Coordinated control of renal Ca(2+) transport proteins by parathyroid hormone.

BACKGROUND: The kidney is one of the affected organs involved in the clinical symptoms of parathyroid hormone (PTH)-related disorders, like primary hyperparathyroidism and familial hypocalciuric hypercalcemia. The molecular mechanism(s) underlying alterations in renal Ca(2+) handling in these disorders is poorly understood. METHODS: Parathyroidectomized and PTH-supplemented rats and mice infused with the calcimimetic compound NPS R-467 were used to study the in vivo effect of PTH on the expression of renal transcellular Ca(2+) transport proteins, including the epithelial Ca(2+) channel transient receptor potential, vanilloid, member 5 (TRPV5), calbindins, and the Na(+)/Ca(2+)-exchanger (NCX1). In addition, the effect of PTH on transepithelial Ca(2+) transport in rabbit connecting tubule/cortical collecting duct (CNT/CCD) primary cultures was determined. RESULTS: Decreased PTH levels in parathyroidectomized rats or NPS R-467-infused mice, resulted in reduced expression of these proteins, which is consistent with diminished Ca(2+) reabsorption, causing the development of the observed hypocalcemia. PTH supplementation of parathyroidectomized rats restored the expression of the renal Ca(2+) transport machinery and serum Ca(2+) levels, independent of serum 1,25-dihydroxyvitamin D(3) levels and renal vitamin D or Ca(2+)-sensing receptor mRNA abundance. Inhibition of the PTH-stimulated transepithelial Ca(2+) transport by the TRPV5-specific inhibitor ruthenium red reduced the PTH-stimulated expression of calbindin-D(28K) and NCX1 in rabbit CNT/CCD primary cultures. CONCLUSION: PTH stimulates renal Ca(2+) reabsorption through the coordinated expression of renal transcellular Ca(2+) transport proteins. Moreover, the PTH-induced stimulation is enhanced by the magnitude of the Ca(2+) influx through the gatekeeper TRPV5, which in turn facilitates the expression of the downstream Ca(2+) transport proteins. Therefore, the renal transcellular Ca(2+) transport proteins, including TRPV5, could contribute to the pathogenesis of PTH-related disorders.

Recovery of renal tubule phosphate reabsorption despite reduced levels of sodium-phosphate transporter.

BACKGROUND: The acute effect of parathyroid hormone (PTH) on phosphate transport has been reported to be mediated by rapid downregulation of sodium-phosphate transporter (NaPi-IIa) protein, but the association was observed with pharmacological doses of PTH. OBJECTIVE: To explore the effects of physiological doses of PTH on NaPi-IIa protein and its relationship to phosphate transport. METHODS: Acute clearance studies were performed in parathyroidectomized rats given a bolus i.v. physiological dose (1 microg) of bovine PTH(1-34) and NaPi-IIa protein concentrations were examined at different time intervals. RESULTS: Fractional excretion of phosphate increased from 0.031+/-0.006 (mean+/-S.E.) to 0.238+/-0.059 (P<0.01 compared with baseline and compared with controls) at 40 min and returned to control values by 120 min. Urinary cAMP concentrations were increased at 20 min only. Superficial cortex brush-border membrane (BBM) NaPi-IIa protein was decreased from baseline at both 40 and 120 min (P<0.01) and did not recover at 240 min (P<0.01 compared with baseline and compared with controls). CONCLUSION: These results confirm that PTH, even in physiological dosage, causes a rapid decrease in BBM NaPi-IIa, but subsequent recovery of phosphate reabsorption is poorly correlated with BBM concentrations of NaPi-IIa protein. This suggests that transport mechanisms other than NaPi-IIa are important in renal phosphate reabsorption.

The role of commercial non-related living kidney transplants.

The motivation for dialysis patients to seek early, even pre-emptive, kidney transplantation from living donors is discussed. In most countries both the waiting time and the numbers of patients awaiting kidney transplantation are increasing. Local geopolitics in Jerusalem have produced a unique window to observe present transplant practices which include widespread international marketing of kidneys from paid living donors. These have been subject of media admonitions and total rejection by professional organizations. In a modern world, traditional medical paternalism to both donors and patients should be balanced by rights for individual autonomy. Since patients, donors and medical professionals are already participating in illicit organ trading, is it not time for us to seriously consider the ethical and logistic implications of legalizing financial remuneration for kidney donation?

Immunohistochemical staining for proliferation antigen as a predictor of chronic graft dysfunction and renal graft loss.

BACKGROUND: Assessment of proliferation rate (PR%) using monoclonal antibody for Ki-67 antigen has recently been found to have prognostic importance in lung and cardiac allografts. We ascertained whether the same might be true for renal allografts. METHODS: Newly cut sections from 20 archival paraffin blocks of renal allograft biopsy material showing acute cellular rejection and/or acute tubular necrosis (ATN) and absence of other pathology were stained using MIB-1 antibody and were further double-stained with anti-CD3, anti-CD20 or anti-CD68 antibodies. Counts of staining of mononuclear interstitial cells were correlated with clinical and pathological data. RESULTS: Mean PR% was significantly greater than that in control renal allografts (13.23 +/- 1.94 vs. 2.84 +/- 1.66, p < 0.01). PR% of cases with ATN and no or borderline rejection was significantly lower than that of the remaining cases with acute rejection pathology (6.68 +/- 1.15 vs. 14.31 +/- 1.62, p < 0.05). However, PR% was neither correlated to histological rejection grade nor to long-term graft outcome. Double labelling failed to identify the cell type of most infiltrating MIB-1 positive cells. CONCLUSIONS: Positive MIB-1 staining helps to identify the presence of rejection but does not appear to predict prognosis or correlate with the Banff classification of rejection pathology.