Management Of Minerals And Bone Disorders After Kidney Transplantation

Kamyar Kalantar-Zadeh, MD, MPH, PhD^1,2,3,4,* et al

Abstract

Purpose of review—Mineral and bone disorders (MBD), inherent complications of moderate and advanced chronic kidney disease (CKD), occur frequently in kidney transplant recipients. However, much confusion exists about the clinical application of diagnostic tools and preventive or treatment strategies to correct bone loss or mineral disarrays in transplanted patients. We have reviewed the recent evidence about the prevalence and consequences of MBD in kidney transplant recipients and examined diagnostic, preventive, and therapeutic options to this end.

Recent findings—Low turnover bone disease occurs more frequently after kidney transplantation according to bone biopsy studies. The risk of fracture is high, especially in the first several months after kidney transplantation. Alterations in minerals (calcium, phosphorus, and magnesium) and biomarkers of bone metabolism (PTH, alkaline phosphatase, vitamin D, and FGF-23) are observed with varying impacts on post-transplant outcomes. Calcineurin inhibitors are linked to osteoporosis, whereas steroid therapy may lead to both osteoporosis and varying degrees of osteonecrosis. Sirolimus and everolimus might have a bearing on osteoblasts' proliferation and differentiation or decrease osteoclast-mediated bone resorption. Selected pharmacologic interventions for the treatment of MBD in transplant patients include steroid withdrawal, the use of bisphosphonates, vitamin D derivatives, calcimimetics, teriparatide, calcitonin, and denosumab.

Summary—MBD following kidney transplantation is common and characterized by loss of bone volume and mineralization abnormalities often leading to low turnover bone disease. Although there are no well-established therapeutic approaches for the management of MBD in renal transplant recipients, clinicians should continue individualizing therapy as needed.

Keywords: Renal osteodystrophy; bisphosphonates; fracture; calcineurin inhibitor; adynamic bone

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Introduction

Transplantation of solid organs is a common and effective treatment modality for the end-stage failure of those organs. The kidney is by far the most frequently transplanted solid organ both in the US and throughout the world.1 Advance in immunosuppressive therapy and transplant techniques over the last decades have improved allograft and patient survival, although the long-term survival advantage of some of these agents still remains to be demonstrated.2 Successful transplantation is capable of reversing many complications of end-stage kidney disease; however, disturbances of bone and mineral metabolism, also referred to as “mineral and bone disorders” (MBD), may persist, while new bone disorders may also emerge as a result of transplant-related medications. The MBD is an inherent feature of chronic kidney disease (CKD) and is commonly observed both in non-dialysis dependent CKD3 and maintenance dialysis patients.4 Although the bone disease has been recognized as a common complication in kidney transplant recipients, the routine application of adequate diagnostic tools and preventive or treatment strategies to correct bone loss or mineral disarrays may often be suboptimal. In this review, we summarize the updated information about the prevalence and consequences of mineral-and-bone disorders (MBD) in kidney transplant recipients and examine diagnostic, preventive, and therapeutic options for these conditions.

Types of Bone Disorders in Kidney Transplant Recipients

The hallmark of MBD is renal osteodystrophy, also known as “kidney bone disease”,4 which is classified into four major groups (Figure 1): (1) high turnover bone disease, (2) adynamic or low turnover bone disease, (3) mixed renal osteodystrophy, and (4) osteomalacia.5,6 Recent evidence suggests that renal osteodystrophy and its primary causes including disordered parathyroid function and disarrays in vitamin D and FGF-23 are related to cardiovascular disease and mortality. Table 1 shows the main characteristics of the 4 traditional types of uremic bone disease.7 The findings from earlier reports on bone abnormalities in patients after renal transplantation are somewhat conflicting.8-15 Heterogeneity of bone lesions has been noted in these early studies,9,13 whereas other studies report a wide range of histopathologic findings including high prevalence of high bone turnover associated with persistence of secondary hyperparathyroidism;8,10,11,16 normal bone formation;9 or low bone turnover (see Table 1).14,15 Prolonged mineralization without osteoid accumulation has been found in some studies as well,8,14,15 whereas frank osteomalacia has been rarely observed in kidney transplant recipients.12,13,17

Findings from Bone Biopsy Studies

In a study by Monier-Faugere et al18 in 56 prevalent kidney transplant patients who underwent bone biopsy, cancellous bone volume/tissue volume was below normal in most patients compared to age- and gender-matched control subjects. Similar bone biopsy findings were reported in a longitudinal study by Cruz et al19 in 20 patients before and then 6 months after kidney transplantation. Pre-transplant bone histomorphometric diagnoses were adynamic bone disease (n=12); mixed bone disease (n=3); mild disease (n=3); and osteitisfibrosa (n=2). After transplantation most patients (n=11) had the adynamic bone disease.

19 Rojas et al.20 showed that osteoid volume, osteoid thickness, osteoid resorption surface, and osteoclast surface were above the normal range before transplant and remained so approximately 35 days after transplantation; however, osteoid and osteoblast surfaces significantly decreased within 35 days post-transplant.20 There was also inhibition of bone formation and mineralization as well as apoptosis, which correlated with the dose of administered glucocorticoids.20 In contrast to the above findings, a longitudinal study by Lehman et al21 reported more heterogeneous biopsy findings.

Pooling together the bone biopsy studies in kidney transplant recipients, low turnover bone diseases including dynamic bone and osteomalacia appear to be common. Most kidney transplant recipients exhibit decreased mineral apposition rate and delayed mineralization which may be accompanied by the dramatic decrease in PTH levels including in patients who had relatively mild bone disease prior to transplantation14 and who received high doses of glucocorticoids.18 Many studies mainly show alterations consistent with a dynamic bone disease and increased deposition of iron in the mineralization front;15 however, some studies suggest decreased bone formation and prolonged mineralization lag time in the presence of persisting bone resorption.8,22,23 Hence, notwithstanding the discrepancies among various bone biopsy studies, the main alteration in bone remodeling after renal transplantation is a decrease in bone formation and mineralization in face of persistent bone resorption, which may lead to an imbalance in remodeling favoring resorption. Likewise, the defective bone formation may be a consequence of alterations in osteoblast function, decreased osteoblastogenesis, or increased osteoblast death rate. More bone biopsy studies in a larger number of kidney transplant recipients are needed to better understand the combined impact of prior bone disease and immune suppressive regimen on bone histology in this patient population.

Decreased Bone Mineral Density and Osteoporosis

Loss of bone mass after kidney transplantation leading to osteopenia or osteoporosis occurs primarily in the first 12 months, predominantly in cortical bone. The most rapid decrease in bone mineral density (BMD) [not to confuse with MBD] measured by dual-energy X-ray absorptiometry occurs in the first 6 months post-transplantation and seems to slow down thereafter, possibly reflecting reduced corticosteroid dose. BMD has been reported to decrease considerably at a mean of 5.5% to 19.5% during the first 6 months after transplantation,14,24,25 but only 2.6–8.2% between months 6 and 12,26,27 and 0.4-4.5% thereafter.28,29

Risk of Fracture

The overall fracture risk after renal transplantation is 3.6–3.8-fold higher than in healthy individuals,30,31, and is 30% higher during the first 3 years after transplantation than in patients on dialysis.30 In a retrospective study with follow-up time up to 33 years, more advanced age and history of diabetic nephropathy were independent predictors of fracture risk, whereas higher activity status was protective.31 Additional risk factors for fracture in kidney transplant recipients include female gender and combined kidney-pancreas transplantation.32-35 Similar to increased mortality risk during the first few weeks after kidney transplantation followed by a substantial decline in mortality thereafter when compared to waitlisted dialysis patients, the relative risk of hip fracture was 34% greater in the first few weeks after transplant surgery compared to dialysis patients but decreased by at least 1% per month until the estimated risk became equal for dialysis and transplant recipients approximately 630 days after transplantation.30 It is important to note that renal transplant recipients are at particular risk of vertebral fracture and that this risk is greater than their risk of lower extremity fractures.31

Mineral Metabolism after Kidney Transplantation

Alterations in mineral metabolism including such biomarkers of bone disease as PTH and alkaline phosphatase are common following successful kidney transplantation. The most recent Kidney Disease Initiative Global Outcomes (KDIGO) guidelines36 proposed periodic monitoring of serum calcium, and phosphorus every 6–12 months, 3–6 months, 1–3 months, in CKD stages 1–3T, 4T, and 5T, respectively, while PTH should also be measured at 3-12 month intervals according to the severity of CKD. Measurement of alkaline phosphatase should be performed annually or more frequently in the presence of elevated PTH according to the same guidelines.

Serum Calcium

There are several factors that may precipitate or worsen hypercalcemia after successful kidney transplantation: (1) persistently elevated serum PTH, (2) correction of hyperphosphatemia; and (3) improved 1,25(OH)2 vitamin D production from the allograft. Although severe hypercalcemia (>3 mmol/l or >12 mg/dL) is rarely observed, hypercalcemic episodes (defined as total serum calcium >2.62 mmol/l or >10.5 mg/dL) were reported in 30% and 12% of renal transplant recipients, 1 year and 5 years after transplantation, respectively.37 In a recent study, post-transplant hypercalcemia was not associated with a specific bone turnover abnormality.38 In one study hyperkalemia appeared to correlate with interstitial micro-calcifications in the renal allograft and poor long-term graft outcomes.39

Serum Phosphorus

Hyperphosphatemia (phosphorus >4.5 mg/dL) is more prevalent in pre-transplant patients, while hypophosphatemia (phosphorus <2.5 mg/dL) is observed much more frequently after renal transplantation, especially in the first few weeks postoperatively.17,40-42 Decreased phosphorus reabsorption in the proximal tubule, potentially related to persistently elevated PTH or FGF-23 levels, and a quasi “hungry bone syndrome” seem to be mechanisms responsible for post-transplantation hypophosphatemia. Hypophosphatemia has been associated with severe alterations in bone turnover that include a decrease in osteoblast activity that leads to rickets and osteomalacia.17,43 Several recent studies indicate that post-transplantation hypophosphatemia frequently is independent of PTH,44 suggesting that

FGF-23,45-47 or perhaps additional humoral factors (other phosphating) contribute to phosphaturia in the early post-transplant period.41,42 Both pre-transplant48 and post- transplant49 serum phosphorous derangements appear to be associated with anemia50 and mortality risk in kidney transplant recipients.

Serum Magnesium

Hypomagnesemia, which is a common condition, especially in the first few weeks after kidney transplantation, is also an independent predictor of new-onset (de novo) diabetes mellitus in renal transplant recipients.51 Seventy to 80% of serum magnesium is freely filtered at the glomerulus and most (up to 97%) is reabsorbed throughout the nephron. Calcineurin inhibitors including cyclosporine A may interfere with magnesium metabolism leading to decreased magnesium reabsorption, urinary magnesium wasting, and hypomagnesemia in renal transplant recipients receiving these immunosuppressive medications.52 A recent study suggested that low serum magnesium levels were associated with a faster rate of decline in kidney allograft function and increased rates of graft loss in renal transplant recipients with chronic cyclosporine nephropathy.52 Whether hypomagnesemia per se contributes to cyclosporine nephropathy, or whether magnesium supplementation may lessen the cyclosporine nephropathy is not clear.

PTH and Alkaline Phosphatase

PTH levels usually decline rapidly (>50%) during the first 3–6 months after kidney transplantation because of a reduction in functional parathyroid gland mass,53 followed by a more gradual decline probably attributable to the slower involution of these glands.16,37 However, persistently elevated levels of serum PTH despite normalization of renal function have been reported in up to 25% of renal transplant recipients 1 year after transplantation.

37,54 These so-called refractory (or tertiary) hyperparathyroidism cases may be the result of monoclonal glandular hyperplasia.55,56 There are several factors that are associated with persistent post-transplant hyperparathyroidism such as prolonged end-stage kidney disease prior to transplantation,37,57,58 decreased residual renal function,59 low levels of 1,25(OH)2-and 25(OH) vitamin D, and reduced expression of vitamin D and calcium-sensing receptors and also reduced expression of FGF-23 receptors in the parathyroid gland. 54,60-62 Both pre-transplant63 and post-transplant39 serum PTH levels are associated with unfavorable outcomes including worse graft function. However, it is important to note that two studies that assessed bone biopsy samples in kidney transplant recipients did not find a correlation between serum PTH levels and bone turnover,18,38 and the diagnostic accuracy of PTH is not quite clear.64 Treatment options for hyperparathyroidism are summarized below. Serum bone-specific alkaline phosphatase is significantly correlated with calcitriol and adequately reflects increased bone formation after renal transplantation.65 Higher levels of alkaline phosphatase, but not PTH in the months prior to kidney transplantation may herald poor post-transplant outcomes (Miklos Z. Molnar and colleagues, personal communication).

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Vitamin D and FGF-23

Low serum 25-OH-D levels are common following solid organ transplantation, both during the immediate postoperative period and in long-term graft recipients.66 According to the KDIGO guidelines36 kidney transplant patients should be assessed for the presence of vitamin D deficiency by examining circulating levels of 25-(OH) vitamin D (calcidiol), and vitamin D deficiency and insufficiency should be corrected using treatment strategies recommended for the general population. Even though the level of 1,25(OH)2 vitamin D (calcitriol) usually increases after successful kidney engraftment, it may still remain lower compared to the normal population.7 The most important predictor of low 1,25(OH)2 vitamin D levels are immunosuppressive therapy, PTH level, and residual renal function.45 The study by Evenepoel et al. found elevated pre-transplantation PTH levels and low post-transplantation levels of FGF23 to be additional predictors of improved post-transplantation 1,25(OH)2 vitamin D levels, although these were weaker than renal graft function.45

FGF-23 per se appears to be a strong and independent predictor of mortality in prevalent kidney transplant recipients.67

Preexisting Osteodystrophy

Virtually all patients who receive a kidney allograft suffer from some degree of preexisting bone disorders. The incidence and prevalence of pre-existing low turnover bone disease may have increased recently, probably due to higher dialysate calcium concentrations (1.75 mmol/L [3.5 mEq/L]), high doses of calcium-containing phosphate binders, and the potentially overzealous utilization of active vitamin D metabolites. It is not clear whether the pre-existing MBD has significant consequences on post-transplant outcomes; nevertheless, some transplant centers consider dialysis patients with high PTH levels as unfavorable candidates for kidney transplantation, which is similar to the policies pertaining to body mass index and obesity that have recently been challenged.68

Effects of Transplantation-Specific Therapies on Bone

Post-transplantation immunosuppressive therapy may have a major impact on the pathogenesis of the bone disease.69-72 The role of corticosteroids is well-known. During the first several months after transplantation, rapid bone loss secondary to steroid-induced acceleration in bone remodeling occurs in cancellous bone.14 A study that involved serial bone biopsies at 22 days and 160 days after transplantation showed impaired osteoblastogenesis and early osteoblast apoptosis probably related to steroid therapy.20 The etiology of glucocorticoid-induced bone disorder is multi-factorial.73-75 Steroids can be directly toxic to osteoblasts and lead to increased osteoclast activity.75 Other steroid effects include decreased calcium absorption in the gut, reduced gonadal hormone production, diminished insulin-like growth factor–1 (IGF-1) production, decreased sensitivity to PTH, increase in receptor activator of NF-kappa beta ligand (RANKL), and increased osteoclastogenesis.75-77

Calcineurin inhibitors including cyclosporine and tacrolimus have been linked to osteoporosis.78,79 Epidemiologic studies that have examined fracture risk, however, could not establish an association between the use of calcineurin inhibitors and fracture risk.31,80 Although mycophenolate mofetil, sirolimus, and azathioprine do not affect bone volume in rodents,81-83 a recent in vitro study suggests sirolimus might interfere with the proliferation and differentiation of osteoblasts,84 while everolimus reduces cancellous bone loss in ovariectomized rats by decreasing osteoclast-mediated bone resorption.85 Calcineurin- inhibitor-induced pain syndrome may happen as a result of osteonecrosis, along with transient marrow edema.86 These painful conditions, which can be diagnosed by X-ray, radionuclide scan, or magnetic resonance imaging are associated with increased intraosseous pressure, compromised vascular supply, marrow edema, and the development of a ‘bone compartment syndrome’.86 Steroid therapy is another known risk factor for osteonecrosis in renal transplant recipients.87 Mechanisms may include the differentiation of mesenchymal stem cells to adipocytes causing increased intraosseous pressure and collapse of marrow sinusoids, and increased osteoblast and osteocyte apoptosis. Calcineurin-inhibitors, particularly cyclosporine A, may increase the risk of osteonecrosis because of vasoconstrictive effects, and sirolimus may influence the development of osteonecrosis by potentiating the effects of calcineurin inhibitors or by influencing the lipid profile.86

Chronic Allograft Nephropathy Associated MBD

Gradually failing allografts may lead to post-transplantation CKD stage 3-5T leading to increased risk of worsening or de novo development of hyperparathyroidism, active vitamin D deficiency and the whole spectrum of “classic” MBD that is observed in transplant-naïve- CKD patients.3,59 In a study of more than 900 transplant patients PTH exhibited a negative correlation with estimated GFR in CKD stages 3-5T (r = -0.29, P <0.001).59 High PTH values correlate with significant bone loss at the hip and other areas.88 Given recent data that delaying the return to dialysis therapy may be associated with better survival in gradually failing kidney transplant recipients,89,90 higher rates of MBD are to be expected in the prevalent transplant population.

Management of MBD in Kidney Transplant Recipients

Several practice guidelines and expert reviews can be used to layout pragmatic recommendations for the prevention, diagnosis, and management of bone disease and mineral disorders in kidney transplant recipients.36,91,92 To date, no randomized controlled trials in kidney transplant recipients have examined the effect of bone-specific therapies on relevant clinical outcomes, including mortality, quality of life, or fracture risk.36 In heart transplant patients alendronate was as effective as calcitriol to prevent bone loss.93 Table 2

shows a list of selected studies pertaining to MBD management in renal transplant recipients. The KDIGO guidelines36 recommend treatment with active vitamin D (calcitriol or alfacalcidol) or bisphosphonates in the first 12 months after kidney transplant in those with estimated GFR>30 mL/min/1.73 m2 and low bone mineral density, and bone biopsy consideration to guide treatment, specifically before the use of bisphosphonates due to the high incidence of dynamic bone disease. The Cochrane Database review, however, indicates that no type of MBD treatment was associated with better survival in kidney transplant recipients, although treatment reduces the risk of fractures.92 Selected pharmacologic interventions for the treatment of MBD in transplant patients are listed in Table 3 and include steroid withdrawal, bisphosphonates, vitamin D derivatives, calcimimetics, teriparatide, calcitonin, and denosumab.

Steroid withdrawal or avoidance

The rationale for minimizing corticosteroid exposure is compelling and based on well-established risks of osteoporosis, avascular necrosis, and other side effects. Some studies found beneficial effects of early tapering of prednisolone on BMD.123,124 In contrast, however, randomized controlled trials have shown that steroid withdrawal, when carried out weeks to months after kidney transplantation, is associated with an increased risk of acute rejection.125,126 Hence, the current KDIGO guidelines36 do not currently recommend steroid withdrawal and avoidance as a routine course of action.

Bisphosphonates

Bisphosphonates (also known as diphosphonates) consist of two phosphonates (PO3) groups and are used to prevent bone mass loss and to treat osteoporosis and other osteopenic conditions. Figure 2 shows an overview of the results of the bisphosphonates studies in kidney transplant recipients. In four studies of multiple doses of pamidronate during the initial months after renal transplantation, prevention of bone loss occurred even after treatment was discontinued.99-102 Most, if not all, studies suggest that pamidronate administration prevents bone loss shortly after transplantation, although the low turnover bone disease may develop or worsen in many patients.99,100 Similar results were found when alendronate was administered.94,105 Intravenous ibandronate was used by Grotz et al.103 in 80 randomly assigned transplant recipients at a dose of 1 mg immediately before the transplant and 2 mg at 3, 6, and 9 months after transplantation and demonstrated prevention of bone loss, spinal deformation, and loss of body height during the first year after kidney transplantation.103 Another randomized controlled trial of 20 kidney transplant recipients showed that zoledronate improved the calcium content of cancellous bone.97 As to whether this early short-term intervention exhibits a sustained bone-sparing effect later in time, in another study zoledronate therapy conferred no sustained benefit versus placebo at 3 years post-transplantation.98 Weekly oral risedronate immediately after renal transplantation can improve BMD, particularly in the femoral neck at 6-month follow-up, without major side effects.104 Hence, bisphosphonate therapy may significantly improve bone mineral density at the femoral neck and lumbar spine and reduce the risk of acute rejection, and might reduce the risk of fracture,127 although bisphosphonates do not appear to have any effect on patient survival or graft loss.92

Vitamin D derivatives and D-mimetics with or without calcium supplement

Several forms of vitamin D derivatives and their therapeutic classification are shown in Table 3. In a well-controlled, blinded study, Josephson et al110 showed that kidney transplant recipients who were given calcium and calcitriol had significantly less bone loss in the lumbar spine and increased BMD in the distal radius and femoral neck compared with transplant patients given calcium alone or placebo. The treated patients did not develop significant hypercalcemia or deterioration of kidney function during the two years of the study.110 Torres et al reported that therapy with low-dose calcium supplements during 1 year, plus intermittent calcitriol for 3 months after transplantation was safe, decreased PTH levels more rapidly, and prevented bone loss at the proximal femur.109 Compared to placebo, calcidiol and oral calcium increased BMD at the lumbar spine and femoral neck. 107,108,128 Paricalcitol, a selective vitamin D receptor activator, also known as D-mimetic, 4,129 is indicated in the prevention and treatment of secondary hyperparathyroidism.

Preliminary results of a randomized controlled trial showed that changes in the profile of urinary peptides occurred due to treatment with paricalcitol;111 however, no study has assessed the association between bone fracture, BMD or outcomes, and administration of paricalcitol.

Calcimimetics

In the past several years the calcimimetic agent cinacalcet has been frequently evaluated for the treatment of hypercalcemia in renal graft patients with ongoing refractory hyperparathyroidism. As shown in some post-transplant trials cinacalcet successfully corrects elevated serum calcium and PTH levels with no negative effect on renal function, 114,115,120,121 and it appears to be safe in kidney transplant recipients.117,122 A favorable effect of cinacalcet on BMD in renal transplant patients was reported by several small studies (see Table 2).116,118,119 Interestingly, cinacalcet might also have a favorable effect on blood pressure in kidney transplant recipients, but not on outcomes.130

Other potential MBD treatment modalities

Another therapeutic agent studied in patients after kidney transplantation is teriparatide, a recombinant human PTH. A recent trial showed that teriparatide administered to kidney transplant patients for 6 months was safe but did not alter BMD in the lumbar spine or distal radius compared with the placebo group.131 However, BMD at the femoral neck remained stable in that given teriparatide, compared with a decrease in the placebo group. In addition, after 6 months, no significant differences between the two groups were detected in fractures, bone histology, vitamin D levels, PTH levels, kidney function, or serologic bone markers.131 Teriparatide can be considered as an alternative treatment of MBD in kidney transplant patients with low PTH and refractory hypocalcemia.132 Another potential therapeutic agent is calcitonin;, although it has no effect on mortality, graft loss, and risk of fracture in patients after kidney transplantation.92,133,134 Exercise training and hormonal therapy are other potential interventions. The effect of regular exercise or hormone replacement therapy on bone loss or risk of fracture has not yet been examined in the kidney transplant recipient, although data from other solid organ transplant patients are promising. 135,136 Denosumab, a RANK-ligand inhibitor for the treatment of postmenopausal osteoporosis;4 can theoretically reduce osteoclastic resorption of trabecular structures and, hence, be used for the treatment of osteonecrosis, but currently, there is no human data. Early stages of osteonecrosis are generally managed conservatively or with core decompression accompanied by bone grafting and more recently the injection of bone morphogenic protein, while iloprost to improve blood flow combined with bisphosphonates deserve further studies.86

Conclusions

Mineral and bone disorders following kidney transplantation are common and characterized by loss of bone volume and mineralization abnormalities leading to low turnover bone disease in most patients. There are several contributing factors including pre-existing osteodystrophy, transplantation-specific therapies, and reduced renal function due to chronic

allograft nephropathy. At this time there are no well-established therapeutic approaches that would provide bone preserving or anabolic effects with a high degree of certainty. However, vitamin D analogs and bisphosphonates are often used for the treatment of MBD after kidney transplantation. Whereas more studies are needed to examine the effects of different therapeutic interventions on bone disorders after kidney transplantation, clinicians should continue to individualize therapy according to their expertise and best judgment.

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1Harold Simmons Center for Chronic Disease Research & Epidemiology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA

2Division of Nephrology and Hypertension, Harbor-UCLA Medical Center, Torrance, CA

3David Geffen School of Medicine at UCLA, Los Angeles, CA

4Department of Epidemiology, UCLA School of Public Health, Los Angeles, CA 5Institute of Pathophysiology, Semmelweis University, Budapest, Hungary 6Division of Nephrology, University of Virginia, Charlottesville, VA, USA 7Division of Nephrology, Salem VA Medical Center, Salem, VA, USA

8Kaiser Permanente, CA

9Institute of Behavioral Sciences, Semmelweis University, Budapest, Hungary

10Dept. of Medicine, Division of Nephrology, McGill Univ. Health Cntr, Montreal, Quebec, Canada

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