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.

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.

Pulmonary 64-MDCT angiography with 30 mL of IV contrast material: vascular enhancement and image quality.

OBJECTIVE: The objective of our study was to determine whether vascular enhancement and image quality can be preserved in pulmonary CT angiography (CTA) performed on a 64-MDCT scanner with 30 mL of IV contrast material. MATERIALS AND METHODS: This retrospective matched-cohort study compared image quality of pulmonary CTA performed using 30 mL of IV contrast material versus 100 mL of IV contrast material. CT images of 50 patients (46 men, four women; mean age, 66 years) who underwent pulmonary CTA on a 64-MDCT scanner using a low dose (30 mL) of iodixanol 320 and another 50 patients (49 men, one woman; mean age, 65 years) who underwent pulmonary CTA using a regular dose (100 mL) of contrast material during the same time period were selected for review. The 30- and 100-mL pulmonary CTA studies were retrospectively evaluated by two thoracic radiologists in random order. Attenuation values were recorded over the main, right main, selected lobar, segmental, and subsegmental pulmonary arteries. Image quality was also subjectively assessed using visual scores on a scale from 1 (nondiagnostic) to 5 (excellent). RESULTS: The average attenuation measurements of the main, right main, selected lobar, segmental, and subsegmental pulmonary arteries were 260, 262, 280, 316, and 338 HU, respectively, on the 30-mL studies and 313, 301, 316, 344, and 349 HU, respectively, on the 100-mL studies. The average visual score was 4.0 for both the 30- and 100-mL groups. A visual score of 4 or 5 was given to 82% of studies in the 30-mL group and 78% of studies in the 100-mL group. CONCLUSION: Contrast agent dose for pulmonary CTA using a 64-MDCT scanner can be significantly reduced without compromising diagnostic image quality.

Erythropoiesis-stimulating protein therapy and the decline of renal function: a retrospective analysis of patients with chronic kidney disease.

BACKGROUND/AIMS: Previous studies have hinted at possible associations between anemia and progression of renal disease. The study objective was to determine whether treatment with erythropoiesis-stimulating proteins (ESPs) can curb the rate of decline in renal function in predialysis patients with chronic kidney disease (CKD). METHODS: Observational, before/after analysis using electronic medical records from the Veterans Administration (VA). Included patients had at least two measurements of serum creatinine levels before and after ESP treatment initiation. The Cockcroft-Gault formula was used to derive estimates of glomerular filtration rate (GFR). Rate of renal function decline prior to and following initiation of therapy were compared. RESULTS: One hundred and twenty two patients with renal impairment levels of Stage 3 (moderate) or Stage 4 (severe) at ESP treatment initiation were identified. Over 80% of patients initiated therapy with either Grade 1 or Grade 2 anemia. The rate of renal function decline was calculated as the slope of the least-squares linear regression line of the inverse serum creatinine over time during the pre-treatment initiation and post-treatment initiation time periods. Overall, patients experienced a slowing in the rate of renal function decline after treatment was initiated (mean pretreatment initiation rate of -0.094 dL/mg/yr versus mean post-treatment initiation rate of -0.057 dL/mg/yr). CONCLUSION: Renal function declined at a slower rate following ESP initiation. Results are consistent with prior studies indicating delayed dialysis initiation in patients treated with ESPs. Analyses were limited by the observational study design and lack of information regarding some potential confounders. Longer-term, prospective trials are needed to determine whether ESPs slow progression of renal disease and the potential magnitude of such an effect.

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.

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.

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.

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.

Current prescriptions for the correction of hyponatraemia and hypernatraemia: are they too simple?

Hypo- and hypernatraemic (dysnatraemic) disorders are among the most common electrolyte disorders encountered by primary care providers and nephrologists. They represent a diagnostic and therapeutic challenge, and inappropriate management can result in serious sequelae. Several formulas addressing the fluid prescription for dysnatraemic patients have been introduced. Many authors stress the importance of considering output as well as input in formulating a treatment plan for the dysnatraemic patient. However, currently available formulas fail to account for ongoing renal and extrarenal fluid and electrolyte losses. We propose a novel, versatile formula based on established principles governing the distribution of Na(+) in body fluids. The formula can be used in a simplified form for a quick but accurate estimate of the change in serum [Na(+)] for any infused fluid, while simultaneously accounting for renal losses. The formula can also be expanded to include more complex losses if desired. Importantly, it forces the caregiver to consider both output and input when formulating a prescription for the dysnatraemic patient.