Hyperparathyroidism of Renal Disease.

Renal hyperparathyroidism (rHPT) is a common complication of chronic kidney disease characterized by elevated parathyroid hormone levels secondary to derangements in the homeostasis of calcium, phosphate, and vitamin D. Patients with rHPT experience increased rates of cardiovascular problems and bone disease. The Kidney Disease: Improving Global Outcomes guidelines recommend that screening and management of rHPT be initiated for all patients with chronic kidney disease stage 3 (estimated glomerular filtration rate, < 60 mL/min/1.73 m(2)). Since the 1990s, improving medical management with vitamin D analogs, phosphate binders, and calcimimetic drugs has expanded the treatment options for patients with rHPT, but some patients still require a parathyroidectomy to mitigate the sequelae of this challenging disease.

Treatment of secondary hyperparathyroidism by high calcium diet is associated with enhanced resistance artery relaxation in experimental renal failure.

BACKGROUND: Vasorelaxation is impaired in renal failure (RF) and hypertension. A high calcium diet enhances vasodilatation and reduces blood pressure in experimental hypertension. Oral calcium salts are used as phosphate binders in RF. However, the effect of increased calcium intake on arterial tone in RF is unknown. METHODS: We investigated the influence of an 8-week high calcium diet (0.3 vs 3.0%) on resistance artery tone in 5/6 nephrectomized (NTX) rats. Calcium was supplemented as carbonate salt, blood pressure measured by tail-cuff, urine collected in metabolic cages, and samples taken for blood chemistry and parathyroid hormone (PTH). Functional studies of isolated third-order branches of the mesenteric artery in vitro were performed using the Mulvany multimyograph. RESULTS: Plasma urea was elevated 1.6-fold and systolic blood pressure by 10 mmHg after NTX, while increased calcium intake was without effect on these variables. Plasma PTH and phosphate were raised following NTX, and suppressed by high calcium diet. Vasorelaxations induced by K(+) channel agonists 11,12-epoxyeicosatrienoic acid and levcromakalim were impaired after NTX. Vasorelaxation induced by acetylcholine was also reduced following NTX, and experiments with N(G)-nitro-L-arginine methyl ester, diclofenac and charybdotoxin + apamin suggested that the K(+) channel-mediated component of endothelium-dependent relaxation was deficient after NTX. Increased calcium intake corrected all impairments of vasodilatation in NTX rats. CONCLUSIONS: Deficient vasorelaxation via K(+) channels was normalized by high calcium diet in experimental RF. This effect was independent of the degree of renal impairment and blood pressure, but was associated with improved calcium metabolism: plasma levels of PTH and phosphate were decreased and ionized calcium was increased.

Correction of the abnormal mineral ion homeostasis with a high-calcium, high-phosphorus, high-lactose diet rescues the PDDR phenotype of mice deficient for the 25-hydroxyvitamin D-1alpha-hydroxylase (CYP27B1).

Mutations in the 25-hydroxyvitamin D-1alpha-hydroxylase gene (CYP27B1; 1alpha-OHase) cause pseudo vitamin D deficiency rickets (PDDR), while mutations in the vitamin D receptor (VDR) cause hereditary vitamin D resistance rickets. Animal models of both diseases have been engineered. The bone phenotype of VDR-ablated mice can be completely rescued by feeding the animals with a high-calcium, high-phosphorus, high-lactose diet. We have attempted to rescue the PDDR phenotype of mice deficient for the 1alpha-OHase gene by feeding them with the high-calcium diet. The rescue regimen consisted of feeding a diet containing 2% calcium, 1.25% phosphorus, 20% lactose (rescue diet) from 3 weeks of age until sacrifice at 8.5 weeks of age. Blood biochemistry analysis revealed that the rescue diet corrected the hypocalcemia and secondary hyperparathyroidism. Despite the restoration of normocalcemia, 1alpha-OHase(-/-) (and 1alpha-OHase(+/-)) animals fed the rescue diet initially gained weight less rapidly than control mice fed normal mouse chow. Although 1alpha-OHase(-/-) mice fed the rescue diet eventually reached the same weight as control animals, the treatment did not entirely correct bone growth, as femur size remained significantly smaller than that of control. Bone histology and histomorphometry confirmed that the rickets and osteomalacia were cured. The rescue diet also restored the biomechanical properties of the bone tissue within normal parameters. These results demonstrate that correction of the abnormal mineral ion homeostasis by feeding with a high-calcium rescue diet is effective to rescue the PDDR phenotype of 1alpha-OHase mutant mice. This treatment, however, does not appear as effective as 1,25(OH)(2)D(3) replacement therapy since bone growth remained impaired.

Hyperplasia of the parathyroid gland without secondary hyperparathyroidism.

BACKGROUND: Low dietary phosphorus (P) prevents parathyroid gland (PTG) hyperplasia and the development of secondary hyperparathyroidism (SH) in uremic rats. The present study explores the effects of P restriction on parathyroid hormone (PTH) synthesis and secretion and PT cell growth in rats with established SH and PTG hyperplasia. METHODS: Normal and 5/6 nephrectomized rats were fed a high P (0.8%) diet. After two weeks, the normal rats and half of the uremic rats were sacrificed (U-HP) while the remaining uremic rats were switched to a low P (0.2%) diet (U-HP-LP). RESULTS: High dietary P induced a significant increase in serum P, PTH, and PTG weight, but not ionized calcium compared to normal animals fed the same diet (N-HP). P restriction returned serum P and PTH to normal levels by one week. In contrast, PTG size did not regress and glands remained enlarged for up to eight weeks with no evidence of apoptosis. Ribonuclease protection assay and metabolic labeling studies demonstrated similar PTH/actin mRNA ratios and 35S-labeled PTH among the three groups. Intracellular intact PTH was higher in U-HP and U-HP-LP rats compared to N-HP animals with no differences between the two uremic groups. PTG-PTH content correlated only with PTG weight, and serum PTH only with serum P. The PTG secretory response to calcium remained intact. CONCLUSIONS: In established chief-cell hyperplasia, P restriction restores normal serum PTH levels without affecting PTG hyperplasia, PTH synthesis, PTG cytosolic PTH or the PTH secretory response to calcium, suggesting an impaired exocytosis of PTH.

Survival of cats with naturally occurring chronic renal failure: effect of dietary management.

Fifty cats with naturally occurring stable chronic renal failure (CRF) were entered into a prospective study on the effect of feeding a veterinary diet restricted in phosphorus and protein with or without an intestinal phosphate binding agent on their survival from initial diagnosis. Twenty-nine cats accepted the veterinary diet, whereas compliance (due to limited intake by the cats or owner resistance to diet change) was not achieved in the remaining 21. At diagnosis, both groups of cats were matched in terms of age, bodyweight, plasma creatinine, phosphate, potassium and parathyroid hormone (PTH) concentrations, packed cell volume and urine specific gravity. Feeding the veterinary diet was associated with a reduction in plasma phosphate and urea concentrations and prevented the increase in plasma PTH concentrations seen in cats not receiving the diet. Cats fed the veterinary diet survived for longer when compared with those that were not (median survival times of 633 versus 264 days). These data suggest that feeding a diet specifically formulated to meet the needs of cats with CRF, together with phosphate binding drugs if required, controls hyperphosphataemia and secondary renal hyperparathyroidism, and is associated with an increased survival time.

Effect of dietary phosphate restriction on renal secondary hyperparathyroidism in the cat.

Twenty-three cats with stable chronic renal failure (CRF) were examined in a prospective study of the effects of feeding a veterinary diet restricted in phosphorus and protein with or without an intestinal phosphate binding agent (aluminium hydroxide) on plasma phosphate and parathyroid hormone (PTH) concentrations. Fifteen cats accepted the veterinary diet; compliance was not achieved in the remaining eight (due to limited intake by the cats or owner resistance to diet change). Feeding the veterinary diet was associated with a significant fall in plasma phosphate and PTH concentrations by five months, with only two cats requiring aluminium hydroxide therapy. The maximum decrease in plasma PTH concentration was not associated with a significant change in plasma 1,25 dihydroxycholecalciferol concentration. Euparathyroidism was achieved in eight cats. Conversely, in cats with CRF fed proprietary diets over the same time period, mean plasma PTH concentrations did not change significantly; indeed, in seven of the eight cats, PTH concentrations increased. Dietary therapy alone or in combination with intestinal phosphate binders does reduce PTH concentrations in cats with CRF and, when effective control of phosphate intake is achieved, plasma PTH can be normalised.

Resolution of metastatic calcification in the paws of a cat with successful dietary management of renal hyperparathyroidism.

A 10-year-old ovariohysterectomised domestic shorthaired cat was presented with multiple nodular calcifications of the footpads and interdigital spaces. Renal insufficiency was diagnosed by routine biochemistry and urinalysis. Additionally, the cat had a calcium and phosphorus solubility product greater than 70 mg/dl and elevated circulating parathyroid hormone. Dietary management of the renal disease resulted in a reduction in the mineral solubility product and normalisation of the concentration of parathyroid hormone accompanied by concurrent resolution of the pedal lesions.

Bone remodeling indices and secondary hyperparathyroidism in celiac disease.

OBJECTIVES: To determine the prevalence of hypovitaminosis D and secondary hyperparathyroidism (SHPT) and to assess bone turnover by using markers of bone formation and resorption in celiac disease (CD). METHODS: Forty-three patients with CD were investigated: group 1, newly diagnosed celiacs (n = 19); group 2, treated celiacs responding histologically to a gluten-free diet (n = 16); group 3, refractory celiacs, unresponsive to a gluten-free diet and immunosuppressive therapy (n = 8). Serum was drawn for intact parathyroid hormone (PTH), 25-hydroxyvitamin D [25(OH)D], ionized calcium (Cai), total alkaline phosphatase (AP), and biochemical markers of bone formation: procollagen I carboxyterminal propeptide (PICP) and osteocalcin (Oc). Urinary indices of bone resorption, deoxypyridinoline (DPD), pyridinoline (PyD), and hydroxyproline (OHP), were measured in a 2-h fasting urine. In 22 patients, computerized tomographic scan for bone mineral density (BMD) was performed. RESULTS: The prevalence in groups 1, 2, and 3, respectively, of hypovitaminosis D (< 50 nmol/L) was 58%, 25%, and 88%, and the prevalence of SHPT (> 5.4 pmol/L) was 25%, 19%, and 25%. Bone resorption markers were significantly elevated in all groups, and bone formation indices were elevated in the newly diagnosed celiacs compared with a group of healthy adults. Low BMD (T-score greater than -1 SD unit) was found in 68% of patients assessed; 36% of patients had a T-score greater than -2.5 SD units. CONCLUSIONS: Hypovitaminosis D and SHPT are common in newly diagnosed and refractory celiacs but are less common in those who respond to a gluten-free diet. Newly diagnosed patients have a high bone turnover state with elevation of both bone formation and resorption indices. Those with refractory disease demonstrate a remodeling imbalance with high bone resorption.

Management of hyperphosphatemia in patients with renal failure.

Phosphate retention plays a major role in the pathogenesis of hyperparathyroidism at all stages of renal insufficiency. Dietary phosphate restriction is mandatory only for adults and is not advised for children because of the recommended diet allowance. Dietary restriction is usually not sufficient, and phosphate binders are almost always necessary when the glomerular filtration rate falls below 40 mL/min. Because long-term administration of aluminum phosphate binders is associated with risk of aluminum intoxication despite the use of so-called "safe doses", alternative phosphate binders should be used. Magnesium hydroxide and carbonate can be used only for dialysis patients because a low dialysate magnesium concentration is necessary to prevent the hazards of hypermagnesemia. Therefore, the major alternative is the use of alkaline salts of calcium. The most recently proposed salt, acetate, has a higher phosphate-binding capacity than carbonate but exposes patients to the same incidence of hypercalcemia despite the use of half the dose of elemental calcium. These salts should be taken with meals in order to complex more dietary phosphate and decrease calcium absorption and therefore the risk of hypercalcemia. Oral calcium alone, without 1 alpha OH-vitamin D3 derivatives, can prevent hyperphosphatemia and hyperparathyroidism in most uremic patients before dialysis and in about half of the patients dialyzed with a dialysate calcium of 1.5 to 1.65 mmol/L. 1 alpha OH-vitamin D3 derivatives, which increase intestinal absorption of phosphate, should be used only when hyperphosphatemia has been prevented by oral calcium and diet and when plasma parathyroid hormone levels increase above three times the upper limit of normal. To decrease hypercalcemic risk, patients should be given 1 alpha OH-vitamin D3 derivatives, preferably at night, as an intermittent bolus (intravenous or oral). In dialysis patients, the dialysate concentration of calcium may have to be further decreased in order to prevent hypercalcemia when high doses of oral calcium are necessary to control hyperphosphatemia.

Self-limited neonatal familial hyperparathyroidism associated with hypercalciuria and renal tubular acidosis in three siblings.

Three siblings with neonatal familial hyperparathyroidism diagnosed at age 4 months, 2 months, and 5 days, respectively, were treated. Hypercalciuria, nephrocalcinosis, and renal tubular acidosis were present in each child. In all three, there were higher responses of serum parathyroid hormone to serum calcium and higher elevation of serum calcium with oral calcium loading. The metabolism of vitamin D and calcitonin seemed to be intact. Hypercalcemia associated with the abnormal response of parathyroid hormone secretion disappeared when the children passed the age of approximately 2 years, although renal tubular acidosis and nephrocalcinosis remained. An autosomal recessive inheritance seems likely.

Long-term suppression of hyperparathyroidism by phosphate binders in uremic children.

Forty-five children with stable chronic renal failure, not on dialysis, were treated conservatively with a regimen of mild dietary phosphate restriction and high-dose phosphate binders for up to 5 years. Both aluminum hydroxide and calcium carbonate were used initially, but almost all patients were taking calcium carbonate towards the end of the period. Serum immunoreactive parathyroid hormone concentrations were significantly decreased and were within the normal range after 1 year and remained normal during treatment. There was no significant change in renal function over the same treatment period. We conclude that calcium carbonate should be used as the phosphate binder of choice in the long-term suppression of hyperphosphatemia and hyperparathyroidism in uremic children.

[Dangers of a wrong diet in patients with renal insufficiency in the predialytic state or during chronic hemodialysis]. / Gefahren der Fehlernährung bei Patienten mit Niereninsuffzienz im prädialytischen Stadium und unter chronischer Hämodialyse

Patients with chronic renal failure and on chronic intermittent hemodialysis have several metabolic risks such as retention of urea and other products of nitrogen metabolism, catabolism, acidosis, edema, dehydration, hyper- and hypotension, hyperkalemia, renal osteopathy, and renal anemia. Uremic coma is usually avoided by balanced nutritional therapy and treatment with hemodialysis. A dietary regimen containing protein with high amounts of essential amino acids is an important part of treatment. In patients on chronic hemodialysis disorders of protein and amino acid metabolism are caused by either deficiency of essential ingredients of the food or by the metabolic defects due to chronic uremia.