Spectrum of renal bone disease in end-stage renal failure patients not yet on dialysis.

BACKGROUND: During the last few years the spectrum of renal osteodystrophy (ROD) in dialysis patients has been studied thoroughly and the prevalence of the various types of ROD has changed considerably. Whereas until a decade ago most patients presented with secondary hyperparathyroidism (HPTH), adynamic bone (ABD) has become the most common lesion within the dialysis population over the last few years. Much less is known about the spectrum of ROD in end-stage renal failure (ESRF) patients not yet on dialysis. METHODS: Transiliac bone biopsies were taken in an unselected group of 84 ESRF patients (44 male, age 54+/-12 years) before enrolment in a dialysis programme. All patients were recruited within a time period of 10 months from various centres (n=18) in Macedonia. Calcium carbonate was the only prescribed medication in patients followed up by the outpatient clinic. RESULTS: HPTH was found in only 9% of the patients, whilst ABD appeared to be the most frequent renal bone disease as it was observed in 23% of the cases next to normal bone (38%). A relatively high number of patients (n=10; 12%) fulfilled the criteria of osteomalacia (OM). Mixed osteodystrophy (MX) was diagnosed in 18% of the subjects. There was no significant difference between groups in age, creatinine, or serum and bone strontium and aluminium levels. Patient characteristics associated with ABD included male gender and diabetes, whilst OM was associated with older age (>58 years). CONCLUSIONS: In an unselected population of ESRF patients already, 62% of them have an abnormal bone histology. ABD is the most prevalent type of ROD in this population. In the absence of aluminium or strontium accumulation the relatively high prevalence of a low bone turnover as expressed by either normal bone or ABD and OM is striking.     

Parathyroid hormone-independent osteoclastic resorptive bone disease: a new variant of adynamic bone disease in haemodialysis patients.

BACKGROUND: Osteitis fibrosa cystica (OFC) caused by secondary hyperparathyroidism is the pre-eminent form of uraemic osteodystrophy. In recent years, however, new bone abnormalities have been described. Among them adynamic bone disease (ABD) has become a focus of growing interest. Marked suppression of dynamic bone measurements with normal or near-normal static bone-forming parameters are the hallmarks of this disorder. Depressed parathyroid hormone (PTH) levels, frequently evident in this entity, have been linked causally with low bone turnover. METHODS: We reviewed bone biopsy specimens from 96 patients with end-stage renal disease undergoing chronic haemodialysis. RESULTS: We found OFC in 50% of our patients, 20% had mixed bone disease, 24% showed bone morphology of ABD and a minority (6%) had osteomalacia, mostly due to aluminium accumulation. In the patients that were affected by ABD there was a distinct subgroup with bone morphology featuring a striking increase in osteoclast number and osteoclast surface, whereas the osteoid volume, osteoid thickness, osteoblast surface, tetracycline uptake and bone formation rates were diminished as in ordinary ABD. Similarly the PTH levels in this subgroup were low or undetectable. CONCLUSION: We describe patients undergoing chronic haemodialysis with static and dynamic bone forming parameters, indistinguishable from that of ABD, but differing from the classic ABD by the presence of increased osteoclastic bone resorption. The suppressed PTH levels in this subgroup suggests that factors other than PTH activate osteoclasts in some patients on chronic haemodialysis. Uraemic cytokines and/or toxic metabolites, including beta-microglobulin, may be involved in this disorder. The precise nature of this bone abnormality remains to be defined by further studies.     

Adynamic bone disease: an update and overview

Adynamic bone disease (ABD) is a variety of renal osteodystrophy characterized by reduced osteblasts and osteoclasts, no accumulation of osteoid and markedly low bone turnover. It has been found in a relatively high percentage of patients on dialysis, either peritoneal or hemodialysis, but also in CKD patients on conservative treatment. The histologic pattern of ABD is generally associated to low levels of PTH. However, PTH serum levels in CKD are generally higher than normal even when associated to ABD. Therefore, it is felt that, basically in uremia, bone tissue is resistant to PTH, so that a relative reduction of its levels is able to induce the emergence of a low turnover state. Several factors theoretically responsible for skeletal resistance to PTH, and able to slow bone turnover have been considered. Among these are downregulation of PTH receptors in bone cells, increased levels of osteoprotegerin, decreased production and circulating levels of bone morphogenetic proteins, the peripheral effect of leptin and also a possible effect of increased N-terminal truncated PTH molecular species, which have been found to counteract the whole molecule, PTH 1-84 on the bone. In conclusion, ABD should probably be considered a skeletal condition induced by overtreatment of secondary hyperparathyroidism and not a disease. However, its development reveals a deranged ability of uremic bone to maintain a normal bone turnover, when PTH serum levels decrease beyond relatively low levels, which would be considered normal in the general population.     

Serum osteoprotegerin and renal osteodystrophy.

BACKGROUND: Numerous growth factors and cytokines are known to modulate bone turnover. An important, recently discovered complex involved in osteoclastogenesis is the osteoprotegerin/osteoprotegerin-ligand (OPG/OPGL) cytokine complex, which is produced by osteoblasts. Many factors, including parathyroid hormone (PTH), appear to affect bone turnover through this pathway. In this disorder, the role of the OPG/OPGL system in the pathogenesis of renal osteodystrophy, a disease with either low or high bone turnover, has not been investigated so far. METHODS: Thirty-nine chronic haemodialysis patients had bone biopsies, including histomorphometric and histodynamic examinations. In addition, the following serum biochemistry parameters were measured: serum OPG, intact PTH, PTH 1-84, total PTH, osteocalcin, total and bone alkaline phosphatases, 25-hydroxycholecalciferol and 1,25-dihydroxycholecalciferol. RESULTS: On average, serum OPG levels were above the normal range. They were lower in adynamic bone disease (ABD) patients, than in patients with predominant hyperparathyroidism (HP) or mixed osteodystrophy (MO). Significant negative correlations were found between serum OPG and PTH levels, and between serum OPG and parameters of bone resorption (ES/BS) and bone formation (ObS/BS and BFR/BS) in HP and MO patients with PTH values < or =1000 pg/ml. For intact PTH levels < or =300 pg/ml, serum OPG was significantly lower in the group with ABD than in those with HP or MO (P<0.05). CONCLUSION: In renal osteodystrophy the OPG/OPGL system is involved in the regulation of bone turnover induced by PTH. The determination of serum OPG levels could be of use in the diagnosis of low turnover bone disease, at least in association with PTH levels < or =300 pg/ml.     

Predictors of bone mineral density in patients on hemodialysis

Renal osteodystrophy is a universal complication of uremia. Renal failure patients are at risk for low bone mineral density (BMD) and fractures. Parathyroid hormone (PTH) plays a pivotal role in the pathophysiology of uremic bone disease. Histomorphometric studies suggest that the maintenance of PTH levels between two and four times the upper limit of normal is associated with the lowest prevalence of two common forms of osteodystrophy: osteitis fibrosa cystica and adynamic bone disease. The purpose of this study was to investigate whether the above recommendation for PTH levels in dialysis patients corresponds to a more optimal BMD with a special emphasis on diabetic versus nondiabetic subjects. Twenty-eight patients with chronic renal failure on hemodialysis underwent measurement of PTH levels, as well as BMD at the lumbar spine, hip, and forearm. They were divided into three groups based on the mean PTH level over the 5 years prior to having BMD measured. Osteoporosis was diagnosed in 55% of men and 87% of women on dialysis. Predictors of BMD were gender, duration on hemodialysis, and diabetes. Our study supports the histomorphometry-based studies suggesting that the maintenance of intact PTH levels two to four times the upper limit of normal may be associated with better skeletal health in uremic patients on hemodialysis, and that the diabetic subgroup is at particular risk for low BMD.     

Adynamic bone disease with negative aluminium staining in predialysis patients: prevalence and evolution after maintenance dialysis

Aplastic bone disease (ABD) is a common form of renal osteodystrophyand is characterized by a defect in bone matrix formation andmineralization without an increase in osteoid thickness. Theprevalence and pathogenesis of ABD in predialysis patients islargely unknown. We prospectively studied 92 unselected predialysispatients with a creatinine clearance <10 ml/min/1.73 m² anda mean age of 45±2 years (61 M, 31 F). None of the studypatients had received any form of vitamin D therapy, and CaCO₃was the primary phosphate binder. Aplastic bone disease wasobserved in 30 (32%) patients. Stainable bone aluminium surfacewas <3% in all ABD patients. Patients with ABD were older(52±3 versus 42±2 years; P<0.01) and had reducedserum intact PTH compared to non-ABD patients (199±25versus 561 ±87 pg/ml; P<0.001). Patients with diabetesmellitus showed lower PTH values (179±31 versus 432±62pg/ml; P<0.001) and a lower incidence of advanced by chperparathyroidismbone lesions (16% versus 46%; P<0.05) than non-diabetic patients.However, diabetes was not clearly associated with low bone turnoverdisease (56% in diabetics versus 41% in non-diabetics; P=0.1). A second bone biopsy was obtained in eleven ABD patients aftera period of 16.6±2.2 months on maintenance dialysis witha dialysate calcium of 7 mg/dl. Bone histology was unchangedin 10 patients, and one evolved to mild hyperparathyroidism.Trabecular bone volume did not change (22.7± 1.7 versus20.7±1.7%), and the stainable bone aluminium surfaceremained <3%. In summary, ABD not associated with positive histological stainingfor aluminium is a common finding in asymptomatic end-stagerenal failure patients in the Canary Islands. Older age andrelatively low PTH values are associated with this form of bonedisease. After a period of 12–36 months of dialysis, progressiveosteopenia and other clinical problems do not occur.     

The reversed ratio of 1-84 PTH (whole PTH)/intact PTH in a patient on hemodialysis associated with primary hyperparathyroidism

Intact PTH measures not only 1-84 PTH, but also other fragments such as 7-84 PTH. Lately, a measurement of 1-84 PTH has been available as whole PTH assay and the ratio of whole PTH/intact PTH is considered to be between 0.5 and 0.7 in patients on hemodialysis. Therefore, intact PTH should be higher than whole PTH. We present a 57-year-old male with chronic renal failure on hemodialysis whose whole PTH was higher than intact PTH (the reversed ratio of whole PTH/intact PTH). He showed one enlarged parathyroid gland by an ultrasonic test, CT examination and RI subtraction study. After this gland was removed by surgery, the ratio of whole PTH/intact PTH normalized. The size of the resected gland was 22 x 15 x 11 mm. The histologic examination revealed adenoma. This indicates that, if patients with chronic renal failure showed the reversed ratio of whole PTH/intact PTH, the possibility that they could have primary hyperparathyroidism in addition to secondary hyperparathyroidism should be considered.     

Histomorphometric analysis of aplastic bone disease in chronic renal failure at initiation of haemodialysis: Relation to aluminum and parathormone

SUMMARY: We studied bone histology of 134 uraemic patients without a history of vitamin D administration at the start of haemodialysis. Patients were categorized according to bone histology as follows: aplastic bone disease (ABD), ostitis fibrosa, mixed type, mild hyperparathyroidism and osteomalacia. On initiation of haemodialysis, ABD was observed in 48.5% of patients. the average age of the ABD group (50.8 ± 12.5 years) was significantly higher than that of patients with other histologies ( P <0.01). Serum parathyroid hormone (PTH) and alkaline phosphatase (ALP) concentrations were lower ( P <0.01) in the ABD group, especially in patients with diabetes mellitus. Patients with diabetes mellitus and ABD had lower serum concentrations of PTH and ALP than non-diabetic patients, suggesting that depressed PTH may be related to ABD. Eleven (55%) of the 20 patients who were receiving A1(OH)₃ also had ABD. A direct relationship was observed between serum aluminum concentration and aluminum-positive bone surface ( r =0.60; P <0.01). Aluminum staining was more frequently observed in the ABD group than in the non-ABD group ( P <0.01). Because serum intact-PTH concentrations correlate with osteoid surface area, fibrosis volume and bone formation rate, it may be a useful marker of bone histology in renal osteodystrophy. These results suggest that, in addition to conservative treatment with A1(OH)₃, other factors may be involved in the formation of ABD which is often present at the start of haemodialysis.     

Renal osteodystrophy: some new questions on an old disorder

The two major lesions of renal osteodystrophy are osteitis fibrosa cystica (OFC) and osteomalacia (OM). OFC is the characteristic bone lesion of uremic hyperparathyroidism. Although renal failure causes predictable parathyroid hyperplasia, the precise pathogenetic mechanism is still not defined. The "hyperphosphatemia-hypocalcemia-parathyroid hormone (PTH) hypersecretion" sequence of events is no longer an adequate model for the pathogenesis of uremic hyperparathyroidism. Other abnormalities associated with uremia include reduced 1,25-dihydroxyvitamin D (1,25D) synthesis, changes in intracellular phosphorus content or transcellular phosphate fluxes, or alteration in PTH metabolism, eg, change in set-point for PTH secretion. Each abnormality interacts with others and contributes to PTH hypersecretion, but none can completely account for the development and persistence of hyperparathyroidism in renal failure. The possibility that uremia may directly cause parathyroid hyperplasia remains open. It is also possible that factor(s) that initiate hyperparathyroidism may turn out to be quite different from that which sustains the hyperparathyroid state. Although both vitamin D-deficient and vitamin D-resistant OM may develop in patients with renal failure, the majority of uremic OM seen currently is "vitamin D-refractory." Although now there is persuasive evidence implicating aluminum (Al) accumulation as the major pathogenetic cause for the mineralization defect seen in this disorder, additional disturbances may play important contributory roles. Such factors would include extraskeletal effects of Al, differences in host-susceptibility to this element, the localization of Al within bone, uremia per se, and the participation of other metals and toxins. Finally, possible interactions between hyperparathyroidism and OM of uremia are speculated on.     

Non-invasive prediction of aluminum bone disease in hemo- and peritoneal dialysis patients.

Between October 1987 and October of 1989, we conducted a prospective study to evaluate non-invasive test strategies for predicting aluminum bone disease (ABD) in a group of largely unselected dialysis patients based on their deferoxamine (DFO) test alone, or the combined results of their DFO test and intact 1-84 parathyroid hormone (PTH) levels. These test parameters were evaluated against the pathological diagnosis of ABD based on bone biopsy ("gold standard"). A total of 445 patients in three dialysis centers in Toronto were serially followed for their clinical, laboratory and risk parameters for renal osteodystrophy during the study, and 259 (142 PD and 117 HD) patients underwent a series of investigations which included the DFO test, measurement of intact 1-84 PTH levels, and an iliac crest bone biopsy. Serum aluminum ([Al]) level greater than or equal to 3700 nM (or 100 micrograms/liter) had a positive predictive value (PPV) of 75% for ABD in our PD and 88% in our HD patients, but its sensitivity was low (10 and 37%). Delta [Al] (that is, incremental rise of serum [Al] from baseline post-DFO) was useful in predicting ABD in our PD but not HD patients. Test combination based on delta [Al] greater than or equal to 5550 nM (or 150 microgram/liter) and PTH levels less than 20 pM (or 200 pg/ml) yielded the best PPV greater than or equal to 95% for ABD in both PD and HD patients. This test cut-off would remain highly predictive of ABD even if the prevalence of ABD decreases to as low as 5% for the PD patients and 10% for the HD patients.(ABSTRACT TRUNCATED AT 250 WORDS)     

Osteocalcin, iPTH, alkaline phosphatase and hand X-ray scores as predictive indices of histomorphometric parameters in renal osteodystrophy

To evaluate the relationship between hyperparathyroid bone X-ray lesion, biochemical parameters and bone histology in chronic renal failure, 59 patients (52 +/- 14.9 years; Crs 4.7 +/- 2.2 mg/dl, mean +/- SD) on conservative treatment and 103 (48 +/- 14 years) on hemodialysis (from 48.4 +/- 36.7 months) were studied. Right-hand X-ray was carried out for evaluation of the scores (0-3) of acroosteolysis (score A) and subperiosteal resorption (score B). Serum iPTH, osteocalcin and alkaline phosphatase (AP) were measured. In addition in a subset of 53 patients, 30 in predialysis and 23 in dialysis, a bone biopsy was performed for histomorphometry. In predialysis the scores A and B correlated with bone GLA protein (BGP) (p less than 0.01), AP (p less than 0.05) and osteoid surface (p less than 0.05) and 0.01 respectively). In hemodialysis the same level of significant correlation (p less than 0.001) was found between the scores and the three humoral parameters. Score A correlated with active osteoblastic surface and active resorption surface while score B correlated with active osteoblastic surface (p less than 0.01), osteoid surface and active resorption surface (p less than 0.05). Multiple regression analysis carried out to establish the predictive variables of bone histologic lesions (active resorption surface and active osteoblastic surface) singled out BGP in predialysis and AP and the two scores in dialysis. We conclude that serum BGP, as compared to PTH and AP, prevails as a valid marker of hyperparathyroid bone lesion in predialysis, while in dialysis it does not seem to add further information to that carried by other variables.(ABSTRACT TRUNCATED AT 250 WORDS)     

High prevalence of adynamic bone disease diagnosed by biochemical markers in a wide sample of the European CAPD population

Background: Adynamic bone disease (ABD) has been described in the current dialysis population to have an unexpectedly high prevalence. Moreover, it is clearly more prevalent in CAPD patients, compared to haemodialysis patients. Recently we demonstrated that both a low (⩽27 U/l) level of bone alkaline phosphatase (BAP) as determined by an optimized agarose gel electrophoretic technique and a low (⩽150 pg/ml) level of iPTH are good markers of ABD with sensitivities of 78.1% and 80.6% and specificities of 86.4% and 76.2% respectively. Methods: In this study (n=212), the prevalence of ABD in the European CAPD population was evaluated by means of these biochemical markers. Clinical data on the patients included were recorded at the moment of blood sampling. In patients under CAPD treatment for longer than 9 months, we calculated an index of calcium exposure through PD fluid. Results: In this population with a low exposure to aluminium, the prevalence of ABD as indicated by either a low level of BAP or PTH was 43%. The following risk factors could be identified: advanced age, shorter time on renal replacement therapy, male gender, and high calcium content of PD fluid. The index of calcium exposure was significantly higher in the patients with low BAP and low iPTH levels compared to those with either BAP>27 U/l or iPTH>150 pg/ml. The latter finding gives further support to the hypothesis that a high calcium load administered to renal failure patients may lead to 'oversuppressed' parathyroids in ABD. In a subgroup of patients with a high level of BAP associated with a low iPTH level a profile previously shown to be associated in the presence of aluminium overload, significantly higher serum aluminium levels were noted, suggesting that even in patients with low exposure to aluminium, this element still can affect bone metabolism. Conclusion: A high prevalence of ABD-as diagnosed by biochemical markers-was observed in the European CAPD population. A number of risk factors could be put forward. The aetiology and pathogenesis of this type of renal osteodystrophy remain to be elucidated, but appear, however, to be multifactorial.     

Race and sex: predictors of the severity of hyperparathyroidism in peritoneal dialysis patients

BACKGROUND: Uraemic hyperparathyroidism remains a common clinical problem. Conversely, oversuppression of parathyroid hormone (PTH), particularly in diabetic patients on peritoneal dialysis, has been implicated in low bone turnover disease. Race may also be an important factor determining susceptibility to hyperparathyroidism and the different forms of renal osteodystrophy. These compounding factors that might influence the severity of hyperparathyroidism have been studied in US dialysis and predialysis populations. Dialysis-dependant Africans and Afro-Caribbeans (AC) are known to have higher circulating PTH concentrations than comparable Caucasians (C) but Indo-Asians (IA) living in temperate climates have not been studied. METHODS: We performed a cross-sectional study of all patients undergoing peritoneal dialysis at St Bartholomew's and The Royal London Hospital on 1 May 2000. The highest historical recorded PTH was recorded with concurrent biochemical and demographic details. Regression models were used for the analysis of covariance and separate manova was performed incorporating the factors that were shown on univariate analysis to be significant. RESULTS: The current study confirmed that in 50 AC patients on peritoneal dialysis, the mean (+/- SEM) peak PTH concentration (93.9 +/- 9.3 pmol/L) was higher than in 148 C (56.7 +/- 4.3 pmol/L) and 67 IA (60.2 +/- 5.7 pmol/L), P < 0.0001 and P < 0.002, respectively. This is despite there being no significant difference in serum calcium concentrations and AC having a lower serum phosphate concentration at the time of peak hyperparathyroidism. There was no significant difference in mean peak PTH concentration between C and IA. Females were also found to have higher peak PTH concentrations, but the presence of diabetes did not influence the peak PTH concentration in this study. CONCLUSION: Although we have demonstrated that patients of African (but not Asian) descent undergoing peritoneal dialysis have more severe hyperparathyroidism than Caucasians, other studies suggest that Afro-Americans develop low bone turnover at higher PTH. This would suggest that PTH values should be interpreted with care and that bone biopsies to determine histology remain important. It may emerge that there are different optimal PTH concentrations according to race.     

Reducing the Risk of Re‐Fracture in the Dialysis Population: Is it Time to Consider Therapy with PTH Analogues?

Dialysis patients are at high risk for fracture, with published rates in excess of a 20% probability of fracture over the next 10 years of dialysis. Unfortunately, there is no accepted methodology for quantifying this risk in advance of the first fracture; conventional bone densitometry performs unreliably in this role, in contrast to its utility in elderly patients with osteoporosis. The KDIGO clinical guidelines emphasize the importance of bone turnover in the development of renal osteodystrophy with high bone turnover strongly associated with uncontrolled secondary hyperparathyroidism, and adynamic bone disease (ABD) defined as a very low bone turnover state associated with functional hypoparathyroidism. It is likely that fractures occur in association with both extremes of uremic bone turnover, in addition to the known risk factors for developing osteoporosis prior to an individual developing end-stage renal failure. No systematic evidence has been forthcoming on therapy to reduce the risk of re-fracture after a dialysis patient presents with a first fracture. Anti-resorptive therapy might be effective in high turnover uremic bone disease and has been demonstrably effective in reducing fracture risk in osteoporotic patients, but there is only post hoc evidence that cinacalcet might reduce the incidence of fractures, and almost no evidence on outcomes from the use of bisphosphonates in dialysis patients. Fractures associated with ABD present a particular challenge. Although aluminum intoxication has been an important cause of skeletal fracturing in the past, this is a rare event today, when nonaluminum containing dietary phosphate binders are routinely prescribed. We suggest that the use of an anabolic agent would be a more plausible approach to the management of ABD (rather than anti-resorptive agents) and propose that a "proof-of-concept" trial with a PTH analogue such as teriparatide should be considered for these patients.     

Insulin-like growth factor system components in hyperparathyroidism and renal osteodystrophy

BACKGROUND: The insulin-like growth factor (IGF) system plays a key role in regulation of bone formation. In patients with renal osteodystrophy, an elevation of some IGF binding proteins (IGFBPs) has been described, but there is no study measuring serum levels of both IGF-I and IGF-II as well as IGFBP-1 to -6 in different forms of renal osteodystrophy and hyperparathyroidism. METHODS: In a cross-sectional study, we investigated 319 patients with mild (N = 29), moderate (N = 48), preuremic (N = 37), and end-stage renal failure (ESRF; N = 205). The ESRF group was treated by hemodialysis (HD; N = 148), peritoneal dialysis (PD; N = 27), or renal transplantation (RTX; N = 30). As controls without renal failure, we recruited age-matched healthy subjects (N = 87) and patients with primary hyperparathyroidism (pHPT; N = 25). Serum levels of total and free IGF-I, IGF-II, IGFBP-1 to -6, and biochemical bone markers including intact parathyroid hormone (PTH), bone alkaline phosphatase (B-ALP), and osteocalcin (OSC) were measured by specific immunometric assays. IGF system components and bone markers were correlated with clinical and bone histologic findings. Mean values +/- SEM are given. RESULTS: With declining renal function a significant increase was measured for IGFBP-1 (range 7- to 14-fold), IGFBP-2 (3- to 8-fold), IGFBP-3 (1.5- to 3-fold), IGFBP-4 (3- to 19-fold), and IGFBP-6 (8- to 25-fold), whereas IGFBP-5 levels tended to decrease (1.3- to 1. 6-fold). In contrast, serum levels of IGF-I, free IGF-I, and IGF-II remained constant in most patients. Compared with renal failure patients, pHPT patients showed a similar decline in IGFBP-5 levels and less elevated levels of IGFBP-1 (3.5-fold), IGFBP-2 (2-fold), IGFBP-3 (1.2-fold), and IGFBP-6 (4-fold) but no elevation of IGFBP-4 levels. In all subjects, free and total IGF-I levels showed significant negative correlations with IGFBP-1, IGFBP-2, and IGFBP-4 (that is, inhibitory IGF system components) and significant positive correlations with IGFBP-3 and IGFBP-5 (that is, stimulatory IGF system components). A positive correlation was observed between IGF-II and IGFBP-6. ESRF patients with mixed uremic bone disease and histologic evidence for osteopenia revealed significantly (P < 0.05) higher levels of IGFBP-2 and IGFBP-4 but lower IGFBP-5 levels. Histologic parameters of bone formation showed significant positive correlations with serum levels of IGF-I, IGF-II, and IGFBP-5. In contrast, IGFBP-2 and IGFBP-4 correlated positively with indices of bone loss. Moreover, dialysis patients with low bone turnover (N = 24) showed significantly (P < 0.05) lower levels of IGFBP-5, PTH, B-ALP, and OSC than patients with high bone turnover. CONCLUSION: Patients with primary and secondary hyperparathyroidism showed lower levels of the putative stimulatory IGFBP-5 but higher levels of IGFBP-1, -2, -3, and -6, whereas total IGF-I and IGF-II levels were not or only moderately increased. The marked increase in serum levels of IGFBP-4 appeared to be characteristic for chronic renal failure. IGFBP-5 correlated with biochemical markers and histologic indices of bone formation in renal osteodystrophy patients and was not influenced by renal function. Therefore, IGFBP-5 may gain significance as a serological marker for osteopenia and low bone turnover in long-term dialysis patients.     

Evaluation of parathyroid hyperplasia by ultrasonographic examination in patients with end-stage renal failure before and at initiation of dialysis

SUMMARY:   Secondary hyperparathyroidism (2HPT), which is related to renal osteodystrophy (ROD), may occur in patients in the comparatively early stage of chronic renal failure (CRF). Secondary hyperparathyroidism patients with parathyroid hyperplasia showed resistance to vitamin D₃ treatment during long-term dialysis. At present, evaluation by ultrasonography is considered to be useful for confirming parathyroid hyperplasia. There are no clinical data associated with imaging evaluation of 2HPT in CRF patients. In the present study, the relationship among clinical and biochemical data, and parathyroid hyperplasia by ultrasonography, was evaluated in 12 patients (six males and six females) with end-stage renal failure (ESRF) before and at initiation of dialysis. Five patients showed an enlargement of parathyroid glands in ultrasonography. Levels of serum-intact parathyroid hormone (PTH) in patients with parathyroid hyperplasia (positive group) were significantly higher than in those without hyperplasia (negative group; 97.6 ± 36.65 vs 17.4 ± 4.45 pmol/L; P  < 0.05). The levels of intact PTH were above 35.0 pmol/L in all five patients with hyperplasia. All patients in the positive group had never taken vitamin D₃ supplements. Calcium-containing phosphate binders were not prescribed before the present study, except in one patient. Parathyroid hyperplasia caused by 2HPT was recognized in patients before and at initiation of dialysis in this study. It appears that untreated 2HPT in CRF patients may progress to advanced 2HPT in ESRF before and/or after the early stage of dialysis. The levels of serum intact PTH are useful in predicting parathyroid hyperplasia.     

Facial leontiasis ossea: a rare presentation of hyperparathyroidism secondary to chronic renal insufficiency

The term renal osteodystrophy is often used in a generic sense to include skeletal disorders of patients with chronic renal failure due to secondary hyperparathyroidism. The prevalence of this condition among patients on hemodialysis is considerably high. However, extreme forms such as facial leontiasis ossea are very rare, only 2 well-characterized cases having been reported thus far in the literature. In the present article we report the case of a female patient who developed hyperparathyroidism secondary to end-stage renal disease which was manifested as facial leontiasis ossea and culminated in dysphagia and respiratory difficulties caused by excess bone tissue growth.     

Pathophysiology and recent advances in the management of renal osteodystrophy.

Bone disease is observed in 75-100% of patients with chronic renal failure as the glomerular filtration rate (GFR) falls below 60 ml/minute. Hyperparathyroid (high turnover) bone disease is found most frequently followed by mixed osteodystrophy, low-turnover bone disease, and osteomalacia. With advancing renal impairment, "skeletal resistance" to parathyroid hormone (PTH) occurs. To maintain bone turnover, intact PTH (iPTH) targets from two to four times the upper normal range have been suggested, but whole PTH(1-84) assays indicate that amino-terminally truncated fragments, which accumulate in end-stage renal disease (ESRD), account for up to one-half of the measured iPTH. PTH levels and bone-specific alkaline phosphatase (BSAP) provide some information on bone involvement but bone biopsy and histomorphometry remains the gold standard. Calcitriol and calcium salts can be used to suppress PTH and improve osteomalacia but there is growing concern that these agents predispose to the development of vascular calcification, cardiovascular morbidity, low-turnover bone disease and fracture. Newer therapeutic options include less calcemic vitamin D analogues, calcimimetics and bisphosphonates for hyperparathyroidism, and sevelamer for phosphate control. Calcitriol and hormone-replacement therapy (HRT) have been shown to maintain bone mineral density (BMD) in certain patients with end-stage renal disease (ESRD). After renal transplantation, renal osteodystrophy generally improves but BMD often worsens. Bisphosphonate therapy may be appropriate for some patients at risk of fracture. When renal bone disease is assessed using a combination of biochemical markers, histology and bone densitometry, early intervention and the careful use of an increasing number of effective therapies can reduce the morbidity associated with this common problem.     

Decreased parathyroid hormone secretion in chronic hemodialysis patients without active vitamin D treatment

Abrstact Sixty-eight out of 149 chronic hemodialysis patients without recent administration of the active vitamin D did not actually show the secondary hyperparathyroidism evaluating by the intact PTH levels. High incidence of diabetes mellitus was recognized in the patients with the normal or low intact PTH level. The 33 patients could be divided into two groups, the responders and nonresponders, in accordance with the intact PTH response to calcium-free hemodialysis technique. The basal C-PTH and intact PTH of the responders were higher than those of the nonresponders, however the levels of plasma ferritin and aluminium, and desferrioxamine loading tests did not show any difference between them. Number of Diabetic patient also distributed evenly between two groups. Diabetes mellitus, aluminium intoxication and iron overload were not fully responsible for the poor secretion of intact PTH in the chronic hemodialysis patients.