Parathyroidectomy and survival in a cohort of Italian dialysis patients: results of a multicenter, observational, prospective study.

BACKGROUND: Severe secondary hyperparathyroidism (SHPT) is associated with mortality in end stage kidney disease (ESKD). Parathyroidectomy (PTX) becomes necessary when medical therapy fails, thus highlighting the interest to compare biochemical and clinical outcomes of patients receiving either medical treatment or surgery. METHODS: We aimed to compare overall survival and biochemical control of hemodialysis patients with severe hyperparathyroidism, treated by surgery or medical therapy followed-up for 36 months. Inclusion criteria were age older than 18 years, renal failure requiring dialysis treatment (hemodialysis or peritoneal dialysis) and ability to sign the consent form. A control group of 418 patients treated in the same centers, who did not undergo parathyroidectomy was selected after matching for age, sex, and dialysis vintage. RESULTS: From 82 Dialysis units in Italy, we prospectively collected data of 257 prevalent patients who underwent parathyroidectomy (age 58.2 ± 12.8 years; M/F: 44%/56%, dialysis vintage: 15.5 ± 8.4 years) and of 418 control patients who did not undergo parathyroidectomy (age 60.3 ± 14.4 years; M/F 44%/56%; dialysis vintage 11.2 ± 7.6 y). The survival rate was higher in the group that underwent parathyroidectomy (Kaplan-Meier log rank test = 0.002). Univariable analysis (HR 0.556, CI: 0.387-0.800, p = 0.002) and multivariable analysis (HR 0.671, CI:0.465-0.970, p = 0.034), identified parathyroidectomy as a protective factor of overall survival. The prevalence of patients at KDOQI targets for PTH was lower in patients who underwent parathyroidectomy compared to controls (PTX vs non-PTX: PTH < 150 pg/ml: 59% vs 21%, p = 0.001; PTH at target: 18% vs 37% p = 0.001; PTH > 300 pg/ml 23% vs 42% p = 0.001). The control group received more intensive medical treatment with higher prevalence of vitamin D (65% vs 41%, p = 0.0001), calcimimetics (34% vs 14%, p = 0.0001) and phosphate binders (77% vs 66%, p = 0.002). CONCLUSIONS: Our data suggest that parathyroidectomy is associated with survival rate at 36 months, independently of biochemical control. Lower exposure to high PTH levels could represent an advantage in the long term.

Inflammation, Oxidative Stress, and Bone in Chronic Kidney Disease in the Osteoimmunology Era.

Bone is not only a mineralized and apparently non-vital structure that provides support for locomotion and protection to inner organs. An increasing number of studies are unveiling new biologic functions and connections to other systems, giving the rise to new fields of research, such as osteoimmunology. The bone marrow niche, a new entity in bone physiology, seems to represent the site where a complex crosstalk between bone and immune/inflammatory responses takes place. An impressive interplay with the immune system is realized in bone marrow, with reciprocal influences between bone cells and haematopoietic cells. In this way, systemic chronic inflammatory diseases realize a crosstalk with bone, resulting in bone disease. Thus, pathogenetic links between chronic kidney disease-mineral bone disorders and osteoporosis, cardiovascular disease, and ageing are common. The aim of this narrative review is to provide a general view of the progresses in the field of bone research and their potential clinical implications, with emphasis on the links with inflammation and the connections to osteoimmunology and chemokines.

A new technique for measuring fistula flow using venous blood gas oxygen saturation in patients with a central venous catheter.

BACKGROUND: Doppler ultrasound (DU) monitoring early after arteriovenous fistula (AVF) creation allows the identification of low blood flow (Qa) requiring prompt revision, but it is costly (needs skilled operators and technical instruments) and is not available in all dialysis units. Therefore alternative first-line methods to measure Qa would be welcomed. We reasoned that once an AVF is created, an increment in central venous oxygen saturation (ScvO2) is predictable and proportional to Qa. METHODS: Accordingly, in patients receiving dialysis through a central venous catheter (CVC) in whom an AVF was created, we measured, by means of blood gas analysis, the ScvO2 increment before and after manual compression of the arteriovenous shunt and verified its correlation with DU-measured Qa. RESULTS: We sampled blood gas in 18 patients with CVC and AVF before and after 30 s manual compression of the AVF. ScvO2 averaged 70.5 ± 3% before and 65.2 ± 3% after AVF closure, with an average drop of 5.1 ± 3% (range 1-12). AVF Qa, which was measured within 24 h by means of DU, averaged 635 ± 349 mL/min (range 50-1300) and was strictly and positively correlated with ΔScvO2 (r = 0.954, P < 0.0001). CONCLUSIONS: Therefore we suggest that in patients with CVC and a newly created AVF, it is possible to monitor AVF Qa without DU by simply measuring blood gas and ΔScvO2. This technique is simple, cheap, repeatable, non-invasive and operator independent and represents a new useful screening test to detect delayed AVF access maturation deserving prompt DU measurement and surgical revision. It helps to quickly identify patients in urgent need of DU verification and possible surgical revision. Regrettably, it is applicable only in patients with CVC.

On the role of skin biopsy in the diagnosis of calcific uremic arteriolopathy: a case-based discussion.

Calciphylaxis is a rare disease characterized by ectopic calcification of skin arterioles resulting in ischemia, thrombosis and necrosis. Since end stage renal disease patients are those mainly affected, the term calcific uremic arteriolopathy (CUA) is also suggested. Early clinical manifestations are subtle, while overt necrotic ulcers may quickly spread and become infected so as to result in ominous outcome. Diagnosis might not be easy due to the number of other ischemic and non-ischemic skin lesions observed in uraemia. Skin biopsy, has been proposed as the diagnostic test and is often considered, but not systematically performed due to the hypothetical risk of further spreading of the lesions. Such ambiguity could be responsible for misdiagnosis or underdiagnosis. We review here five consecutive cases recorded in our Unit, all submitted to skin biopsy but with inconsistent results which generated some clinical frustration. Thus, we decided to carefully re-evaluate all of them together with pathologists and dermatologists. However, even after this ex-post discussion, we could not reach a complete agreement on the final diagnosis. In the meanwhile, papers were published in the literature that started to shed some light on the role of skin biopsy in the diagnosis of CUA.

Multicenter study on parathyroidectomy (PTX) in Italy: preliminary results.

BACKGROUND: When medical therapy is unable to achieve biochemical control of secondary hyperparathyroidism, parathyroidectomy (PTX) is indicated, fortunately in a minority of patients. Thus, data on PTX prevalence and biochemical control are limited and, in particular in Italy, date back to 1999. METHODS: We designed a prospective, observational and multicenter study to collect data from dialysis units distributed throughout the Italian regions. Clinical data were collected with a dedicated data sheet. RESULTS: From January to December 2010, 149 Centers serving a total of 12,515 patients provided data on 528 living PTX cases (PTX prevalence = 4.2%). Prevalence was higher in hemo- than in peritoneal dialysis (4.5 vs. 1.9%, X2 = 21.52; p < 0.001), with non-significant regional differences (range 0.8-7.4%). PTX patients were younger (57.6 ± 12.5 vs. 67.1 ± 14.5 years; p < 0.001), more frequently female (56 vs. 38%, X2 = 68.05, p < 0.001) and had been on dialysis for a longer time (14.63 ± 8.37 vs. 4.8 ± 6.0 years, p < 0.001) compared to the 11,987 who did not undergo neck surgery. Median time since surgery was 6.0 years (3.0-9.0; 50%, IQR). The most frequent type of surgery was subtotal PTX (sPTX = 55.0%), significantly higher than total PTX (tPTX = 38.7%) or total PTX plus auto-transplantation (aPTX = 6.3%) (X2 = 5.18; Bonferroni post-hoc test, sPTX vs. tPTX + aPTX = p < 0.05). As for parathyroid hormone (PTH), calcium and phosphate control, cases targeting the KDOQI ranges were 18, 50.1 and 54.4%, respectively. The most prevalent biochemical condition was low PTH (62.7%). CONCLUSION: PTX prevalence in Italy is stable compared to previous observations, is higher in hemodialysis than in peritoneal dialysis and results in a suboptimal biochemical control.

Positioning novel biologicals in CKD-mineral and bone disorders.

Renal osteodystrophy (ROD), the histologic bone lesions of chronic kidney disease (CKD), is now included in a wider syndrome with laboratory abnormalities of mineral metabolism and extra-skeletal calcifications or CKD-mineral and bone disorders (CKD-MBD), to highlight the increased burden of mortality. Aging people, frequently identified as early CKD, could suffer from either the classical age-related osteoporosis (OP) or ROD. Distinguishing between these two bone diseases may not be easy without bone biopsy. In any case, besides classical therapies for ROD, nephrologists are now challenged by the possibility of using new drugs developed for OP. Importantly, while therapies for ROD mostly aim at controlling parathyroid secretion with bone effects regarded as indirect, new drugs for OP directly modulate bone cells activity. Thus, their action could be useful in specific types of ROD. Parathyroid hormone therapy, which is anabolic in OP, could be useful in renal patients with low turnover bone disease. Denosumab, the monoclonal antibody against receptor activator of NF-κB ligand (RANK-L) that inhibits osteoclast activity and proliferation, could be beneficial in cases with high turnover bone. Use of romosozumab, the monoclonal antibody against sclerostin, which both stimulates osteoblasts and inhibits osteoclasts, could allow both anabolic and anti-resorptive effects. However, we should not forget the systemic role now attributed to CKD-MBD. In fact, therapies targeting bone cells activity could also result in unpredicted extra-bone effects and affect cardiovascular outcomes. In conclusion, the new biologicals established for OP could be useful in renal patients with either OP or ROD. In addition, their potential non-bone effects warrant investigation.

News on biomarkers in CKD-MBD.

The increased awareness of the potential role played by mineral and bone disorder in the appearance of cardiovascular disease in renal patients has produced research efforts aimed at discovering possible pathogenic links. Accordingly, the diagnostic significance of the classic bone markers of mineral disorders and of the new markers in the setting of chronic kidney disease-mineral and bone disorders (CKD-MBD) needs to be re-evaluated along with increasing information. In this article we include classic markers of bone metabolism and some of the noncollagenous bone proteins that are gaining experimental and clinical significance in CKD-MBD. Among classic markers of secondary hyperparathyroidism and of renal osteodystrophy, we analyzed parathyroid hormone, alkaline phosphatase, tartrate-resistant acid phosphatase, and bone collagen-derived peptides. We underlined, for each, the relevance of parent proteins (peptides or isoforms) that affect assay methods and, eventually, the diagnostic or prognostic significance. Also, we considered their relationship with cardiovascular mortality. Among the numerous noncollagenous bone proteins, we examined matrix Gla protein (MGP), osteocalcin (OC), osteoprotegerin, and the small integrin-binding ligand N-linked glycoprotein family. For MGP and OC we report the relevant involvement with the process of calcification (MGP) and with glucose and energy metabolism (OC). Both of these proteins require vitamin K to become active and this is a specific problem in renal patients who frequently are deficient of this vitamin. Finally, recent acquisitions on the fascinating family of the small integrin-binding ligand N-linked glycoprotein proteins are recapitulated briefly to underline their potential clinical interest and their complex involvement with all aspects of CKD-MBD. Their diagnostic role in clinical practice awaits further studies.

[Update on the pathogenesis and possible therapeutic approach to vascular calcifications in patients with chronic renal failure]. / Update sulla patogenesi e sul possibile approccio terapeutico alle calcificazioni vascolari nel paziente con insufficienza renale.

Chronic renal failure is a well-known risk condition for cardiovascular disease and in particular vascular calcifications. In fact, with respect to the normal population, where only ''classic'' risk factors have been described, kidney patients also have non-classic risk conditions. Among these, alterations in divalent ions, parathyroid hormone and vitamin D are of utmost importance. Further, several substances are recognized to have inhibitory or inductive effects in the pathogenesis of vascular calcifications, affecting either the calcium salts precipitation phenomenon or the phenotypic transformation of vascular smooth muscle cells into osteoblast-like cells (the latter phenomenon being regarded as a determinant of calcification of the tunica media). Given that vascular calcifications are irreversible, therapeutic strategies are aimed at preventing their formation or at blunting their progression (which is especially accelerated in renal patients). For this purpose it is essential to pursue optimal biochemical control of secondary hyperparathyroidism, but we must consider that in the individual patient the choice of drugs and their dosage can be essential for the development of calcifications. Given the physiological importance of inhibitory substances, we can hypothesize their future use in this setting. Finally, we must consider that by administering drugs known to interfere with inhibitors (like warfarin) or with the normal process of mineralization (like bisphosphonates), we can hypothetically favor or respectively prevent vascular calcifications.

Does any therapy exist for vascular calcifications in uremia?

The pathogenesis of vascular calcifications in uremia is not completely understood, but is regarded as multifactorial, involving traditional and nontraditional risk factors. In particular, derangements in divalent ions are considered of outmost importance, but also the role of physiologic inhibitors of calcification is now claimed. The most powerful physiologic inhibitor of calcification is pyrophosphate, but its biochemical instability precludes its clinical use to date. The pharmacologic analogs of pyrophosphate, bisphosphonates, cannot be easily tested for this purpose in renal patients, given their renal clearance. The list of proteins involved in calcification is a growing one, and experimental models point to the potential clinical relevance of matrix Gla protein, fetuin, osteopontin, osteoprotegerin and bone morphogenetic protein-7. Induction of metabolic acidosis, although theoretically useful, is not recommended, while administration of sodium thiosulphate could be beneficial, but its safety awaits confirmation. Actually, the only available therapies for vascular calcifications are those directed toward achievement of the biochemical targets for calcium, phosphate and parathyroid hormone with the hope, but not the certainty, that this will be efficacious. However, to this purpose, selection of the most appropriate strategy in the individual patient seems essential.

The bone and the kidney.

Renal tubular diseases may present with osteopenia, osteoporosis or osteomalacia, as a result of significant derangements in body electrolytes. In case of insufficient synthesis of calcitriol, as in renal failure, the more complex picture of renal osteodystrophy may develop. Hypothetically, also disturbed renal production of BMP-7 and Klotho could cause bone disease. However, the acknowledgment that osteocytes are capable of producing FGF23, a phosphaturic hormone at the same time modulating renal synthesis of calcitriol, indicates that it is also bone that can influence renal function. Importantly, a feed-back mechanism exists between FGF23 and calcitriol synthesis, while Klotho, produced by the kidney, determines activity and selectivity of FGF23. Identification of human diseases linked to disturbed production of FGF23 and Klotho underlines the importance of this new bone-kidney axis. Kidney and bone communicate reciprocally to regulate the sophisticated machinery responsible for divalent ions homeostasis and for osseous or extraosseous mineralisation processes.