not indicative of coronary occlusion. A retrospective study showed that one third of our patients with ureteral calculi also had elevated serum creatine phosphokinase activity. The origin of this increased enzyme activity might be from skeletal muscle. Our studies analyzing the creative phosphokinase content of the ureter indicate the contribution from the ureter would be negligible.     

Hypophosphataemia and muscle phosphate metabolism in severely injured patients

Severe trauma is associated with increased expenditure of energy, which leads to heightened cellular requirements for regeneration of high energy phosphates (HEP). The effect of multiple traumata and of burns (18 and 12 patients, respectively) on serum phosphate (S-P) and muscle phosphate metabolism was studied. Blood and muscle samples were obtained 2, 4, 8 and 30 days after the injury. The results of analyses were compared with findings in 14 non-traumatized controls. S-P showed a decrease 2 and 4 days after the injury, despite a phosphate supply of 0.4 mmol/kg BW/day. Reduction of HEP and inorganic phosphate of muscle tissue (Pi) was observed on post-trauma days 2, 4, 8 and 30. No correlation was found between Pi and S-P. The fall in S-P, HEP and Pi was not affected by increasing the phosphate supply from 0.4 to 1.0 mmol/kg BW/day. In patients older than 60 years, the reduction of S-P, and adenosine triphosphate was greater than in the younger patients. The results suggest that the S-P decrease was due to loss via the urine and a shift from extracellular to intracellular compartment. The fall in Pi and HEP probably was caused by impaired ability of the cells to utilize the phosphate available in serum, and direct cellular loss of phosphate resulting from hypermetabolism and catabolism.     

Preliminary identification of prognostic factors from clinical outcome in 38 cases of rhabdomyolysis

Background Rhabdomyolysis is a systemic metabolic disorder caused by leakage of muscle cell constituents into the blood after necrosis of skeletal muscle due to traumatic and nontraumatic causes. This study was done to identify the significant prognostic factors for rhabdomyolysis. Methods The relationship between the outcomes and various clinical characteristics was investigated retrospectively from January 1991 to December 1996, in 38 patients with rhabdomyolysis (29 men and 9 women). Results Among the 8 patients who died, old age, diabetes mellitus, acute renal failure, and disseminated intravascular coagulation were significantly more common than in the 30 survivors. The BUN, serum sodium, serum potassium, serum phosphorus, and blood glucose levels were also significantly higher in the patients who died. There was no significant correlation between the outcome and the patient's sex, the serum levels of creatine phosphokinase and other enzymes leaking from muscle, the blood and urine pH, base excess, and blood pressure, or the use of hemodialysis. Conclusions In patients with rhabdomyolysis, advanced age, diabetes mellitus, acute renal failure, and disseminated intravascular coagulation were factors associated with a poor prognosis, and so require aggressive treatment.     

Heterotopic ossification of the hip as a complication of tetanus

Heterotopic ossification is a very rare complication of tetanus. In one case heterotopic ossification occurred around both hip joints. The values of serum creatine phosphokinase had been elevated significantly when the patient had major muscle spasms. The elevation in serum alkaline phosphatase values following that in creatine phosphokinase values persisted for about four weeks. Partial resection of the bone mass about the right hip joint resulted in a satisfactory improvement in performance of daily activities. The specimens incised at operation revealed both lamellar and woven bone surrounded by fibrous connective tissue. Very near the bone mass were severely degenerated muscle fibers. In addition, evidence suggesting metaplasia of fibroblasts to osteoblasts was seen in some areas. Clinical and laboratory data indicate trauma as a main etiologic factor of heterotopic ossification following tetanus. Heterotopic bone formation should be considered if elevation of the serum alkaline phosphatase values persists beyond the period of elevation of serum creatine phosphokinase values. Artificial ventilation may be beneficial for preventing heterotopic ossification following tetanus if it is administered before there is significant elevation of the serum creatine phosphokinase values.     

Carbohydrate metabolism in potassium-depleted rats

Carbohydrate metabolism was examined in different organs of rats with dietary potassium deprivation for 4 weeks. Thereafter, a 24- or 48-hour starvation period caused a significant decrease of skeletal muscle and liver glycogen content in K+-depleted (KD) rats, whereas kidney glycogen concentration increased and heart glycogen remained unchanged. In contrast, liver glucose concentration was significantly higher in starved KD animals without changes in muscle, heart, and kidney glucose concentrations. Potassium depletion caused a highly significant decrease of plasma and muscle potassium concentrations, metabolic alkalosis, reduced plasma insulin, and increased creatine phosphokinase levels. Blood lactate, pyruvate, and oxoglutarate levels were significantly enhanced in fasted KD rats, whereas blood citrate, beta-hydroxybutyrate, and glucose concentrations were unchanged. Blood acetoacetate level, however, was significantly reduced following potassium depletion. Therefore, beta-hydroxybutyrate/acetoacetate ratio increased significantly, whereas lactate/pyruvate ratio was not influenced. Our results clearly indicate impaired carbohydrate metabolism in potassium-depleted rats.     

Sevelamer hydrochloride reverses parathyroid gland enlargement via regression of cell hypertrophy but not apoptosis in rats with chronic renal insufficiency.

BACKGROUND: Dietary phosphate restriction suppresses parathyroid hormone (PTH) secretion, synthesis, and parathyroid cell proliferation in experimental animals with chronic renal insufficiency (CRI), independently of serum calcium and 1,25(OH)2D3 levels. This study was conducted to examine whether sevelamer hydrochloride (sevelamer), a metal-free phosphate binder, could regress an advanced parathyroid gland (PTG) hyperplasia and enlargement in rats with CRI. METHODS: Male Sprague-Dawley rats were fed a diet containing adenine for 6 weeks to establish CRI. Normal rats and adenine-treated rats were sacrificed to obtain the PTG (baseline group). The adenine diet was changed to a normal diet or diet containing 1 or 3% sevelamer for another 4 weeks. Time course changes of serum levels of calcium, phosphorus, and PTH were measured. At the end of the study, the PTG was weighed and examined histologically. RESULTS: Adenine-treated rats developed severe CRI with marked elevation of serum phosphorus and PTH. The PTG weight markedly increased with enlarged cell volume (i.e. cell hypertrophy) at baseline. Sevelamer treatment rapidly lowered serum phosphorus and PTH levels within 6 days, and after 4 weeks, reduced the PTG weight by 38% compared to adenine-treated rats at baseline. The reduction in PTG weight was due to regression of cell hypertrophy, but not to decreased cell number by apoptosis. Decreased expression of calcium receptor in the PTG at baseline was partially recovered by the sevelamer treatment. CONCLUSIONS: The sevelamer treatment can reduce the PTG weight with a reduction in serum PTH levels via regression of cell hypertrophy but not apoptosis in rats with CRI. Reduced PTG function might contribute to the regression of cell hypertrophy.     

How dietary phosphate, renal failure and calcitriol administration affect the serum calcium-phosphate relationship in the rat.

BACKGROUND: The effect of hyperphosphataemia on serum calcium regulation in renal failure has not been well studied in a setting in which hypercalcaemia is not parathyroid hormone (PTH) mediated. In azotemic rats with a normal serum calcium concentration, an increased dietary phosphate burden affects serum calcium regulation because of its effects on skeletal resistance to PTH, calcitriol production, and possibly intestinal calcium absorption. Our goal was to determine how hyperphosphataemia affected the development of hypercalcaemia during calcitriol-induced hypercalcaemia and PTH suppression in azotemic rats with established hyperparathyroidism. METHODS: Rats underwent a two-stage 5/6 nephrectomy or corresponding sham operations. After surgery, rats were given a high phosphate diet (P 1.2%) for 4 weeks to exacerbate hyperparathyroidism and were then changed to a normal diet (P 0.6%) for 2 weeks to normalize serum calcium values in the azotemic rats. At week 7, rats were divided into five groups and sacrificed after receiving three intraperitoneal doses of calcitriol (CTR, 500 pmol/100 g) or vehicle at 24 h intervals. The five groups and dietary phosphate content were: group 1, normal renal function (NRF)+0.6% P+vehicle; group 2, NRF+0.6% P+CTR; group 3, renal failure (RF)+0.6% P+vehicle; group 4, RF+1.2% P+CTR; and group 5, RF+0.6% P+CTR. Both the 0.6% and 1.2% phosphate diets contained 0.6% calcium. RESULTS: Serum creatinine values were increased (P<0.05) in 5/6 nephrectomized rats (groups 3, 4 and 5), as were serum calcium values (P<0.05) in CTR-treated rats (groups 2, 4 and 5) and serum phosphate values (P<0.05) in CTR-treated azotemic rats (groups 4 and 5). Serum PTH values were suppressed (P<0.05) in CTR-treated hypercalcemic rats (groups 2, 4 and 5) and increased (P<0.05) in azotemic rats not given CTR (group 3). In the azotemic groups (groups 3, 4 and 5), an inverse correlation was present between serum calcium and phosphate in each group, despite a wide variation in serum calcium values. The slope of the inverse relationship between serum calcium and phosphate was steeper in CTR-treated azotemic rats on a 1.2% phosphate (group 4) diet than on a 0.6% phosphate (group 5) diet (P=0.02). Thus, for a similar increase in the serum phosphate concentration, serum calcium values decreased more in group 4 than in group 5. The independent effect of dietary phosphate on serum calcium values was also confirmed by analysis of covariance. Finally, the serum calcium concentration was shown to be greater for any given serum phosphate value in CTR-treated rats than in those not on CTR. CONCLUSIONS: In azotemic rats with calcitriol-induced hypercalcaemia, the magnitude of hypercalcaemia is affected by: (i) the serum phosphate concentration; and (ii) differences in dietary phosphate content. Calcitriol administration also acts to shift upwards the relationship between serum calcium and phosphate so that a higher serum calcium concentration can be maintained for any given serum phosphate value.     

Phosphate depletion arrests progression of chronic renal failure independent of protein intake

Following 5/6 nephrectomy, 18 rats were fed a normal diet. After 30 days, serum creatinine (SCr), urine protein excretion and urine volume were increased compared to pre-nephrectomy (0.27 +/- 0.1 vs. 1.62 +/- 0.6 mg/deciliter, 17.0 +/- 10.3 vs. 257.6 +/- 13.4 mg/24 hr, and 16.6 +/- 4.4 vs. 39.2 +/- 11.7 ml/24 hr, respectively, all P less than 0.001). At this time, when serum phosphorus (SPi) and serum calcium (SCa2+) were normal, the rats were separated into two groups, matched and paired by body weight and SCr, and housed separately in metabolic cages. Animals of one group ingested a normal diet supplemented with dihydroxyaluminum aminoacetate (DHAAA), 15 g%, to induce phosphate depletion (PD). The second group ingested the same diet supplemented with 7.5% glycine and was the phosphate replete (PR) group. All rats were pair fed throughout the study to maintain similar caloric, protein, carbohydrate, vitamin, and mineral intakes. At six weeks after separation, SPi was decreased in PD vs. PR group (2.85 +/- 0.8 vs. 6.71 +/- 1.2 mg/deciliter, P less than 0.001) and SCa2+ was increased in the PD group (11.98 +/- 0.7 vs. 10.03 +/- 0.7 mg/deciliter, P less than 0.001). Urine urea nitrogen, body weight, and sodium, potassium and solute excretion were similar between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Optimizing tourniquet application and release times in extremity surgery. A biochemical and ultrastructural study

Despite numerous studies investigating the pathophysiology of tourniquet ischemia, definitive data at the cellular level have been lacking and no consensus regarding safe tourniquet-application times in extremity surgery has emerged. In light of the particular vulnerability of skeletal muscle to ischemic injury, we determined the degree of muscular metabolic derangement and cell damage produced by seven different protocols of tourniquet application and release, each providing three hours of total tourniquet time. We performed thirty-six experiments on canine hind limbs, comparing the following time-patterns of tourniquet application: I--three sequential one-hour periods, II--two sequential one and one-half-hour periods, III--two hours followed by one hour, and IV--a single continuous three-hour application. Five and fifteen-minute reperfusion intervals between ischemic periods were compared for the first three time-patterns, creating a total of seven different tourniquet protocols. Muscular metabolic derangement and cell injury were evaluated by monitoring changes in the cellular bioenergetic state (high-energy phosphate profile), cell pH, post-ischemic leakage of creatine phosphokinase, and ultrastructural cell degeneration. At the intracellular level, the metabolic recovery of muscle during reperfusion was much faster than previous studies focusing on extracellular parameters have indicated. In all instances complete intracellular bioenergetic recovery occurred within five minutes after tourniquet release. The use of one or more five-minute reperfusion intervals significantly reduced the degree of ischemic cell injury, as indicated by a decrease in creatine phosphokinase leakage and myofibrillar destruction. No additional benefit was derived by extending the reperfusion periods to fifteen minutes. The longest period of continuous ischemia in each tourniquet-application protocol bore the closest relationship with the amount of cell damage produced. Within the spectrum of observed pathological changes, time-patterns I and II produced comparatively little muscle damage.     

Changes in red blood cell transmembrane potential, electrolytes, and energy content in septic shock

Septic shock was induced in adult baboons by the infusion of live Escherichia coli. A progressive derangement in skeletal muscle cell function was documented by the direct measurement of declining transmembrane potential difference (PD). A concurrent depolarization of the red blood cell (RBC) was characterized by cellular uptake of chloride, sodium, and water, and loss of potassium. The decrease in RBC PD was significantly greater than the change predicted to occur from acidosis alone. These findings are compatible with changes in membrane permeability and decreased active transport. The continuous accumulation of RBC adenosine triphosphate during shock suggests decreased energy utilization rather than decreased energy production as a factor leading to diminished active ion transport.     

Sevelamer hydrochloride prevents ectopic calcification and renal osteodystrophy in chronic renal failure rats

BACKGROUND: Hyperphosphatemia is associated with severe complications, including ectopic calcification of soft tissues, secondary hyperparathyroidism, and renal osteodystrophy (ROD). Sevelamer hydrochloride is a nonabsorbed calcium- and metal-free phosphate binder that lowers serum phosphorus levels in hemodialysis patients. This study examined the efficacy of sevelamer in preventing ectopic calcification of soft tissues and ROD in adenine-induced renal failure rats. METHODS: Male, 12-week-old Wistar-Jcl rats were freely fed an adenine diet (0.75 g adenine in 100 g normal diet) for four weeks. After three weeks of the adenine diet, when serum phosphorus levels had significantly increased, the rats were freely fed a normal diet that contained 1% or 2% of sevelamer for another five weeks. Time course changes of serum levels of phosphorus, calcium, and parathyroid hormone (PTH) were measured. At the end of the study, calcium and phosphorus levels in the heart and aorta were measured, and the calcification of kidney, heart, aorta, and stomach were histopathologically examined. The severity of ROD was evaluated by a histopathologic and morphometric analysis of the femurs. RESULTS: Compared with the adenine controls (N = 10), the sevelamer-treated (1%, N = 6; and 2%, N = 10) groups of adenine-induced renal failure rats had reduced serum phosphorus, serum calcium x phosphorus product, and serum PTH levels. Moreover, in the treatment groups, sevelamer suppressed calcification of the aorta media, and also the osteoid volume, fibrosis volume, and porosity ratio of femurs. CONCLUSION: These results suggest that sevelamer treatment might contribute to the suppression of ectopic calcification and ROD.     

Bone maturation in the vitamin D,phosphate deficient rat and the response to acid loading

Summary Vitamin D and phosphate deficiency were produced in rats in order (a) to evaluate the degree of bone mineral and matrix maturation using a bromoform/toluene density gradient technique; and (b) to compare the aforementioned bone maturational changes due to vitamin D and phosphate deprivation to those produced with superimposed severe acidosis. Rats were fed a diet deficient in vitamin D and phosphorus (0.2%) from 3 weeks through 7 weeks of age. To examine the additional contribution of dietary calcium, we gave one-half of the animals either a low (0.06%) or high (1.3%) calcium diet. Following the 4 weeks of vitamin D deficiency, one-half of each group was given 1.8% NH₄Cl in the drinking water for 4 succeeding days to induce an acute, severe acidosis. The degree of bone maturation was quantitated via bromoformtoulene density gradient fractionation; total mineral and hydroxyproline (collagen) levels were quantitated as well. The vitamin D-deficient rats deprived of adequate dietary phosphate responded by conserving phosphorus, and as a consequence total bone phosphorus levels were maintained within that level for control rats. This conservation was independent of calcium intake but was extremely sensitive to acute acid loading, where a significant reduction in total bone phosphorus was noted. The bone maturational profile obtained from the vitamin D-phosphate deficient rats, however, revealed a significant accumulation of less mature or dense bone collagen and mineral with a corresponding decrease in the most mature or dense moieties. In contrast to the reduction of the total bone phosphorus content by acute acidosis, the skeletal collagen-mineral maturational profile was not significantly affected by the short-term systemic acidosis. The observed retardations in the bone collagen and mineral maturation of the vitamin D-deficient, phosphate-deprived state provide an additional observation which may well relate to the progressive osteopenia documented in states of chronic, mild acidosis.     

Sustained-release bezafibrate corrects lipid abnormalities in patients on continuous ambulatory peritoneal dialysis

A study was undertaken in 24 Chinese patients on maintenance continuous ambulatory peritoneal dialysis, using bezafibrate in its sustained-release form to correct lipid abnormalities. Six patients who received 400 mg/day developed severe muscle weakness with grossly elevated creatine phosphokinase activities within 3 weeks. The drug was discontinued and the symptoms disappeared. The remaining 18 patients received 400 mg/week for 8 weeks. There was a significant decrease in serum triglyceride (2.74 +/- 0.33 to 1.86 +/- 0.17 mmol/l at the 4th week and 1.65 +/- 0.4 mmol/l at the 8th week). Concomitantly, serum total cholesterol decreased. Serum high-density lipoprotein cholesterol increased significantly (from 1.18 +/- 0.082 to 1.36 +/- 0.060 mmol/l at the 4th week and 1.40 +/- 0.103 mmol/l at the 8th week). Post-heparin lipoprotein and hepatic lipases were measured by a substrate-specific method. The former increased significantly (p = 0.000) after bezafibrate treatment while the latter did not change. All parameters of lipid metabolism returned towards baseline 4 weeks after discontinuation of therapy. The drug was well tolerated at 400 mg/week and there was no significant rise in serum creatine phosphokinase.     

Role of creatine phosphokinase in predicting acute renal failure in hypocalcemic exertional heat stroke.

Recruits frequently develop hypocalcemia in exertional heat stroke (ExHS) with rhabdomyolysis and acute renal failure (ARF) from intensive training. It usually indicated severe skeletal muscle damage. However, the relative risk of ARF in ExHS patients complicated with hypocalcemia was unknown. The present study was undertaken to evaluate the value of peak serum creatine phosphokinase (CPK) level in predicting ARF in ExHS patients with hypocalcemia. Sixty-eight army recruits with ExHS were hospitalized at the Tri-Service General Hospital, Taiwan: 17 with ARF and hypocalcemia (group A); 7 with ARF but without hypocalcemia (group B); 20 without ARF but with hypocalcemia (group C); and 24 without ARF or hypocalcemia (group D). In the 24 patients with ARF (groups A and B) the serum phosphate and peak CPK levels were significantly higher than in patients without ARF (groups C and D; p < 0.001), serum calcium levels were also significantly lower in the former (p < 0.001). In the 37 patients with hypocalcemia (groups A and C), the peak serum CPK levels were significantly higher than in those without hypocalcemia (groups B and D; p < 0.001). There was a higher proportion of hypocalcemic patients with peak serum CPK levels greater than 10,000 U/l among ARF compared with patients without ARF (chi 2 = 12.48, p < 0.001). In 24 patients with ARF, there was a negative correlation between serum Ca and peak CPK levels (t = 3.37, r = -0.58, p < 0.01). However, a positive correlation was found between serum creatinine and peak serum CPK levels in 37 patients with hypocalcemia (t = 2.47, r = 0.39, p < 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)     

Calcium phosphate supersaturation regulates stone formation in genetic hypercalciuric stone-forming rats

BACKGROUND: Hypercalciuria is the most common metabolic abnormality observed in patients with nephrolithiasis. Hypercalciuria raises urine supersaturation with respect to the solid phases of calcium oxalate and calcium phosphate, leading to an enhanced probability for nucleation and growth of crystals into clinically significant stones. However, there is little direct proof that supersaturation itself regulates stone formation. Through successive inbreeding of the most hypercalciuric progeny of hypercalciuric Sprague-Dawley rats, we have established a strain of rats, each of which excrete abnormally large amounts of urinary calcium and each of which forms calcium phosphate kidney stones. We used these hypercalciuric (GHS) rats to test the hypothesis that an isolated reduction in urine supersaturation, achieved by decreasing urine phosphorus excretion, would decrease stone formation in these rats. METHODS: Thirty 44th-generation female GHS rats were randomly divided into three groups. Ten rats received a high-phosphorus diet (0.565% phosphorus), 10 a medium-phosphorus diet (0.395% phosphorus), and 10 a low-phosphorus diet (0.225% phosphorus) for a total of 18 weeks. The lowered dietary phosphorus would be expected to result in a decrease in urine phosphorus excretion and a decrease in urinary supersaturation with respect to the calcium phosphate solid phase. Every two weeks, 24-hour urine collections were obtained. All relevant ions were measured, and supersaturation with respect to calcium oxalate and calcium hydrogen phosphate were determined. At the conclusion of the experiment, each rat was killed, and the kidneys, ureters, and bladder were dissected en block and x-rayed to determine whether any stones formed. A decrease in stone formation with a reduction in urinary supersaturation would support the hypothesis that supersaturation alone can regulate stone formation. RESULTS: Decreasing the dietary phosphorus intake led to a progressive decrease in urine phosphorus excretion and an increase in urine calcium excretion, the latter presumably caused by decreased intestinal calcium phosphate binding and increased calcium absorption. With decreasing dietary phosphorus intake, there was a progressive decrease in saturation with respect to the calcium phosphate solid phase. Fifteen of the 20 kidneys from the 10 rats fed the high-phosphorus diet had radiographic evidence of kidney stone formation, whereas no kidneys from the rats fed either the medium- or low-phosphorus diet developed kidney stones. CONCLUSIONS: A decrease in urine phosphorus excretion not only led to a decrease in urine supersaturation with respect to the calcium phosphate solid phase but to an elimination of renal stone formation. The results of this study support the hypothesis that variation in supersaturation alone can regulate renal stone formation. Whether a reduction of dietary phosphorus will alter stone formation in humans with calcium phosphate nephrolithiasis remains to be determined.     

Protective effects of oral creatine supplementation on spinal cord injury in rats

STUDY DESIGN: To evaluate a potential protective effect of increased creatine levels in spinal cord injury (SCI) in an animal model. OBJECTIVES: Acute SCI initiates a series of cellular and molecular events in the injured tissue leading to further damage in the surrounding area. This secondary damage is partly due to ischemia and a fatal intracellular loss of energy. Phospho-creatine in conjunction with the creatine kinase isoenzyme system acts as a potent intracellular energy buffer. Oral creatine supplementation has been shown to elevate the phospho-creatine content in brain and muscle tissue, leading to neuroprotective effects and increased muscle performance. SETTING: Zurich, Switzerland. METHODS: Twenty adult rats were fed for 4 weeks with or without creatine supplemented nutrition before undergoing a moderate spinal cord contusion. RESULTS: Following an initial complete hindlimb paralysis, rats of both groups substantially recovered within 1 week. However, creatine fed animals scored 2.8 points better than the controls in the BBB open field locomotor score (11.9 and 9.1 points respectively after 1 week; P=0.035, and 13 points compared to 11.4 after 2 weeks). The histological examination 2 weeks after SCI revealed that in all rats a cavity had developed which was comparable in size between the groups. In creatine fed rats, however, a significantly smaller amount of scar tissue surrounding the cavity was found. CONCLUSIONS: Thus creatine treatment seems to reduce the spread of secondary injury. Our results favour a pretreatment of patients with creatine for neuroprotection in cases of elective intramedullary spinal surgery. Further studies are needed to evaluate the benefit of immediate creatine administration in case of acute spinal cord or brain injury.     

Severe hyperparathyroidism with bone abnormalities and metastatic calcification in rats with adenine-induced uraemia.

BACKGROUND: Marked parathyroid hyperplasia with bone diseases and vascular calcification are unsolved issues in dialysis patients. In this study, we made azotemic model rats by adenine feeding and analyzed the development and progression of the abnormalities. METHODS: Renal failure was induced in 8-week-old male Wistar rats by feeding 0.75% adenine-containing diet for 6 weeks. Serum parameters, parathyroid hyperplasia, bone changes and metastatic calcification were examined at 2, 4 and 6 weeks. RESULTS: Progressive increase of serum creatinine and inorganic phosphate, and decreased levels of serum calcium and 1,25(OH)2D3 were confirmed. Markedly enlarged parathyroid glands and extremely high PTH levels were observed in all adenine-fed rats compared with the control (PTH: 199.3+/-58.0 vs 10.5+/-3.0 pmol/l, P<0.01, respectively, at 6 weeks). In cortical bone of the femur, the morphometric parameters showed increased bone resorption with increased fibrosis, whereas in the trabecular bone, bone resorption decreased and bone volume increased with a larger amount of osteoid compared with the control. Metastatic calcification in aorta, coronary artery and other soft tissues were also found in adenine-fed rats. CONCLUSIONS: Uraemic rats made by adenine diet developed severe abnormalities of calcium metabolism in a relatively short period and therefore they may serve as a useful model for the analysis of parathyroid hyperplasia and vascular calcification in chronic renal failure.