Francesco Fontana

Everolimus, Cyclosporine, and Thrombotic Microangiopathy: Clinical Role and Preventive Tools in Renal Transplantation

INTRODUCTION Thrombotic microangiopathy (TMA) is characterized by endothelial cell injury and formation of fibrin thrombi within capillary and arterioles. In renal allograft recipients, TMA mainly presents as hemolytic uremic syndrome. Its occurrence is rare, and diagnosis requires a high degree of suspicion. Drug toxicity, in particular from calcineurin inhibitors (CNIs) and mTOR inhibitors (mTORi), is the most common cause posttransplant and has recently been emphasized in the setting of lung transplantation. OBJECTIVE The goal of this study was to investigate the role of mTORi as an added risk factor in the development of TMA to propose strategies for modulation of immunosuppressive (IS) therapy. PATIENTS AND METHODS From a database of 496 renal graft recipients, we analyzed 350 renal graft biopsy specimens gathered at our center from 1998 to 2012. In patients undergoing combined therapy with mTORi and CNI, we compared drugs levels in TMA-affected and TMA-free groups, using mTORi and CNI TLC and the summation of [everolimus TLC+(cyclosporine C2/100)] (Σ) as a surrogate marker of combined exposition to 2 drugs. Receiver-operating characteristic analysis of association of EVL TLC+(C2/100) was performed for patients exposed to mTORi. RESULTS Histologic features of TMA were found in 36 patients (prevalence of 7.3%). The caseload was divided into 2 groups: not drug-related TMA (n=19) and drug-related TMA (n=17). Despite the prevalence of TMA in patients exposed to mTORi being greater (8 of 153; prevalence, 5.3%) compared with therapies without mTORi (9 of 324; prevalence, 2.8%), statistical difference was not reached. Patients treated with mTORi who developed de novo drug-related TMA had higher blood levels of IS drugs compared with those who did not develop TMA. Receiver-operating characteristic analysis found a significant threshold of 12.5 ng/mL (area under the curve, 0.803; P=.006). CONCLUSIONS Results confirm the pivotal role of IS drugs in the onset of de novo TMA. On the basis of literature, we could speculate a sequence of endothelial damage by CNI, on which everolimus fits hindering the repair of endothelial injury. Therefore, high blood levels of CNI and mTORi seem to predispose patients to posttransplant TMA. Combined monitoring of these 2 drugs might be used to prevent the complication. Σ [everolimus TLC + (cyclosporine C2/100)]>12.5 ng/mL should be avoided as a surrogate risk factor for adverse effects.

The importance of cytogenetic and molecular analyses in eosinophilia-associated myeloproliferative neoplasms: an unusual case with normal karyotype and TNIP1- PDGFRB rearrangement and overview of PDGFRB partner genes

Fusion genes derived from the platelet-derived growth factor receptor beta (PDGFRB) or alpha (PDGFRA) play an important role in the pathogenesis of eosinophilia-associated myeloproliferative neopla...

Noninvasive Blood Pressure Measurement in Maintenance Hemodialysis Patients: Comparison of Agreement between Oscillometric and Finger-Cuff Methods

Background: The Nexfin monitor is a device used for measuring arterial blood pressure (BP) continuously and noninvasively through finger-cuff technology. Since it was validated against the auscultatory method using a sphygmomanometer, the aim of this study was to test the ability of the Nexfin to evaluate brachial arterial pressure (BAP) in maintenance hemodialysis patients, quantifying accuracy and precision. Methods: Forty hemodynamically stable hemodialysis patients underwent serial measurements of Nexfix arterial pressure (NAP) and BAP, respectively, through Nexfin and oscillometric devices. All BP measurements were recorded before starting hemodialysis. Results: The mean age of the patients was 68.9 ± 14.9 years with 65% older than 65 years and 30% older than 75; eleven subjects (27%) were diabetic. Vascular calcification, evaluated from the aortic arch to the iliac bifurcation, was detected in 87.5% of patients. Bland-Altman analysis comparing NAP measurements with BAP revealed the following outcomes: a mean bias ± limits of agreements (LA) of 15.3 ± 34.8 mm Hg (29% error) for systolic BP, a mean bias ± LA of -0.9 ± 20.34 mm Hg (32% error) for diastolic BP and a mean bias ± LA of 4.5 ± 21.34 mm Hg (26% error) for mean arterial pressure (MAP). Nexfin had poor precision in the reconstruction of diastolic and mean BP and was extremely inaccurate when evaluating systolic BP. Diabetes mellitus, peripheral neuropathy, and increase in systolic BAP significantly predicted the disagreement in systolic pressure measurement between NAP and MAP, F (3.34) = 10.787, p < 0.005, R2 = 0.488. Conclusion: The Nexfin does not meet the criteria of interchangeability with oscillometric method in our hemodialysis patients. The negative influence of diabetes, neuropathy, and increase of systolic BAP on the reconstruction of systemic systolic pressure raises concerns about the feasibility of Nexfin in patients with a high prevalence of vasculopathy.

Immunophenotypic profile and clinical outcome of monoclonal B-cell lymphocytosis in kidney transplantation

Monoclonal B‐cell lymphocytosis (MBL) is a lymphoproliferative disorder characterized by clonal expansion of a B‐cell population in peripheral blood of otherwise healthy subjects. MBL is divided into CLL (chronic lymphocytic leukemia)‐like, atypical CLL‐like and non‐CLL MBL. The aim of this study was to evaluate immunophenotypic characteristics and clinical outcomes of MBL in kidney transplant (KT) recipients. We retrospectively evaluated 593 kidney transplant (KT) recipients in follow‐up at our center. Among them, 157 patients underwent peripheral blood flow cytometry for different clinical indications. A 6‐color panel flow cytometry was used to diagnose MBL. This condition was detected in 5 of 157 KT recipients. Immunophenotypic characterization of MBL showed four cases of non‐CLL MBL and one case of CLL‐like MBL. At presentation, median age was 65 years (range 61‐73). After a median follow‐up of 3.1 years (95%CI; 1.1‐5) from diagnosis, patients did not progress either to CLL or to lymphoma. The disorder did not increase the risk of malignancy, severe infections, graft loss and mortality among our KT recipients. Surprisingly, all cases were also affected by concomitant monoclonal gammopathy of undetermined significance, which did not progress to multiple myeloma during follow‐up. In conclusion, our data suggest that MBL is an age‐related disorder, with non‐CLL MBL being the most common subtype among KT recipients.

Preoperative management of arteriovenous fistula (AVF) for hemodialysis

Native arteriovenous fistula (AVF) is the favorite access for hemodialysis (HD). The National Kidney Foundations Kidney Disease Outcomes Quality Initiative (KDOQI) recommends its creation in most patents with renal failure. Unfortunately, intensive efforts to promote native AVF in patents with marginal vessels have increased the rate of primary fistula failure. A non-functioning fistula prompts the use of central venous catheter (CVC) that, unlike AVF, has been associated with an increased risk of morbidity and mortality among patents receiving HD. We believe that successful and timely AVF placement relies on the development of a multidisciplinary integrated preoperative program divided into five stages: (i) management of patents with advanced chronic kidney disease (CKD), (ii) management of preoperative risk factors for AVF failure, (iii) planning of native AVF, (iv) assessment of patent eligibility and (v) preoperative vascular mapping. Focusing specifically on native AVF, we review scientific evidence regarding preoperative management of this vascular access in order to favor construction of long-term functioning fistula minimizing development of severe complications.

Hemorheology in kidney transplantation:A role for cardiovascular risk?

Uremic patients undergoing dialysis (HD) present a cardiovascular risk of death 10-20 fold higher than general population, but also kidney transplantation keeps considerable cardiovascular burden.Hemorheologic profile alterations have been described in HD; comprehensive data on kidney transplant recipients (KT) are missing. Aim of our study is to characterize the hemorheological profile in KT, and to compare these data with HD and healthy volunteers (HV).We investigated 47 HV, 90 HD and 108 KT.We confirm hemorheological alterations in HD. KT, when compared to HD, normalizes many parameters: plasma viscosity, whole blood viscosity at 1-Hz and 200-Hz shear rate, erythrocyte aggregation index and yield stress. KT show a markedly lower erythrocyte deformability (ED). We found no differences among hemorheological parameters between the different classes of immunosuppressive drugs used.In conclusion, HD show various hemorheological defects; this could support the high incidence of cardiovascular complications. KT improves most hemorheological alterations; nevertheless, ED is reduced in KT, maintaining a detrimental injury at microcirculatory level and leading to the progression of fibrosis till to end-stage injury. Impaired ED in KT could also contribute to progression of interstitial fibrosis and tubular atrophy (IF/TA) in grafts.

Rhodococcus Equi Pneumonia in Kidney Transplant Recipient Affected by Acute Intermittent Porphyria: a Case Report

Rhodococcus equi is a gram-positive coccobacillus responsible for severe infections in patients with weakened immune systems. R equi generally causes pnumonia that may evolve into fatal systemic infection if left untreated. Here, we present a case of a 67-year-old woman affected by acute intermittent porphyria (AIP) who developed R equi pneumonia 7 months after kidney transplantation. Although clinical features at presentation were nonspecific, lung computed tomography showed right perihilar consolidation with a mass-like appearance causing bronchial obstruction. Appropriate antibiotic including intravenous meropenem and oral azithromycin that was then switched to oral levofloxacin and oral azithromycin along with reduction of immunosuppressive therapy resolved pneumonia without provoking an acute attack of porphyria. AIP limited the choice of antibiotics for the treatment of R equi infection because some potentially porphyrinogenic antibacterial agents were avoided. Based on this experience, azithromycin and meropenem can be safely administered for the treatment of R Equi infection in patients with AIP.

Gastric Mucormycosis in a Liver and Kidney Transplant Recipient: Case Report and Concise Review of Literature

Mucormycosis is an uncommonly encountered fungal infection in solid organ transplantation. The infection is severe and often results in a fatal outcome. The most common presentations are rhino-sino-orbital and pulmonary disease. We describe a rare case of gastric mucormycosis in a patient with a combined liver-kidney transplant affected by glycogen storage disease type Ia. A 42-year-old female patient presented with gastric pain and melena 26 days after transplantation. Evaluation with upper endoscopy showed two bleeding gastric ulcers. Histological examination of gastric specimens revealed fungal hyphae with evidence of Mucormycetes at subsequent molecular analysis. Immunosuppressive therapy was reduced and antifungal therapy consisting of liposomal amphotericin B and posaconazole was promptly introduced. Gastrointestinal side effects of posaconazole and acute T-cell rejection of renal graft complicated management of the case. A prolonged course of daily injections of amphotericin B together with a slight increase of immunosuppression favored successful treatment of mucormycosis as well as of graft rejection. At 2-year follow-up, the woman was found to have maintained normal renal and liver function. We conclude that judicious personalization of antimicrobial and antirejection therapy should be considered to resolve every life-threatening case of mucormycosis in solid organ transplantation.

Clinical outcome of kidney transplantation in HIV-infected recipients: a retrospective study:

Kidney transplantation is a safe and effective option for HIV-positive (HIV+) patients. We conducted a retrospective study on HIV+ kidney transplant recipients who underwent transplantation from March 2008 to September 2016. Inclusion criteria for transplantation were CD4+ T-cell count ≥200 per mm3 and undetectable HIV load. The current study reports the outcome of 19 HIV+ recipients, mostly of Caucasian origin (79%) with a median age of 50 years (interquartile range [IQR], 42–52), who were followed up for a median period of 2.4 years (IQR, 1.2–4.6) after transplantation. Compared with HIV-negative (HIV−) controls, HIV+ recipients had similar one- and three-year graft and patient survival, but significantly lower five-year patient survival (P = 0.03). The differences in graft outcome became less evident with the analysis of death-censored graft survival rates. Cumulative incidence of allograft rejection at one year was 32.9%. Rates of infections were not particularly elevated and HIV replication remained well controlled in all but one patient. A high prevalence of metabolic and endocrine complications (68%) was reported after transplantation. Further studies are needed to evaluate long-term outcomes of HIV+ recipients who underwent kidney transplantation.

Efficacy of Belimumab for active lupus nephritis in a young Hispanic woman intolerant to standard treatment: a case report

BackgroundLupus nephritis (LN) is a frequent severe complication of Systemic Lupus Erythematosus (SLE), especially in patients of non-Caucasian ethnicity. Induction treatment for LN consists in the combination of steroids plus a second agent (cyclophosphamide or mycophenolate mofetil) or, as a second-line, calcineurin inhibitors or Rituximab. Induction treatment for LN can be complicated by a series of side effects, the most severe being serious infections. Belimumab is a fully humanized monoclonal antibody that targets soluble B lymphocyte stimulator (BLyS), approved for treatment of serologically active SLE in addition to standard of care.Case presentationA young Hispanic woman was diagnosed with SLE at the age of 15. After several immunosuppressive treatments for arthritic symptoms (high-dose steroids, mycophenolate mofetil, Rituximab, cyclophosphamide) leading to serious complications and scarce clinical improvement, she developed severe LN. Induction treatment with a combination of intravenous high-dose methylprednisolone and cyclophosphamide was started but, after few days, the patient developed cryptococcal meningitis. After institution of appropriate antifungal therapy, treatment with Tacrolimus was attempted but poorly tolerated by the patient and withdrawn. Eventually, Belimumab was initiated off-label as a last resource to treat LN. Belimumab was well tolerated by the patient and resulted in a rapid and marked improvement in clinical symptoms and reduction in proteinuria, serum complement levels and anti-dsDNA titer; of note, the patient developed no infectious complications.ConclusionsWe report the case of a severe LN in a young Hispanic woman who did not respond to conventional and second-line induction therapies, due both to intolerance and to the development of serious infectious complications. Eventually, Belimumab was successfully added to steroids and was well tolerated by the patient, resulting in a marked improvement in clinical and biochemical parameters. We suggest that Belimumab should be considered as a potentially efficacious treatment in patients with LN who cannot tolerate conventional therapies.