Evidence for a PTH-independent humoral mechanism in post-transplant hypophosphatemia and phosphaturia

Green, Jacob; Debby, Hilla; Lederer, Eleanor; Levi, Moshe; Zajicek, Hubert; Bick, Tova

doi:10.1046/j.1523-1755.2001.0600031182.x

Cited by 82 publications

(69 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…There may also be a clinical relevance to our findings. Patients who are given CsA after organ transplantation often have a marked phosphaturia and resultant hypophosphatemia that may require supplementation with oral P (47)(48)(49). The studies presented here provide insight into the mechanisms involved.…”

Section: Discussionmentioning

confidence: 87%

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Moz¹,

Levi²,

Lavi-Moshayoff³

et al. 2004

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Abstract. The sensing and response to extracellular phosphate (Pi) concentration is preserved from prokaryotes to mammals and ensures an adequate supply of Pi in the face of large differences in its availability. In mammals, the kidneys are central to Pi homeostasis. Renal Pi reabsorption is mediated by a Na/Pi co-transporter that is regulated by a renal Pi sensing system and humoral factors. The signal transduction by which Pi regulates type II Na/Pi activity is largely unknown. It is shown that calcineurin inhibitors specifically and dramatically decrease type II Na/Pi gene expression in a proximal tubule cell line and in vivo. Mice with genetic deletion of the calcineurin A␤ gene had a marked decrease in type II Na/Pi mRNA levels and remarkably did not show the expected increase in type II Na/Pi mRNA levels after the challenge of a low-Pi diet. In contrast, the regulation of renal 25(OH)-vitamin D 1␣-hydroxylase gene expression by Pi was intact. This is the first demonstration that calcineurin has a crucial role in the signal transduction pathway regulating renal Pi homeostasis both in vitro and in vivo. These results suggest that the use of calcineurin inhibitors contributes to the renal Pi wasting seen in renal transplant patients.Phosphate (Pi) homeostasis is essential to life and is dependent on active renal reabsorption. In diseases of phosphorus (P) homeostasis, such as X-linked hypophosphatemia or oncogenic osteomalacia, there is a tremendous renal P loss with severe bone disease (1). In contrast, in chronic renal failure, the P retention leads to secondary hyperparathyroidism with disabling bone disease and vascular calcification associated with a high mortality (2). The kidney has an intrinsic P sensing system that regulates the activity of apical brush border membrane type II Na/Pi co-transporters (3). However, it is still not known how the organism senses changes in serum P.There are three mammalian Na/Pi co-transporter families: types I through III. Type II Na/Pi activity is responsible for Ͼ80% of renal P reabsorption and contains three isoforms-IIa through c-of which IIa is the major factor in renal P reabsorption and regulation in adult mice (4). Type II Na/Pi activity is increased by a low serum P and decreased by parathyroid hormone (PTH) and FGF23 (4 -8). The regulation of type II Na/Pi is at the level of recruitment of new transporters to the apical proximal tubule membrane, the level of synthesis of new transporters and their breakdown (5,9). In addition, there is regulation at the level of type II Na/Pi gene expression, which in vivo is mainly posttranscriptional (10,11). In the rat, a cis acting element in the type II Na/Pi co-transporter (Na/Pi-2) mRNA at the junction of the coding region and the 3'-untranslated region (UTR) interacts with trans acting renal cytosolic proteins and determines Na/Pi-2 mRNA stability in response to dietary P restriction (12). An additional level of regulation of Na/Pi-2 is its translational control by a low-P diet (10).The renal type II Na/Pi co-transporte...

show abstract

Section: Discussionmentioning

confidence: 87%

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Moz¹,

Levi²,

Lavi-Moshayoff³

et al. 2004

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…Several recent studies strongly indicate that posttransplantation hypophosphatemia frequently is independent of PTH, suggesting the presence of a circulating humoral factor (phosphatonin) that induces phosphaturia in CKD and early transplantation (41,42). This factor increases the fractional excretion of phosphate by inactivation of the Na/Pi co-transporter, leading to inhibition of phosphate transport from the cell membrane to the cytosol (42).…”

Section: Pathogenesis Of Posttransplantation Bone Diseasementioning

confidence: 99%

Bone Disease after Renal Transplantation

Weisinger¹,

Carlini²,

Rojas³

et al. 2006

Clinical Journal of the American Society of Nephrology

121

View full text Add to dashboard Cite

It has been well established that a rapid decrease in bone mineral density (BMD) occurs in the first 6 to 12 mo after a successful renal transplantation and persists, albeit at a lower rate, for many years. This rapid BMD loss significantly increases the fracture risk of these patients to levels that are even higher than those of patients who have chronic kidney disease stage 5 and are on dialysis. The presence of low BMD in renal transplant patients as a predictor of risk fracture is controversial. Indeed, as has been suggested also for patients with postmenopausal osteoporosis, there is not a compelling correlation between the decline in BMD and skeletal fractures. However, bone disease after renal transplantation probably represents a unique bone disorder that must encompass underlying renal osteodystrophy. In fact, this syndrome results from multiple factors that include pretransplantation bone status, use of glucocorticoids and other immunosuppressive drugs, hypophosphatemia, and alterations of the calcium-vitamin D axis. Recent studies have demonstrated decreased osteoblast number, reduced bone formation rate, delayed mineralization, and increased osteoblast and osteocyte apoptosis. Bisphosphonates and vitamin D metabolites may be valuable in preventing or diminishing early bone loss. However, clinicians should be careful with the use of bisphosphonates and oversuppression of bone, especially in patients with low bone turnover. New prospective, controlled trials are required to confirm the real efficacy of these drugs, particularly in long-term renal transplant patients.Clin J Am Soc Nephrol 1: 1300 -1313, 2006. doi: 10.2215/CJN.01510506 K idney, heart, lung, and liver transplantation have become fairly common and successful. As the number of transplants has grown, new challenges have arisen in the management of long-term complications of transplantation. Posttransplantation bone disease represents one such important complication, because it is observed in a substantial proportion of patients. As a consequence, bone mass loss and bone fractures are common in these patients and cause substantial morbidity.In patients with chronic kidney disease (CKD), renal osteodystrophy that begins during the early stages of the disease usually worsens during dialysis and may persist after transplantation, although in many patients, improvement in these bone lesions are observed. In addition to preexisting bone lesions, not only factors that hamper recovery but also new factors could affect bone structure after transplantation. These include the potential deleterious effects on bone of the different immunosuppressive agents, the impaired renal function that frequently is observed in renal transplant patients, and several others factors that are particular to each patient, such as postmenopausal status, presence of diabetes, gender, and time after transplantation. Changes in Bone Mineral DensityBone mineral density (BMD) as assessed by dual x-ray absorptiometry has been used as a noninvasive method to assess bone mass loss...

show abstract

“…Exposed surface proteins on intact confluent monolayers were biotinylated using EZ-link Sulfo-NHS-Biotin and isolated using Streptavidin agarose beads (Pierce) essentially as described (27). Confluent MDCKI cell monolayers were placed on ice and washed three times with 0.1 M phosphate-buffered saline (PBS-C/M, pH 7.4: 0.1 mM CaCl 2 ; 1.0 mM MgCl 2 ).…”

Section: Biotinylation and Streptavidin Precipitation Of Cell Surfacementioning

confidence: 99%

Annexin II Is Present on Renal Epithelial Cells and Binds Calcium Oxalate Monohydrate Crystals

Kumar¹,

Farell²,

Deganello³

et al. 2003

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Abstract. Attachment of newly formed crystals to renal epithelial cells appears to be a critical step in the development of kidney stones. The current study was undertaken to identify potential calcium oxalate monohydrate (COM) crystal-binding proteins on the surface of renal tubular cells. Apical membranes were prepared from confluent monolayers of renal epithelial cells (MDCKI line), and COM crystal affinity was used to isolate crystal-binding proteins that were then subjected to electrophoresis and electroblotting. Microsequencing of the most prominent COM crystal-binding protein (M r of 37 kD) identified it as annexin II (Ax-II). When exposed proteins on the surface of intact monolayers were biotinylated and then isolated using streptavidin agarose beads, Ax-II was detected, suggesting that at least a portion is exposed on the apical cell surface. Ax-II was not completely extracted by 0.1 M Na 2 CO 3 , suggesting that at least a portion of cellular Ax-II is an intrinsic membrane-bound protein. Using confocal immunofluorescence microscopy, Ax-II was visualized together with Caveolin-1 (Cav-1) on the apical membrane of intact MDCKI cells. Cells pretreated with a monoclonal anti-Ax-II antibody bound significantly fewer COM crystals, whereas anti-LDL receptor antibody did not decrease COM binding, further suggesting a functional role for Ax-II during adhesion of crystals to intact cells. These results suggest that Ax-II avidly binds COM crystals and is present on the apical surface of MDCKI cells.

show abstract

Evidence for a PTH-independent humoral mechanism in post-transplant hypophosphatemia and phosphaturia

Cited by 82 publications

References 38 publications

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Calcineurin Aβ Is Central to the Expression of the Renal Type II Na/Pi Co-transporter Gene and to the Regulation of Renal Phosphate Transport

Bone Disease after Renal Transplantation

Annexin II Is Present on Renal Epithelial Cells and Binds Calcium Oxalate Monohydrate Crystals

Contact Info

Product

Resources

About