Conference Brief - Understanding Pathways for the Pathogenesis of Renal Osteodystrophy

Craig B Langman, MD Faculty and Disclosures CME Released: 06/30/2006; Valid for credit through 06/30/2007

CME Information

Introduction
Chronic kidney disease (CKD) begins with early manifestations of reduced glomerular filtration rate and progresses to frank metabolic complications of mineral metabolism at modest time points along the continuum, ending with the need for maintenance dialysis or kidney transplantation. This condition is termed renal osteodystrophy (ROD). ROD was first described as renal rickets by Colley in the 1880s.[1] The demonstration of the kidney as the site of activation of vitamin D by 25-hydroxyvitamin D-1-alpha-hydroxylase[2] was quickly followed by the production of a pharmacologic product, calcitriol, which could be used as replacement for patients with failing kidneys and secondary hyperparathyroidism (SHPT). However, after 2 decades of use in patients on maintenance dialysis, calcitriol has not been shown to optimally control SHPT.[3] In addition, we have learned that an epidemic of vascular disease, marked by pathologic arterial calcification, occurs in maintenance dialysis patients and is intimately related to SHPT and its therapy.[4] Further, the presence of uremic vasculopathy influences the bone disease phenotype itself, with a larger fraction of patients having adynamic bone disease, a fracturing bone disease in which the cellular elements for normal bone remodeling are strikingly absent.[5,6] Finally, for the small fraction of adult patients on maintenance dialysis who receive a kidney transplant, bone disease remains a long-term problem.[7] With this background, highlights from presentations on exciting developments in mineral metabolism and osteodystrophy from the National Kidney Foundation Spring Clinical Meetings in Chicago, Illinois, are included.

Pathogenesis of SHPT
Central to the understanding of the pathogenesis of SHPT, a nearly universal finding in patients with CKD, by the time when they arrive who are in need of dialysis or renal transplantation, is the recognition that the kidney both controls ultimate phosphate balance and is the most important site for the production of active vitamin D, 1,25-dihydroxyvitamin D that circulates in the blood. Until recently, we have been unable to understand exactly why levels of 1,25-

dihydroxyvitamin D were reduced in CKD or why serum phosphorus levels remain nearly normal until patients require dialysis. Postulates for the mechanisms of reduced renal 25-hydroxyvitamin D-1-alpha-hydroxylase include the presence of chronic metabolic acidosis, insufficient functional kidney mass, kidney resistance to the stimulatory effects of parathyroid hormone (PTH) on that enzyme activity, and perhaps an added component of vitamin D substrate (25-hydroxyvitamin D) deficiency. Mechanisms for the absence of hyperphosphatemia until the need for dialysis were thought to be reflective of the kidney's ability to excrete more phosphorus per unit of functioning nephron as CKD ensued. However, it was shown more than 2 decades ago that kidney 25-hydroxyvitamin D-1-alpha-hydroxylase could be upregulated by limiting dietary phosphate intake.[8] This important observation in humans with CKD, in modern parlance, lay dormant until recently and because of the recent discovery of phosphatonins, has great relevance for our understanding of the mechanism of SHPT. Phosphatonins Phosphatonins are hormone or hormonelike substances that have been shown to be important in the control of overall phosphate homeostasis. The phosphatonins include fibroblast growth factor 23 (FGF-23); matrix extracellular phosphoglycoprotein (MEPE); soluble FRP-4[9]; and perhaps most recently described, circulating klotho protein.[10] To date, we have limited information about FGF-23 in CKD, noted Myles Wolf, MD, MMSc,[11] of Harvard Medical School, Boston, Massachusetts. The demonstration that FGF-23 is important in primary hypophosphatemic disorders of X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, and tumor-induced osteomalacia led to investigations of FGF-23 levels in normal individuals with varying dietary phosphate intake,[12] and then in patients with CKD, in which progressive disease was associated with higher levels and increased phosphaturia.[13] Of note, establishing the link between phosphate homeostasis and 1,25-dihydroxyvitamin D levels in CKD, FGF-23 levels were also found to be associated with a reduction in the circulating level of active vitamin D hormone in progressive CKD. This is not all that surprising in that FGF-23 has been shown to regulate the activity of kidney 25-hydroxyvitamin D-1-alpha-hydroxylase in normal mice.[14] Perhaps, disordered mineral metabolism in CKD begins with modest elevations in FGF-23 that promote phosphaturia, but in the process, downregulate blood levels of 1,25-dihydroxyvitamin D. Can we also establish a link between enhanced calcific arteriopathy to FGF-23? To address this question, Craig B. Langman, MD,[15] of Chicago, reviewed the signaling system and molecular biology of FGF-23. FGF-23 FGF-23 signals through an FGF receptor that appears to be associated with an integral membrane protein called klotho. Of interest, due to a genetic manipulation to knock out the klotho gene, klotho null mice have a marked arterial calcific disease duplicative of the calcific arteriopathy that occurs in dialysis patients. Remarkably, in vivo klotho gene delivery can ameliorate vascular

endothelial dysfunction, increase nitrous oxide production, reduce elevated blood pressure, and prevent medial hypertrophy and perivascular fibrosis in a rat model with multiple atherogenic risk factors, including hypertension, diabetes, obesity, and hyperlipidemia.[16] In addition, the level of klotho RNA expression has been shown to be greatly reduced in the kidneys of patients with chronic renal failure and dietary phosphate restriction-induced klotho expression.[17] Although far from settled, it remains a tenable hypothesis that there are additional disturbances in the FGF-23 signaling system that promote systemic abnormalities in vascular biology that are now recognized to be a component of ROD. We await future studies of FGF-23 and its signaling system in this regard in order to better understand how to care for patients with ROD. However, measuring FGF-23 levels in addition to PTH levels has enabled us to predict a response to exogenous calcitriol therapy in dialysis patients.[18] However, before we run back to the bedside, we have also learned that calcitriol infusion acutely increases FGF-23 in dialysis patients.[19] Recently, experimental studies have demonstrated that osteoblast in bone is the source of FGF-23 under the influence of 1,25dihydroxyvitamin D,[20] but how this translates to the clinical arena in patients with CKD remains to be determined. Finally, a slight twist in the FGF-23 story is reported by Wolf and colleagues,[21] who demonstrated that hypophosphatemia that persists after kidney transplantation is associated with an increase in FGF-23 levels. This explains the hypophosphatemia and inappropriately low levels of 1,25-dihydroxyvitamin D -- relative to the known stimulatory power of hypophosphatemia. Although the study authors suggest that perhaps there is an escape of FGF23 regulation ("tertiary" hyperphosphatonism), more data and information are needed to understand the metabolism of FGF-23 and its signaling system in hypophosphatemia after kidney transplantation. Before we leave the issue of disordered vitamin D metabolism in ROD, let's remember that we postulated at the beginning of this brief that substrate 25-hydroxyvitamin D deficiency can reduce blood levels of 1,25-dihydroxyvitamin D. This finding was demonstrated recently in a large proportion of patients with CKD,[22] and was amplified by Qunibi,[23] who demonstrated the predominance of vitamin D deficiency in a study of 196 patients in CKD stage I-V. Although the incidence of vitamin D deficiency is shockingly high (> 80%), the incidence is not greater in patients with later stages of CKD. Such data add weight to the recommendations of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines to assess for vitamin D substrate deficiency in CKD-associated SHPT.[24]

Kidney Disease: Improving Global Outcomes

Speaking of guidelines, Stuart Sprague, DO,[25] of Evanston, Illinois, explained the rationale and discussed some of the new features of the Kidney Disease: Improving Global Outcomes (KDIGO) Global Bone and Mineral Initiative. The concept of ROD was complicated enough before the discussion of phosphatonins above. In addition, the link between SHPT, alterations in mineral metabolism, bone histology, and cardiovascular calcification is a bit mind-numbing, even for ROD experts.

KDIGO[26] was founded to look at many aspects of CKD, and one of its first products was a restatement about ROD,[27] in which a simple system to classify patients with CKD that is based on bone histology, biochemical abnormalities, and vascular calcifications is put forth for consideration. Hopefully, the ability to classify patients by the KDIGO method will lead to better understanding of patient outcomes and therapeutic approaches. Perhaps the best approach for patients is exemplified by Grabbe,[28] in which daily nocturnal home hemodialysis was associated with the virtual absence (86% reduction) over time of the need for medication to treat ROD. At the end of 24 months with this dialysis method, the average number of bone medications in 47 patients given a total of 1700 prescriptions was only 0.17! This has important economic implications, because data presented by Johnson and associates[29] demonstrated that there was an increase in healthcare costs associated with patients whose level of PTH exceeded National Kidney Foundation Kidney Disease Outcomes Quality Initiative suggested levels by successive quintiles, except for the very highest quintile -- and for which the study authors and others have no explanation. Although home-based dialysis may or may not be more expensive,[30] it likely produces better outcomes in the broadest sense in patients with ROD, and should be considered, if economically available, as an optimal care strategy. For those readers who follow the field of mineral and bone metabolism, the word "osteoporosis" has yet to appear in these pages! There remains much confusion about bone mass in patients with CKD, especially in patients on maintenance dialysis. There does seem to be some correlation with higher levels of PTH and lower bone density in some but not all sites measured, and adynamic bone disease may be associated with less of a reduction, although it likely has poorer bone quality that leads to more frequent fractures.[31] At this time, no therapeutic agents have been shown to repair osteoporosis in the dialysis population. What then of kidney transplant recipients? Michelle Josephson, MD, FACP,[32] of Chicago, attempted to unravel the complicated skeletal biology in this setting. Transplant-associated bone disease is a fracturing disease, and the prevalence in transplant recipients is high compared with appropriate population-based cohorts.[33] Bone mineral density (BMD), in the context of postmenopausal osteoporosis as defined by the World Health Organization t scores,[34] likely does not apply to chronic disease and may not apply to patients given medications that affect the bone. Kidney transplant recipients, for example, receive corticosteroids, well known to have a negative effect on BMD, and more important, to be associated with an increased fracture rate out of proportion to that seen with reduced BMD. Other important considerations in transplant recipients include the higher prevalence of substrate 25-hydroxyvitamin D deficiency (here, too); hypogonadism; and the effects of other, potent immunosuppressive agents on bone mineral metabolism.[35] Although BMD in the kidney transplant recipient improves with discontinuation of corticosteroid therapy, the risk for fracture does not seem to correlate with BMD. Bone disease, as defined by histomorphometry and subsequent clinical outcome correlates, including fracture, does not exist in this population. However, a recent publication reported the changes in bone histology as patients progressed from maintenance dialysis to transplantation.[36] Although most patients retained abnormal bone histology for 6 months after the transplantation, their adynamic bone disease appeared to transition to hyperparathyroid bone disease. Unfortunately, there are no

specific biomarkers to aid in the diagnosis of bone disease after kidney transplantation. Newer markers, including osteoprotegerin and soluble receptor of NK-kappa-b ligand, that arise from the osteoblast itself may transform our understanding in the near future.[37] Is there any therapy for transplant-associated bone disease and fracture prevention? Certainly, avoidance of dietary calcium deficiency, substrate 25-hydroxyvitamin D deficiency, and recognition of corticosteroid excess are minimum considerations. Interest in the use of bisphosphonates remains high, but unlike in the care of postmenopausal osteoporosis, there are only data linking the use of these drugs to increased BMD, not reduction in fracture rate.[38] Thus, we are again left with uncertain strategies for the care of our patients' bones. How can I sum up our current understanding of bone and mineral metabolism? I think that our understanding of pathways for the pathogenesis of ROD and its classifications, outcomes, and influences on bones after kidney transplantation are in a state of great flux. Central to our understanding, however, is the link between patients' vascular biology, bone biology, and new techniques emerging in bioengineering and pharmacogenetics that will allow for a new wave of diagnostic strategies and therapeutic approaches for the cure of the nagging problem of ROD before another century passes.

References
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