Sandro Mazzaferro

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.

Bone: a new endocrine organ at the heart of chronic kidney disease and mineral and bone disorders.

Recent reports of several bone-derived substances, some of which have hormonal properties, have shed new light on the bone-cardiovascular axis. Deranged concentrations of humoral factors are not only epidemiologically connected to cardiovascular morbidity and mortality, but can also be causally implicated, especially in chronic kidney disease. FGF23 rises exponentially with advancing chronic kidney disease, seems to reach maladaptive concentrations, and then induces left ventricular hypertrophy, and is possibly implicated in the process of vessel calcification. Sclerostin and DKK1, both secreted mainly by osteocytes, are important Wnt inhibitors and as such can interfere with systems for biological signalling that operate in the vessel wall. Osteocalcin, produced by osteoblasts or released from mineralised bone, interferes with insulin concentrations and sensitivity, and its metabolism is disturbed in kidney disease. These bone-derived humoral factors might place the bone at the centre of cardiovascular disease associated with chronic kidney disease. Most importantly, factors that dictate the regulation of these substances in bone and subsequent secretion into the circulation have not been researched, and could provide entirely new avenues for therapeutic intervention.

Renal anaemia and EPO hyporesponsiveness associated with vitamin D deficiency: the potential role of inflammation

Resistance to erythropoiesis-stimulating agents (ESAs) has been observed in a considerable proportion of patients with chronic kidney disease (CKD) and it is reportedly associated with adverse outcomes, such as increased cardiovascular morbidity, faster progression to end-stage renal disease (ESRD) and all-cause mortality. The major causes of ESA resistance include chronic inflammation producing suppressive cytokines of early erythroid progenitor proliferation. In addition, pro-inflammatory cytokines stimulate hepcidin synthesis thus reducing iron availability for late erythropoiesis. Recent studies showing an association in deficiencies of the vitamin D axis with low haemoglobin (Hb) levels and ESA resistance suggest a new pathophysiological co-factor of renal anaemia. The administration of either native or active vitamin D has been associated with an improvement of anaemia and reduction in ESA requirements. Notably, these effects are not related to parathyroid hormone (PTH) values and seem to be independent on PTH suppression. Another possible explanation may be that calcitriol directly stimulates erythroid progenitors; however, this proliferative effect by extra-renal activation of 1α-hydroxylase enzyme is only a hypothesis. The majority of studies concerning vitamin D deficiency or supplementation, and degree of renal anaemia, point out the prevalent role of inflammation in the mechanism underlying these associations. Immune cells express the vitamin D receptor (VDR) which in turn is involved in the modulation of innate and adaptive immunity. VDR activation inhibits the expression of inflammatory cytokines in stromal and accessory cells and up-regulates the lymphocytic release of interleukin-10 (IL-10) exerting both anti-inflammatory activity and proliferative effects on erythroid progenitors. In CKD patients, vitamin D deficiency may stimulate immune cells within the bone marrow micro-environment to produce cytokines, inducing impaired erythropoiesis. Immune activation involves the reticuloendothelial system, increasing hepcidin synthesis and functional iron deficiency. Consequences of this inflammatory cascade are erythropoietin (EPO) resistance and anaemia. Given the key role of inflammation in the response to EPO, the therapeutic use of agents with anti-cytokines properties, such as vitamin D and paricalcitol, may provide benefit in the prevention/treatment of ESA hyporesponsiveness.

Progression of Coronary Artery Calcification in Renal Transplantation and the Role of Secondary Hyperparathyroidism and Inflammation

BACKGROUND AND OBJECTIVES Transplantation should favorably affect coronary calcification (CAC) progression in dialysis; however, changes in CAC score in the individual patient are not reliably evaluated. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS The authors used special tables of reproducibility limits for each score level to study, by multislice computed tomography and biochemistries, the 2-year changes in CAC in 41 transplant patients (age 48 +/- 13 yr, 25 men, dialysis vintage 4.8 +/- 4.3 yr, underwent transplant 6.2 +/- 5.5 yr prior). Thirty balanced dialysis patients served as controls. RESULTS In the study group, Agatston score was stable, and C-reactive protein decreased, whereas fetuin and osteoprotegerin increased. In the control group, Agatston score increased, parathyroid hormone and phosphate decreased, and inflammation markers were persistently twice as high as in the study group. With regard to individual changes, 12.2% transplant patients worsened, compared with 56.6% of patients in dialysis (P < 0.0001). Patients without calcification at entry showed slower progression in transplantation (8.3%) than in dialysis (44.4%; P < 0.034), and the difference was similar to that observed in cases with CAC (17.6% versus 61.9%; P < 0.007). Discriminant analysis indicated parathyroid hormone, the modality of therapy (dialysis or transplantation), and erythrocyte sedimentation rate as the variables most associated with worsening. CONCLUSIONS Renal transplantation lowers but does not halt CAC progression. Inflammation and hyperparathyroidism are associated with progression in the populations studied.

Vascular Calcification and Uremia: What Do We Know?

In the last decade, the nephrology community has focused its attention on the main cause of morbidity and mortality in chronic renal failure patients: cardiovascular disease. In addition, recent studies pointed out that vascular calcification (VC) is a major cause of cardiovascular disease in the dialysis population. Interestingly, the pathogenesis of VC and soft tissue calcification in chronic kidney disease (CKD) has been extensively investigated. Nowadays we know that VC is associated not only with passive calcium phosphate deposition, but also with an active, cell-mediated process. To better understand the pathogenesis of VC in CKD, numerous regulatory proteins have been studied, because of their ability to inhibit mineral deposition in the vessels. We here examine the state of the art of those substances recognized as regulatory key factors in preventing VC in uremic conditions, such as fetuin A (α2-Heremans-Schmid glycoprotein), matrix γ-carboxyglutamic acid protein, pyrophosphate, osteoprotegerin and bone morphogenetic protein. We conclude that at present it is too early to introduce these novel markers into clinical practice.

Serum Levels of Calcification Inhibition Proteins and Coronary Artery Calcium Score: Comparison between Transplantation and Dialysis

Vascular calcifications in CKD are now linked to serum alterations of both divalent ions and calcification inhibitory proteins. Due to possible biochemical differences between dialysis (D) and transplantation (Tx), we examined the entity and severity of these biochemical modifications and of coronary artery calcium score separately in these two populations. We assayed, besides standard markers of inflammation, divalent ions and serum levels of fetuin, matrix Gla protein (MGP) and osteoprotegerin (OPG), in 51 Tx patients (age 45 ± 12 years; 30 males, 21 females; previous D duration 4.8 ± 4.2 years; Tx since 6.6 ± 5.5 years; Cr 1.8 ± 0.6 mg/dl) and in 49 D patients (age 49 ± 14 years; 30 males,19 females; D duration 5.6 ± 4.8 years). Additionally, coronary calcium score (AS) was evaluated by cardiac multi-slice CT. Compared with D patients, Tx patients had better values of divalent ions and inflammation markers, and lower prevalence (65 vs. 86%; p < 0.02) and severity (AS = 570 ± 1,637 vs. 1,311 ± 3,128; p < 0.008) of coronary calcification. In addition, a tendency toward normalization for all of the three calcification inhibitory proteins was evident. In both Tx and D, AS correlated with age and OPG (Tx: rs = 0.439, p < 0.001, and rs = 0.510, p < 0.0001; D: rs = 0.471, p < 0.001, and rs = 0.403, p < 0.005, respectively); in D patients, a correlation was present also with D duration (rs = 0.435; p < 0.002), other markers of inflammation and, notably, fetuin (rs = –0.442; p < 0.002). Regression analysis selected previous time on D in Tx patients (rm = 0.400; p < 0.004), and C-reactive protein and OPG in D patients (rm = 0.518; p < 0.004) as the most predictive parameters of AS. Discriminant analysis confirmed the major role of age and D duration in the appearance of AS and evidenced male gender as a distinct risk condition. At variance, Tx duration was never associated with AS. In conclusion, as compared to D, renal Tx patients show serum levels of calcification inhibition proteins and of divalent ions closer to normal. As this is associated with a lower prevalence and severity of AS, it is suggested that Tx antagonize the accelerating role of D in the progression of vascular calcification. Assessment of both coronary calcifications and serum levels of calcification inhibitory proteins may be of value to identify those subjects at higher risk of development and progression of vascular lesions, among whom males have the highest rate.

Histomorphometric assessment of bone turnover in uraemic patients: comparison between activation frequency and bone formation rate

Histomorphometric assessment of bone turnover in uraemic patients: comparison between activation frequency and bone formation rate

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)

Pro: Cardiovascular calcifications are clinically relevant

It is increasingly acknowledged that mineral and bone disorders (MBDs) contribute to the excessively high cardiovascular (CV) disease morbidity and mortality observed in patients with chronic kidney disease (CKD). There is ongoing debate as to whether screening for CV calcification, one of the hallmarks of CKD-MBD, should be implemented in clinical practice in patients with CKD. Issues to be considered in this controversy relate to prevalence, severity, relevance, and last but not least, modifiability and reversibility of vascular and valvular calcifications in the setting of CKD. The recent expansion of the armamentarium to treat CKD-MBD (calcium-free phosphate binders and calcimimetics) creates new opportunities. Mounting experimental and clinical evidence indicates that progression of CV calcification may indeed be attenuated. Whether this will translate into better outcomes remains to be proven. We acknowledge that hard outcome data so far are limited and, overall, yielded inconclusive results. Nevertheless, in an era in which personalized medicine has gained much popularity, we consider it reasonable, awaiting the results of additional studies, to screen for CV calcification in selected individuals. This policy may help to stratify CV risk and to guide therapy. We speculate that such an approach will ultimately improve outcomes and reduce health costs.

When, How, and Why a Bone Biopsy Should Be Performed in Patients With Chronic Kidney Disease

In chronic kidney disease the excessive production of parathyroid hormone increases the bone resorption rate and leads to histologic bone signs of secondary hyperparathyroidism. However, in other situations, the initial increase in parathyroid hormone and bone remodeling may be slowed down excessively by a multitude of factors including age, ethnic origin, sex, and treatments such as vitamin D, calcium salts, calcimimetics, steroids, and so forth, leading to low bone turnover or adynamic bone disease. Both high and low bone turnover diseases actually are observed equally in chronic kidney disease patients treated by dialysis, and all types of renal osteodystrophy are associated with an increased risk of skeletal fractures, reduced quality of life, and poor clinical outcomes. Unfortunately, the diagnosis of these bone abnormalities cannot be obtained correctly by current clinical, biochemical, and imaging methods. Therefore, bone biopsy has been, and still remains, the gold standard analysis for assessing the exact type of renal osteodystrophy. It is also the unique way to assess the mechanisms of action, safety, and efficacy of new bone-targeting therapies.