Micaela Manni

Renal bone disease in 76 patients with varying degrees of predialysis chronic renal failure: a cross-sectional study

BACKGROUND Renal osteodystrophy has been studied less extensively in predialysis than in dialysis patients. Different types or histological patterns in their natural evolution from moderate to advanced severity of renal insufficiency are only partially known, with special regard to adynamic bone disease and its relationship with osteomalacia. METHODS We conducted a cross-sectional retrospective study on 76 unselected patients with chronic renal failure undergoing conservative treatment, with a wide range of severity of renal insufficiency. All the patients were subjected to bone biopsy for histological and histomorphometric evaluation. The patients, 44 males and 32 females ranging in age from 18 to 72 years and with serum creatinine 1.2-11.4 mg/dl, had not been exposed to aluminium-containing drugs and had never been treated with vitamin D or calcitriol. RESULTS Ten patients had normal bone, nine were diagnosed with adynamic bone disease, 26 with mild mixed osteodystrophy, seven with predominant osteomalacia, 22 with advance mixed osteodystrophy, and two with predominant hyperparathyroidism. Patients with adynamic bone disease had less severe chronic renal failure than the other pathological subgroups, intact PTH above the upper limit of normal, normocalcaemia, and reduced serum osteocalcin in line with a significantly lower ObS/BS. Osteomalacia was found in a more advanced stage of chronic renal failure with relative hypocalcaemia and more severe metabolic acidosis. A creatinine clearance of 20 ml/min served as a clear demarcation between this histological group and adynamic bone disease. CONCLUSIONS It is postulated that adynamic bone disease is a form of renal osteodystrophy, separate from osteomalacia, appearing when bone resistance to PTH develops, probably a transient stage to more hyperparathyroid histological classes with increasing severity of chronic renal failure.

Renal Osteodystrophy in Predialysis and Hemodialysis Patients: Comparison of Histologic Patterns and Diagnostic Predictivity of Intact PTH

Background: Comparison of renal osteodystrophy in predialysis and hemodialysis has been rarely reported. Distinct patterns of renal osteodystrophy could be found in these conditions. In addition the use of parathyroid hormone (PTH) and other markers for noninvasive diagnosis may result in different predictive values in predialysis and hemodialysis patients. Methods: 79 consecutive patients with conservative chronic renal failure and 107 patients on hemodialysis were studied. All patients were subjected to bone biopsy for histological and histomorphometric evaluation. The patients had no exposure to aluminium before dialysis and relatively low exposure while on hemodialysis. Results: In the predialysis patients, bone biopsies showed 9 cases of adynamic bone disease (ABD) and 8 cases of osteomalacia (OM), 50 patients with mixed osteodystrophy and 2 cases of hyperparathyroidism. Among the hemodialysis patients 12 cases had ABD, 3 cases OM, 30 mixed osteodystrophy, and 61 patients hyperparathyroidism. In the predialysis patients with chronic renal failure, bone aluminium was on average 4.5 mg/kg dry weight, while in dialysis patients the average value was 35.4 mg/kg dry weight. Discriminant analysis of low turnover osteodystrophy (ABD and OM) by intact PTH showed higher accuracy in dialysis than in predialysis patients. Correlation studies of intact PTH versus bone formation rate, osteoblast surface/bone surface and osteoclast surface/bone surface showed significantly steeper slopes in dialysis than in predialysis patients, which indicates that bone resistance to PTH is more marked in predialysis patients. Conclusions: The prevalence of ABD and OM in the geographic area investigated is lower than in other reports. Aluminium exposure does not seem to be the cause of low turnover osteodystrophy in the present population. The predictive value of intact PTH in the noninvasive diagnosis of renal bone disease is higher in hemodialysis patients than in predialysis patients. Predialysis chronic renal failure, when compared to the dialysis stage, seems to be characterized by resistance of bone tissue to PTH.

Parathyroidectomy in Chronic Renal Failure: Short- and Long-Term Results on Parathyroid Function, Blood Pressure and Anemia

To evaluate the long-term results of parathyroidectomy (PTX) on parathyroid function, blood pressure and anemia, data of 45 patients with secondary Hyperparathyroidism in dialysis who had undergone PTX were collected retrospectively from 8 different dialysis units. The patients, 25 M and 20 F, mean age 56 ± 11 years, who were followed up for an average period of 3.3 ± 2.3 years, were divided into four groups according to the surgical procedure: 19 patients had had a subtotal PTX; 10 patients had undergone total PTX with autotransplantation (AT); 10 patients had had total PTX without AT, and 6 patients had undergone partial PTX. Taking a reduction in intact PTH >50% as sign of successful PTX, only 5 patients did not attain this result. Considering values of PTH between 20 and 200 pg/ml at the mid-term observation (1–2 years) as the optimal result, values under 20 pg/ml as an expression of permanent hypoparathyroidism, and those above 200 pg/ml as indicating persistent/recurrent hyperparathyroidism, 65.5% of patients operated with subtotal PTX and total PTX + AT had a therapeutic success, versus 31.2% of patients in the other two groups, due to excess permanent hypoparathyroidism and persistent/recurrent hyperparathyroidism; 20 of 45 patients with preoperative hypertension experienced a statistically and clinically significant decrease in blood pressure levels. An increase in serum hemoglobin was also observed, despite a reduction of administered erythropoietin. In conclusion, the results of PTX obtained from this multicenter study are comparable to those reported by single leading centers. Recommended surgical procedures are subtotal PTX and total PTX with AT. The fall in blood pressure in hypertensive patients is clinically significant, and improvement in anemia is also observed with a reduction in erythropoietin dosage.

Ischemic Nephropathy in an Elderly Nephrologic and Hypertensive Population

Background: Atherosclerotic renovascular disease is a frequent cause of end-stage renal failure leading to dialysis in the elderly population. Its prevalence is known from autopsy or retrospective arteriographic investigations. This prospective study was conducted in 133 subjects with the inclusion criteria of hypertension and/or chronic renal failure starting after 50 years of age. Renal failure was unrelated to other known causes of renal disease. Methods: The patients were subjected to echo-color doppler ultrasonography of renal arteries (104) and/or to renal scintigraphy (112). Thirteen of 27 patients with positivity using one or both noninvasive techniques were subjected to digital selective angiography. Results: All the patients with positivity of echo-color doppler technique were true positives, with a consequent predictive value reaching 100%. Renal scintigraphy was of markedly lower predictive value. Based on the echo-color doppler investigation, percentage positivity for hemodynamically significant stenosis (>50%) was 3.2 (16.3% had mild nonsignificant stenosis of renal arteries) in the 50- to 59-year-old group, 20% (plus 12.5% with nonsignificant stenosis) in the 60- to 69-year-old group and 25% (plus 17.8% nonsignificant stenosis) in the >70-year age group. Patients with significant stenosis also had a significantly higher degree of renal insufficiency and received a higher number of hypotensive drugs (p < 0.013). The percentage of hypertensive patients was not different in the stenotic and nonstenotic groups. Conclusions: A large percentage of the elderly population is affected by renal vascular obstructive disease and is at risk of developing end-stage renal failure. Considering the wide number of cases with foreseeable renal arterial stenosis in the vast population meeting the selection criteria, it is possible to conclude that not all cases evolve to renal failure due to different rates of progression or to untimely nonrenal death.

Cardiac calcifications : Fetuin-A and other risk factors in hemodialysis patients

Cardiac calcifications are a frequent finding in hemodialysis for chronic renal failure. Several factors may play a role in the intimal and medial calcification of coronary arteries such as age and some known atherogenetic factors. In addition, Fetuin-A has been proposed as a protective agent through solubilization of calcium phosphate salt. Fetuin-A is also a marker of inflammatory-nutritional state, and its changes could be an expression of this condition. The aim of this cross-sectional study is to evaluate the relative importance of risk factors of calcifications with special regard to Fetuin-A. The study was conducted with 132 hemodialysis patients. They were subjected to multislice computed tomography for evaluation of calcium deposits in the heart. In addition, the patients were sampled for evaluation of calcium-phosphate parameters, lipid profile, nutritional and inflammatory markers, and also Fetuin-A. There was a wide variability of the extent of calcium deposits expressed as Agatston score, with only 9.3% of patients without calcifications. Age, hemodialysis age, sex, calcium-phosphate parameters, and lipid profile were important risk factors, together with nutritional and inflammatory status of the patients. An inverse correlation between coronary calcium score and Fetuin-A emerged from a multiple regression analysis. However, there was no significant difference in serum Fetuin-A among different grades of calcium score. By dividing the patients in tertiles of serum Fetuin-A, an association between low levels of Fetuin-A and high calcification score was found. Fetuin-A as dependent variable was strictly linked to prealbumin serum levels. In addition, there was a clear link between cardiac calcification scores and inflammatory-nutritional markers. Serum calcium and treatment with calcitriol emerged as predictive variables of coronary score. Fetuin-A could be involved in the process of calcification both in the case of markedly low serum levels, due to decreased prevention of calcium phosphate precipitation, and also as a marker of inflammation, a well-known risk factor of atherogenesis. Treatment with intravenous calcitriol could marginally enhance cardiac calcifications, probably through its hypercalcemic effect.

Risk factors of one year increment of coronary calcifications and survival in hemodialysis patients

BackgroundHeart and coronary calcifications in hemodialysis patients are of very common occurrence and linked to cardiovascular events and mortality. Several studies have been published with similar results. Most of them were mainly cross-sectional and some of the prospective protocols were aimed to evaluate the results of the control of altered biochemical parameters of mineral disturbances with special regard to serum calcium, phosphate and CaxP with the use of calcium containing and calcium free phosphate chelating agents. The aim of the present study was to evaluate in hemodialysis patients classic and some non classic risk factors as predictors of calcification changes after one year and to evaluate the impact of progression on survival.Methods81 patients on hemodialysis were studied, with a wide age range and HD vintage. Several classic parameters and some less classic risk factors were studied like fetuin-A, CRP, 25-OHD and leptin. Calcifications, as Agatston scores, were evaluated with Multislice CT basally and after 12-18 months.ResultsCoronary artery calcifications were observed in 71 of 81 patients. Non parametric correlations between Agatston scores and Age, HD Age, PTH and CRP were significant. Delta increments of Agatston scores correlated also with serum calcium, CaxP, Fetuin-A, triglycerides and serum albumin. Logistic regression analysis showed Age, PTH and serum calcium as important predictors of Delta Agatston scores. LN transformation of the not normally distributed variables restricted the significant correlations to Age, BMI and CRP. Considering the Delta Agatston scores as dependent, significant predictors were Age, PTH and HDL. A strong association was found between basal calcification scores and Delta increment at one year. By logistic analysis, the one year increments in Agatston scores were found to be predictors of mortality. Diabetic and hypertensive patients have significantly higher Delta scores.ConclusionsProgression of calcification is of common occurrence, with special regard to elevated basal scores, and is predictive of survival. Higher predictive value of survival is linked to the one year increment of calcification scores. Some classic and non classic risk factors play an important role in progression. Some of them could be controlled with appropriate management with possible improvement of mortality.

Procollagen Type I C-Terminal Extension Peptide in Predialysis Chronic Renal Failure

Collagen type 1 is the most abundant protein of bone. Serum levels of type 1 procollagen carboxy-terminal extension peptide (Procoll-1-C) may give a measure of the rate of synthesis of the collagen of bone and be therefore a marker of bone turnover. We have studied 38 patients with predialysis chronic renal failure; 14 of them were under long-term treatment with 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] for prevention of secondary hyperparathyroidism. In all patients a transiliac bone biopsy for histomorphometry and determination of dynamic parameters was performed following double tetracycline labeling. In addition serum Procoll-1-C, intact and C-terminal parathyroid hormone (PTH), osteocalcin and alkaline phosphatase were determined. In the patients not receiving 1,25(OH)2D3, serum levels of Procoll-1-C were higher than normal. Procoll-1-C did not correlate with any of the humoral parameters, including serum creatinine, nor with static histomorphometric parameters. Contrarily to osteocalcin, the collagen type 1 marker correlated significantly with all dynamic parameters. Treatment with 1,25(OH)2D3 was accompanied by lower levels of osteocalcin, iPTH (n.s.), osteoblastic surface and by normal levels of Procoll-1-C (p < 0.001, compared to untreated patients), without substantial change in bone formation parameters (bone formation rate). In conclusion Procoll-1-C in predialysis chronic renal failure is a marker of bone turnover unparalleled by other markers. 1,25(OH)2D3 administration is associated with lower serum levels of the peptide unaccompanied by a decrement of bone formation parameters, therefore with an apparently better utilization of collagen type 1 in the mineralization process.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Turnover, Osteopenia and Vascular Calcifications in Hemodialysis Patients

Background: Several classical risk factors are at the base of vascular calcifications in hemodialysis patients. Among these, according to a general opinion, also bone turnover plays a role, which, however, requires a better definition. In addition, it has been suggested that there is a relationship between primary osteoporosis and vascular calcifications. This bone biopsy-based study on a hemodialysis patient cohort is a contribution to the evaluation of these alleged relations. Methods: This study has been carried out on a cohort of 32 patients on maintenance hemodialysis, who were subjected to transiliac bone biopsy for histomorphometric, histodynamic and bone aluminum deposit evaluation. The patients were also examined with multislice computerized tomography for quantitation of heart and coronary calcifications. Results: The patients were affected by renal osteodystrophy with a wide range of bone formation rate values. A significant negative correlation was found between the rate of bone turnover and log-transformed cardiac calcification score (p < 0.003). There were also negative significant correlations between the cardiac and coronary calcification score log and trabecular number (p < 0.02 and p < 0.05, respectively), while the correlations were positive with trabecular separation (p < 0.03 and p < 0.05, respectively). However, multiregression analysis, forward method, selected only age, hemodialysis age and serum Ca as predictive variables of cardiac and coronary calcification score log, while the histomorphometric and histodynamic variables were excluded. Conclusions: In this study, in spite of the suggestive findings of the univariate statistical approach, a further multivariate analysis was indicative of a spurious association between calcification scores and both bone turnover and histomorphometric parameters of trabecular mass and connectivity. Bone turnover and trabecular mass do not appear to be prominently connected with the extent of cardiac and coronary calcifications in hemodialysis patients.

Procollagen type 1 C-terminal extension peptide serum levels following parathyroidectomy in hyperparathyroid patients

Procollagen type 1 is mainly synthesized by osteoblasts and, after cleavage of the N- and C-terminal extension peptides, is utilized for collagen fibril deposition in the osteoid tissue. Serum levels of C-terminal extension peptide (Pcoll-1-C) of the procollagen molecule has been considered a useful marker for the evaluation of the rate of osteoblastic procollagen synthesis. To appraise whether in vivo parathyroid hormone (PTH) plays a suppressive role in the synthesis of procollagen type 1, a study has been carried out in 16 patients, 10 with severe secondary hyperparathyroidism of chronic renal failure and 6 with primary hyperparathyroidism. Following parathyroidectomy (PTX), in chronic renal failure patients a 94% fall in serum intact iPTH and a decline of serum calcium to hypocalcemic levels requiring calcitriol administration were observed. Serum Pcoll-1-C increased markedly with a peak after 7 days and a subsequent decline. Similar changes were observed for alkaline phosphatase and osteocalcin. In primary hyperparathyroidism, PTX was followed by an 88% drop in iPTH and mild hypocalcemia not requiring calcitriol administration. Also in this group serum Pcoll-1-C increased significantly with the same time course, unaccompanied by changes in alkaline phosphatase and osteocalcin. In 4 unsuccessfully neck-operated control patients no change in serum Pcoll-1-C levels was recorded during a period of 2 weeks postoperatively. In conclusion, acute withholding of parathyroid hypersecretion is accompanied by an abrupt and transitory increase of serum Pcoll-1-C, not dependent on calcitriol administration. Hypocalcemia following PTX may in part be due to uncoupling of bone formation and resorption.

Immunohistochemical localization and mRNA expression of matrix Gla protein and fetuin-A in bone biopsies of hemodialysis patients

Matrix Gla protein (MGP) and fetuin-A are inhibitors of arterial calcifications. In blood of rats, calcium–phosphate–fetuin–MGP complexes, produced in bone, have been identified. Indeed, an association between bone resorption, release of such complexes, and arterial calcifications has been reported. We have investigated the synthesis and localization of fetuin-A and MGP in bone of hemodialysis patients and the possible contribution of bone cells in arterial calcifications. Bone biopsies from 11 hemodialysis patients were used for histology, in situ hybridization of fetuin-A and MGP messenger RNA (mRNA), immunohistochemistry of fetuin-A, and total, carboxylated, and non-carboxylated MGP proteins. Patients showed various types of renal osteodystrophy, or normal bone. MGP was synthesized and expressed (total and carboxylated) by osteoblasts, osteocytes, and most osteoclasts, while fetuin-A by osteoblasts and osteocytes. Fetuin-A and carboxylated MGP proteins were positive in the calcified matrix, while total MGP was negative. Osteoid seams were negative to fetuin-A, lightly positive to carboxylated MGP, and occasionally positive to total MGP. Undercarboxylated MGP was mostly undetectable. In adult humans, fetuin-A is produced also by osteoblasts, and not only by hepatocytes, as previously believed. MGP, essentially carboxylated, is synthesized by osteoblasts and most osteoclasts. Increased bone turnover can be an important contributor to arterial calcifications.