[Kidney and bone update : the 5-year history and future of CKD-MBD. The changes after the introduction of CKD-MBD as a new entity].

Recent clinical studies have indicated that mineral metabolism disorder in chronic kidney disease (CKD) is not a disease confined to bone, but a systemic disease that determine the prognosis by promoting vascular calcification. In the context of this paradigm shift, KDIGO (Kidney Disease : Improving Global Outcomes) introduced a new disease entity "CKD-bone and mineral disorder (MBD) " in 2005, and released clinical practice guideline on the management of CKD-MBD in 2009. This guideline is based on strict systemic evidence review and has had considerable effect on clinical practice. However, on the other hand, it became apparent that only a few clinical studies could support the recommendation of this guideline with high-quality evidence. There is a compelling need for accumulation of clinical findings with high-quality evidence.

[Kidney and bone update : the 5-year history and future of CKD-MBD. Bone biopsy and histomorphometrical analysis].

In the KDIGO CKD-MBD guideline, the disorder "renal osteodystrophy" is defined as bone histological changes, which can be diagnosed only by bone biopsy. New bone diagnosis method, "TMV classification" is introduced instead of classical classification system. In order to diagnose TMV classification, undecalcified bone specimen after tetracycline double labeling is required. In TMV classification, "T" stands for bone turnover and is evaluated by bone formation rate (BFR/BS) or activation frequency (Acf) . "M" stands for bone mineralization and is evaluated by mean osteoid thickness (O.Th) and mineralization lag time (Mlt) . "V" stands for cancellous bone volume and is diagnosed by total bone volume (BV/TV) .

Chronic kidney disease-mineral-bone disorder: a new paradigm.

Disturbances in mineral and bone metabolism are prevalent in chronic kidney disease (CKD) and an important cause of morbidity, decreased quality of life, and extraskeletal calcification that have been associated with increased cardiovascular mortality. These disturbances have traditionally been termed renal osteodystrophy and classified on the basis of bone biopsy. Kidney Disease: Improving Global Outcomes (KDIGO) recently sponsored a Controversies Conference to evaluate this definition. The recommendations were that (1) the term renal osteodystrophy be used exclusively to define alterations in bone morphology associated with CKD and (2) the term CKD-mineral and bone disorder (CKD-MBD) be used to describe the broader clinical syndrome that develops as a systemic disorder of mineral and bone metabolism as a result of CKD. CKD-MBD is manifested by an abnormality of any one or a combination of the following: laboratory-abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; bone-changes in bone turnover, mineralization, volume, linear growth, or strength; and calcification-vascular or other soft-tissue calcification. The pathogenesis and clinical manifestations of these components of CKD-MBD are described in detail in this issue of Advances in Chronic Kidney Disease.

Renal osteodystrophy after successful renal transplantation: a histomorphometric analysis in 57 patients.

Renal transplantation is the treatment of choice for patients with end-stage renal disease. It corrects most of the metabolic abnormalities that cause renal osteodystrophy. Nevertheless, renal osteodystrophy persists in many transplant recipients. The aim of this study was to investigate frequency and histomorphometric pattern of bone disease after renal transplantation. Bone biopsy specimens were taken from the iliac crest of 57 patients, including 28 women (26-70 years old) and 29 men (27-67 years old). Indications for biopsy were hypercalcemia, elevation of parathyroid hormone, and, in 19 cases, without suspected bone abnormalities based on laboratory parameters. The mean time of dialysis prior to renal transplantation was 43 months (range, 6-91 months in women and 10-111 months in men) and the mean interval between transplantation and bone biopsy was 53.5 months (range, 4-191 months in women and 5-90 months in men). Fourteen patients were treated with either 25-hydroxyvitamin D3 and/or 1-alpha hydroxyvitamin D3 or 1,25 dihydroxyvitamin D3, 3 with phosphate-binding agents. The immunosuppression consisted of cyclosporine, azathioprine, and prednisolone. The cumulative dosage of corticosteroids was 5569+/-5305 mg. For static and dynamic histomorphometry, we used American Society of Bone and Mineral Research nomenclature. Mild osteitis fibrosa and osteitis fibrosa, the most frequent forms of renal osteodystrophy, were observed in 13. (22.8%) and 14 patients (24.6%), respectively. Mixed uremic osteodystrophy was found in 7 patients (12.3%), adynamic renal bone disease in 3 patients (5.3%), and osteomalacia in 2 patients (3.5%). In 13 patients (22.8%), reduced bone mass and structural damage without typical signs of renal osteodystrophy, such as endosteal fibrosis or osteoclasia, were detected, and 5 patients (8.7%) showed normal histomorphometric parameters. We concluded that renal osteodystrophy, especially forms with high bone turnover, persisted in many patients after successful renal transplantation. This finding may be due to preexisting conditions, such as duration of dialysis and degree of hyperparathyroidism. Bone disease is increased by corticosteroid and immunosuppressive therapy after renal transplantation and requires close monitoring.

[Parathyroid and bone. Management of parathyroid function and evaluation of bone metabolism in hemodialysis patients].

Disturbances in mineral and bone metabolism due to loss of kidney function greatly influence morbidity and quality of life, so Kidney Disease: Improving Global Outcomes (KDIGO) proposed the concept of chronic kidney disease-mineral and bone disorder (CKD-MBD). Japanese Society for Dialysis Therapy has created guidelines for the management of secondary hyperparathyroidism associated prognosis in hemodialysis patients, and we are managing parathyroid function of hemodialysis patients under this guideline. Bone biopsy is not recommended as part of routine evaluation for CKD-MBD because bone biopsy is the invasive examination. KDIGO proposed new histological classification of renal osteodystrophy, TMV classification, for standardizing a result of bone histomorphometry. We expect that new guideline improve the prognosis of hemodialysis patients.

Renal osteodystrophy: what's in a name? Presentation of a clinically useful new model to interpret bone histologic findings.

Renal osteodystrophy begins early in the course of chronic kidney disease and occurs almost without exception in all patients with Stage 5 disease (CKD-5). Bone biopsies and evaluation of mineralized bone sections after double tetracycline-labeling are currently considered the gold standard for diagnosis and classification of renal osteodystrophy. Nevertheless, bone biopsies are rarely employed. This is, at least in part, related to the paucity of nephrologists trained in performance of the procedure and the fact that reports of the histologic results are not easily translatable to clinical practice. Results are usually given qualitatively, using non-uniform classifications or by histomorphometric evaluations which are esoteric to most nephrologists. We suggest here that histomorphometric evaluation can be reserved for research and special situations. Also, the customarily used qualitative classification should be replaced by a clinically useful nomenclature, provided the interpretation is done by an individual with sufficient experience in bone pathology. We present a new interactive nomenclature for renal osteodystrophy that addresses abnormalities of turnover, abnormalities of bone balance, and abnormalities of mineralization. The new nomenclature, thus, includes disorders of high- and low-turnover with consideration of the interrelation with positive or negative bone balance with or without mineralization defect. In this schema, changes in bone status are described as deviations from a norm, and treatment is geared toward normalizing values rather than creating any absolute change in one direction or another. It is hoped that such a classification will be easily usable, clinically more relevant, and more amenable to individualized treatment guidance.

Risk factors for renal osteodystrophy: a multivariant analysis.

To assess the risk factors associated with renal osteodystrophy, we examined the database of 256 patients who were prospectively studied in three Toronto dialysis centers between October of 1987 and 1989. The potential risk factors examined included age, sex, type and duration of dialysis, type and dose of phosphate binders, vitamin D treatment, and history of diabetes mellitus, renal allograft failure, parathyroidectomy, and bilateral nephrectomy. All patients had undergone a bone biopsy and were categorized into one of four disease groupings: (1) osteitis fibrosa and mixed bone disease, (2) aluminum bone disease, (3) mild bone disorder, and (4) aplastic bone disorder. The mean (+/- SD) age of the patients at bone biopsy was 57 +/- 15 years, and 62% were men. Forty-five percent of patients were treated by hemodialysis and 55% by peritoneal dialysis. The mean duration of dialysis was 4 +/- 4 years. Twenty-five percent were also diabetic. The most common disorder was the aplastic (or "adynamic") bone disorder, found in 34% of patients. Aluminum bone disease was found in 27%, osteitis fibrosa or mixed bone disease in 27%, and mild bone disorder in 12% of patients. Cumulative intake of aluminum gels was associated with aluminum bone disease, whereas peritoneal dialysis with supraphysiologic calcium concentrations, ingestion of calcium carbonate, and diabetes mellitus were associated with both mild bone disorder and aplastic bone disorder. These three latter risk factors may be important in predisposing patients to a low bone turnover state through modulation of parathyroid hormone secretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Biochemical measurements in the prediction of histologic subtype of renal transplant bone disease in women.

Renal transplant osteodystrophy encompasses several histologic subtypes. Bone histomorphometric examination reliably distinguishes these groups but is invasive, is time-consuming, and delays diagnosis. Establishing a noninvasive method of correctly predicting histologic subtype in an individual to direct management is an attractive proposition. We identified 19 female renal transplant recipients with histologic evidence of hyperparathyroid bone disease (HPTH) and 14 with adynamic bone (ADB). We evaluated serum osteocalcin and bone-specific alkaline phosphatase as bone formation markers and urinary hydroxyproline (Hypro) and deoxypyridinoline cross-links as bone resorption markers. Mean concentrations for all markers were higher in the HPTH group, reaching significance for Hypro (HPTH, 24.8 +/- 4.2 micromol/mmol creatinine; ADB, 13.2 +/- 5.0 micromol/mmol creatinine; P = 0.01). A cutoff of 16.4 micromol/mmol creatinine for Hypro (Youden's index, 0.65) gave a sensitivity of 93% and specificity and positive predictive value (PPV) of 72% in predicting HPTH. In combination, Hypro greater than 16.4 micromol/mmol creatinine and parathyroid hormone greater than 80 pg/mL gave a specificity of 100%, sensitivity of 32%, and PPV of 100%. Conversely, for predicting ADB, Hypro less than 15.1 micromol/mmol creatinine (Youden's index, 0.45) gave a specificity of 93%, sensitivity of 53%, and PPV of 91%. Hypro less than 15.1 micromol/mmol creatinine plus osteocalcin less than 6.8 microg/L gave a specificity of 84.2%, sensitivity of 64.3%, and PPV of 75%. Significant associations between markers and histomorphometry were evident only for Hypro and osteocalcin (with osteoblast surface) and all markers (except deoxypyridinoline cross-links) with cortical volume. Markers have limited utility in identifying histologic subtype (Hypro was most effective) and, with the exception of Hypro and osteocalcin, showed little association with cell surface markers of bone cell activity.

The relevance of mineralization lag time in the evaluation of histologic changes in renal osteodystrophy.

We examined bone biopsies from 47 patients on chronic hemodialysis, and analyzed the histomorphometric and biochemical findings and histologic quantitation of bone aluminium, looking primarily at mineralization lag time (Mlt) to evaluate its usefulness in categorization of renal osteodystrophy (ROD). The patients were categorized as having either relatively normal Mlt (< 35 days, n = 21 patients), moderately prolonged Mlt (35-100 days, n = 13 patients) or markedly prolonged Mlt (> 100 days, n = 13 patients). The group with relatively normal Mlt showed significantly higher C-terminal parathyroid hormone (PTHc) levels (26,141 +/- 19,270 vs 7,226 +/- 6,073 and 4,434 +/- 4,000 pg/ml) than the moderately or markedly prolonged Mlt groups (p < .01) and was associated with histologic characteristics of osteitis fibrosa or mild hyperparathyroidism (BFR/BS range 0.146-0.947 mcm3/mcm2/d). The group with markedly prolonged Mlt included one patient with classic and 11 with adynamic osteomalacia (BFR/BS range 0.009-0.099) and had greater bone aluminum (Al.S/OS 35.3 +/- 26.7% vs 7.2 +/- 9.0%) than the normal Mlt group (p < .01). The group with moderately prolonged Mlt included two patients with aplastic bone disease (Mlt 80.0 and 84.6 days, and Al.S/OS 100.0 and 72.3%) and 11 patients with features of hyperparathyroidism and osteomalacia (BFR/BS range 0.068-0.243) with variable but generally intermediate bone aluminum deposition (Al.S/OS 22.5 +/- 19.9%). Like BFR/BS and other dynamic parameters Mlt correlates with morphologic types of ROD which primarily reflect bone turnover, but it may also suggest varying degrees of mineralization impairment in a spectrum ranging from high to low turnover types of ROD. Its usefulness in this respect should not be overlooked.

Biological markers in the diagnosis of the different forms of renal osteodystrophy.

Renal osteodystrophy continues to be a long-term complication associated with high rates of morbidity in patients with chronic renal failure. Although bone histomorphometry is the most reliable diagnostic method, several new biochemical markers of bone turnover have been proposed in recent years for the evaluation of bone remodelling in uremic patients. This review assesses the value and the limitations of serum markers of bone formation and resorption in the diagnosis of the major types of renal osteodystrophy. In addition, we consider the hypothetical role of serum beta2-microglobulin and of some local mediators involved in the process of bone cell activation and inhibition, such as circulating cytokines and their inhibitors and receptors.

Different patterns of renal osteodystrophy in Iberoamerica.

The various forms of renal osteodystrophy are predominant hyperparathyroid bone disease, mixed uremic osteodystrophy, low turnover osteomalacia, and adynamic bone disease. The present study analyses a total number of 1,209 bone biopsies from 5 different countries (Brazil, Uruguay, Argentina, Portugal, and Spain). Low turnover osteomalacia and mixed uremic osteodystrophy were more common in Brazil, Uruguay, and Argentina than in Portugal and Spain whereas predominant hyperparathyroid bone disease was seen more often in Portugal and Spain. In all centers, independent of the aluminum staining technique used, the extent of aluminum deposited in bone was greater in patients presenting with low bone turnover, whether from low turnover osteomalacia or adynamic bone disease, than in the predominant hyperparathyroid bone disease. In summary, even though recent reports have indicated that, over the last decade, the incidence of aluminum-induced toxicity was reduced, aluminum still seems to be implicated in a great percentage of symptomatic low bone remodelling lesions in Iberoamerica.

[Renal osteodystrophy in Maracaibo]. / Osteodistrofia renal en Maracaibo.

In the present work we report the bone histologies obtained from the iliac crest of 49 patients on chronic hemodialysis in Maracaibo. All of them were dialyzed thrice weekly with untreated tap water containing high aluminum (Al) levels. Their mean blood Al levels were found to be higher than 100 micrograms/L. Histomorphometry was used for the diagnosis of the underlying renal osteodystrophic type. Al-staining techniques (Aluminum) were applied for detection of bone Al deposits. Additionally, bone Al content was determined quantitatively by means of graphite furnace atomic absorption spectroscopy. A mixed type of osteodystrophy (type III according to Delling's classification) consisting in the simultaneous presence of hyperparathyroid bone lesions (osteitis fibrosa, OF) and a hyperosteoidosis (osteomalacia, OM) was found in 63.3% of the studied patients. The other patients (37.7%) exhibited a pure osteomalacia (OM). Bone Al deposits at the mineralization front were observed in 70% of cases and were frequently associated with bone pain, spontaneous fractures and skeletal deformities. We conclude that bone biopsy should be performed in all patients presenting bone pain and high blood Al levels.

[Diagnosis and classification of renal osteodystrophy].

Bone histomorphometry is essential to diagnosis of renal osteodystrophy. Sherrard et al classified renal osteodystrophy into the 5 groups according to Fb.V/TV, OV/BV and BFR/TV of cancellous bone (Osteitis fibrosa, Mixed uremic osteodystrophy, Osteomalacia, Mild lesion, Aplastic disease). In addition, because endocortical bone loss is generally irreversible, the evaluation of this region in the transiliac bone biopsy specimen also seems to be important.

Value of the new bone classification system in pediatric renal osteodystrophy.

BACKGROUND AND OBJECTIVES: Although lesions of renal osteodystrophy have traditionally been defined by bone turnover, alterations in skeletal mineralization and volume are also prevalent and may contribute to significant morbidity in patients with chronic kidney disease (CKD). The study presented here was undertaken to compare the traditional spectrum of renal osteodystrophy defined by bone turnover to a new classification system that includes T (turnover), M (mineralization), and V (volume) and to determine the value of biochemical parameters as predictors of specific TMV lesions. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Pediatric patients (n = 161) treated with peritoneal dialysis were enrolled into the study. RESULTS: Increased bone turnover and abnormal mineralization were prevalent (57% and 48%, respectively); bone volume was normal or increased in all subjects. Predictive algorithms for different skeletal diagnoses were established by Classification and regression tree analysis. Serum parathyroid hormone (PTH) less than 400 pg/ml in combination with alkaline phosphatase values less than 400 IU/L provided the highest correct prediction rate for patients with both normal bone turnover and normal mineralization. Levels of PTH were higher and serum calcium levels were lower in patients with defective mineralization, irrespective of bone turnover. CONCLUSIONS: Although no single biochemical marker is able to provide a complete assessment of renal osteodystrophy, a combination of serum calcium, alkaline phosphatase, and PTH levels may lead to a more precise noninvasive assessment of turnover and mineralization abnormalities in this population.