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Background: Studies evaluating the effect of conversion from calcineurin inhibitor (CNI) to sirolimus (SRL) in renal transplant recipients (RTRs) have shown conflicting results, and only few short-term uncontrolled studies are available in patients with chronic allograft dysfunction. This is the first controlled study to evaluate long-term survival and both renal and cardiac outcomes in nondiabetic RTRs with allograft dysfunction who were converted from CNI to SRL., Methods: We evaluated 13 RTRs with biopsy-proven allograft dysfunction who underwent early conversion from CNI to SRL, and 26 controls with normal graft function taking CNI. All continued both steroids and mycophenolate mofetil. SRL was titrated to trough levels of 4-8 ng/mL. Outcome measures included 3-year event-free survival, acute rejection rate and 3-year changes in Modification of Diet in Renal Disease (MDRD) Study equation estimated glomerular filtration rate (eGFR) and left ventricular mass index (LVMi) as assessed by echocardiography., Results: Compared with controls, patients on SRL showed better 3-year event-free survival (p=0.024; log-rank test), significant eGFR increase (+5.5 ± 8.9 vs, -6.4 ± 14.7 ml/min per 1.73 m2, p=0.011), LVMi regression (-9.0 ± 7.6 g/m(2.7) vs. 1.0 ± 10.1 g/m(2.7), p=0.0038) and similar acute rejection rate. Three-year change in eGFR was the only significant predictor of event-free survival by Cox regression analysis (hazard ratio = 0.96; 95% confidence interval, 0.93-0.99; p=0.017), whereas SRL was the strongest predictor of both eGFR increase (beta coefficient, 0.342; p=0.01) and LVM reduction (beta coefficient, -0.609; p=0.0001) by multivariate regression analysis., Conclusions: Conversion from CNI to SRL in RTRs with allograft dysfunction proved to be associated with better survival, improved renal graft function and regression of cardiac hypertrophy.

Background: Although conversion from calcineurin inhibitors to mammalian target of rapamycin inhibitors proved to be effective in regressing left ventricular hypertrophy (LVH) in renal transplant recipients (RTRs) with chronic allograft dysfunction, there are currently no reports of randomized trials on this issue involving de novo RTRs administered everolimus (EVL)., Methods: This randomized, open-label, controlled trial evaluated the effect of EVL on the left ventricular mass index (LVMi) of 30 nondiabetic RTRs (21 men; age 28-65 years). Ten were allocated to EVL plus reduced-exposure cyclosporine A (CsA), and 20 to standard dose CsA. LVMi was assessed by echocardiography both at baseline and 1 year later. Blood pressure (BP), hemoglobin, serum creatinine, lipids, trough levels of immunosuppressive drugs, and daily proteinuria were also evaluated twice monthly. Antihypertensive therapy that did not include renin-angiotensin system blockers was administered to achieve BP less than or equal to 130/80 mm Hg., Results: Changes in BP were similar in the two groups (between group difference 1.2 ± 5.7 mm Hg, P=0.84 for systolic, and -1.5 ± 3.7, P=0.69, for diastolic BP), whereas LVMi significantly decreased in the EVL group alone (between group difference 9.2 ± 3.1 g/m(2.7), P=0.005), due to a reduction in both the interventricular septum and the left ventricular posterior wall thickness. EVL therapy together with baseline LVMi were the only significant predictors of LVH regression according to a multivariate model that explained 49% of the total LVMi variance (P=0.0015)., Conclusions: An immunosuppressive regimen consisting of EVL plus reduced exposure CsA proved to be effective in regressing LVH in RTRs regardless of BP, mainly by reducing left ventricular wall thickness.

Left ventricular hypertrophy (LVH) contributes to elevated cardiac mortality with graft function in renal transplant recipients. Antihypertensive therapy, and especially angiotensin-converting enzyme (ACE) inhibitors, proved to be effective in regressing the LVH of renal transplant recipients, at least in part by interacting with immunosuppressive agents, thus raising the possibility that immunosuppressive therapy might affect changes in the left ventricular mass (LVM) of recipients. This review mainly focuses on the potential role of mammalian target of rapamycin (mTOR) inhibition to regress cardiac hypertrophy in both experimental models and in the clinical setting. We comment on the results of experimental studies conducted on animal models, which showed regression of cardiac hypertrophy by sirolimus (SRL). We also discuss clinical studies that show that conversion from calcineurin inhibitors to SRL is effective to achieve regression of LVH in both kidney and cardiac transplant recipients, mainly by reducing the true left ventricular wall hypertrophy., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Persistence of left ventricular hypertrophy (LVH) following renal transplantation is associated with unfavorable outcomes in renal transplant recipients. This review presents clinical data on LVH after renal transplantation and the role of antihypertensive therapy, especially ACE inhibitors, to reduce left ventricular mass, as well as the effects of interactions between antihypertensive medications acting on the renin-angiotensin system and immunosuppressive agents to regress LVH among renal transplant recipients. The effectiveness of sirolimus (SRL) to reduce posttransplantation LVH is also discussed in light of both animal model studies and 2 clinical trials in transplant recipients that showed the efficacy of this immunosuppressive agent to treat LVH in both kidney and heart transplant recipients.

Background: Although arterial hypertension is a powerful predictor of graft failure, only few studies have evaluated 24-hr blood pressure (BP) profile in renal transplant recipients (RTRs)., Methods: We performed ambulatory blood pressure monitoring (ABPM) in 94 RTRs (65 men; age 28-71 years) with 1-year functioning grafts. Serum biochemical parameters, daily proteinuria, and transplantation-related data were evaluated in all subjects., Results: ABPM showed that only 5% of RTRs were normotensives (BP<130/80 mm Hg) and identified 29% of patients with nocturnal hypertension. A strong, direct correlation was shown between each set of both systolic BP and diastolic BP measured by ABPM and serum creatinine, daily proteinuria, and serum triglycerides (P at least <0.025 for each). Serum creatinine immediately after transplantation and 1-yr asleep diastolic BP were the only significant predictors of 1-yr creatinine (P<0.0001; r=0.49), whereas awake systolic BP was the only predictor of daily proteinuria (r=0.39; P=0.005) by multiple regression analysis., Conclusions: BP assessed by ABPM proved to be a stronger predictor of renal graft damage than traditional immunologic factors. ABPM improved the diagnostic accuracy of arterial hypertension in RTRs and was the only effective tool in disclosing the association of BP with 1-year renal transplant outcome.

This is the first case of documented treatment failure of JCV nephritis, despite a reduction of immunosuppressive agents and the use of antiviral therapy. We consistently detected high levels of JCV viremia, which correlated with the progressive deterioration of the graft and caused the final loss of the kidney, suggesting that JCV plays an etiological role in the onset of severe nephropathy in kidney transplant patients.

Background: Left ventricular hypertrophy (LVH) after renal transplantation may be affected by immunosuppressive therapy., Study Design: Nonrandomized controlled trial evaluating the effect of sirolimus (SRL) on LVH of renal transplant recipients (RTRs)., Setting & Participants: 13 RTRs without diabetes who had received a single-kidney transplant from a deceased donor with chronic allograft dysfunction and biopsy-proven allograft nephropathy who were converted from calcineurin-inhibitor (CNI) to SRL treatment; 26 controls matched for age and year of transplantation who were not converted from CNI to SRL treatment., Intervention: Conversion from CNI to SRL therapy., Outcomes & Measurements: Left ventricular mass determination by using echocardiography at baseline and again 1 year later. Blood pressure (BP), hemoglobin level, serum creatinine level, uric acid level, lipid levels, trough levels of immunosuppressive drugs, and daily proteinuria were assessed at least twice monthly. Conventional antihypertensive therapy was used to achieve BP of 130/80 mm Hg or less., Results: The study population included 26 men and 13 women (age, 25 to 66 years). Changes in BP were similar in the 2 groups (between-group difference, -4 +/- 5 mm Hg; P = 0.5 for systolic BP; -2 +/- 3; P = 0.6 for diastolic BP), whereas left ventricular mass significantly decreased in the SRL group alone (between-group difference, 8.6 +/- 2.4 g/m(2.7); P < 0.001) because of a decrease in both the interventricular septum and left ventricular posterior wall. LVH regressed in 12 of 13 patients on SRL therapy and 10 of 26 controls (P = 0.002)., Limitations: Nonrandomized design. Single-center study with small sample size., Conclusions: Conversion from CNI to SRL therapy may regress LVH in RTRs regardless of BP changes, mainly by decreasing left ventricular wall thickness, thus suggesting nonhemodynamic-effect mechanisms of SRL on left ventricular mass.

Background: Interventional studies of left ventricular hypertrophy (LVH) in renal transplant recipients are scarce and to date evaluated only patients immediately after renal transplantation., Study Design: Randomized controlled trial that assessed the effectiveness of angiotensin-converting enzyme (ACE) inhibitors in regressing persistent LVH after successful transplantation., Setting & Participants: 70 renal transplant recipients (47 men; age, 30 to 68 years) without diabetes previously randomly assigned to either cyclosporine or tacrolimus therapy, with LVH persisting 3 to 6 months after transplantation., Intervention: Subjects were randomly assigned to either lisinopril (ACE-inhibitor group; 36 patients) or no therapy (control group; 34 subjects)., Outcomes: Main outcome was change in left ventricular mass index (LVMi) at month 18., Results: A consistent decrease in both systolic (SBP) and diastolic blood pressure (DBP) was observed in both groups (between-group differences, -1.7 +/- 3.3 mm Hg; 95% confidence interval [CI], -4.8 to 8.2; P = 0.6 for SBP; 0.3 +/- 2.2 mm Hg; 95% CI, -4.8 to 4.1; P = 0.9 for DBP), whereas LVMi regressed more in the ACE-inhibitor group (between-group difference, 10.1 +/- 16.3 g/m(2.7); 95% CI, 4.2 to 16.1; P < 0.01). A significant interaction of ACE inhibitors with cyclosporine in affecting LVMi change was shown by means of post hoc multiple regression analysis (P < 0.01; differences between cyclosporine and tacrolimus group, 13.3 +/- 3.9 g/m(2.7); 95% CI, 5.3 to 21.2; P < 0.01 in the ACE-inhibitor group; 3.7 +/- 4.2 g/m(2.7); 95% CI, -4.7 to 12.2; P = 0.4 in the control group)., Limitations: Single-center study with small sample size. Interaction of ACE inhibitors with cyclosporine treatment emerged from post hoc analysis., Conclusion: A prolonged course of ACE-inhibitor therapy is effective in regressing the persistent LVH of renal transplant recipients by mechanisms independent of effects on BP. This regression seems to be at least in part the effect of an interaction between ACE inhibitors and cyclosporine.

Background: Fracture is a disabling clinical outcome after transplantation, but there is little histopathological information on long-term renal recipients with severe osteopenia., Methods: Twenty kidney recipients (8.3+/-1.9 years after transplantation), 13 males and 7 females (five postmenopausal) with nearly normal renal function, affected by severe osteopenia (T-score: males= -4.9+/-0.28; females= -5.08+/-0.47) underwent bone biopsy and morphometric X-ray absorptiometry to evaluate vertebral fractures., Results: Histopathological diagnosis was osteoporosis-osteopenia in seven patients, osteitis fibrosa in six, prevalent osteomalacic lesion in six, and "normal" bone in one patient. Significant increases in osteoid volume (OV/BV), osteoid surface, osteoblastic surface (ObS/BS) and osteoid thickness were observed. OV/BV and Obs/BS ratios were inversely correlated to cumulative doses of MPRED (r2=0.85 P<.0001 for both ratios), whereas age, sex, time after transplantation, iPTH levels, and cumulative cyclosporine A dose were not related to osteoblastic indices. Osteoclast surface was slightly increased. Widened mineralization lag times were observed, with normalcy of the bone formation rate. Half of the patients showed fractured vertebrae. No differences in T scores were found when patients were subdivided into groups "with" or "without" vertebral fractures. A higher prevalence of fractures was observed in patients with osteoporosis-osteopenia compared to other osteopathies (P<0.02). No relationships between bone volume versus T-scores were observed., Conclusions: In long-term renal transplant recipients, severe osteopenia does not predict osteoporosis alone. The main abnormality we found was an increase in osteoblastic activity with a slight mineralization defect. The heterogeneous bone illness we observed would suggest performing bone biopsy in these patients.

Alport syndrome (AS) is a genetic disease of type IV collagen involving non-homogeneous patterns of inheritance characterized clinically by the presence of progressive haematuric nephritis leading to end-stage renal disease (ESRD), hearing loss and/or ophthalmologic abnormalities. The aim of this study was to investigate, in a cohort of AS patients who had undergone a kidney graft (KG) or who were still on a waiting list for a KG, (a) whether there is a correlation between AS and HLA antigen expression, and (b) long-term graft outcome in transplant patients. The AS cohort was represented by 34 ESRD patients, of whom 25 received a KG and the remaining nine were still on a waiting list. AS transplant patients represented 2.78% of 899 first KGs performed at our centre (Transplantation Department at S. Martino Hospital, Genoa) between 1983 and 2002. Grafts were procured from cadaveric donors in 18 cases and from living, related donors in seven cases. All AS transplant patients had a post-transplant follow-up period of at least 12 months. Results showed that: (i) the frequency of the HLA-DRB1*16 antigen was significantly increased in the whole AS cohort as compared to 128 healthy subjects (HS) (corrected P-value 0.0026; relative risk 7.20) as well as to 232 non-AS ESRD patients on a waiting list for KG (corrected P-values 0.0156; relative risk 4.67); (ii) 5- and 10-year graft survivals in the AS transplant patients were 80 and 73%, respectively, and did not differ from those of a control group represented by 25 non-AS KG recipients matched for sex, age, number of HLA mismatches and immunosuppressive treatment. Increased frequency of HLA-DRB1*16 in AS patients may reflect a linkage disequilibrium with genes coding for collagen synthesis.

Background: Patients undergoing kidney transplantation demonstrate a higher risk of developing cancer as the result of immunosuppressive treatment and concurrent infections., Methods: The incidence of cancer in a cohort of patients who underwent kidney transplantation between 1990 and 2000, and who survived the acute phase (10 days), was analyzed as part of the North Italy Transplant program., Results: A total of 3,521 patients underwent transplantation during a 10-year period in 10 of 13 participating centers; the length of follow-up after kidney transplant was 67.7+/-36.0 months. During the follow-up, 172 patients developed cancer (39 with Kaposi sarcoma, 38 with lymphoproliferative diseases, and 95 with carcinomas [17 kidney, 11 non-basal cell carcinoma of the skin, 10 colorectal, 8 breast, 7 gastric, 7 lung, 6 bladder, and 3 mesothelioma]). The average time to cancer development after transplant was 40.1+/-33.4 months (range 0-134 months). Twenty-four patients developed cancer within 6 months from the transplant (10 with carcinomas, 7 with Kaposi sarcoma, and 7 with lymphoproliferative diseases). Three patients demonstrated a second primary cancer. The average cancer incidence was 4.9%. The incidence of cancer was 0.01 per year. Independent determinants of cancer development were age, gender, and immunosuppressive protocol including induction. Ten-year mortality was significantly higher in patients with cancer (33.1%) than among patients without cancer (5.3%). The relative risk of death in subjects with cancer was 5.5 (confidence interval 4.1-7.4)., Conclusions: These preliminary data underline the importance of long-term surveillance of transplant recipients, choice of immunosuppressive treatment, and careful donor selection.

Background: The persistence of secondary hyperparathyroidism after renal transplantation is frequent and often complicated by overt hypercalcemia. Recent investigations have shown an effect of the different vitamin D receptor (VDR) genotypes on parathyroid hormone (PTH) secretion in both primary and secondary hyperparathyroidism. The aims of this study were (i) to assess whether persistent secondary hyperparathyroidism after renal transplantation is characterized by any change in calcium-controlled PTH secretion, and (ii) whether different VDR allelic distributions might play any role on this setting., Methods: Eighty-one cadaveric renal transplantation recipients, followed-up for at least 12 months, were checked for PTH, other primary metabolic and clinical variables, and VDR B/b alleles (BsmI). In 22 of these the following parameters were evaluated: (a) kinetics parameters of the Ca-PTH relation curve; (b) vertebral mineral density; (c) calcitriol serum levels; (d) PTH-related peptide serum levels; and (e) urinary hydroxyproline., Results: According to the stabilised PTH levels (reached by the third month), the patients were divided in two groups: group A (N = 40, PTH < 80 pg/ml) and group B (N = 41, PTH > 80 pg/ml). Group B differed from group A in that patients had higher PTH levels at the time of transplantation, were older in age, and spent more time on dialysis. Group B had increased maximal and minimal PTH levels, and higher set-point levels than Group A. The patients with the BB pattern of VDR genotype were characterized by the lowest PTH levels both at time of transplantation and after stabilization, and lower set point values than patients with Bb and bb patterns., Conclusions: Our study suggests that (i) the severity of pre-existing secondary hyperparathyroidism is the main factor determining its persistence after renal transplantation, (ii) persistent secondary hyperparathyroidism is characterized by an autonomous pattern of PTH secretion, (iii) the VDR BB genotype seems to be related to lower PTH levels.

Study of 45 renal allograft nephrectomy specimens revealed the presence of relatively uncommon arterial vascular lesions: atheromatosis (12 cases) and a double layer of smooth muscle in the intima (Double Media) (4 cases). Histopathologic features of atheromatosis showed the presence of large lipid-laden cells localized in the intimal layer of arteries. Diagnosis of acute vascular rejection (AVR) was made in 19 cases. Diagnosis of chronic vascular rejection (CVR) was found in 4 cases. 22 cases showed lesions of both AVR and CVR. In 12 cases there was infiltration of the intima and media wall by foam cells closely resembling an atheromatous lesion. Four cases of Double Media were found in allografts with survival varying from 51 to 344 days. The presence of either atheromatous or double media does not correlate statistically with immunosuppressive treatment, blood pressure or with the presence of hypertriglyceridemia and/or hypercholesterolemia. Immunohistochemical investigation of atheromatosis revealed total negativity of the foam cells with antisera to: actin, myosin, desmin and myoglobin. Variable reactivity was observed with antisera to vimentin. Myointimal cells of Double Media expressed slight positivity for actin and vimentin. The double media lesion seems to be the result of a reparative vascular process secondary to rejection changes. Atheromatosis seems to be closely correlated to episodes of acute rejection. Vascular lesions in grafts are harbinger of poor prognosis. Double media lesion and atheromatosis do not seem to have a more unfavourable prognostic significance on the evolution of the transplants.

14 cases of transplant glomerulopathy have been observed in 254 specimen taken from 152 renal allografted patients. Lesions have been studied at light, immunofluorescence and ultrastructural level. Following morphological parameters have been evaluated by semiquantitative method: focal mesangial sclerosis, mesangial matrix, mesangial cellularity, glomerular basement membrane thickening, double contours and crescents. Intermediate and advanced stages prevailed with the evidence of capillary aneurysms in 2 out 14 cases. Electron microscopy showed thickening of the glomerular basement membrane with finely lamellar and electron lucent thickening of the lamina rara interna. Transplant glomerulopathy lesions need differential diagnosis with thrombotic microangiopathy and can be considered equivalent of chronic vascular rejection.