Luciana Bonfante

Alendronate Prevents Further Bone Loss in Renal Transplant Recipients

The aim of this study was to investigate the effects of alendronate, calcitriol, and calcium in bone loss after kidney transplantation. We enrolled 40 patients (27 men and 13 women, aged 44.2 ± 11.6 years) who had received renal allograft at least 6 months before (time since transplant, 61.2 ± 44.6 months). At baseline, parathyroid hormone (PTH) was elevated in 53% of the patients and the Z scores for bone alkaline phosphatase (b‐ALP) and urinary type I collagen cross‐linked N‐telopeptide (u‐NTX) were higher than expected (p < 0.001). T scores for the lumbar spine (−2.4 ± 1.0), total femur (−2.0 ± 0.7), and femoral neck (−2.2 ± 0.6) were reduced (p < 0.001). After the first observation, patients were advised to adhere to a diet containing 980 mg of calcium daily and their clinical, biochemical, and densitometric parameters were reassessed 1 year later. During this period, bone density decreased at the spine (−2.6 ± 5.7%; p < 0.01), total femur (−1.4 ± 4.2%; p < 0.05), and femoral neck (−2.0 ± 3.0%; p < 0.001). Then, the patients were randomized into two groups: (1) group A—10 mg/day of alendronate, 0.50 μg/day of calcitriol, and 500 mg/day of calcium carbonate; and (2) group B—0.50 μg/day of calcitriol and 500 mg/day of calcium carbonate. A further metabolic and densitometric reevaluation was performed after the 12‐month treatment period. At the randomization time, group A and group B patients did not differ as to the main demographic and clinical variables. After treatment, bone turnover markers showed a nonsignificant fall in group B patients, while both b‐ALP and u‐NTX decreased significantly in alendronate‐treated patients. Bone density of the spine (+5.0 ± 4.4%), femoral neck (+4.5 ± 4.9%), and total femur (+3.9 ± 2.8%) increased significantly only in the alendronate‐treated patients. However, no trend toward further bone loss was noticed in calcitriol and calcium only treated subjects. No drug‐related major adverse effect was recorded in the two groups. We conclude that renal transplanted patients continue to loose bone even in the long‐term after the graft. Alendronate normalizes bone turnover and increases bone density. The association of calcitriol to this therapy seems to be advantageous for better controlling the complex abnormalities of skeletal metabolism encountered in these subjects.

Evaluation of Cytomegalovirus (CMV)-Specific T Cell Immune Reconstitution Revealed That Baseline Antiviral Immunity, Prophylaxis, or Preemptive Therapy but not Antithymocyte Globulin Treatment Contribute to CMV-Specific T Cell Reconstitution in Kidney Transplant Recipients

BACKGROUND The ultimate goal of organ transplantation is the reestablishment of organ function and the restoration of a solid immunity to prevent the assault of potentially deadly pathogens. T cell immunity is crucial in controlling cytomegalovirus (CMV) infection. It is still unknown how preexisting antiviral T cell levels, prophylaxis, or preemptive antiviral strategies and pharmacological conditioning affect immune reconstitution. METHODS Seventy preemptively treated CMV-seropositive recipients, 13 prophylaxis-treated CMV-seronegative recipients of seropositive donor transplants, 2 seropositive recipients of seronegative donor kidneys, and 27 pretransplant subjects were enrolled in a cross-sectional study and analyzed for CMV viremia (DNAemia) and CMV-specific T cell response (interferon-gamma enzyme-linked immunospot assay) before transplantation and at 30, 60, 90, 180, and 360 days after transplantation. RESULTS CMV-seropositive transplant recipients displayed a progressive but heterogeneous pattern of immune reconstitution starting from day 60 after transplantation. CMV-seronegative recipients did not mount a detectable T cell response throughout the prophylaxis regimen. A single episode of CMV viremia (CMV copy number, 7000-170,000 copies/mL) was sufficient to prime a protective T cell immune response in CMV-seronegative recipients. Antithymocyte globulin treatment did not significantly affect CMV-specific T cell response. CONCLUSIONS Baseline immunity, antiviral therapy but not antithymocyte globulin treatments profoundly influence T cell reconstitution in kidney transplant recipients.

Prevalence of CKD in Northeastern Italy: Results of the INCIPE Study and Comparison with NHANES

BACKGROUND AND OBJECTIVES Sufficiently powered studies to investigate the CKD prevalence are few and do not cover southern Europe. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS For the INCIPE study, 6200 Caucasian patients ≥40 years old were randomly selected in northeastern Italy in 2006. Laboratory determinations were centralized. The albumin to creatinine ratio in urine and estimated GFR from calibrated creatinine (SCr) were determined. A comparison with 2001 through 2006 NHANES surveys was performed. RESULTS Prevalence of CKD was 13.2% in northeastern (NE) Italy (age and gender standardized to the U.S. 2007 Caucasian population). Prevalence of CKD in U.S. Caucasians is higher (20.3%), the major difference being in CKD 3. Risk factors for CKD are more prevalent in the United States than in Italy. With use of CKD 3a and 3b stages, CKD prevalence decreased in NE Italy (8.5%) and in the United States (12.8%). CONCLUSIONS The prevalence of CKD is high in NE Italy, but lower than that in the United States. A large part of the difference in CKD prevalence in NE Italy versus that in the United States is due to the different prevalence of CKD 3. The higher prevalence of a number of renal risk factors in persons from the United States explains in part the different dimensions of the CKD problem in the two populations.

Glycosaminoglycans prevent the functional and morphological peritoneal derangement in an experimental model of peritoneal fibrosis

Chronic peritoneal dialysis results in fibrosis of the peritoneal membrane, which leads to progressive reduction in dialytic efficacy. It was recently shown that the intraperitoneal administration of glycosaminoglycans (GAGs) improves the efficiency of peritoneal dialysis in CAPD patients. To verify whether the favorable effects of GAGs are purely functional or involve a morphological amelioration of the peritoneal membrane structure, a study was carried out in an animal model of plasticizer-induced peritoneal fibrosis. Rats, in which chronic renal failure had been induced by subtotal nephrectomy, received either placebo, plasticizers (i.p.), or GAGs (s.c.), or plasticizers (i.p.) and GAGs (s.c.). Urea dialysate-to-plasma equilibrium, urea and albumin peritoneal clearance, and glucose reabsorption were determined. The peritoneal membrane was evaluated morphometrically and histologically. In plasticizer-treated animals, peritoneal function tests and morphology were dramatically deranged. On the contrary, the subcutaneous administration of GAGs in plasticizer-treated rats maintained the peritoneal physiology and normal structure. The subcutaneous administration of GAGs protects peritoneal functions by affecting the remodeling of the peritoneum, rather than by a purely functional or simple mechanical effect.

Comparison of Cytomegalovirus (CMV) Enzyme-Linked Immunosorbent Spot and CMV Quantiferon Gamma Interferon-Releasing Assays in Assessing Risk of CMV Infection in Kidney Transplant Recipients

ABSTRACT Assessing cytomegalovirus (CMV)-specific cell-mediated immunity (CMI) represents an appealing strategy for identifying transplant recipients at risk of infection. In this study, we compared two gamma interferon-releasing assays (IGRAs), Quantiferon-CMV and CMV enzyme-linked immunosorbent spot (ELISPOT), to determine the ability of each test to predict protective CMV-specific T-cell responses. Two hundred twenty-one Quantiferon-CMV and ELISPOT tests were conducted on 120 adult kidney transplant recipients (KTRs), including 100 CMV-seropositive transplant recipients (R+) and 20 CMV-seronegative transplant recipients of a CMV-positive donor (D+/R−). As a control cohort, 39 healthy adult subjects (including 33 CMV-seropositive and 6 CMV-seronegative subjects) were enrolled. CMV IgG serology was used as a reference for both tests. In the CMV-seropositive individuals, the ELISPOT and Quantiferon-CMV assays provided 46% concordance with the serology, 12% discordance, 18% disagreement between ELISPOT or Quantiferon-CMV and the serology, and 24% gray areas when one or both tests resulted in weak positives. None of the CMV-seronegative subjects showed detectable responses in the ELISPOT or the Quantiferon-CMV test. In transplant recipients, both the ELISPOT and Quantiferon-CMV assays positively correlated with each other and negatively correlated with CMV DNAemia in a significant way (P < 0.05). During the antiviral prophylaxis, all 20 D+/R− KTRs we examined displayed undetectable Quantiferon-CMV and ELISPOT results, and there was no evidence of CMV seroconversion. The receiving operator curve (ROC) statistical analysis revealed similar specificities and sensitivities in predicting detectable viremia (areas under the curve [AUC], 0.66 and 0.62 for Quantiferon-CMV and ELISPOT, respectively). ELISPOT and Quantiferon-CMV values of >150 spots/200,000 peripheral blood mononuclear cells (PBMCs) and >1 to 6 IU gamma interferon (IFN-γ) were associated with protection from CMV infection (odds ratios [OR], 5 and 8.75, respectively). In transplant recipients, the two tests displayed similar abilities for predicting CMV infection. Both the ELISPOT and Quantiferon-CMV assays require several ameliorations to avoid false-negative results.

Persistent secondary hyperparathyroidism and vertebral fractures in kidney transplantation: role of calcium-sensing receptor polymorphisms and vitamin D deficiency.

Bone morbidity remains a major problem even after successful renal transplantation. We investigated the role of calcium‐sensing receptor (CaSR) polymorphisms and 25‐hydroxyvitamin D levels on the persistence of secondary hyperparathyroidism (SHPT) and their relationships with vertebral fractures (VFx) in 125 renal allograft recipients transplanted 44 ± 23 months before. All patients underwent evaluation of the main biochemical parameters of calcium metabolism as well as vertebral and femoral bone density. In 87 patients, CaSR polymorphisms (A986S, R990G, and Q1011E) also were assessed. X‐ray images of the lateral spine were obtained in 102 subjects to perform vertebral morphometry. High parathyroid hormone (PTH) and 25‐hydroxyvitamin D lower than 80 nmol/L were found in 54% and 97% of patients, respectively, with 40% of these showing vitamin D levels lower than 30 nmol/L. VFx were detected in 57% of the subjects. After multiple adjustments, 25‐hydroxyvitamin D, age, and hemodialysis duration, but not CaSR polymorphisms, were found to be significant predictors of high PTH, whereas age and time since transplant were positively related with lower 25‐hydroxyvitamin D values. PTH and time since transplant were significantly associated with VFx. Patients with two or more VFx showed serum PTH levels 50% higher than patients without fractures. We therefore conclude that persistent SHPT is a very common feature after renal transplantation and that, unlike CaSR polymorphisms, low 25‐hydroxyvitamin D is involved in its pathogenesis. High PTH levels, in turn, are associated with an increased VFx risk, which confirms the need for strategies aimed at lowering serum PTH in this setting as well.

Calcineurin inhibitor‐free immunosuppression in dual kidney transplantation from elderly donors

Abstract:  Background:  Kidneys from expanded‐criteria donors may be particularly susceptible to calcineurin inhibitor (CI)‐mediated vasoconstriction and nephrotoxicity. In the early post‐transplant phase, using CI may prolong ischemic injury and, in the long term, chronic CI nephrotoxicity is an even greater concern. To avoid the acute and chronic consequences of CI in kidneys from marginal donors, CI‐free protocols have been introduced for maintenance immunosuppressive therapy. A CI‐free protocol of anti‐thymocyte globulin (ATG) induction, sirolimus, mycophenolate mofetil (MMF) and steroids has been adopted at our center in recipients of dual kidney transplantation (DKT) from elderly donors (EDs).

Carotid artery lesions in patients with nondiabetic chronic renal failure

Atherosclerotic complications are the leading cause of death in chronic renal failure (CRF) patients. Therefore, we wished to investigate the prevalence of carotid artery lesions (CALs) in these subjects. Two groups were evaluated by high-resolution echo Doppler: group 1 included 103 patients (68 males and 35 females) affected by nonnephrotic CRF and group 2 included 100 control subjects (60 males and 40 females). The prevalence of hypertension was 84% in both groups. The exclusion criteria included diabetes mellitus and symptoms of cerebrovascular disease. In the two groups we evaluated clinical history, physical examination, total cholesterol, triglycerides, fibrinogen, blood cell counts, blood urea nitrogen, creatinine, 24-hour proteinuria, and urine analysis. In group 1 patients the following lipid profile parameters were also evaluated: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, lipoprotein(a), ApoAI, ApoAII, and ApoB. Group 1 had higher triglycerides and fibrinogen than group 2. A lower body mass index was found in group 1 than in group 2. The prevalence of CALs was significantly higher in the CRF patients than in the control subjects (62% v 47%; P = 0.04). The difference between the two groups was more striking among normotensive patients (62% v 19%; P = 0.03). All CRF patients affected by peripheral arterial disease and 86% of those having coronary artery disease had associated CALs. In CRF patients the severity of CALs was positively correlated to age, white blood cell count, triglycerides, and fibrinogen. Nondiabetic CRF patients have a higher prevalence of carotid artery lesions than control subjects. Several factors besides hypertension, including lipids, blood coagulation, and leukocytes, could contribute to the accelerated atherosclerosis of CRF patients.

Outcomes of endovascular aneurysm repair on renal function compared with open repair

OBJECTIVE Recent studies have shown that progressive renal dysfunction may develop in patients after endovascular aneurysm repair (EVAR). Data are conflicting about the effect of EVAR on renal function compared with open repair (OR). The purpose of this study was to compare the effects of EVAR, both with transrenal fixation (TRF) and infrarenal fixation (IRF), vs OR on renal function detected with renal perfusion scintigraphy (RPS). METHODS A prospective study was carried out from January 2003 to December 2007. Exclusion criteria included factors that could influence post-procedural renal function as: preoperative creatinine clearance level <65 mL/min for men and 60 mL/min for women, renal artery stenosis >60%, renal accessory artery planned to be covered by the endograft, single functioning kidney, hemodialysis, and kidney transplant. To evaluate renal function, an RPS was performed preoperatively, at 30 days, at 6 and 12 months, and then yearly. The glomerular filtration rate (GFR) was estimated with the Gates method. RESULTS During the study period, 403 patients were enrolled; 243 (60%) had OR and 160 (40%) EVAR; among these, 83 (51%) had a TRF and 77 (48%) an IRF; 55 patients were excluded from the study. No statistical differences were observed between groups for demographics and risk factors. Statistically significant differences emerged between OR and EVAR for early postoperative death (4% vs 0%; P = .01). Follow-up ranged from 54 to 126 months (mean, 76 months) for OR and from 54 to 124 months (mean, 74 months) for EVAR (P = NS). Kaplan-Meier analysis survival rate at 9 years was 70% for OR and 58% for EVAR with a risk of secondary procedure of 9% and 34%, respectively (P < .0001). A deterioration of the GFR was observed during the follow-up in both groups with a decrease after 9 years of 11% in the EVAR group and 3% in the OR group respective to baseline (P < .001). A remarkable difference emerged on renal function between EVAR patients who required a secondary procedure compared with the other EVAR patients (P < .005). No significant differences emerged between TFR and IRF for GFR decline during the follow-up period. CONCLUSIONS After EVAR, there is a continuous decline in renal function with respect to OR, regardless of fixation level and independently of pre-existing renal insufficiency. The risk of GFR impairment after EVAR should be taken into consideration in selecting patients with preoperative renal insufficiency.

Is the Red Cell Morphology Really Useful to Detect the Source of Hematuria

Morphological analysis of urinary red blood cells by phase-contrast microscopy to identify the source of bleeding was, and still is, widely used also as a starting point for workup. To evaluate the reliability of this approach, we studied 129 outpatients presenting with persistent isolated microhematuria; 31 subjects also had mild proteinuria (1 g/day), while 21 had pathological albumin levels. All patients were followed for a period of 6 years. During this time, 6 patients underwent renal biopsy for the onset of macrohematuria episodes and proteinuria of 2-3 g/day. Glomerular bleeding was identified in only 14.7% of the patients, despite the persistent microhematuria and the presence of proteinuria or microalbuminuria. The renal origin of the urinary erythrocytes correlated with histological findings in only 2 of 6 patients with dysmorphic erythrocytes who developed proteinuria (exceeding 1 g/day), and none with isomorphic erythrocytes showed urological abnormalities. These results challenge the validity and reliability of morphological analysis to identify the source of bleeding along the urinary tract.