Multidisciplinary team approach for CKD-associated osteoporosis.

Chronic kidney disease mineral and bone disorder (CKD-MBD) contributes substantially to the burden of cardiovascular disease and fractures in patients with CKD. An increasing arsenal of diagnostic tools, including bone turnover markers and bone imaging, is available to support clinicians in the management of CKD-associated osteoporosis. Although not mandatory, a bone biopsy remains useful in the diagnostic workup of complex cases. In this special report, the European Renal Osteodystrophy (EUROD) initiative introduces the concept of a kidney-bone multidisciplinary team (MDT) for the diagnosis and clinical management of challenging cases of CKD-associated osteoporosis. In 2021, the EUROD initiative launched virtual clinical-pathological case-conferences to discuss challenging cases of patients with CKD-associated osteoporosis, in whom a bone biopsy was useful in the diagnostic workup. Out of these, we selected 4 representative cases and asked a kidney-bone MDT consisting of a nephrologist, an endocrinologist and a rheumatologist to provide comments on the diagnostic and therapeutic choices. These cases covered a broad spectrum of CKD-associated osteoporosis, including bone fracture in CKDG5D, post-transplant bone disease, disturbed bone mineralization, severely suppressed bone turnover, and severe hyperparathyroidism. Comments from the MDT were, in most cases, complementary to each other and additive to the presented approach in the cases. The MDT approach may thus set the stage for improved diagnostics and tailored therapies in the field of CKD-associated osteoporosis. We demonstrate the clinical utility of a kidney-bone MDT for the management of patients with CKD-MBD and recommend their establishment at local, national, and international levels.

Comorbidity and Medication Trends in Chronic Kidney Disease and Incident Atrial Fibrillation: A Nationwide Cohort Study.

INTRODUCTION: Chronic kidney disease (CKD) is associated with an increased incidence of atrial fibrillation (AF). Also, patients with AF are prone to adverse kidney outcomes. We examined comorbidities and medication use in patients with CKD and incident AF. METHODS: The Finnish AntiCoagulation in Atrial Fibrillation (FinACAF) is a nationwide retrospective register-linkage study including data from 168,233 patients with incident AF from 2007 to 2018, with laboratory data from 2010 onwards. Estimated glomerular filtration rate (eGFR) was available for 124,936 patients. The cohort was divided into 5 CKD stages with separate groups for dialysis and kidney transplantation. RESULTS: At AF diagnosis eGFR <60 mL/min/1.73 m2 was found in 27%, while 318 (0.3%) patients were on dialysis, and 188 (0.2%) had a functioning kidney transplant. Lowering eGFR yielded more comorbidities and medications. During 2010-2018 in patients with eGFR <60 mL/min/1.73 m2 prevalence of hypertension, dyslipidaemia, and diabetes increased from 82 to 88%, from 50 to 66% and from 25 to 33%, respectively (<0.001). Throughout the observation period, lipid-lowering medication was underused. CONCLUSION: More than one-fourth of patients with incident AF also had CKD stage 3-5 (eGFR <60 mL/min/1.73 m2). Both comorbidities and medication use increased with worsening kidney function. Prevalence of major cardiovascular (CV) risk factors increased during 2010-2018, but the use of survival-affecting medications, such as lipid-lowering medication, was suboptimal at all stages of CKD. More attention should be given to the optimal treatment of risk factors in this high CV risk population.

Bone volume, mineral density, and fracture risk after kidney transplantation.

BACKGROUND: Disordered mineral metabolism reverses incompletely after kidney transplantation in numerous patients. Post-transplantation bone disease is a combination of pre-existing chronic kidney disease and mineral disorder and often evolving osteoporosis. These two frequently overlapping conditions increase the risk of post-transplantation fractures. MATERIAL AND METHODS: We studied the prevalence of low bone volume in bone biopsies obtained from kidney transplant recipients who were biopsied primarily due to the clinical suspicion of persistent hyperparathyroidism between 2000 and 2015 at the Hospital District of Helsinki and Uusimaa. Parameters of mineral metabolism, results of dual-energy x-ray absorptiometry scans, and the history of fractures were obtained concurrently. One hundred nine bone biopsies taken at a median of 31 (interquartile range, IQR, 18-70) months after transplantation were included in statistical analysis. Bone turnover was classified as high in 78 (72%) and normal/low in 31 (28%) patients. The prevalence of low bone volume (n = 47, 43%) was higher among patients with low/normal turnover compared to patients with high turnover [18 (58%) vs. 29 (37%), P = 0.05]. Thirty-seven fragility fractures in 23 (21%) transplant recipients corresponding to fracture incidence 15 per 1000 person-years occurred during a median follow-up 9.1 (IQR, 6.3-12.1) years. Trabecular bone volume did not correlate with incident fractures. Accordingly, low bone mineral density at the lumbar spine correlated with low trabecular bone volume, but not with incident fractures. The cumulative corticosteroid dose was an important determinant of low bone volume, but not of incident fractures. CONCLUSIONS: Despite the high prevalence of trabecular bone loss among kidney transplant recipients, the number of fractures was limited. The lack of association between trabecular bone volume and fractures suggests that the bone cortical compartment and quality are important determinants of bone strength and post-transplantation fracture.

Clinical Prediction of High-Turnover Bone Disease After Kidney Transplantation.

Bone histomorphometric analysis is the most accurate method for the evaluation of bone turnover, but non-invasive tools are also required. We studied whether bone biomarkers can predict high bone turnover determined by bone histomorphometry after kidney transplantation. We retrospectively evaluated the results of bone biopsy specimens obtained from kidney transplant recipients due to the clinical suspicion of high bone turnover between 2000 and 2015. Bone biomarkers were acquired concurrently. Of 813 kidney transplant recipients, 154 (19%) biopsies were taken at a median of 28 (interquartile range, 18-70) months after engraftment. Of 114 patients included in the statistical analysis, 80 (70%) presented with high bone turnover. Normal or low bone turnover was detected in 34 patients (30%). For discriminating high bone turnover from non-high, alkaline phosphatase, parathyroid hormone, and ionized calcium had the areas under the receiver operating characteristic curve (AUCs) of 0.704, 0.661, and 0.619, respectively. The combination of these markers performed better with an AUC of 0.775. The positive predictive value for high turnover at a predicted probability cutoff of 90% was 95% while the negative predictive value was 35%. This study concurs with previous observations that hyperparathyroidism with or without hypercalcemia does not necessarily imply high bone turnover in kidney transplant recipients. The prediction of high bone turnover can be improved by considering alkaline phosphatase levels, as presented in the logistic regression model. If bone biopsy is not readily available, this model may serve as clinically available tool in recognizing high turnover after engraftment.

Changes in Bone Histomorphometry after Kidney Transplantation.

BACKGROUND AND OBJECTIVES: Over the past decade, the management of CKD-mineral and bone disorder has changed substantially, altering the pattern of bone disease in CKD. We aimed to evaluate the natural history of kidney bone disease in contemporary kidney transplant recipients and patients on dialysis. DESIGN, SETTINGS, PARTICIPANTS, & MEASUREMENTS: Sixty one patients on dialysis who were referred to kidney transplantation participated in this prospective cohort study during November 2009 and December 2010. We performed baseline bone biopsies while the patients were on dialysis and repeated the procedure in 56 patients at 2 years after kidney transplantation or 2 years after baseline if transplantation was not performed. Measurements of mineral metabolism and bone turnover, as well as dual energy x-ray absorptiometry scans, were obtained concurrently. RESULTS: A total of 37 out of 56 participants received a kidney transplant, of which 27 underwent successful repeat bone biopsy. The proportion of patients with high bone turnover declined from 63% at baseline to 19% at 2 years after kidney transplantation, whereas the proportion of those with low bone turnover increased from 26% to 52%. Of 19 participants remaining on dialysis after 2 years, 13 underwent successful repeat biopsy. The proportion of patients remaining on dialysis with high bone turnover decreased from 69% to 31%, and low bone turnover increased from 8% to 38%. Abnormal bone mineralization increased in transplant recipients from 33% to 44%, but decreased in patients remaining on dialysis from 46% to 15%. Trabecular bone volume showed little change after transplantation, but low bone volume increased in patients remaining on dialysis. Bone mineral density did not correlate with histomorphometric findings. CONCLUSIONS: Bone turnover decreased over time both in patients remaining on dialysis and in kidney transplant recipients. Bone mineral density and bone biomarkers were not associated with bone metabolism changes detected in bone biopsy specimens.

Recurrent allograft C3 glomerulonephritis and unsuccessful eculizumab treatment.

There is a great lack of efficient treatments for membranoproliferative glomerulonephritis (MPGN) and recently emerged complement therapies have been proposed to be useful. We report a patient with a complement-mediated MPGN having recurrencies in kidney allografts and an unsuccessful treatment with complement inhibitor, eculizumab (anti-C5 monoclonal antibody). Nephritic factor (C3Nef), an autoantibody against C3bBb, in the patient serum activated C3 but not C5 showing that major damage was mediated by C3 activation with clearly less involvement of C5 explaining unresponsiveness to eculizumab. Analyzing C3Nef-mediated C3 and C5 activation separately could help in choosing the right patients for eculizumab therapy.

Atypical hemolytic-uremic syndrome.

Atypical hemolytic-uremic syndrome (aHUS) is a rare form of thrombotic microagiopathy caused dysregulation of the alternative pathway of the complement resulting in tissue. In aHUS, activation of the alternative pathway of the complement is in an aberrant way directed against endothelial cells and blood cells. This is either due to a mutation in a complement factor, most commonly factor H, or an autoantibody against a complement regulator. In some patients the underlying disorder is not identified despite thorough examinations. Typical aHUS-patients have acute kidney injury and microangiopathic hemolysis and, to a varying degree, disturbances of other organs. An effective inhibitor of the final product of complement, eculizumab, has revolutionized the treatment of these patients.

Bone histomorphometry and indicators of bone and mineral metabolism in wait-listed dialysis patients.

AIMS: The aim of this study was to evaluate the associations between bone histomorphometry and bone volume measured by dual-energy X-ray absorptiometry (DXA) in wait-listed dialysis patients. Further, the circulating markers of mineral metabolism and bone turnover were compared. MATERIAL AND METHODS: Bone biopsies were performed on 61 wait-listed dialysis patients. Plasma samples were obtained for indicators of mineral metabolism and bone turnover. Bone mineral density (BMD) was determined by DXA and bone histomorphometry was performed. RESULTS: Bone histomorphometry could be determined in 52 patients (72% men, 54% on hemodialysis and median dialysis vintage 18 months). Adynamic bone disease was present in 21% of patients and 4% had osteomalacia. High turnover bone disease (mixed uremic osteodystrophy and osteitis fibrosa) was observed in 48% of patients (17% and 31%, respectively). 10% of patients had normal bone histomorphometry while 17% had mild osteitis fibrosa. Mineralization defect was found in 33% of patients. There was a strong correlation between femoral neck (FN) T-score and histologically measured cancellous bone volume (p = 0.004), FN T-score having a good negative predictive value for low cancellous bone volume. Plasma osteocalcin levels were significantly higher in the high-turnover group and lower in the mineralization defect group (p = 0.014 and p = 0.02, respectively). CONCLUSIONS: Our study confirms the high frequency of abnormal bone histology in wait-listed dialysis patients. Low bone turnover was less common than previously reported. Noninvasive markers had a limited value for assessing bone histology, whereas femoral BMD reflected bone volume well.

[When and for whom to start dialytic therapy?]. / Milloin ja kenelle aloitan dialyysihoidon?

Patients with increasingly multiple diseases are admitted to dialytic therapies. In acute situations, the indications for dialytic therapy are refractory hyperkalemia, acidosis, fluid load and other symptoms of uremia. In chronic insufficiency the treatment is started when the estimated glomerular filtration rate (eGFR) is 5 to 10 ml/min/1.73m2 and the patient presents with symptoms of renal insufficiency. Dialytic therapy is not the best choice for everybody, because the alleviation of symptoms achieved with the therapy remains minor in comparison with the impairment of the quality of life and the risk of various complications associated with the therapy.

[Chronic renal failure causes bone fragility and blood vessel stiffening]. / Munuaisten krooninen vajaatoiminta haurastuttaa luuston ja jäykistää verisuonet.

Chronic renal failure results in disturbances of bone formation, degradation and mineralization and changes in bone volume. These bone changes as well as biochemical abnormalities of the blood have also been found to be associated with soft-tissue and blood vessel calcification. In fact, the patients suffer not only from skeletal problems but also from rapidly progressing arterial stiffening, which leads to early cardiovascular morbidity and mortality. Essential therapy consists of early management of hyperphosphatemia and supplementation of active vitamin D.

Bone mineral density in end-stage renal disease patients: association with wasting, cardiovascular disease and mortality.

BACKGROUND: Bone and mineral disorders may contribute to extraosseous ossifications and cardiovascular disease (CVD) in end-stage renal disease (ESRD) patients. We have investigated the relationship between bone mineral density (BMD) and inflammation, wasting, CVD and mortality in ESRD patients. METHODS: BMD (dual energy X-ray absorptiometry) and biochemical, nutritional and inflammatory markers were assessed in 277 incident ESRD patients (GFR 7.1 +/- 0.2 ml/min) who were then followed prospectively for a mean of 27 (range 1-60) months. Carotid plaques were determined in 103 patients. RESULTS: Patients with carotid plaques, clinical manifestation of CVD and wasting (assessed by subjective global assessment) had significantly lower BMD than their counterparts. Low BMD was associated with high all-cause and cardiovascular mortality. Even after adjustment for several confounders and risk factors, all-cause (HR = 2.1, CI: 1.1-3.9, p = 0.02) and cardiovascular (HR = 2.8, CI: 1.2-6.3, p = 0.02) mortality remained significantly associated with low BMD. CONCLUSIONS: Low BMD is associated with wasting and CVD, and is an independent predictor of all-cause and cardiovascular mortality in ESRD patients.

Why do dialysis patients develop a heart of stone and bone of china?

Vascular calcification is a common complication of end-stage renal disease (ESRD). The mechanisms responsible are complex and have so far been considered to be mainly the result of a passive mechanism due to elevated PO(4) levels and high Ca x PO(4) ion product resulting in saturated plasma. However, recent results suggest that also other features, commonly observed in the uremic milieu, such as chronic inflammation, hyperleptinemia and a dysregulation of various mineral-regulating proteins might also contribute to an enhanced calcification process. Moreover, as an inverse relationship between vascular calcification and bone density has been documented in ESRD, it could be speculated that pathologically low bone remodelling (adynamic bone disease) associated with active vitamin D treatment and low parathyroid hormone (PTH) levels may predispose to ectopic calcification of vessels, valves and heart. As patients with vascular calcification have a higher intake of calcium-containing PO(4) binders, novel, non-calcium containing PO(4) binders may diminish the risk of progressive vascular calcification in this patient group. Further studies are needed to elucidate the respective role of chronic inflammation, hyperleptinemia and PTH-lowering therapies in this fatal complication of ESRD.

[Why do patients with kidney diseases end up with a heart of stone? Disturbances in calcium-phosphate balance and chronic inflammation important causes]. / Varför får njursjuka ett hjärta av sten? Störd kalk-fosfatbalans och kronisk inflammation viktiga orsaker.

Despite rapid improvement in dialysis technology during the last 20 years the mortality rate is still very high in patients with end-stage renal disease (ESRD), and is in fact comparable to that of many cancer patients with metastases. The main cause of mortality in ESRD is cardiovascular disease (CVD), and cardiac mortality for dialysis patients aged 45 years or younger is more than 100-fold greater than in the general population. Recent evidence suggests that the high cardiovascular mortality rate in this patient population is associated with extensive vascular and valvular calcification. Although hyperphosphatemia may be the major cause of vascular calcification in this patient group it has been suggested that chronic inflammation also contributes to this process. Indeed, recent evidence suggests that inflammatory mediators, such as pro-inflammatory cytokines and adipocytokines, may promote vascular calcification in vitro. Moreover, a2-Heremans Schmid glycoprotein (fetuin), an intrinsic inhibitor of the calcification process, is down-regulated during chronic inflammation. Lower levels of fetuin have recently been found to predict mortality in ESRD. Thus, further studies are needed to elucidate the roles of calcium-free phosphate binders as well as focused anti-inflammatory treatment strategies in the prevention of vascular and valvular calcification in ESRD.