Secondary hyperparathyroidism: review of the disease and its treatment

BACKGROUND: Most patients with chronic kidney disease (CKD) stage 5 develop secondary hyperparathyroidism (SHPT). SHPT is an adaptive response to CKD and its associated disruptions in the homeostatic control of serum phosphorus, calcium, and vitamin D. The poor control of mineral and parathyroid hormone (PTH) levels characteristic of SHPT is associated with serious clinical consequences. OBJECTIVE: This review discusses the pathophysiology and consequences of SHPT, as well as the efficacy and limitations of current treatment modalities. METHODS: Literature searches were conducted using the MEDLINE, EMBASE, and BIOSIS databases. Additional information was obtained from Internet web sites, textbooks, and nephrology congress abstracts. RESULTS: Patients with uncontrolled SHPT are at higher risk for cardiovascular morbidity and mortality, hospitalization, bone disease, vascular and soft-tissue calcification, and vascular access failure than patients whose mineral and PTH levels are well managed. New National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) targets for calcium, phosphorus, calcium-phosphorus product, and PTH control have recently been published with the aim of improving the management of mineral metabolism in CKD patients. Data from observational studies suggest that the majority of patients currently have PTH and mineral levels outside these target ranges. CONCLUSIONS: Given the inadequacies of current therapies, novel agents are being developed that may help improve the management of SHPT.     

Mineral and bone disorders in patients on dialysis: physiology and clinical consequences.

Chronic kidney disease-mineral and bone disorder (CKD-MBD) arises from a series of independent, yet interrelated, disturbances in bone and mineral metabolism. The consequences of failing to control CKD-MBD include increased mortality, cardiovascular and soft-tissue calcification, renal osteodystrophy, and endocrine and bone marrow disturbances. An understanding of the physiology and clinical consequences of the disease illustrates the necessity of simultaneously controlling parathyroid hormone (PTH), calcium, phosphorus, and calcium-phosphorus product (Ca x P), as recommended by the Kidney Disease Outcomes Quality Initiative (KDOQ).     

Klotho在慢性肾脏病血管钙化中作用的研究进展

慢性肾脏病(chronic kidney disease,CKD)发病率逐年升高,慢性肾脏病患者随其肾功能下降并发骨矿物质代谢紊乱(mineral and bone disorder,MBD),主要表现为钙磷代谢异常、继发性甲状旁腺功能亢进症、血管钙化(vascular calcification,VC)等,严重影响患...     

Calcium Balance and Negative Impact of Calcium Load in Peritoneal Dialysis Patients

Like hemodialysis patients, peritoneal dialysis (PD) patients are facing an excessively increased burden of vascular and valvular calcification. According to some surveys, more than 80% of prevalent PD patients are complicated with vascular calcification, and more than one third have heart valve calcification.Dysregulated phosphate metabolism is well recognized to play an important role in inducing vascular calcification, but increasing evidence is suggesting that dysregulated calcium metabolism also promotes vascular calcification and might in fact be more potent than phosphate in inducing that calcification. Growing evidence from randomized controlled trials shows more progression of vascular calcification and higher mortality among chronic kidney disease (CKD) patients receiving calcium-based phosphate binders than among those receiving non-calcium-containing phosphate binders. Those results raise important safety concern about the use of high-dose calcium-based phosphate binders in the CKD population, including both non-dialysis and dialysis patients (especially anuric dialysis patients), who have markedly reduced urinary calcium excretion. To prevent calcium overload, this review recommends restricting the dose of calcium-based phosphate binders in CKD patients, especially those who are elderly, who have increased cardiovascular risk, who already have baseline vascular or valvular calcification, or who have low intact parathyroid hormone and adynamic bone disease.     

Chronic kidney disease and vascular remodelling: molecular mechanisms and clinical implications

CKD (chronic kidney disease) is a severe and complex disease with a very high prevalence of CV (cardiovascular) complications. CKD patients are exposed to haemodynamic disturbances in addition to severe metabolic abnormalities that lead to a specific form of arterial remodelling, which contributes to the development of CV disease. Arterial calcification is a major event in the arterial remodelling process and is strongly linked to mineral metabolism abnormalities associated with CKD. Arterial remodelling is not limited to arterial calcification and modifications in arterial wall composition are also observed. Activation of the RAS (renin-angiotensin system), ET-1 (endothelin-1), endothelial dysfunction, oxidative stress and ADMA (asymmetric ω-NG,NG-dimethylarginine), as well as the anti-aging molecule Klotho, are implicated in this process. The present review details the mechanisms involved in arterial calcification and arterial remodelling associated with CKD, and provides the clinical consequences of large and small artery stiffness and remodelling in CKD patients.     

Cinacalcet: An oral calcimimetic agent for the management of hyperparathyroidism

BACKGROUND: Uncontrolled hyperparathyroidism (HPT), particularly HPT resulting from chronic kidney disease (CKD), is associated with significant morbidity and cardiovascular mortality. Traditional medical therapy (eg, vitamin D sterols, calcium, phosphate binders) has been inadequate for the management of HPT and its vascular and skeletal complications. OBJECTIVE:: The goal of this article was to review the efficacy and safety profile of cinacalcet, a second-generation calcimimetic, in the management of HPT secondary to CKD, primary HPT, and parathyroid carcinoma. METHODS: MEDLINE, Web of Science, and International Pharmaceutical Abstracts were searched from 1995 to July 2005 using the terms cinacalcet, AMG 073, KRN 1493, calcimimetics, hypercalcemia, and hyperparathyroidism. RESULTS: Compared with placebo, cinacalcet significantly reduced parathyroid hormone levels within 2 to 4 hours after administration (P < 0.05). In Phase III trials involving 1136 patients with secondary HPT, 56% of those who received cinacalcet achieved the National Kidney Foundation Kidney Disease Outcomes Quality Initiative target of a reduction in parathyroid hormone to <300 pg/mL, 65% achieved a calcium-phosphorus product <55 mg2/dL2, and a respective 49% and 46% achieved normalized serum calcium and phosphorus levels (P < 0.001). Cinacalcet's effects were similar regardless of patients' demographic characteristics, duration or mode of dialysis, severity of HPT, or use of concomitant medical therapy. Preliminary evidence suggests that cinacalcet may reverse cortical bone loss. Cinacalcet was well tolerated, with nausea (31%) and vomiting (27%) being the most commonly reported adverse effects. Hypocalcemia was transient in 5% of patients, was usually asymptomatic, and was corrected by dose reduction. CONCLUSIONS: Based on the available evidence, cinacalcet is effective and well tolerated in the treatment of secondary HPT and refractory parathyroid carcinoma. Its use in primary HPT appears promising. Further investigations are needed to determine if cinacalcet can prevent the long-term complications of HPT and reduce mortality.     

CKD3~5期维持性血液透析患者腹主动脉钙化的发生及其进展相关因素

目的:探讨慢性肾脏病(chronic kidney disease,CKD)3~5期维持性血液透析患者腹主动脉钙化(abdominal aortic calcification,AAC)发生及进展情况,分析其影响因素。方法:选取2017年1月至2018年3月阜阳市第二人民医院80例CKD3~5期维持性血液透析患者,分析影响患者AAC发生及进展的危险因素。结果:80例CKD3~5期维持性血液透析患者中包括无钙化者44例,钙化者36例;Logistic回归分析结果显示,年龄、高血压病史、糖尿病病史、冠心病史、C反应蛋白、血磷、三酰甘油、全段甲状旁腺激素是CKD3~5期维持性血液透析患者AAC发生的独立危险因素,25羟维生素D是影响AAC的保护因素;随访2年,共有67例患者复查腹部侧位X线片完成随访,其中AAC进展组32例(新发14例),非AAC进展组35例;Logistic回归分析结果显示,年龄、血磷、C反应蛋白、三酰甘油、全段甲状旁腺激素是CKD3~5期维持性血液透析患者AAC进展的独立危险因素,25羟维生素D、高密度脂蛋白是影响AAC进展的保护因素。结论:年龄、高血磷、高血压病史、糖尿病病史、冠心病史、高水平C反应蛋白、低水平25羟维生素D、高三酰甘油、高全段甲状旁腺激素是血液透析患者AAC发生的独立危险因素,高水平血磷及低水平25羟维生素D、高三酰甘油、高全段甲状旁腺激素、高密度脂蛋白胆固醇是血液透析患者AAC进展的独立危险因素。     

Obesity and coronary artery disease risk in Native Americans

With the aging of the US population and the increase in hypertension, diabetes mellitus, and obesity, the prevalence of chronic kidney disease (CKD) is increasing in the United States. Its prevalence rate has risen to 13.1% of the US population. Patients with CKD experience poor outcomes and have high health care costs. Chronic kidney disease is also a major cardiovascular disease risk factor. In fact, most people with CKD die of heart disease before they progress to end-stage renal disease. The National Kidney Foundation has produced evidencebased guidelines known as the Kidney Disease Outcomes Quality Initiative (KDOQI). These guidelines outline many things that the primary care physician can do to delay the progression of CKD, and to arrange for early referral for the prevention of future complications. However, there is limited knowledge and uptake of these guidelines because of their length and and complexity. Patients with CKD risk factors, hypertension, diabetes mellitus, cardiovascular disease, a family history of CKD, and those older than 60 years should be screened using 2 tests: 1) the estimated glomerular filtration rate and 2) the urinary albumin-creatinine ratio. These tests allow the diagnosis and stratification of CKD into 5 stages. This article synthesizes the key evidence-based behaviors and clinical action plan that primary care physicians can implement to treat CKD and its complications.     

Non-calcium-containing phosphate binders: comparing efficacy, safety, and other clinical effects

Phosphate-binder therapy for hyperphosphataemia is key to the treatment of patients with chronic kidney disease (CKD)-mineral and bone disorder (MBD). Calcium-free phosphate binders are increasingly favoured since calcium-based agents potentially cause harmful calcium overload and vascular calcification that confound the benefits of reducing serum phosphorus. Several calcium-free phosphate binders are available, including the non-absorbed agent sevelamer and the absorbed agents, e.g. lanthanum and magnesium salts. Randomised controlled studies consistently show that sevelamer and lanthanum carbonate offer equivalent lowering of serum phosphorus and often effectively achieve phosphorus targets versus calcium salts, with sevelamer having a positive effect on bone disease, vascular calcification, and patient-level outcomes in dialysis patients in several trials. There is also evidence that lanthanum carbonate can improve bone health, but data are limited to its effects to vascular calcification or patient-level outcomes. Magnesium salts have also been shown to reduce serum phosphorus levels, but clear evidence is lacking on bone, vascular, or clinical outcomes. It also remains to be established whether long-term systemic accumulation of lanthanum and magnesium, in tissues including bone, has clinically relevant toxic effects. This review summarises the evidence of efficacy and safety for newer calcium-free phosphate binders in CKD-MBD management.     

Current concepts and management strategies in chronic kidney disease-mineral and bone disorder

ABSTRACT: The term renal osteodystrophy describes the pathological changes in bone structure in chronic kidney disease (CKD); however, this term fails to describe adequately the adverse changes in mineral and hormonal metabolism in CKD that have grave consequences for patient survival. CKD-mineral and bone disorder (CKD-MBD) is a broader, newly defined term that should be used instead of renal osteodystrophy to define the mineral, bone, hormonal, and calcific cardiovascular abnormalities that are seen in CKD. The new paradigm in the management of renal bone disease is to "think beyond the bones" and strive to improve cardiovascular outcomes and survival. This means treating other aspects of the disease process that go beyond merely controlling parathyroid hormone levels. Primary physicians need to take a proactive approach to the management of CKD-MBD because the disorder begins early in the course of CKD, well before a patient is referred to a nephrologist. This review outlines the evidence behind the understanding of CKD-MBD, its implications for overall mortality, and the latest recommendations for management of CKD-MBD in patients with predialysis CKD.     

Chronic kidney disease-mineral and bone disorder (CKD-MBD)

Changes in mineral and bone metabolism are prevalent in chronic kidney disease. There are several types of renal bone disease, called 'renal osteodystrophy (ROD)'. ROD includes osteitis fibrosa, osteomalacia, adynamic bone disorder, and mixed osteodystrophy. Osteitis fibrosa is high turnover bone due to secondary hyperparathyroidism. Osteomalacia is low turnover bone concomitant of increased osteoid. Adynamic bone disorder is low turnover bone due to excessive suppression of the parathyroid glands and recently represents the major bone lesion in dialysis patients. More recently, the term 'Chronic Kidney Disease-Mineral and Bone Disorder(CKD-MBD)' was proposed to describe the clinical syndrome that develops as a systemic disorder of mineral and bone metabolism due to chronic kidney disease such as vascular calcification.     

慢性肾脏病5期与5D期患者血清矿物质及骨代谢异常调查

目的比较慢性肾脏病(CKD)5期与5D期患者血清矿物质及骨代谢异常(MBD)状况。方法回顾性分析240例终末期肾脏病患者的临床资料。根据血液透析情况将患者分为CKD5期组(非透析)和CKD5D期组(已透析),比较2组血清矿物质及骨代谢相关指标(血清钙、磷、全段甲状旁腺素、碱性磷酸酶等),评估血钙、血磷和甲状旁腺激素的达标情况。结果CDK5D期组患者血清全段甲状旁腺素(iPTH)、校正血钙、钙磷乘积、血清白蛋白高于CKD5期组,估算肾小球滤过率(eGFR)低于CKD5期组,差异均有统计学意义(P<0.01)。CKD5期组、CDK5D期组患者高磷血症发生率分别为83.75%、91.25%,低钙血症发生率分别为31.25%、17.50%,高钙血症发生率分别为1.88%、30.00%,高甲状旁腺激素发生率分别为37.50%、63.75%。结论终末期肾脏病患者伴有严重的钙、磷和甲状旁腺激素指标异常,CKD5期患者突出表现为高磷、低钙和高甲状旁腺激素。CKD5D期患者的CKD-MBD状况并未因血液透析而得到改善,反而变得更加严重,突出表现为高磷、高钙和高甲状旁腺激素。     

The role of the primary care physician in managing early stages of chronic kidney disease

Recent increases in obesity, diabetes, and hypertension, along with the aging of the US population, are driving a dramatic rise in the prevalence of chronic kidney disease (CKD). Despite this increase, the majority of Americans with early-stage CKD remain unaware of their disease. Primary care physicians are at the forefront of efforts for early recognition of CKD and management to control its progression. Patients with CKD should be referred to nephrologists no later than the point at which their estimated glomerular filtration rate reaches 30 mL/min. Nephrology evaluation at this point is essential to facilitate timely preparation for care of end-stage renal disease through preemptive transplantation or planned transition to dialysis. In addition to stringent control of underlying hypertension and/or diabetes, mineral metabolic parameters (serum parathyroid hormone, phosphorus, calcium, and bicarbonate) in patients with advancing CKD should be managed closely to avoid adverse effects on the cardiovascular and skeletal systems.     

Chronic kidney disease and cardiovascular disease--using the ANNA Standards and Practice Guidelines to improve care. Part 1: the epidemiology of chronic kidney disease: the risk factors and complications that contribute to cardiovascular disease.

Recent National Kidney Foundation Kidney Disease Outcome Quality Initiative Guidelines for cardiovascular disease recommend that patients with chronic kidney disease be considered at highest risk for development of cardiovascular disease and that cardiac risk factor reduction begin with diagnosis of chronic kidney disease. Risk factors for cardiovascular disease in patients with chronic kidney disease include both traditional and nontraditional renal-related cardiac risk factors. The ANNA Nephrology Nursing Standards of Practice and Guidelines for Care can provide the foundation for planning care to patients with CKD and not only slow the progression of CKD but reduce exposure to cardiac risk factors. This article, on the epidemiology of chronic kidney disease and the risk factors and complications that contribute to cardiovascular disease, is the first in a series of three articles on the risk factors and complications related to chronic kidney disease and its impact on cardiovascular disease.     

The self-management experience of people with mild to moderate chronic kidney disease.

This qualitative, exploratory study examined the self-management experiences of people with mild to moderate chronic kidney disease (CKD, Stages 1-3) to elicit participants' perceptions of health, kidney disease, and supports needed for self-management. Findings revealed a process of renegotiating life with chronic kidney disease, which encompassed Discovering Kidney Disease and Learning To Live With Kidney Disease. A number of themes were identified including searching for evidence, realizing kidney disease is forever, managing the illness, taking care of the self and the need for disease-specific information. The findings indicate participants with early CKD want to self-manage their illness in collaboration with health care providers. As well, people with early CKD need guidance and support from health professionals to successfully self-manage. Nephrology nurses are uniquely positioned to provide this support while collaborating with other care providers to facilitate self-management.     

Earlier onset and greater severity of disordered mineral metabolism in diabetic patients with chronic kidney disease

OBJECTIVE

Disordered mineral metabolism is a common complication of chronic kidney disease (CKD) and a novel risk factor for CKD progression, cardiovascular disease, and mortality. Although diabetes is the leading cause of CKD and is associated with worse clinical outcomes than other etiologies, few studies have evaluated mineral metabolism in CKD according to diabetes status.

RESEARCH DESIGN AND METHODS

Using the Chronic Renal Insufficiency Cohort Study, we tested the hypothesis that diabetes is independently associated with lower serum calcium and higher serum phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF23).

RESULTS

Compared with participants without diabetes (n = 1,936), those with diabetes (n = 1,820) were more likely to have lower estimated glomerular filtration rate (eGFR), lower serum albumin, and higher urinary protein excretion (all P < 0.001). Unadjusted serum phosphate, PTH, and FGF23 levels were higher and calcium was lower among those with compared with those without diabetes (all P < 0.001). After multivariate adjustment, diabetes remained a significant predictor of serum phosphate, PTH, and FGF23 but not calcium. The eGFR cut point at which 50% of participants met criteria for secondary hyperparathyroidism or elevated FGF23 was higher in participants with diabetes compared with those without (PTH: eGFR 30–39 vs. 20–29, P < 0.001; FGF23: eGFR 50–59 vs. 40–49, P < 0.001).

CONCLUSIONS

Disordered mineral metabolism begins earlier in the course of CKD and is more severe among CKD patients with compared with those without diabetes. Future studies should explore mechanisms for these differences and whether they contribute to excess risks of adverse clinical outcomes among diabetic patients with CKD.An estimated 25.8 million people in the U.S. suffer from diabetes, a leading risk factor for cardiovascular disease (CVD) and the most common cause of chronic kidney disease (CKD) (1,2). Although improved understanding of diabetes-related complications has led to advances in clinical management of affected individuals, recent studies show that even with delivery of optimal care, high risks of CVD and CKD persist (3). Moreover, compared with patients without diabetes, those with diabetes experience faster progression to end-stage renal disease (ESRD) and higher rates of CVD events and mortality (2). Thus, identifying novel pathophysiologic mechanisms that may contribute to these differences and can be targeted for intervention is a critical priority for diabetes and CKD management.Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD) refers to the clinical syndrome of laboratory abnormalities, bone disease, and extraskeletal calcification, including the arterial system (4). Among the earliest manifestations of CKD-MBD are vitamin D deficiency, disordered calcium and phosphate homeostasis, and secondary elevations of parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23). Mounting experimental and epidemiologic data support these alterations in mineral metabolism as novel risk factors for ESRD, CVD, and mortality (5,6). The evidence is especially strong for elevated serum phosphate and FGF23, which independently predict risks of CKD progression, CVD, and mortality (7,8). Differences in mineral metabolism according to diabetes status have been described in patients with ESRD (9,10), but a detailed characterization of the syndrome according to diabetes status is lacking in earlier stages of CKD. We measured mineral metabolites in baseline samples from 3,756 participants in the Chronic Renal Insufficiency Cohort (CRIC) Study, a racially and ethnically diverse prospective CKD cohort with a high prevalence of diabetes. We hypothesized that individuals with diabetes would have more severe abnormalities of mineral metabolism at comparable levels of renal dysfunction than patients without diabetes (lower serum calcium, higher serum phosphate, PTH, and FGF23 levels).     

K/DOQI gets to the heart of managing dyslipidemias in patients with CKD.

There is a wealth of data in the general population regarding interventions to reduce cardiovascular risk. Unfortunately, most of these studies exclude patients with chronic kidney disease. As a result, the lack of CKD specific data has resulted in a lack of attention and intervention. With the epidemic levels of cardiovascular disease in patients on dialysis, the NKF has established these K/DOQI guidelines in an effort to get to the "heart" of dyslipidemias and ultimately to assist the health care team in their effort to improve CKD patient outcomes. In addition, the National Kidney Foundation currently has draft K/DOQI Clinical Practice Guidelines for Cardiovascular Disease in the public review process. These new guidelines will elaborate on areas not covered in the dyslipidemia guidelines.     

PTH,vitamin D,and the FGF‐23–klotho axis and heart: Going beyond the confines of nephrology

Background

Profound disturbances in mineral metabolism are closely linked to the progression of chronic kidney disease. However, increasing clinical and experimental evidence indicates that alterations in phosphate homoeostasis could have an even stronger impact on the heart.

Aim

The aim of this review is to provide the reader with an update of how alterations in mineral metabolism are related to direct and indirect cardiotoxic effects beyond the nephrology setting.

Results

Evidence exists that alterations in mineral metabolism that are related to changes in parathyroid hormone (PTH), vitamin D, and the FGF‐23–klotho axis have direct pathological consequences for the heart. Alterations in plasma PTH levels are associated with cardiac dysfunction and detrimental cardiac remodelling. Several clinical studies have associated vitamin D deficiency with the prevalence of cardiovascular disease (CV) and its risk factors. Recent evidences support deleterious direct and nonphosphaturic effects of FGF‐23 on the heart as hypertrophy development. In contrast, reduced systemic klotho levels are related to CV damage, at least when advanced age is present. In addition, we discuss how these mineral metabolism molecules can counteract each other in some situations, in the context of failed clinical trials on cardiac protection as is the case of vitamin D supplementation.

Conclusions

Among all mineral components, an increase in systemic FGF‐23 levels is considered to have the greatest CV impact and risk. However, it is quite possible that many intracellular mechanisms mediated by FGF‐23, especially those related to cardiomyocyte function, remain to be discovered.     

Effects of statins on renal function

Patients with chronic kidney disease (CKD) are much more likely to die of cardiovascular disease than end-stage renal disease. Dyslipidemia is highly prevalent in patients with CKD and may contribute to the elevated cardiovascular risk as well as CKD progression. Statins are lipid-lowering drugs that appear to protect the kidneys via cholesterol reduction as well as noncholesterol-mediated mechanisms. Subgroup analyses of major clinical studies and meta-analyses of smaller trials indicate that statin therapy slows the decline of the glomerular filtration rate. Additionally, statins appear to reduce proteinuria in patients with CKD. Statins are well recognized to reduce cardiovascular morbidity and mortality in patients with and without documented cardiovascular disease and in certain high-risk populations, such as persons with diabetes mellitus. However, conclusive evidence for improved cardiovascular outcomes with statin therapy for CKD is not yet available. Several ongoing studies are evaluating the effect of statins on cardiovascular end points in patients with CKD and may provide data needed to support adjunctive use of these agents in this high-risk population.     

Diagnostic challenges of kidney diseases in HIV-infected patients

Introduction: Chronic kidney disease (CKD) is a prevalent comorbidity in persons living with HIV infection (PLWH) associated with an increase in cardiovascular morbidity and all-cause mortality. Furthermore, early diagnosis of CKD is difficult in PLWH.

Areas covered: We reviewed the main diagnostic tools for CKD in PLWH, and discussed their strengths and limits. We performed a literature search on PubMed to identify reviews and clinical trials dealing with attractive kidney biomarkers of CKD in PLWH, with the following key words: ‘HIV AND kidney’, ‘HIV AND Kidney biomarkers’, ‘CKD AND Kidney biomarkers’.

Expert commentary: Currently, CKD diagnosis is based on the estimation of Glomerular Filtration Rate (GFR), and measurement of proteinuria by urine protein/creatinine ratio (uPCR). These parameters are independent and complementary predictors of outcomes. GFR estimates are lacking in accuracy in PLWH. The best GFR estimate is CKD-EPI study equation. Moreover, low-grade proteinuria is associated with an increased risk of kidney disease progression in PLWH, and guidelines derived from the general population may lack sensitivity. Different biomarkers of kidney diseases like N-acetyl beta glucosaminidase (NAG), Kidney Injury Molecule-1 (KIM-1), and Alpha-1-microglobulin may predict kidney disease progression and mortality in PLWH. Others may help clinicians detect antiretroviral-induced tubulopathy, or predict cardiovascular events. More studies are needed to validate the routine use of these types of biomarkers.