Luigi Lombardi

Neutrophil gelatinase-associated lipocalin (NGAL) reflects iron status in haemodialysis patients

BACKGROUND An iron deficiency is often present in haemodialysis (HD) patients; however, although transferrin saturation (TSAT) of <20% and/or serum ferritin of <200 ng/mL should express iron scarcity, in HD patients high ferritin levels could be related to inflammation rather than reflecting optimal iron stores. METHODS The aim of the present study was to evaluate serum levels of neutrophil gelatinase-associated lipocalin (NGAL), a small siderophore-binding protein, in a cohort of 56 chronic HD patients in order to determine its possible relationships with iron status. RESULTS NGAL levels were markedly higher in HD patients than in healthy controls; furthermore, HD patients with TSAT <20% had lower NGAL values than healthy controls, whereas the correction of iron deficiency by means of chronic i.v. iron administration significantly increased NGAL values from baseline. Findings from univariate and multivariate analyses demonstrated that NGAL was a significant predictor of hsCRP, spKT/V and TSAT. In ROC analysis, a NGAL cut-off level of <or=473 ng/mL had a greater sensitivity and specificity than a ferritin level of <200 ng/mL in identifying iron deficiency among HD patients. CONCLUSIONS The findings demonstrated that HD patients have altered NGAL values probably because this protein is involved in the maintenance of iron equilibrium. Finally, NGAL might be proposed as a new tool in the assessment of iron deficiency and in the management of iron therapy for HD patients.

Physical Performance and Clinical Outcomes in Dialysis Patients: A Secondary Analysis of the Excite Trial

Background/Aims: Scarce physical activity predicts shorter survival in dialysis patients. However, the relationship between physical (motor) fitness and clinical outcomes has never been tested in these patients. Methods: We tested the predictive power of an established metric of motor fitness, the Six-Minute Walking Test (6MWT), for death, cardiovascular events and hospitalization in 296 dialysis patients who took part in the trial EXCITE (ClinicalTrials.gov Identifier: NCT01255969). Results: During follow up 69 patients died, 90 had fatal and non-fatal cardiovascular events, 159 were hospitalized and 182 patients had the composite outcome. In multivariate Cox models - including the study allocation arm and classical and non-classical risk factors - an increase of 20 walked metres during the 6MWT was associated to a 6% reduction of the risk for the composite end-point (P=0.001) and a similar relationship existed between the 6MWT, mortality (P<0.001) and hospitalizations (P=0.03). A similar trend was observed for cardiovascular events but this relationship did not reach statistical significance (P=0.09). Conclusions: Poor physical performance predicts a high risk of mortality, cardiovascular events and hospitalizations in dialysis patients. Future studies, including phase-2 EXCITE, will assess whether improving motor fitness may translate into better clinical outcomes in this high risk population.

Exercise in Patients on Dialysis: A Multicenter, Randomized Clinical Trial.

Previous studies have suggested the benefits of physical exercise for patients on dialysis. We conducted the Exercise Introduction to Enhance Performance in Dialysis trial, a 6-month randomized, multicenter trial to test whether a simple, personalized walking exercise program at home, managed by dialysis staff, improves functional status in adult patients on dialysis. The main study outcomes included change in physical performance at 6 months, assessed by the 6-minute walking test and the five times sit-to-stand test, and in quality of life, assessed by the Kidney Disease Quality of Life Short Form (KDQOL-SF) questionnaire. We randomized 296 patients to normal physical activity (control; n=145) or walking exercise (n=151); 227 patients (exercise n=104; control n=123) repeated the 6-month evaluations. The distance covered during the 6-minute walking test improved in the exercise group (mean distance±SD: baseline, 328±96 m; 6 months, 367±113 m) but not in the control group (baseline, 321±107 m; 6 months, 324±116 m; P<0.001 between groups). Similarly, the five times sit-to-stand test time improved in the exercise group (mean time±SD: baseline, 20.5±6.0 seconds; 6 months, 18.2±5.7 seconds) but not in the control group (baseline, 20.9±5.8 seconds; 6 months, 20.2±6.4 seconds; P=0.001 between groups). The cognitive function score (P=0.04) and quality of social interaction score (P=0.01) in the kidney disease component of the KDQOL-SF improved significantly in the exercise arm compared with the control arm. Hence, a simple, personalized, home-based, low-intensity exercise program managed by dialysis staff may improve physical performance and quality of life in patients on dialysis.

Fitness for Entering a Simple Exercise Program and Mortality: A Study Corollary to the Exercise Introduction to Enhance Performance in Dialysis (Excite) Trial

Background/Aims: In this corollary analysis of the EXCITE study, we looked at possible differences in baseline risk factors and mortality between subjects excluded from the trial because non-eligible (n=216) or because eligible but refusing to participate (n=116). Methods: Baseline characteristics and mortality data were recorded. Survival and independent predictors of mortality were assessed by Kaplan-Meier and Cox regression analyses. Results: The incidence rate of mortality was higher in non-eligible vs. eligible non-randomized patients (21.0 vs. 10.9 deaths/100 persons-year; P<0.001). The crude excess risk of death in non-eligible patients (HR 1.96; 95% CI 1.36 to 2.77; P<0.001) was reduced after adjustment for risk factors which differed in the two cohorts including age, blood pressure, phosphate, CRP, smoking, diabetes, triglycerides, cardiovascular comorbidities and history of neoplasia (HR 1.60; 95% CI 1.10 to 2.35; P=0.017) and almost nullified after including in the same model also information on deambulation impairment (HR 1.16; 95% CI 0.75 to 1.80; P=0.513). Conclusions: Deambulation ability mostly explains the difference in survival rate in non-eligible and eligible non-randomized patients in the EXCITE trial. Extending data analyses and outcome reporting also to subjects not taking part in a trial may be helpful to assess the representability of the study population.

Parathyroid Hormone and Mobilization of Circulating Bone Marrow-Derived Cells in Uremic Patients

Background Parathyroid hormone (PTH) revealed a positive action on progenitor cells released from bone marrow, and many mechanisms supported PTH as a tool to improve stem cell-based therapy in experimental models of ischemia. Elevated PTH resulted in increased mobilization of progenitors into the peripheral blood of patients affected by untreated primary hyperparathyroidism. A frequent finding in uremic patients is a higher PTH level, and different therapeutic strategies are adopted and implemented to achieve an intermediary PTH level. On the contrary, the amount of progenitors commonly results to be extremely reduced. Objective In the present study, we investigated, in a cohort of uremic patients, the effect of different levels of PTH on mobilization of progenitor cell populations. Methods Eighty patients (26 women, 54 men) were enrolled. Following the Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines, patients were divided in 3 groups for PTH levels: low-PTH group with a PTH level lower than 150 pg/mL (n = 25), KDOQI-PTH group with a PTH level between 150 and 300 pg/mL (n = 37), and high-PTH group with a PTH level higher than 300 pg/mL (n = 18). Patients with high levels of PTH were treated differently to achieve KDOQI targets: 5 received intravenous calcitriol and P binders, 3 received intravenous paracalcitriol, and 10 received cinacalcet. We quantified, by the combination of surface markers (CD45+, CD34+, CD31+, and c-kit+), the number of hematopoietic and endothelial progenitor cells. Results High-PTH group demonstrated a significantly higher level of CD45+/CD34+/c-kit+ with respect to low-PTH and KDOQI-PTH groups (1.02 [SD, 0.12] vs. 0.56 [SD, 0.14] cells/uL, P < 0.01; and 1.02 [SD, 0.12] vs. 0.46 [SD, 0.20] cells/uL, P < 0.05). CD45+/CD34+/CD31+ levels resulted significantly increased in the KDOQI-PTH group compared with those observed in the low- (1.83 [SD, 0.72] vs 1.26 [SD, 0.83] cells/μL, P = 0.04) and high-PTH groups (1.83 [SD, 0.72] vs 1.20 [SD, 1.15] cells/μL, P = 0.04). Receiver operating characteristic analyses were performed to define the ability of CD45+/34+/31+ to identify the presence of an optimal PTH status (>150 but <300 pg/mL) among all hemodialysis patients. The area under the curve of CD45+/34+/31+ was 0.674 (95% confidence interval [CI], 0.501-0.819) with a best cutoff level of 1.36 cells/μL (sensitivity, 80.0; specificity, 59.1; P < 0.05). After 4 months, we demonstrated an increase in endothelial progenitor cell number in 13 patients with secondary hyperparathyroidism that achieved KDOQI targets in PTH levels after pharmacological treatment. Conclusions Our data confirm, with acknowledged limitations due to the low number of patients, the effect of PTH on bone marrow-derived progenitor cells emphasizing that, in our cohort, an intermediary PTH level, achieved following specific guidelines, results in an equilibrate balance between different subsets of progenitor cells.

Successful conception and pregnancy in p-ANCA-associated vasculitis in course of treatment with immunosuppressive drugs and renal replacement therapy.

Dear Editor, Pregnancy in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is a rare event. This infrequency depends both on the reduction of fertility and the teratogenicity induced by immunosuppressive drugs, the use of which is essential at the occurrence of ANCA-vasculitis relapses. In addition, end-stage renal disease (ESRD), which occurs in 51% of ANCA-vasculitis patients, per se represents a cause of severe reproductive dysfunction and despite increased experience and improvement in dialysis techniques, the risks of pregnancy both for mother and fetus are undoubtedly higher for women on dialysis than for healthy women. Data from the American Registry of Pregnancy in Dialysis Patients showed no difference in pregnancy outcome between hemodialysis and peritoneal dialysis (PD) patients, but when renal replacement therapy is obtained by PD, specific adjunctive risk factors might insist on a change in conception. In fact, the hypertonic fluid dwelling in the intra-peritoneal space interferes with the ovum migration and possible peritonitis episodes may result in tubal obstruction. A 32-year-old woman was admitted to our hospital for constitutional symptoms, rash, abdominal pain and hypertension. Laboratory investigations revealed an acute impairment of renal function (serum creatinine 7.8 mg/dL and blood urea nitrogen 78 mg/dL) associated with proteinuria (2.5 g/24 h), micro-hematuria, elevated myeloperoxidase – ANCA (MPO-ANCA) serum levels (2150 U/mL; reference range, < 5 U/mL). Abdominal ultrasound evidenced preserved bilateral renal size. Based on clinical and laboratory evidences, a diagnosis of acute ANCA-associated vasculitis was suspected and a confirmatory renal biopsy proposed, but the patient refused to consent. According to current literature, ANCA-associated vasculitis should be empirically treated when a strong clinical suspicion the disease exists, while an histological tissue diagnosis is to be obtained in a timely manner. The coexistence of both criteria led our medical team to start therapy. A patient informed consent, including information about the teratogenic and post-natal risks of the treatment, was consequently obtained. The therapeutic approach included: (i) five plasma exchange sessions; (ii) two courses of steroid pulses (methylprednisolone 1 g 9 3 consecutive days) followed by oral prednisone 0.5 mg/ kg body weight, then tapered to 10 mg/day, and this dosage was maintained for 6 months; (iii) cyclophosphamide 3 mg/kg body weight/day for 6 months; and (iv) supportive therapy with hemodialysis, ramipril, furosemide, lansoprazole and erythropoietin. At the end of a 3-month follow-up, renal function did not improve and the patient was switched from hemodialysis to PD, according to her own choice. Cyclophosphamide was withdrawn at the end of the fifth month given the clinical silence of the disease and the absence of renal functional improvement. One month later, the patient was still free of disease-related symptoms with serum MPO-ANCA levels < 5 U/mL, thus was evaluated as a potential renal transplant recipient. Blood pregnancy test was performed according to the laboratory screening required for renal transplant waiting list inclusion. Unexpectedly, elevated levels of betahuman chorionic gonadotropin (beta-hCG) were detected. A gynecologic examination and a pelvic ultrasound were promptly required and the status of pregnancy confirmed, with an estimated gestational age of 21 weeks. The placenta was normally inserted and amniotic fluid index was normal. Despite having been informed about the possible teratogenicity of ongoing therapy, the patient decided to carry on with the pregnancy. Of course, ramipril, furosemide and lansoprazole were immediately discontinued, belonging to Federal Drug Administration pregnancy-risk categories D, C and B, respectively. The PD dose was increased to five exchanges/day and the dialysate dwell volume was reduced to 1.5 L, obtaining an increased dialysis efficiency. During the

Parathyroid hormone variability parameters for identifying high turnover osteodystrophy disease in hemodialysis patients: an observational retrospective cohort study.

Abnormalities in bone morphology that develop secondary to chronic kidney disease are defined as renal osteodystrophy and are identified by bone biopsy. As systematic and sequential bone biopsy is not practicable on a large number of patients, various chemical bone markers are commonly used to detect the bone remodeling status in chronic kidney disease and to grade bone disease in the clinical setting. Recent literature has considered the effect of absolute levels of parathyroid hormone (PTH) on clinical outcomes and not the measurement of their change over time, the PTH variability. In a retrospective observational study, we examined PTH variability parameters in a group of hemodialysis patients as independent risk factors for high vs. low turnover osteopathy, and investigated their usefulness with respect to commonly used markers of renal osteodystrophy. The study was conducted on 90 chronic hemodialysis patients undergoing regular treatment at the same dialysis centre (Catanzaro, Italy) with standard bicarbonate dialysis. Patients were classified into either high or medium–low turnover osteopathy for the diagnosis based on renal osteodystrophy using the following criteria: PTH ≥ 400 pg/mL associated with bone ALP ≥ 20 ng/mL. We used a regression‐based measurement of PTH variability, which was characterized by different parameters: PTH‐Res‐SD, PTH‐Slope, PTH‐Intercept, PTH‐Abs‐Var, and PTH‐Res‐SD. In our analysis, these parameters of PTH variability were demonstrated to be good independent predictive factors for high turnover osteodystrophy, and they had a greater sensitivity than the use of a single and/or mean PTH measurements in renal osteodystrophy classification.