Nutritional and Inflammatory Aspects of Low Parathyroid Hormone in Maintenance Hemodialysis Patients-A Longitudinal Study.

BACKGROUND: Low serum parathyroid hormone (PTH) is an accepted marker for adynamic bone disease which is characterized by increased morbidity and mortality in maintenance hemodialysis (MHD) patients. In light of the known cross-sectional associations between PTH and malnutrition-inflammation syndrome, we aimed to examine the longitudinal associations between PTH with changes in nutritional and inflammatory parameters and clinical outcomes in MHD patients with low PTH. METHODS: This historical prospective and longitudinal study analyzed a clinical database at a single hemodialysis center, containing the medical records of 459 MHD patients (mean age of 71.4 ± 12.9 years old, 171 women), treated between the years 2007-2020. Bone turnover, nutritional and inflammatory marker levels were recorded at 0, 6, 12, 18, 24, 30, and 36 months followed by a median of 24 additional months of clinical observations. According to previous use of vitamin D analogs and/or calcium-sensing receptor agonists, the study participants were divided into treatment-related and disease-related groups. A linear mixed effects model was adjusted for baseline demographics and clinical parameters. RESULTS: Of 459 MHD patients, 81 (17.6%) had PTH lower than 150pg/mL. Among them, 30 patients had treatment-related and 51 had disease-related low PTH. At baseline, MHD patients with treatment-related low PTH had a higher rate of diabetes compared to the disease-related group. In a linear mixed effects model, increased PTH over time was associated with decreased levels of alkaline phosphatase and C-reactive protein and with increased hemoglobin and albumin, but not the geriatric nutritional risk index at 3-year follow-up. The survival rate did not differ between the groups, with the risk of hospitalizations due to fractures being higher (HR: 4.04 with 95% CI: 1.51-10.8) in the disease-related group. Statistical significance of this association was abolished after adding C-reactive protein or alkaline phosphatase to the multivariate models. CONCLUSIONS: Low serum PTH in MHD patients behaves differently depending on its cause, with a higher risk of fractures in the disease-related group. This association is dependent on inflammation. Our results should be verified in larger epidemiological studies.

Bone Health ECHO Case Report: Fractures and Hypercalcemia in a Patient with Stage 5 Chronic Kidney Disease.

Bone Health ECHO (Extension for Community Healthcare Outcomes) is a virtual community of practice with the aim of enhancing global capacity to deliver best practice skeletal healthcare. The prototype program, established at the University of New Mexico, has been meeting online weekly since 2015, focusing on presentation and discussion of patient cases. These discussions commonly cover issues that are relevant to a broad range of patients, thereby serving as a force multiplier to improve the care of many patients. This is a case report from Bone Health ECHO about a patient with stage 5 chronic kidney disease, hypercalcemia, and low bone density, and the discussion that followed.

A Novel Mutation in GATA3 Gene in a Case of Hypoparathyroidism, Deafness, and Renal Dysplasia Syndrome.

A 39-year-old male was incidentally detected to have hypertension and chronic kidney disease (CKD) with left solitary functioning kidney in 2017. He has bilateral sensorineural hearing loss since adolescence. He was initially suspected to have adynamic bone disease in view of low parathyroid hormone levels and was started on teriparatide injections and calcium supplements. Despite all these measures, he had persistent hypocalcemia and low parathyroid hormone levels. Hence, Hypoparathyroidism, Deafness, and Renal dysplasia (HDR) syndrome was suspected, and the patient was evaluated for the same. Genetic analysis revealed the presence of a de novo and a novel frameshift mutation in GATA-binding protein 3 (GATA3) gene on chromosome 10p. To the best of our knowledge, this is the first case report of HDR syndrome being diagnosed by genetic analysis in India.

Pathophysiology of bone disease in chronic kidney disease: from basics to renal osteodystrophy and osteoporosis.

Chronic kidney disease (CKD) is a highly prevalent disease that has become a public health problem. Progression of CKD is associated with serious complications, including the systemic CKD-mineral and bone disorder (CKD-MBD). Laboratory, bone and vascular abnormalities define this condition, and all have been independently related to cardiovascular disease and high mortality rates. The "old" cross-talk between kidney and bone (classically known as "renal osteodystrophies") has been recently expanded to the cardiovascular system, emphasizing the importance of the bone component of CKD-MBD. Moreover, a recently recognized higher susceptibility of patients with CKD to falls and bone fractures led to important paradigm changes in the new CKD-MBD guidelines. Evaluation of bone mineral density and the diagnosis of "osteoporosis" emerges in nephrology as a new possibility "if results will impact clinical decisions". Obviously, it is still reasonable to perform a bone biopsy if knowledge of the type of renal osteodystrophy will be clinically useful (low versus high turnover-bone disease). However, it is now considered that the inability to perform a bone biopsy may not justify withholding antiresorptive therapies to patients with high risk of fracture. This view adds to the effects of parathyroid hormone in CKD patients and the classical treatment of secondary hyperparathyroidism. The availability of new antiosteoporotic treatments bring the opportunity to come back to the basics, and the knowledge of new pathophysiological pathways [OPG/RANKL (LGR4); Wnt-ß-catenin pathway], also affected in CKD, offers great opportunities to further unravel the complex physiopathology of CKD-MBD and to improve outcomes.

Adynamic bone disease: Revisited.

The bone and mineral disorders form an integral part of the management of a chronic kidney disease (CKD) patient. Amongst various types of bone pathologies in chronic kidney disease-mineral bone disorder (CKD-MBD), the prevalence of adynamic bone disease (ABD) is increasing. The present review discusses the updated pathophysiology, risk factors, and management of this disorder.

Imaging of Chronic Kidney Disease-Mineral and Bone Disorder.

The characteristic radiological appearances of metabolic bone and soft tissue diseases in chronic renal failure are described and illustrated in the context of advancing understanding of the complex metabolic changes that occur in chronic kidney disease and its management.

Adynamic bone disease: Revisited / Enfermedad ósea adinámica: Una revisión

The bone and mineral disorders form an integral part of the management of a chronic kidney disease (CKD) patient. Amongst various types of bone pathologies in chronic kidney disease-mineral bone disorder (CKD-MBD), the prevalence of adynamic bone disease (ABD) is increasing. The present review discusses the updated pathophysiology, risk factors, and management of this disorder. (AU)

Los trastornos óseos y minerales son una parte fundamental del tratamiento del paciente con enfermedad renal crónica (ERC). Entre los distintos tipos de patologías óseas en la enfermedad renal crónica-trastorno mineral óseo (ERC-TMO), la prevalencia de la enfermedad ósea adinámica (EOA) está aumentando. En esta revisión se analizan los datos actuales sobre la fisiopatología, los factores de riesgo y el tratamiento de este trastorno. (AU)

Differentiating the causes of adynamic bone in advanced chronic kidney disease informs osteoporosis treatment.

Patients with chronic kidney disease (CKD) have an increased fracture risk because of impaired bone quality and quantity. Low bone mineral density predicts fracture risk in all CKD stages, including advanced CKD (CKD G4-5D). Pharmacological therapy improves bone mineral density and reduces fracture risk in moderate CKD. Its efficacy in advanced CKD remains to be determined, although pilot studies suggest a positive effect on bone mineral density. Currently, antiresorptive agents are the most commonly prescribed drugs for the prevention and therapy of osteoporosis. Their use in advanced CKD has been limited by the lack of large clinical trials and fear of causing kidney dysfunction and adynamic bone disease. In recent decades, adynamic bone disease has evolved as the most predominant form of renal osteodystrophy, commonly associated with poor outcomes, including premature mortality and progression of vascular calcification. Evolving evidence indicates that reduction of bone turnover by parathyroidectomy or pharmacological therapies, such as calcimimetics and antiresorptive agents, are not associated with premature mortality or accelerated vascular calcification in CKD. In contrast, chronic inflammation, oxidative stress, malnutrition, and diabetes can induce low bone turnover and associate with poor prognosis. Thus, the conditions causing suppression of bone turnover rather than the low bone turnover per se may account for the perceived association with outcomes. Anabolic treatment, in contrast, has been suggested to improve turnover and bone mass in patients with advanced CKD and low bone turnover; however, uncertainty about safety even exceeds that of antiresorptive agents. Here, we critically review the pathophysiological concept of adynamic bone disease and discuss the effect of low bone turnover on the safety and efficacy of anti-osteoporosis pharmacotherapy in advanced CKD.

Adynamic bone disease: Revisited.

The bone and mineral disorders form an integral part of the management of a chronic kidney disease (CKD) patient. Amongst various types of bone pathologies in chronic kidney disease-mineral bone disorder (CKD-MBD), the prevalence of adynamic bone disease (ABD) is increasing. The present review discusses the updated pathophysiology, risk factors, and management of this disorder.

Understanding Bone Disease in Patients with Diabetic Kidney Disease: a Narrative Review.

PURPOSE OF REVIEW: Both diabetes and kidney disease associate with the development of bone disease and an increased risk of fragility fractures. The etiologies of bone disease in patients with diabetic kidney disease (DKD) are multiple and complex. This review explores the association between DKD and bone disease and discusses how the presence of both diabetes and kidney disease may impair bone quality and increase fracture risk. Diagnostic tools as well as future research areas are also discussed. RECENT FINDINGS: Patients with DKD have an increased risk of fragility fracture, most pronounced in patients with type 1 diabetes, and in DKD a high prevalence of adynamic bone disease is found. Recent studies have demonstrated disturbances in the interplay between bone regulating factors in DKD, such as relative hypoparathyroidism and alterations of bone-derived hormones including fibroblast growth factor-23 (FGF-23), sclerostin and klotho, which lead to bone disease. This review examines the current knowledge on bone disease in patients with DKD, clinical considerations for patient care, as well as subjects for future research.

Teriparatide Treatment for Hypercalcemia Associated With Adynamic Bone Disease.

Hypercalcemia most often results from primary hyperparathyroidism and malignancy. Adynamic bone disease (ABD) is a form of renal osteodystrophy characterized by reduced bone turnover, which can limit the ability of bone to release or store calcium, potentially leading to low, normal, or high serum calcium levels. We describe a 51-year-old dialysis-dependent female with hypercalcemia after parathyroidectomy. A demeclocycline-labeled bone biopsy confirmed adynamic bone disease. Teriparatide, a recombinant form of parathyroid hormone (PTH) used to treat postmenopausal osteoporosis, was prescribed for 12 months and normalized serum calcium levels. Although previous case reports and series have described favorable changes in spine bone mineral density when teriparatide was prescribed for ABD, ours is the first documented case in which teriparatide resolved hypercalcemia due to ABD. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

[CKD-MBD in Peritoneal Dialysis].

CKD-MBD is a systemic disorder of the mineral and bone metabolism as a result of CKD. The clinical relevance of this syndrome has led to the identification of the biochemical targets to be achieved in order to improve the outcome of the patient. However, in hemodialysis (HD) and peritoneal dialysis (DP) patients, these targets are not reached. Hyperphosphatemia is a predictor of cardiovascular and all-cause mortality. In DP the removal of phosphorus (P) occurs by diffusion and convection, with a contribution of ultrafiltration of about 11%. P clearance is time dependent, with differences between CAPD and APD and depending on membrane transport characteristics. Residual renal function plays a key role in the P balance. Calcium (Ca) clearance in PD depends on the calcium levels, calcium concentration in dialysate and ultrafiltration. Positive Ca balance brings to Adynamic Bone Disease. Several bone-derived substances, some of them with hormonal action, have shed new light on the bone- cardiac axis. The hormonal functions of bone are likely to be related to histological lesions that develop during chronic renal failure. Compared to the past, recent data show less obvious differences in bone histomorphometry parameters between HD patients and PD patients. However, in PD patients fewer fractures are reported, probably due to different bone quality.

A case report of severe calciphylaxis - suggested approach for diagnosis and treatment.

BACKGROUND: Calciphylaxis is a serious complication in patients with chronic kidney disease associated mineral and bone disorder. It can occur in conditions with low and high bone turnover. So far, there are no definite diagnostic and therapeutic guidelines which may prevent the devastating outcome in many calciphylaxis patients. We report a case which clearly illustrates that knowledge of the underlying bone disorder is essential for a directed treatment. Based on this experience we discuss a systematic diagnostic and therapeutic approach in patients with calciphylaxis. CASE PRESENTATION: We report a patient with severe calciphylaxis. Initial evaluation showed an elevated serum parathormone concentration and a bone-specific alkaline phosphatase activity in the upper normal range; however, the bone biopsy clearly showed adynamic bone disease. Extended dialysis with low calcium dialysate concentration and citrate anticoagulation, and administration of teriparatide led to a further increase in bone-specific alkaline phosphatase activity and most importantly, resulted in an activated bone turnover as confirmed by a second bone biopsy 11 weeks later. CONCLUSIONS: This case illustrates that laboratory tests cannot reliably differentiate between high and low bone turnover in calciphylaxis patients. More importantly, this case highlights the fact that specific therapies that alter bone metabolism cannot be applied without knowledge of the bone status. On this background, we suggest that bone biopsies should be an integral part in the diagnosis and therapeutic decision in these patients and should be evaluated in further studies.

Adynamic bone disease is a predominant bone pattern in early stages of chronic kidney disease.

Chronic kidney disease (CKD) is complicated by disturbances of mineral and bone metabolism which start early in the course of the disease. It has long been assumed that high turnover bone lesions induced by secondary hyperparathyroidism are the predominant type of renal osteodystrophy from the start. However, there is increasing evidence in favor of the view that in early CKD stages low bone turnover is prevailing, with adynamic bone disease being the predominant form. Since serum parathyroid hormone levels increase progressively early on, and the most probable explanation is resistance to the skeletal action of this hormone. An early inhibition of the Wnt pathway with an increase in sclerostin and other inhibitors of Wnt signaling may be involved. Finally, a variety of other uremic toxins such as indoxyl sulfate and phosphate may play an important role in the pathogenesis of the low turnover bone disease observed in early stages of CKD. The optimal strategies to prevent and to treat adynamic bone disease in incipient CKD yet need to be defined. Targeting uremic toxins such as sclerostin, phosphate, and indoxyl sulfate may be relevant.

Bone-specific alkaline phosphatase and bone turnover in African American hemodialysis patients.

INTRODUCTION: Noninvasive measures of bone activity include intact parathyroid hormone (iPTH) and bone-specific alkaline phosphatase (BSAP). Whether BSAP measurement alone or in combination with other biochemical data provides more reliable information about bone turnover than iPTH alone in African Americans on hemodialysis is unknown. METHODS: This cross-sectional study aimed to determine the optimal predictor and cutoff points for BSAP, iPTH, calcium and phosphorus in classifying bone biopsy findings. Forty-three African American hemodialysis patients were available for analysis. Biochemical data on the day of biopsy across a spectrum of qualitative histologic bone features were compared. Classification and regression tree analysis was used to determine both the optimal predictor and cutoff points for BSAP, iPTH, calcium and phosphorus in identifying bone turnover status. FINDINGS: Seven subjects had adynamic disease, 31 had mild/moderate hyperparathyroid bone features, and five had severe hyperparathyroid bone disease. BSAP was the optimal predictor of bone biopsy with a cutoff point of 22 ng/mL. Calcium and phosphorus had no predictive value. At BSAP ≤ 22 ng/mL, subjects had either adynamic bone disease or mild/moderate hyperparathyroid bone disease but iPTH was not useful in further classifying biopsy findings. When BSAP was >22 ng/mL, subjects had either mild/moderate or severe hyperparathyroid bone disease, and iPTH was useful in further classifying biopsy findings. With BSAP > 22 ng/mL and iPTH < 726 pg/mL, all subjects had mild/moderate bone turnover features. DISCUSSION: Compared to iPTH, BSAP was shown to be the optimal predictor of biopsy findings with an optimal cutoff at 22 ng/mL.

Integral pharmacological management of bone mineral disorders in chronic kidney disease (part II): from treatment of phosphate imbalance to control of PTH and prevention of progression of cardiovascular calcification.

INTRODUCTION: Chronic kidney disease-mineral and bone disorders (CKD-MBD) are associated with costly complications and dismal hard-outcomes. AREAS COVERED: In two comprehensive articles we review contemporary and future pharmacological options for treatment of phosphate (P) imbalance (part 1) and hyperparathyroidism (this part 2), taking into account CKD-accelerated cardiovascular calcification (CVC) processes. EXPERT OPINION: Improvements in CKD-MBD require an integral approach, addressing all three components of the CKD-MBD triad. Here, initial guidance to control hyperparathyroidism is provided, taking into account the presence/absence of CVC. We include also measures for patients at risk of adynamic bone disease or suffering from calciphylaxis. Many epidemiological studies (relating to vitamin D) and thorough analyses of recent randomized clinical trials (of cinacalcet) point towards benefits of attempting to improve biochemical parameters while trying to, at least, avoid progression of CVC by more rational use of intestinal P-binders and low-dose vitamin D derivatives and/or calcimimetics. This approach does not seem to be far away from significantly improving hard-outcomes, at least in the dialysis population. The availability of new drugs and the performance of randomized clinical trials should ultimately lead to define earlier, clearer, and more cost-effective patient stratification and biochemical targets with consequent significant clinical improvements.

Changing bone patterns with progression of chronic kidney disease.

It is commonly held that osteitis fibrosa and mixed uremic osteodystrophy are the predominant forms of renal osteodystrophy in patients with chronic kidney disease. Osteitis fibrosa is a high-turnover bone disease resulting mainly from secondary hyperparathyroidism, and mixed uremic osteodystrophy is in addition characterized by a mineralization defect most often attributed to vitamin D deficiency. However, there is ancient and more recent evidence that in early chronic kidney disease stages adynamic bone disease characterized by low bone turnover occurs first, at least in a significant proportion of patients. This could be due to the initial predominance of bone turnover-inhibitory conditions such as resistance to the action of parathyroid hormone (PTH), reduced calcitriol levels, sex hormone deficiency, diabetes, and, last but not least, uremic toxins leading to repression of osteocyte Wnt/ß-catenin signaling and increased expression of Wnt antagonists such as sclerostin, Dickkopf-1, and sFRP4. The development of high-turnover bone disease would occur only later on, when serum PTH levels are able to overcome peripheral PTH resistance and the other inhibitory factors of bone formation. Whether FGF23 and Klotho play a direct role in the transition from low- to high-turnover bone disease or participate only indirectly via regulating PTH secretion remains to be seen.

Management of adynamic bone disease in chronic kidney disease: A brief review.

The Kidney Disease: Improving Global Outcomes (KDIGO) work group released recommendations in 2006 to define the bone-related pathology associated with chronic kidney disease as renal osteodystrophy. In 2009, KDIGO released revised clinical practice guidelines which redefined systemic disorders of bone and mineral metabolism due to chronic kidney disease as chronic kidney disease-mineral and bone disorders. Conditions under this overarching term include osteitis fibrosa cystica, osteomalacia, and adynamic bone disease. We aim to provide a brief review of the histopathology, pathophysiology, epidemiology, and diagnostic features of adynamic bone disease, focusing on current trends in the management of this complex bone disorder.

Teriparatide and bone turnover and formation in a hemodialysis patient with low-turnover bone disease: a case report.

Teriparatide, a recombinant form of parathyroid hormone, is an anabolic agent approved for use in women and men with osteoporosis. However, it is not well studied in people with chronic kidney disease (CKD). We report on a patient with stage 5 CKD treated with dialysis who presented to our clinic with multiple fractures, including bilateral nondisplaced pelvic fractures resulting in chronic pain and interfering with the patient's ability to work. Bone histomorphometry demonstrated low-turnover bone disease, and he was treated with 20µg of teriparatide (subcutaneous injection) every morning for 24 months. Within 6 months of initiating therapy, the patient's pain resolved and he was able to resume work. Serum calcium and phosphate levels remained within reference ranges throughout his treatment, and he sustained no further fractures. During 24 months of treatment, bone mineral density was maintained at the lumbar spine, and there was an increase of 4% at the femoral neck and total hip. A second transiliac bone biopsy demonstrated improvements in static and dynamic parameters of bone formation. In our patient, 24-month treatment with teriparatide was safe and effective; however, larger studies are needed to determine the efficacy of teriparatide in the dialysis-dependent CKD population.