Bone remodeling after renal transplantation

Bone remodeling after renal transplantation. Several studies have indicated that bone alterations after transplantation are heterogeneous. Short-term studies after transplantation have shown that many patients exhibit a pattern consistent with adynamic bone disease. In contrast, patients with long-term renal transplantation show a more heterogeneous picture. Thus, while adynamic bone disease has also been described in these patients, most studies show decreased bone formation and prolonged mineralization lag-time faced with persisting bone resorption, and even clear evidence of generalized or focal osteomalacia in many patients. Thus, the main alterations in bone remodeling are a decrease in bone formation and mineralization up against persistent bone resorption, suggesting defective osteoblast function, decreased osteoblastogenesis, or increased osteoblast death rates. Indeed, recent studies from our laboratory have demonstrated that there is an early decrease in osteoblast number and surfaces, as well as in reduced bone formation rate and delayed mineralization after transplantation. These alterations are associated with an early increase in osteoblast apoptosis that correlates with low levels of serum phosphorus. These changes were more frequently observed in patients with low turnover bone disease. In contrast, PTH seemed to preserve osteoblast survival. The mechanisms of hypophosphatemia in these patients appear to be independent of PTH, suggesting that other phosphaturic factors may play a role. However, further studies are needed to determine the nature of a phosphaturic factor and its relationship to the alterations of bone remodeling after transplantation

Altered response of adenylate cyclase to parathyroid hormone during compensatory renal growth

Altered response of adenylate cyclase to parathyroid hormone during compensatory renal growth. The loss of renal mass is associated with functional adaptations in the remaining nephrons to maintain homeostasis. Although parathyroid hormone (PTH) is important in the adaptations to phosphate, the mechanisms are not completely defined. In the present studies we examined the response of the adenylate cyclase system to PTH in renal cortical membranes of rat kidneys ten days after unilateral nephrectomy. The kidneys obtained at the time of the initial nephrectomy were used as controls. Unilateral nephrectomy resulted in contralateral compensatory renal growth, as demonstrated by a 24 ± 4.7% (P < 0.01) increase in weight in the remaining kidney. Glomerular filtration rate (GFR) after unilateral nephrectomy was 62% of the control, while basal fractional phosphate excretion was higher in rats with unilateral nephrectomy (7.7 ± 2.1% vs. 2.9 ± 0.8%, P < 0.05). PTH infusion resulted in a similar increase of fractional phosphate excretion and urinary cAMP in both groups. In the absence of added guanine nucleotides, PTH-dependent adenylate cyclase activity in cortical membranes from kidneys with compensatory growth was decreased as compared to controls (Vmax807.5 ± 62.7 pmol cAMP/mg protein/30min vs. 1,384.8 ± 116.1, respectively, P < 0.01). The apparent affinity for PTH stimulation of adenylate cyclase (Kact) was unchanged. Magnesium-dependent adenylate cyclase activity was also decreased in the membranes from kidneys with compensatory growth. However, the kinetics of adenylate cyclase for the substrates ATP-Mg or ATP-Mn were similar. The addition of Gpp(NH)p resulted in a similar maximal response to PTH in the two groups, indicating an increased response of the enzyme to PTH in the presence of the guanine nucleotide. Cholera toxin-dependent ADP-ribosylation of the stimulatory guanine nucleotide binding protein (Gs) showed a marked decrease in the apparent content of the alpha subunit in membranes from kidneys with compensatory growth compared to controls. On the contrary, pertussis toxin-dependent ADP-ribosylation of the inhibitory guanine nucleotide binding protein (Gi) did not show differences in the content of the alpha subunit in both groups of membranes. Since the transduction of the hormone signal from the receptor is mediated by G proteins, the present studies suggest that during compensatory renal growth a decrease in the alpha subunit of Gs could account for the impaired response of adenylate cyclase to PTH in vitro, which could be overcome by high concentrations of guanine nucleotides

The pathogenesis of osteodystrophy after renal transplantation as detected by early alterations in bone remodeling

The pathogenesis of osteodystrophy after renal transplantation as detected by early alterations in bone remodeling.BackgroundLoss of bone mass after transplantation begins in the early periods after transplantations and may persist for several years, even in patients with normal renal function. While the pathogenesis of these abnormalities is still unclear, several studies suggest that preexisting bone disease, glucocorticoid therapy, and alterations in phosphate metabolism may play important roles. Recent studies indicate that osteoblast apoptosis and impaired osteoblastogenesis play important roles in the pathogenesis of glucocorticoid-induced osteoporosis.ObjectivesTo examine the early alterations in osteoblast number and surfaces during the period following renal transplantation.MethodsTwenty patients with a mean age of 36.5 ± 12 years were subjected to bone biopsy 22 to 160 days after renal transplantation. In 12 patients, a control biopsy was performed on the day of transplantation. Bone sections were evaluated by histomorphometric analysis and cell DNA fragmentation by the methods of terminal deoxynucleotidyl transferase-mediated uridine triphosphate nick end labeling (TUNEL), using immunoperoxidase and direct immunofluorescence techniques.ResultsThe main alterations in posttransplant biopsies were a decrease in osteoid and osteoblast surfaces, adjusted bone formation rate, and prolonged mineralization lag time. Peritrabecular fibrosis was markedly decreased. None of the pretransplant biopsies revealed osteoblast apoptosis. In contrast, TUNEL-positive cells in the proximity of osteoid seams or in the medullary space were observed in nine posttransplant biopsies of which four had mixed bone disease, two had adynamic bone disease, one had osteomalacia, one had osteitis fibrosa, and one had mild hyperparathyroid bone disease. Osteoblast number in posttransplant biopsies with apoptosis was lower as compared with posttransplant biopsies without apoptosis. In addition, most of them showed a marked shift toward quiescence from the cuboidal morphology of active osteoblasts. Serum phosphorus levels were lower in patients showing osteoblast apoptosis and correlated positively with osteoblast number and negatively with the number of apoptotic osteoblasts. In addition, posttransplant osteoblast surface correlated positively with parathyroid hormone (PTH) levels and negatively with glucocorticoid cumulative dose.ConclusionThe data suggest that impaired osteoblastogenesis and early osteoblast apoptosis may play important roles in the pathogenesis of posttransplant osteoporosis. The possible mechanisms involved in the pathogenesis of theses alterations include posttransplant hypophosphatemia, the use of glucocorticoids, and the preexisting bone disease. PTH seems to have a protective effect by preserving osteoblast survival

Capturing and monitoring global differences in untreated and treated end-stage kidney disease, kidney replacement therapy modality, and outcomes

A large gap between the number of people with end-stage kidney disease (ESKD) who received kidney replacement therapy (KRT) and those who needed it has been recently identified, and it is estimated that approximately one-half to three-quarters of all people with ESKD in the world may have died prematurely because they could not receive KRT. This estimate is aligned with a previous report that estimated that >3 million people in the world died each year because they could not access KRT. This review discusses the reasons for the differences in treated and untreated ESKD and KRT modalities and outcomes and presents strategies to close the global KRT gap by establishing robust health information systems to guide resource allocation to areas of need, inform KRT service planning, enable policy development, and monitor KRT health outcomes

Increasing access to integrated ESKD care as part of Universal Health Coverage

The global nephrology community recognizes the need for a cohesive strategy to address the growing problem of end-stage kidney disease (ESKD). In March 2018, the International Society of Nephrology hosted a summit on integrated ESKD care, including 92 individuals from around the globe with diverse expertise and professional backgrounds. The attendees were from 41 countries, including 16 participants from 11 low- and lower-middle–income countries. The purpose was to develop a strategic plan to improve worldwide access to integrated ESKD care, by identifying and prioritizing key activities across 8 themes: (i) estimates of ESKD burden and treatment coverage, (ii) advocacy, (iii) education and training/workforce, (iv) financing/funding models, (v) ethics, (vi) dialysis, (vii) transplantation, and (viii) conservative care. Action plans with prioritized lists of goals, activities, and key deliverables, and an overarching performance framework were developed for each theme. Examples of these key deliverables include improved data availability, integration of core registry measures and analysis to inform development of health care policy; a framework for advocacy; improved and continued stakeholder engagement; improved workforce training; equitable, efficient, and cost-effective funding models; greater understanding and greater application of ethical principles in practice and policy; definition and application of standards for safe and sustainable dialysis treatment and a set of measurable quality parameters; and integration of dialysis, transplantation, and comprehensive conservative care as ESKD treatment options within the context of overall health priorities. Intended users of the action plans include clinicians, patients and their families, scientists, industry partners, government decision makers, and advocacy organizations. Implementation of this integrated and comprehensive plan is intended to improve quality and access to care and thereby reduce serious health-related suffering of adults and children affected by ESKD worldwide

Status of care for end stage kidney disease in countries and regions worldwide:international cross sectional survey

ObjectiveTo determine the global capacity (availability, accessibility, quality, and affordability) to deliver kidney replacement therapy (dialysis and transplantation) and conservative kidney management.DesignInternational cross sectional survey.SettingInternational Society of Nephrology (ISN) survey of 182 countries from July to September 2018.ParticipantsKey stakeholders identified by ISN's national and regional leaders.Main outcome measuresMarkers of national capacity to deliver core components of kidney replacement therapy and conservative kidney management.ResultsResponses were received from 160 (87.9%) of 182 countries, comprising 97.8% (7338.5 million of 7501.3 million) of the world's population. A wide variation was found in capacity and structures for kidney replacement therapy and conservative kidney management-namely, funding mechanisms, health workforce, service delivery, and available technologies. Information on the prevalence of treated end stage kidney disease was available in 91 (42%) of 218 countries worldwide. Estimates varied more than 800-fold from 4 to 3392 per million population. Rwanda was the only low income country to report data on the prevalence of treated disease; 5 (&lt;10%) of 53 African countries reported these data. Of 159 countries, 102 (64%) provided public funding for kidney replacement therapy. Sixty eight (43%) of 159 countries charged no fees at the point of care delivery and 34 (21%) made some charge. Haemodialysis was reported as available in 156 (100%) of 156 countries, peritoneal dialysis in 119 (76%) of 156 countries, and kidney transplantation in 114 (74%) of 155 countries. Dialysis and kidney transplantation were available to more than 50% of patients in only 108 (70%) and 45 (29%) of 154 countries that offered these services, respectively. Conservative kidney management was available in 124 (81%) of 154 countries. Worldwide, the median number of nephrologists was 9.96 per million population, which varied with income level.ConclusionsThese comprehensive data show the capacity of countries (including low income countries) to provide optimal care for patients with end stage kidney disease. They demonstrate substantial variability in the burden of such disease and capacity for kidney replacement therapy and conservative kidney management, which have implications for policy

Bone Disease in Chronic Kidney Disease and Kidney Transplant

Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) comprises alterations in calcium, phosphorus, parathyroid hormone (PTH), Vitamin D, and fibroblast growth factor-23 (FGF-23) metabolism, abnormalities in bone turnover, mineralization, volume, linear growth or strength, and vascular calcification leading to an increase in bone fractures and vascular disease, which ultimately result in high morbidity and mortality. The bone component of CKD-MBD, referred to as renal osteodystrophy, starts early during the course of CKD as a result of the effects of progressive reduction in kidney function which modify the tight interaction between mineral, hormonal, and other biochemical mediators of cell function that ultimately lead to bone disease. In addition, other factors, such as osteoporosis not apparently dependent on the typical pathophysiologic abnormalities resulting from altered kidney function, may accompany the different varieties of renal osteodystrophy leading to an increment in the risk of bone fracture. After kidney transplantation, these bone alterations and others directly associated or not with changes in kidney function may persist, progress or transform into a different entity due to new pathogenetic mechanisms. With time, these alterations may improve or worsen depending to a large extent on the restoration of kidney function and correction of the metabolic abnormalities developed during the course of CKD. In this paper, we review the bone lesions that occur during both CKD progression and after kidney transplant and analyze the factors involved in their pathogenesis as a means to raise awareness of their complexity and interrelationship