Daniela Sardella

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.

Detection of osteoprotegerin (OPG) and its ligand (RANKL) mRNA and protein in femur and tibia of the rat

Osteoprotegerin (OPG) and the receptor activator of nuclear factor (NF)-kB ligand (RANKL) are key regulators of osteoclastogenesis. The present study had the main aim of showing the localization of OPG and RANKL mRNA and protein in serial sections of the rat femurs and tibiae by immunohistochemistry (IHC) and in situ hybridization (ISH). The main results were: (1) OPG and RANKL mRNA and protein were co-localized in the same cell types, (2) maturative/hypertrophic chondrocytes, osteoblasts, lining cells, periosteal cells and early osteocytes were stained by both IHC and ISH, (3) OPG and RANKL proteins were mainly located in Golgi areas, and the ISH reaction was especially visible in active osteoblasts, (4) immunolabeling was often concentrated into cytoplasmic vacuoles of otherwise negative proliferative chondrocytes; IHC and ISH labeling increased from proliferative to maturative/hypertrophic chondrocytes, (5) the newly laid down bone matrix, cartilage-bone interfaces, cement lines, and trabecular borders showed light OPG and RANKL immunolabeling, (6) about 70% of secondary metaphyseal bone osteocytes showed OPG and RANKL protein expression; most of them were ISH-negative, (7) osteoclasts were mostly unstained by IHC and variably labeled by ISH. The co-expression of OPG and RANKL in the same bone cell types confirms their strictly coupled action in the regulation of bone metabolism.

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.

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.

Atherosclerotic ischemic renal disease. Diagnosis and prevalence in an hypertensive and/or uremic elderly population

BackgroundAtherosclerotic ischemic renal disease is a frequent cause of end-stage renal failure leading to dialysis among the elderly; Its prevalence is inferred from autopsy or retrospective arteriographic studies. This study has been conducted on 269 subjects over 50 with hypertension and/or CRF, unrelated to other known causes of renal disease.MethodsAll 269 patients were studied either by color-flow duplex sonography (n = 238) or by renal scintigraphy (n = 224), and 199 of the 269 patients were evaluated using both of these techniques. 40 patients, found to have renal artery stenosis (RAS), were subjected to 3D-contrast enhancement Magnetic Resonance Angiography (MRA) and/or Selective Angiography (SA). An additional 23 cases, negative both to scintigraphy and to ultrasound study, underwent renal angiography (MRA and/or SA).ResultsColor-duplex sonography, carried out in 238 patients, revealed 49 cases of RAS. MR or SA was carried out in 35 of these 49 patients, and confirmed the diagnosis in 33. Color-duplex sonography showed a PPV value of 94.3% and NPV of 87.0% while renal scintigraphy, carried out in 224 patients, had a PPV of 72.2% and a NPV of 29.4%. Patients with RAS showed a higher degree of renal insufficiency compared to non stenotic patients while there were no differences in proteinuria. RAS, based on color-duplex sonography studies, was present in 11% of patients in the age group 50–59, 18% in the 60–69 and 23% at age 70 and above.ConclusionsA relatively large percentage of the elderly population with renal insufficiency and/or hypertension is affected by RAS and is at risk of developing end-stage renal failure. Color-duplex ultrasonography is a valid routine method of investigation of population at risk for renal artery stenosis.

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)

Atherosclerotic renal artery stenosis: one year outcome of total and separate kidney function following stenting.

BackgroundRenal artery stenosis (RAS) is a known cause of hypertension and ischemic nephropathy. Stenting of the artery is a valid approach, in spite of cases of unexpected adverse evolution of renal function.MethodsIn this study, 27 patients with unilateral RAS were subjected to stenting and followed for a period of one year, while 19 patients were observed while on medical treatment only. The group of 27 patients, 67.33 ± 6.8 years of age, creatinine of 2.15 ± 0.9 mg/dl, following stenting, were followed at intervals with biochemical tests, renal scintigraphy and doppler ultrasonography. The control group (70.0 ± 6.1 years, creatinine 1.99 ± 0.7 mg/dl) was also followed for one year.ResultOne year after stenting mean creatinine clearance (Ccr) increased from 36.07 ± 17.2 to 40.4 ± 21.6 ml/min (NS). Arterial BP, decreased after 1,3,6, and 12 months (p < 0.05). The number of antihypertensive drugs also decreased (p < 0.05). A significant increase in proteinuria was also observed. In the control group both Ccr, BP and proteinuria did not show significant changes. Based on renal scintigraphy and Ccr at subsequent times, it was possibile to evaluate the timecourse of renal function in both kidneys of the stented patients. In the stented kidneys Ccr increased significantly. On the controlateral kidney a decrease of renal function (p < 0.05) was observed. Resistance index appeared to be a risk factor of the functional outcome.ConclusionsStenting of RAS due to atherosclerosis is followed by stabilization or improvement of Ccr, mainly at the stented kidney, while contralateral renal function showed a decrease.

Urinary Composition and Lithogenic Risk in Normal Subjects following Oligomineral versus Bicarbonate-Alkaline High Calcium Mineral Water Intake

Objective: A normal dietary calcium intake to reduce intestinal oxalate absorption is essential to avoid recurrence of calcium oxalate stone formation. It is also important in the prevention of osteopenia in idiopathic hypercalciuria. The calcium content of waters used for hydration may vary from very low to relatively high and is an important factor in prevention or additional risk of stone formation. Therefore, the effect of drinking mineral waters of different calcium concentrations on lithogenic risk factors was studied in normal volunteers. Materials and Methods: Normal subjects were divided into two groups of 11 and 10 individuals each. All followed a prescribed diet with an average calcium content of 800 mg/day. The water intake for hydration consisted of 2 liters of an oligomineral water with a low calcium content, <20 mg/l (group A) or of a bicarbonate alkaline water with a high calcium content, 370 mg/l (group B). Results: Diuresis increased similarly in both groups; urine calcium increased by about 80 mg/day in group B. A rise in urine oxalate was observed in both groups, along with the increased urine volume. Osmolar excretion increased in group B; urine osmolality decreased significantly only in group A. In spite of the increase in calciuria in group B, Ca/citrate ratio was constant, due to an increase in citrate excretion. Inter-group differences in terms of activity products of calcium phosphate, calculated according with Tiselius’s methods, were found. The differences in AP(CaP) index 1 and AP(CaP) index 2 were significant, with higher values in group B, who drank the bicarbonate alkaline mineral water. Conclusions: Increased water intake between meals to prevent renal stone recurrence should preferably be achieved with a relatively low calcium water and calcium-rich mineral waters should be avoided.