COVID-19 and kidney: role of SARS-CoV-2 infection in the induction of renal damage.

OBJECTIVE: SARS-CoV-2 causes acute respiratory disease, interstitial and alveolar pneumonia, and involves numerous organs and systems such as the kidney, heart, digestive tract, blood, and nervous system. We aimed to evaluate the incidence of renal manifestations in patients diagnosed with COVID-19 infection. PATIENTS AND METHODS: We performed a monocentric, cross-sectional, observational study, conducted on 114 patients with SARS-CoV-2. Clinical and laboratory parameters [renal function, serum electrolytes, inflammatory state, blood gas analysis, Interleukin 6 (IL-6) and urinalysis] were evaluated. The same values were checked out after two months (T1), however after negativization. RESULTS: We enrolled 114 patients (59 males) with a mean age of 63.8 ± 13.9 years. We found hematuria in 48 patients (55.8%), proteinuria in 33 patients (38.4%), leukocyturia in 61 patients (70.9%), acute kidney injury (AKI) in 28 patients (24.6%), AKI in chronic kidney disease (CKD) in 24 patients (21.1%). Moreover, we found a significant increase of inflammatory indexes as C Reactive Protein (CRP), lactic dehydrogenase (LDH), alpha 1 and alpha 2 globulins with a subsequent reduction at T1 (p = 0.016, p < 0.001, p = 0.005, p = 0.007; respectively). Hemoglobin and erythrocyte values significantly decreased (p < 0.001, p = 0.003, respectively), and we found lymphopenia (p < 0.001). Also, we found elevated levels of the D-Dimer (p < 0.001) and a significant increase in the International Normalized Ratio (INR) (p = 0.038). We also showed a significant improvement after negativization in oxygen partial pressure (p = 0.001) and oxygen saturation (p < 0.001) and a significant increase in pH (p = 0.018) and bicarbonate concentration (p = 0.042). Moreover, we found a significant increase in IL-6 (p = 0.004). Also, we reported mild hyponatremia and hypokalemia with subsequent significant recovery (p < 0.001, p < 0.001, respectively) and mild hypochloremia with a recovery to the limits of statistical significance (p = 0.053). At the entrance, we found an increase in serum glucose with a significant reduction during recovery (p < 0.001). CONCLUSIONS: The prevalence of AKI and/or CKD and/or abnormal urinalysis in patients diagnosed with COVID-19 on admission seems to be high and appears as a negative prognostic factor. Urinalysis appears to be very useful in unveiling the potential kidney impairment of COVID-19 patients; therefore, urinalysis could be used to reflect and predict the disease severity. We also recommend a careful evaluation of metabolic alterations, inflammatory states, and electrolytic disorders in COVID-19 patients.

Screening of QTc interval and global autonomic activity in autosomal dominant polycystic kidney disease and atherosclerotic renal artery stenosis hypertensive patients.

OBJECTIVE: Arterial hypertension (AH) represents a major risk factor for cardiovascular disease and is associated to several complications, such as prolonged corrected QT (QTc) interval and impaired heart rate variability (HRV). Secondary causes of AH include autosomal dominant polycystic kidney disease (ADPKD) and atherosclerotic renal artery stenosis (ARAS), both known to be related to arrhythmic risk and autonomic imbalance. The aim of the study is to evaluate whether global autonomic activity and QTc interval differently affect ADPKD and ARAS hypertensive patients. PATIENTS AND METHODS: An observational study was performed on 59 patients: 16 ADPKD patients and 19 diagnosed with ARAS, compared to 24 healthy controls (HC). All patients underwent clinical evaluation, biochemical lab tests, 24-hour electrocardiogram (ECG) and renal Doppler ultrasound. HRV was assessed through the analysis of 24-hour ECG to detect standard deviation of normal-to-normal RR intervals (SDNN). QTc interval was defined as prolonged when > 440 msec. RESULTS: SDNN was significantly lower in ADPKD and ARAS patients than HC (p < 0.0001) and no significant differences were found between ADPKD and ARAS patients (p > 0.05). QTc was found significantly higher in ARAS patients than HC (p = 0.001) and in ARAS patients than ADPKD patients (p = 0.004). CONCLUSIONS: The pathogenesis of hypertension in ADPKD and ARAS patients is related to the activation of the renin angiotensin aldosterone system (RAAS). In ADPKD, cyst enlargement leads to kidney ischemia and renin release, associated to endothelial dysfunction, low nitric oxide and sympathetic tone activation. Differently, reduction in renal perfusion pressure activates RAAS and renal adrenergic nerves in ARAS patients. We can speculate that prolonged QTc interval is more present in ARAS vs. ADPKD hypertensive patients due to a greater activation of RAAS. We suggest adding 24-hour HRV evaluation in association with traditional risk factors in course of ADPKD and ARAS hypertension to better stratify cardiovascular risk in these groups of patients.

Uroflowmetry alterations in patients with autosomal dominant polycystic kidney disease.

OBJECTIVE: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a heterogeneous inherited disease characterized by renal and extrarenal manifestations with progressive fluid-filled cyst development leading to end-stage renal disease. Our aim was to evaluate the prevalence of obstructive urological disease in ADPKD patients and possible associations with endothelial dysfunction, nutritional, metabolic and inflammatory markers. PATIENTS AND METHODS: The study included ADPKD patients and control group, who carried out uroflowmetry, an assessment of renal function, metabolic and nutritional parameters and an evaluation of endothelial dysfunction and atherosclerotic markers, such as Renal Resistive Index (RRI), Intima-Media Thickness (IMT) and Flow-Mediated Dilation (FMD). RESULTS: We enrolled 37 ADPKD patients (20 males with 51.0 ± 14.3 years) and 34 control group (18 males with 60.7 ± 14.4 years). We showed a significant reduction in Max Flow Rate (Qmax) (p ≤ 0.001), age (p = 0.006), FMD (p = 0.023) and Voiding Volume (p = 0.053), in addition to a significant increase in Voiding Time and Diastolic Blood Pressure (p ≤ 0.001, p = 0.049; respectively) in ADPKD patients with respect to control group. Moreover, we found a negative correlation between Qmax and creatinine (r= -0.44, p = 0.007), RRI (r= -0.49, p ≤0.001) and intact Parathyroid Hormone (r = -0.329, p = 0.046), while we found a positive correlation between Qmax and MDRD (r = 0.327, p = 0.048) and between Voiding Time and serum uric acid (r= 0.34, p = 0.039) in ADPKD patients with respect to control group. CONCLUSIONS: In our study, we showed an elevated prevalence of urological functional diseases in ADPKD patients; therefore, we suggest to include uroflowmetry in the assessment of these patients, considering the non-invasiveness, repeatability and low cost of the exam. An early intervention could slow down the progression of renal damage and an early screening of the main cardiovascular risk factors could reduce the high morbidity and mortality in ADPKD patients.

Effects of infliximab on sister chromatid exchanges and chromosomal aberration in patients with rheumatoid arthritis.

The aim of this study was to evaluate in a 24-weeks the effect of anti-TNF-alpha, infliximab, on cytogenetic biomarkers in peripheral lymphocytes of patients with rheumatoid arthritis (RA). A total of 40 patients with RA met the criteria to be treated with methotrexate (15 mg/week) were evaluated. Twenty patients, randomly selected, were treated with infliximab in addition to methotrexate (group I), whereas the other 20 patients continued with only methotrexate treatment (group M). Twenty healthy volunteers matched for age, gender and smoking habits served as control group (group C). At baseline, sister chromatid exchange rate was 7.20 ± 2.21 in group I, 7.40 ± 1.60 in group M and 4.97 ± 1.32 in group C (P < 0.01 vs group I and M). After 24-weeks, sister chromatid exchange rate was 7.87 ± 2.54 in group I and 7.81 ± 1.95 in group M (P = ns). High frequency cells count was 4.9 % and 4.7 % in the groups I and M, respectively, at the end of the study (P = ns). The basal chromosomal aberration frequency was 4.90 % in group I and 5.20 % in groups M; after 24-weeks, this was 5.10 % in group I and 5.10 % in groups M (P = ns). Infliximab treatment, for 24 weeks, did not increase the cytogenetic biomarkers in patients with RA. Our data show that the use of infliximab has not a genotoxic effect in patients with RA.

Further vitamin D analogs.

In this brief review we point out the specificities of the vitamin D system that are necessary to understand why each change in the molecule can result in significantly different biologic effects. Vitamin D, with a specific receptor in most of the tissues, has innumerable potential therapeutic applications in many clinical fields. However, excessive pharmacologic increments of circulating natural metabolites carry the risk of significant side effects. To avoid this, natural vitamin D molecules have been modified to more selectively stimulate some tissues. Changes have been attempted on particular parts of the molecule in order to affect some specific step of the complex machinery that characterize the vitamin D system. The first modifications were those in the side chain of the molecule, which are expected to affect, either or both, the steps of binding to transfer protein or the interaction with catabolic enzymes. More recently other regions, like A-ring (involved with receptor interaction) or CD bicyclic ring (involved with molecule stability), have been modified to obtain always more selective products. Notably each modification of the molecule also affects its shape thus further and variably modifying its interaction with the VDR, with the transport proteins or the catabolic enzymes. As a consequence, the biologic effects of new molecules become less predictable and require in vitro evaluation, experimental animal studies and a complete and specific clinical validation in specific disease states. With thousands of analogs synthesized in the laboratories, only a minority are approved for clinical employment. Besides secondary hyperparathyroidism and osteoporosis, Vitamin D analogs can be employed in other clinical conditions like cancer and autoimmunity diseases. We briefly report on some new experimental or already approved analogs in their main clinical fields of employment.

Vitamin D metabolites and/or analogs: which D for which patient?

Numerous drugs with vitamin D activity are available for clinical use and it may not be easy for the nonspecialist to select the most suitable for the individual patient. In this paper we review the main characteristics of the available drugs and provide evidence about any potential specific clinical indications, with special emphasis on renal patients, in order to facilitate the optimal choice. Natural vitamin D products (i.e. those identical to natural metabolites) are first examined, followed by the most frequently used synthetic molecules (i.e. bioengineered molecules not-existing in nature), which are generally indicated as " analogs". Either cholecalciferol, ergocalciferol or calcifediol can be employed in subjects with normal renal function and in CKD stage 3-5 patients to correct vitamin D deficiency and improve, respectively, age- or growth-related bone disease and secondary hyperparathyroidism. Calcifediol can be considered more rapid and effective. In all cases, especially with increasing doses, the risk of hypercalcemia must be taken into account. Calcitriol, which can be regarded as the active hormonal form of vitamin D, has the most potent hypercalcemic effect in both normal and renal failure patients. In renal patients calcitriol is a potent inhibitor of parathyroid activity, but the risk of hypercalcemia, now regarded as harmful, is evident whenever pharmacologic doses are used. Alfacalcidol, requiring 25-hydroxylation to become the active hormonal form of vitamin D3, is prescribed in normal subjects to treat osteoporosis and in renal patients to cure hyperparathyroidism and renal bone disease. Doxercalciferol, transformed into the active hormonal form of vitamin D2 following 25-hydroxylation, is mostly studied in renal patients in whom it cures secondary hyperparathyroidism, possibly with a lower calcemic effect than calcitriol. Paricalcitol, a vitamin D2 analog not requiring activation, has been specifically developed to suppress PTH in renal patients with a limited calcemic effect. As such it is now regarded as a powerful drug useful to treat even severe cases of secondary hyperparathyroidism. Importantly, reno-protective and cardio-protective effects of this analog have been recently evaluated by means of randomized clinical trials in renal patients with partially positive renal effects and negative cardiac results, thus additional studies are needed for confirmation. 22-oxacalcitriol, a vitamin D3 analog with a limited calcemic effect available in Japan, is mostly used in renal patients affected by secondary hyperparathyroidism. The clinical activity of some vitamin D analogs is such that they can be employed in diseases like cancer and autoimmunity. The clinical activity of some vitamin D analogs is such that they can be employed in diseases like cancer and autoimmunity. In summary, available drugs with vitamin D like activity are not all the same either in terms of pharmacological actions, and side-effects. They have specific characteristics that may be useful to know in order to operate the best choice in the individual patient.

Efficacy of genistein aglycone on some cardiovascular risk factors and homocysteine levels: A follow-up study.

BACKGROUND AND AIM: Recent evidence suggests that genistein aglycone may act beneficially on surrogate cardiovascular risk markers in postmenopausal women. We assessed the effects of genistein aglycone on some cardiovascular risk factors and homocysteine levels after 3-years of continued therapy in a cohort of osteopenic, postmenopausal women. METHODS AND RESULTS: The parent study was a randomized, double-blind, placebo-controlled trial involving 389 postmenopausal women with low bone mass for 24 months. Subsequently, a subcohort (138 patients) continued therapy for an additional year. Participants received 54mg of genistein aglycone (n=71) or placebo (n=67), daily. Both arms received calcium and vitamin D(3) in therapeutic doses. Moreover, 4 weeks before randomization procedures and during our follow-up study, all patients received dietary instructions in an isocaloric fat-restricted diet. Blood lipid profiles, fasting glucose and insulin, insulin resistance (HOMA-IR), fibrinogen, osteoprotegerin (OPG) and homocysteine at baseline and after 24 and 36 months of treatment were measured. Compared to placebo, genistein significantly decreased fasting glucose and insulin, HOMA-IR, fibrinogen and homocysteine after 24 and 36 months of treatment. By contrast, isoflavone administration did not affect high-density lipoprotein cholesterol and triglycerides though serum OPG was higher in the genistein recipients. There were no differences in adverse events or discomfort between groups. Results on routine biochemical, liver function, and hematologic testing did not change over time in placebo or genistein group. CONCLUSIONS: After 3-years of treatment, genistein aglycone plus calcium, vitamin D(3) and a healthy diet showed positive effects on some cardiovascular risk factors and homocysteine levels in a cohort of postmenopausal women with low bone mass.

[Understanding the different functions of vitamin D]. / Vitamina D: capirne ed analizzarne le diverse funzioni.

Exposure of the skin to sunlight is now considered the most important source of vitamin D in Western countries. It is presumed to contribute approximately two thirds of the total requirement, leaving the remaining one third to the few foods naturally rich in this vitamin. In the skin, vitamin D is synthesized as a cholesterol chain which undergoes structural modifications following exposure to UVB rays. Once produced in the skin or absorbed in the gut as cholecalciferol, vitamin D enters the blood to be transported by a specific vitamin D binding protein, which is synthesized in the liver and has a powerful buffering capacity. The transport system carries the metabolites to the sites of further activation (25-hydroxylation in the liver and 1alpha-hydroxylation in the kidney), ultimately resulting in the production of calcitriol. This last compound, now regarded as a hormone, circulates freely in minimal amounts and, compared with the other metabolites, shows the highest affinity for the vitamin D receptor (VDR). The mechanism of VDR activation is rather complex, resulting in either stimulation or inhibition of protein synthesis. Importantly, besides its presence in parathyroid, bone, kidney and intestine, this receptor has been demonstrated in several tissues, where its stimulation results in a reduced proliferation rate and increased differentiation. Accordingly, vitamin D is now regarded as a complex hormonal system, involved not only in the regulation of divalent ions and bone, but also in the proliferation and differentiation of numerous cell types with potential involvement in several diseases like cancer, immune diseases, diabetes, hypertension and heart failure.

[Calcimimetics, phosphate binders, vitamin D and its analogues for treating secondary hyperparathyroidism in chronic kidney disease: guideline from the Italian Society of Nephrology]. / Utilizzo della vitamina D e analoghi, dei chelanti del fosforo e dei calciomimetici nella terapia dell'iperparatiroidsmo secondario e della patologia ossea nelle nefropatie croniche: Linea Guida.

BACKGROUND: The current 3rd edition of the Italian Society of Nephrology guidelines has been drawn up to summarize evidence of key intervention issues on the basis of systematic reviews (SR) of randomized trials (RCT) or RCT data only. In the present guideline, evidence of the use of calcimimetics, phosphate binders, vitamin D and vitamin D analogues for treating secondary hyperparathyroidism in chronic kidney disease (CKD) is presented. METHODS: SR of RCT and RCT on interventions for secondary hyperparathyroidism in CKD were identified referring to a Cochrane Library and Renal Health Library search (2005 update). RESULTS: Three SR and 8 RCT were found addressing this intervention issue. Methodological quality of available RCT was suboptimal according to current methodological standards. Calcimimetics used in patients receiving haemodialysis or peritoneal dialysis are more effective than placebo in controlling secondary hyperparathyroidism (reduced parathyroid hormone levels, calcium levels and phosphorus levels). All phosphate binders are effective in controlling hyperphosphatemia but different doses are to be used with different agents to achieve similar targets. Dosing needs to be adjusted according to phosphorus levels. Vitamin D and its analogues are recommended in CKD patients, although there is no significant evidence of superiority of individual agents in head-to-head comparisons. Dosing should be based on baseline parathyroid hormone levels, but the risk of hypercalcemia should also be considered. CONCLUSION: Available evidence suggests that calcimimetics, phosphate binders and vitamin D or its analogues are effective in the treatment of secondary hyperparathyroidism. Superiority of individual agents or doses is still deeply debated. Further studies are necessary to test these issues.

[Comparison among ecography, scintigraphy and surgery in the localization of parathyroid glands in uremic patients undergoing parathyroidectomy]. / Confronto tra ecografia, scintigrafia e chirurgia nella localiz- zazione delle ghiandole paratiroidi nei pazienti uremici in dialisi sottoposti a paratiroidectomia.

BACKGROUND: Sensitivity and specificity of the most widely employed techniques of parathyroid glands localization, namely echography and scintigraphy, are mostly obtained with short-term follow-up data and do not underline the existence of a methodological problem. As a matter of fact, both methods identify only pathological glands, with no "normal" results; therefore "true negatives" cannot be obtained. Aim of our study was to compare, by means of a statistically appropriate approach, the results of echography, scintigraphy and surgery with the data obtained after a mid term follow-up period, enabling us to discover all parathyroid glands. METHODS: Twenty six consecutive dialysis patients (14M/12F; age 50+/-12 years) underwent echography and scintigraphy immediately before a total parathyroidectomy with autotransplantation and were followed-up for 6 months to recognize all the existing glands (PTH levels and scintigraphy). RESULTS: Total identified glands were: 73 by scintigraphy, 86 by echography, 99 by surgery and 103 by follow-up data. The concordance indexes (K0) between the number of glands effectively present in the individual patient (follow-up data) and those identified with each method were rather low with scintigraphy (0.071) and echography (0.218), and acceptable (0.578) with surgery. The number of patients correctly classified was: 9/26 (34,6%) with scintigraphy, 13/26 (50%) with echography and 22/26 (85%) with surgery. Finally, the number of wrongly identified glands (from zero to three) in each patient was similar with scintigraphy (65,4%) and echography (50%) and significantly better with surgery (15,6%; p<0.01). CONCLUSIONS: The most reliable technique to identify parathyroid glands in uremic subjects is surgery, nonetheless a meticulous clinical follow-up is necessary to recognize all of them.

Gender differences in serum markers of bone resorption in healthy subjects and patients with disorders affecting bone.

To assess how two different serum markers of bone resorption may reflect changes in bone turnover, we compared age- and sex-related changes in serum C-terminal telopeptide of type I collagen (betaCTx) and tartrate-resistant acid phosphatase activity (TRAP) in 136 healthy men and 184 normal women. Serum levels of the two markers were also assessed in several groups of patients of both sexes presenting with the most common metabolic and endocrine bone diseases: established osteoporosis (n = 77), primary hyperparathyroidism (n = 44), glucocorticoid excess (n = 17), chronic renal failure (n = 39), active Paget's disease of bone (n = 5), humoral hypercalcemia of malignancy (n = 3), osteomalacia (n = 3), hyperthyroidism (n = 10), post-surgical hypoparathyroidism (n = 10), acromegaly (active disease, n = 8) and Cushing's syndrome (n = 10). In men the regression of betaCTx with age showed an initial decrease in bone resorption followed by an increase thereafter, starting from the sixth decade of life. No age-related change in serum TRAP activity was observed. In women, by contrast, a slight but significant linear correlation of both serum betaCTx and TRAP with age (r = 0.223, p<0.003 and r = 0.333, p<0.0001, respectively) was found, the two markers being positively correlated (r = 0.238, p<0.002). In each class of patients the mean Z-scores of betaCTx were significantly higher than those of TRAP activity. Moreover, compared with normal subjects, serum betaCTx seems to be characterized by a superior sensitivity relative to TRAP measurement, at least in the disorders studied.

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

AIMS: The histomorphometric assessment of bone formation rate (BFR/BS) in bone biopsies from uraemic patients is of crucial importance in differentiating low from high turnover types of renal osteodystrophy. However, since BFR/BS relies on osteoblasts, activation frequency (Ac.f), encompassing all remodelling phases, has recently been preferred to BFR/BS. This study was carried out to consider whether estimation of Ac.f is superior, in practical terms, to that of BFR/BS in distinguishing between different rates of bone turnover in uraemic patients. METHODS AND RESULTS: Bone biopsies from 27 patients in predialysis (20 men and seven women; mean age 53 +/- 12 years) and 37 in haemodialysis (22 men and 15 women; mean age 53 +/- 12 years) were examined. The types of renal osteodystrophy were classified on the basis of morphology. Bone formation rate and Ac.f were evaluated according to standardized procedures. The Ac.f was calculated both as a ratio between BFR/BS and wall thickness (W.Th) and as a reciprocal of erosion, formation and quiescent periods (EP, FP and QP). Patients were affected by renal osteodystrophy with predominant hyperparathyroidism (two predialysis and 16 dialysis), predominant osteomalacia (three predialysis and seven dialysis) or that of advanced (nine predialysis and five dialysis) or mild (seven predialysis and four dialysis) mixed type or adynamic type (six predialysis and five dialysis). Activation frequency, which with either formula requires the measurement of W.Th, i.e. the thickness of bone structural units (BSUs), was not calculated in three dialysis patients with severe hyperparathyroidism and in one predialysis and four dialysis patients with severe osteomalacia, because only incomplete BSUs were found. In dialysis, EP was higher in the adynamic than in the other types of osteodystrophy. During both predialysis and dialysis, FP was higher in osteomalacia than in the other forms of osteodystrophy, and in adynamic osteopathy than in hyperparathyroidism or in advanced and mild mixed osteodystrophy. During predialysis and dialysis, QP was higher in the adynamic than in the other forms of osteodystrophy. Correlations were found between BFR/BS and Ac.f, during predialysis (r=0.97) and dialysis (r=0.95). CONCLUSIONS: The superiority of Ac.f in assessing bone turnover, in comparison to BFR/BS, is conceptual rather than practical. The highest values for FP in osteomalacia and for QP in adynamic bone allow a clearer characterization of these low turnover conditions.

Changes in bone turnover after parathyroidectomy in dialysis patients: role of calcitriol administration.

BACKGROUND: Available data on changes in serum levels of bone markers after parathyroidectomy (PTx) in dialysis patients are not uniform. Changes are thought to be due to either a reduction in PTH activity per se or to a direct effect of vitamin D therapy on bone cells. We aimed to verify whether treatment with vitamin D modifies serum levels of markers of bone synthesis (alkaline phosphatase (AP), osteocalcin (BGP), procollagen type I C-terminal peptide (PICP)) and resorption (collagen type I C-terminal peptide (ICTP)) within a period of 15 days in haemodialysis patients with severe secondary hyperparathyroidism following PTx. METHODS: We randomized two groups (A, treatment and B, placebo, 10 patients each) with comparable basal PTH values and measured bone markers 3, 7 and 15 days after surgery. All patients were treated with calcium supplements (i.v. and p.o.), and group A also received calcitriol (2.4+/-1.0 microg/day, p.o.). RESULTS: In both groups, PTx induced significant changes in all the markers evaluated, except for BGP in group B. Compared to basal values, ICTP decreased from 481+/-152 ng/ml in group A and 277+/-126 ng/ml in group B to 267+/-94 and 185+/-71 ng/ml (M+/-SD) respectively, and PICP increased from 307+/-139 ng/ml in group A and 309+/-200 ng/ml in group B to 1129+/-725 and 1231+/-1267 ng/ml (M+/-SD) respectively, within 3 days of surgery. AP values increased after 15 days from 1115+/-734 mU/ml in group A and 1419+/-1225 mU/ml in group B to 1917+/-1225 and 1867+/-1295 mU/ml (M+/-SD) respectively. On the contrary, mean values of BGP were never different from basal levels after PTx in either group. In the two groups, the pattern of changes of all the bone markers after PTx was almost identical. Group A patients predictably required lower doses of oral calcium supplements to correct hypocalcaemia (16. 9+/-5.7 vs 22.1+/-5.0 g/10 days; M+/-SD, P<0.04). CONCLUSIONS: The opposite behaviour of serum PICP and ICTP after PTx, in both the treated and untreated groups suggests that quantitative uncoupling between bone synthesis and resorption is responsible for hypocalcaemia. This phenomenon, as reflected by the evaluated bone markers, is unaffected by calcitriol. Based on our data we conclude that immediately after parathyroid surgery, vitamin D therapy does not influence bone cell activity, but improves hypocalcaemia mainly through its known effect on intestinal calcium absorption.

Immunohistochemical study of fatty acid synthase, Ki67, proliferating cell nuclear antigen, and p53 expression in hyperplastic parathyroids.

Patients with secondary hyperparathyroidism following chronic renal disease frequently develop hyperplastic parathyroids. Hyperplastic parathyroids have an increased number of chief cells, a decreased amount of stromal fat, and a nodular or diffuse histologic pattern. Hyperplastic parathyroids may also express higher proliferative activity compared with controls. We evaluated the morphologic features and immunohistochemical expression of fatty acid synthase (FAS), Ki67, proliferating cell nuclear antigen, and p53 protein in 78 hyperplastic parathyroids from 20 patients with secondary hyperparathyroidism. Twenty normal parathyroids incidentally removed during nonneoplastic thyroid surgery were used as controls. Our results showed that hyperplastic glands overexpress FAS (P =.06). Statistical analysis also revealed a significant association between FAS and p53 protein (P =.006) and between FAS and hyperplastic glands with a predominant nodular pattern (P =.02). Hyperplastic parathyroids from patients with chronic renal failure strongly express FAS. Fatty acid synthase may therefore be a potential biological indicator of highly proliferating parathyroid cells.

Prospective evaluation of total parathyroidectomy and autotransplantation for the treatment of secondary hyperparathyroidism.

OBJECTIVE: To evaluate the clinical effectiveness of total parathyroidectomy with autotransplantation for the treatment of hyperparathyroidism and the recurrence rate of hyperparathyroidism after this procedure. DESIGN: A prospective study of total parathyroidectomy and autotransplantation in 19 consecutive patients with severe secondary (renal) hyperparathyroidism. SETTING: University hospital department of surgery. PATIENTS: Nineteen patients operated on for the treatment of secondary hyperparathyroidism between March 1993 and March 1996. Eighteen had been receiving longterm hemodialysis, and 1 had a functioning renal graft. INTERVENTION: Total parathyroidectomy and autotransplantation of excised parathyroid tissue into the brachioradialis muscle of the arm opposite that in which the arteriovenous fistula had been placed for dialysis. MAIN OUTCOME MEASURES: Clinical and biochemical improvement, morbidity, mortality, and recurrence rates of hyperparathyroidism after the procedure. RESULTS: The conditions of 13 (72%) of 18 patients followed up improved, and the clinical and laboratory variables indicating secondary hyperparathyroidism returned to normal. One patient died 50 days after surgery. In 2 patients (10%), mild hypoparathyroidism developed, and in 1 patient (5%), persistent hyperparathyroidism developed and required reoperation. In 2 patients (10%), recurrent hyperparathyroidism developed, and 1 (5%) required reoperation. CONCLUSIONS: Total parathyroidectomy with autotransplantation effectively relieves the symptoms of hyperparathyroidism, and the recurrence rate of hyperparathyroidism is low. Because all procedures used resulted in good control of clinical and biochemical variables, the method used for the surgical treatment of secondary hyperparathyroidism depends on the surgeon's preference.

Bone markers in the diagnosis of low turnover osteodystrophy in haemodialysis patients.

BACKGROUND: Renal osteodystrophy includes a number of low and high turnover bone histologic patterns which require a bone biopsy for their full identification. The role of intact PTH and several classical and more recent bone markers in the non-invasive diagnosis of renal bone disease in patients with CRF in HD requires further definition since available published data are limited. METHODS: In addition to intact PTH, alkaline phosphatase (AP) and osteocalcin (BGP), bone alkaline phosphatase isoenzyme (BALP), tartrate resistant acid phosphatase (TRAP), C-terminal cross-linked peptide of collagen type 1 (ICTP) and deoxypyridinoline (DPD) were measured in the serum of 41 patients on haemodialysis, subjected at the same time to transiliac bone biopsy for histomorphometric, histodynamic and aluminium histochemical examination. Histodynamic evaluation following double tetracycline label, was carried out in 37 patients. The patients had no evidence of active cytolytic and cholestatic liver disease and a history of very limited aluminium exposure. RESULTS: The patients had differing degrees of hyper-parathyroidism, with intact PTH ranging from normal to very elevated levels. Serum values of the markers BGP, ICTP and DPD, normally excreted through the kidneys, were on average very high. The correlation coefficients of the humoral parameters vs dynamic variables, such as BFR/BS, were high. The highest values were: intact PTH 0.798, AP 0.900, BALP 0.891, ICTP 0.807. The patients, grouped in low turnover osteodystrophy (LTO; 9), mixed osteodystrophy (MO; 9) and prevalent hyperparathyroidism (HP; 23), showed significant difference in the levels of most humoral and static and dynamic parameters (ANOVA). Bone aluminium histochemistry was negative in all cases. Discrimination of LTO patients from the other groups by humoral parameters, at the highest value of accuracy, showed 100% sensitivity and 93.7% specificity with a cut-off of 12.9 ng/ml for BALP; 88.9% sensitivity and 93.7% specificity with a cut-off of 21.5 ng/ml for DPD, and 88.9% sensitivity and 90.6% specificity with a cut-off of 79.7 pg/ml for intact PTH. The other markers had lower values. A standardized z-score approach for evaluation of all humoral parameters was also carried out. Using all variables, a correct classification of MO/HP and of LTO was possible in 93.8 and 88.9% of the cases, respectively. Predictive power was 96.8 and 80%, respectively for MO/HP and LTO. When the only variables used were intact PTH and BALP, a correct classification of MO/HP and LTO was possible in 90.6% and 88.9%, respectively. Predictive value of MO/HP was 96.7% and for LTO 72.7%. Predictive values using PTH and AP were 96.3% and 57.2%, respectively. CONCLUSION: Intact PTH and several relatively new bone markers are of certain value in the non-invasive diagnosis of renal osteodystrophy. However some of the humoral markers carry the same quality of information and the use of intact PTH and BALP may be adequate in the discrimination of bone histologic patterns. In cases exempt from liver disease, PTH and AP may be used as a less costly alternative. Bone biopsy could be chiefly limited to cases with borderline humoral values and to all those with a suspected aluminium overload.

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.

Extent of alkaline phosphatase cytochemistry vs. extent of tetracycline fluorescence in the evaluation of histodynamic variables of bone formation.

Alkaline phosphatase (ALP) activity is a new histomorphometric index of the extent of osteoblastic surfaces involved in mineralization. To assess its validity in the evaluation of bone formation, we carried out a comparative study between histomorphometric values obtained on the basis of the extent of tetracycline labeling and of the length of ALP-positive endosteal surfaces. The following variables were compared (indicated by ALP when based on the extent of ALP positivity): trabecular mineralizing surface (MS/BS vs. ALP.S/BS); osteoid mineralizing surface (MS/OS vs. ALP.S/OS); bone formation rate (BFR/BS vs. ALP.BFR/BS); and adjusted appositional rate (Aj.AR vs. ALP.Aj.AR). Bone biopsies from 39 patients with chronic renal failure and different types of renal osteodystrophy were considered (48 +/- 12 years of age; 19 men and 20 women). Patients were double labeled with tetracycline and biopsies were embedded in glycol-methacrylate at +4 degrees C. Patients showed various types of renal osteodystrophy and were assigned to different groups of pathologies. Although it differed in incidence according to the different groups, ALP activity was found in typical plump osteoblasts bordering osteoid seams and in flat cells, either in contact with osteoid or along the quiescent surfaces of bone in continuity with it. Tetracycline codistributed with all these features to variable extents, according to groups. In all patients, however, ALP.S/BS and ALP.S/OS respectively exceeded MS/BS and MS/OS. In consequence of this, ALP.BFR/BS and ALP.Aj.AR were greater than BFR/BS and Aj.AR, respectively. For each of the variable considered, differences among groups of patients with different types of renal osteodystrophy were highly significant. Good correlations were found between the variables measured with the two methods.(ABSTRACT TRUNCATED AT 250 WORDS)

Diagnostic value of serum peptides of collagen synthesis and degradation in dialysis renal osteodystrophy.

The assay of serum peptides of bone collagen formation and degradation could potentially provide an indirect estimate of the rate of bone turnover. In our study we have measured serum levels of the carboxy-terminal propeptide of type I procollagen (PICP) as a marker of bone formation and serum levels of the pyridinoline cross-linked telopeptide domain of type I collagen (ICTP) as a marker of bone resorption in 53 patients (47.7 +/- 10 years, M +/- SD) on haemodialysis (for 9.5 +/- 3.8 years) and affected by renal osteodystrophy. Besides PICP and ICTP, patients were also sampled for serum intact and C-terminal PTH, osteocalcin (BGP) and alkaline phosphatase (AP). A transiliac bone biopsy for histomorphometry was also performed in all. As expected both PTH assays, BGP and AP, were correlated reciprocally and to histomorphometric parameters. As for serum levels of PICP, they were on average increased (268.5 +/- 104.9 ng/ml, M +/- SD) compared to normals (range 66-176), but not correlated to classical humoral markers of hyperparathyroidism (PTH and AP), with the exception of BGP (with a rather low r value: 0.365, P < 0.01), nor to histomorphometric indices of bone resorption and formation.(ABSTRACT TRUNCATED AT 250 WORDS)