Sequential administration of anti-complement component C5 eculizumab and type-2 anti-CD20 obinutuzumab for the treatment of early antibody-mediated rejection after kidney transplantation: A proof of concept.

Kidney transplant (KT) candidates with donor-specific antibodies (DSA) exhibit exceedingly high antibody-mediated rejection (ABMR) and allograft loss rates. Currently, treatment of ABMR remains an unmet clinical need. We report the use of the anti-C5 eculizumab and the type-2 anti-CD20 obinutuzumab in two patients with early ABMR. Eculizumab (900 mg IV) led to complete inhibition of the terminal complement cascade (unremarkable AP50 and CH50 activity) and prompt stoppage of complement-dependent antibody-mediated allograft injury (clearance of intra-graft C4d and C5b-9 deposition). Despite complement inhibition, obinutuzumab (1000 mg IV) determined full and long-lasting peripheral B-cell depletion, with significant reduction in all DSA. Graft function improved, remaining stable up to three years of follow-up. No signs of active ABMR and rebound DSA were detected. Obinutuzumab B-cell depletion and inhibition of DSA production were not affected by complement blockage. Further studies are needed to confirm the potential benefit of obinutuzumab in association with complement inhibitors.

Human cytomegalovirus-related gastrointestinal disease after kidney transplantation: A systematic review.

BACKGROUND: Human-cytomegalovirus (hCMV) infection involving the gastrointestinal tract represents a leading cause of morbidity and mortality among kidney transplant (KT) recipients (KTRs). Signs and symptoms of the disease are extremely variable. Prompt anti-viral therapy administration and immunosuppression modification are key factors for optimizing management. However, complex work-up strategies are generally required to confirm the preliminary diagnosis. Unfortunately, solid evidence and guidelines on this specific topic are not available. We consequently aimed to summarize current knowledge on post-KT hCMV-related gastrointestinal disease (hCMV-GID). METHODS: We conducted a systematic review (PROSPERO ID: CRD42023399363) about hCMV-GID in KTRs. RESULTS: Our systematic review includes 52 case-reports and ten case-series, published between 1985 and 2022, collectively reporting 311 cases. The most frequently reported signs and symptoms of hCMV-GID were abdominal pain, diarrhea, epigastric pain, vomiting, fever, and GI bleeding. Esophagogastroduodenoscopy and colonoscopy were the primary diagnostic techniques. In most cases, the preliminary diagnosis was confirmed by histology. Information on anti-viral prophylaxis were extremely limited as much as data on induction or maintenance immunosuppression. Treatment included ganciclovir and/or valganciclovir administration. Immunosuppression modification mainly consisted of mycophenolate mofetil or calcineurin inhibitor minimization and withdrawal. In total, 21 deaths were recorded. Renal allograft-related outcomes were described for 26 patients only. Specifically, reported events were acute kidney injury (n = 17), transplant failure (n = 5), allograft rejection (n = 4), and irreversible allograft dysfunction (n = 3). CONCLUSIONS: The development of local and national registries is strongly recommended to improve our understanding of hCMV-GID. Future clinical guidelines should consider the implementation of dedicated diagnostic and treatment strategies.

Advancing immunosuppression in liver transplantation: A narrative review.

Immunosuppression is essential to ensure recipient and graft survivals after liver transplantation (LT). However, our understanding and management of the immune system remain suboptimal. Current immunosuppressive therapy cannot selectively inhibit the graft-specific immune response and entails a significant risk of serious side effects, i.e., among others, de novo cancers, infections, cardiovascular events, renal failure, metabolic syndrome, and late graft fibrosis, with progressive loss of graft function. Pharmacological research, aimed to develop alternative immunosuppressive agents in LT, is behind other solid-organ transplantation subspecialties, and, therefore, the development of new compounds and strategies should get priority in LT. The research trajectories cover mechanisms to induce T-cell exhaustion, to inhibit co-stimulation, to mitigate non-antigen-specific inflammatory response, and, lastly, to minimize the development and action of donor-specific antibodies. Moreover, while cellular modulation techniques are complex, active research is underway to foster the action of T-regulatory cells, to induce tolerogenic dendritic cells, and to promote the function of B-regulatory cells. We herein discuss current lines of research in clinical immunosuppression, particularly focusing on possible applications in the LT setting.

Update on current and potential application of extracellular vesicles in kidney transplantation.

Kidney transplantation (KT) is the best treatment for end-stage kidney disease. However, early diagnosis of graft injury remains challenging, mainly because of the lack of accurate and noninvasive diagnostic techniques. Improving graft outcomes is equally demanding, as is the development of innovative therapies. Many research efforts are focusing on extracellular vesicles, cellular particles free in each body fluid that have shown promising results as precise markers of damage and potential therapeutic targets in many diseases, including the renal field. In fact, through their receptors and cargo, they act in damage response and immune modulation. In transplantation, they may be used to determine organ quality and aging, the presence of delayed graft function, rejection, and many other transplant-related pathologies. Moreover, their low immunogenicity and safe profile make them ideal for drug delivery and the development of therapies to improve KT outcomes. In this review, we summarize current evidence about extracellular vesicles in KT, starting with their characteristics and major laboratory techniques for isolation and characterization. Then, we discuss their use as potential markers of damage and as therapeutic targets, discussing their promising use in clinical practice as a form of liquid biopsy.

Allograft Vesicoureteral Reflux after Kidney Transplantation.

Allograft vesicoureteral reflux (VUR) is a leading urological complication of kidney transplantation. Despite the relatively high incidence, there is a lack of consensus regarding VUR risk factors, impact on renal function, and management. Dialysis vintage and atrophic bladder have been recognized as the most relevant recipient-related determinants of post-transplant VUR, whilst possible relationships with sex, age, and ureteral implantation technique remain debated. Clinical manifestations vary from an asymptomatic condition to persistent or recurrent urinary tract infections (UTIs). Voiding cystourethrography is widely accepted as the gold standard diagnostic modality, and the reflux is generally graded following the International Reflux Study Committee Scale. Long-term transplant outcomes of recipients with asymptomatic grade I-III VUR are yet to be clarified. On the contrary, available data suggest that symptomatic grade IV-V VUR may lead to progressive allograft dysfunction and premature transplant loss. Therapeutic options include watchful waiting, prolonged antibiotic suppression, sub-mucosal endoscopic injection of dextranomer/hyaluronic acid copolymer at the site of the ureteral anastomosis, and surgery. Indication for specific treatments depends on recipient's characteristics (age, frailty, compliance with antibiotics), renal function (serum creatinine concentration < 2.5 vs. ≥ 2.5 mg/dL), severity of UTIs, and VUR grading (grade I-III vs. IV-V). Current evidence supporting surgical referral over more conservative strategies is weak. Therefore, a tailored approach should be preferred. Properly designed studies, with adequate sample size and follow-up, are warranted to clarify those unresolved issues.

New-Onset Diabetes after Kidney Transplantation.

New-onset diabetes mellitus after transplantation (NODAT) is a frequent complication in kidney allograft recipients. It may be caused by modifiable and non-modifiable factors. The non-modifiable factors are the same that may lead to the development of type 2 diabetes in the general population, whilst the modifiable factors include peri-operative stress, hepatitis C or cytomegalovirus infection, vitamin D deficiency, hypomagnesemia, and immunosuppressive medications such as glucocorticoids, calcineurin inhibitors (tacrolimus more than cyclosporine), and mTOR inhibitors. The most worrying complication of NODAT are major adverse cardiovascular events which represent a leading cause of morbidity and mortality in transplanted patients. However, NODAT may also result in progressive diabetic kidney disease and is frequently associated with microvascular complications, eventually determining blindness or amputation. Preventive measures for NODAT include a careful assessment of glucose tolerance before transplantation, loss of over-weight, lifestyle modification, reduced caloric intake, and physical exercise. Concomitant measures include aggressive control of systemic blood pressure and lipids levels to reduce the risk of cardiovascular events. Hypomagnesemia and low levels of vitamin D should be corrected. Immunosuppressive strategies limiting the use of diabetogenic drugs are encouraged. Many hypoglycemic drugs are available and may be used in combination with metformin in difficult cases. In patients requiring insulin treatment, the dose and type of insulin should be decided on an individual basis as insulin requirements depend on the patient's diet, amount of exercise, and renal function.

Utility and safety of early allograft biopsy in adult deceased donor kidney transplant recipients.

INTRODUCTION: Delayed graft function (DGF) is considered a risk factor for rejection after kidney transplantation (KTx). Clinical guidelines recommend weekly allograft biopsy until DGF resolves. However, who may benefit the most from such an aggressive policy and when histology should be evaluated remain debated. METHODS: We analyzed 223 biopsies in 145 deceased donor KTx treated with basiliximab or anti-thymocyte globulin (rATG) and calcineurin inhibitor-based maintenance. The aim of the study was to assess the utility and safety of biopsies performed within 28 days of transplant. Relationships between transplant characteristics, indication, timing, and biopsy-related outcomes were evaluated. RESULTS: Main indication for biopsy was DGF (87.8%) followed by lack of improvement in graft function (9.2%), and worsening graft function (3.1%). Acute tubular necrosis was the leading diagnosis (89.8%) whereas rejection was detected in 8.2% specimens. Rejection was more frequent in patients biopsied due to worsening graft function or lack of improvement in graft function than DGF (66.7% vs. 3.5%; P = 0.0075 and 33.3% vs. 3.5%; P = 0.0104, respectively) and in biopsies performed between day 15 and 28 than from day 0 to 14 (31.2% vs. 3.7%; P = 0.0002). Complication rate was 4.1%. Management was affected by the information gained with histology in 12.2% cases (7% considering DGF). CONCLUSIONS: In low-immunological risk recipients treated with induction and calcineurin inhibitors maintenance, protocol biopsies obtained within 2 weeks of surgery to rule out rejection during DGF do not necessarily offer a favourable balance between risks and benefits. In these patients, a tailored approach may minimize complications thus optimizing results.

Characterization of an in vitro model to study the possible role of polyomavirus BK in prostate cancer.

Prostate cancer (PCa) is the most common male neoplasms in the Western world. Various risk factors may lead to carcinogenesis, including infectious agents such as polyomavirus BK (BKPyV), which infects the human renourinary tract, establishes latency, and encodes oncoproteins. Previous studies suggested that BKPyV plays a role in PCa pathogenesis. However, the unspecific tropism of BKPyV and the lack of in vitro models of BKPyV-infected prostate cells cast doubt on this hypothesis. The aim of the present study was to determine whether BKPyV could (a) infect normal and/or tumoral epithelial prostate cells and (b) affect their phenotype. Normal epithelial prostate RWPE-1 cells and PCa PC-3 cells were infected with BKPyV for 21 days. Cell proliferation, cytokine production, adhesion, invasion ability, and epithelial-to-mesenchymal transition (EMT) markers were analyzed. Our results show that (a) RWPE-1 and PC-3 cells are both infectable with BKPyV, but the outcome of the infection varies, (b) cell proliferation and TNF-α production were increased in BKPyV-infected RWPE-1, but not in PC-3 cells, (c) adhesion to matrigel and invasion abilities were elevated in BKPyV-infected RWPE-1 cells, and (d) loss of E-cadherin and expression of vimentin occurred in both uninfected and infected RWPE-1 cells. In conclusion, BKPyV may change some features of the normal prostate cells but is not needed for maintaining the transformed phenotype in the PCa cells The fact that RWPE-1 cells exhibit some phenotype modifications related to EMT represents a limit of this in vitro model.

Three-yr safety and efficacy of everolimus and low-dose cyclosporine in de novo pediatric kidney transplant patients.

The three yr results of a multicenter trial in de novo pediatric KT treated with a proliferative signal inhibitor and low dose CNI are presented. Thirty-seven children (9.1 ± 5 yr old) received basiliximab, cyclosporine A (CyA C2:1400 ng/mL), (MMF C0:1.5-3 µg/mL), and prednisone. Three wk later everolimus was started (C0:5-10 ng/mL), CyA was reduced (C2:600 ng/mL after 90 days 300 ng/mL), and MMF discontinued. During the three-yr period patient and graft survivals were 96%. One patient died for causes unrelated to the immunosuppression. Cumulative acute rejection rate including protocol and indication biopsies was 21.9%. None of the patients had signs of chronic humoral rejection. Incidence of dnDSA was 5%, 11%, and 22% at one, two, and three yr post-transplant, respectively. Mean glomerular filtration rate measured at one yr and three yr post-transplant was 105.5 ± 31 and 110.7 ± 27 mL/min/1.73 m(2), respectively. A growth velocity of 7.7 ± 6.7 cm/yr was achieved with positive catch-up growth. No malignancy or post-transplant lymphoproliferative diseases were diagnosed. In conclusion, the treatment based on basiliximab induction, everolimus, low-dose cyclosporine, and low-dose prednisone leads to good long-term efficacy in de novo pediatric KT recipients.

Longitudinal study of human polyomaviruses viruria in kidney transplant recipients.

INTRODUCTION: Immunosuppression after kidney transplantation (KTx) exposes recipients to Human Polyomaviruses (HPyVs) infections, whose natural history is still misunderstood. METHODS: Allograft biopsies, and urine from 58 donor-recipient pairs were collected before KTx (T0) and 1 (T1), 15 (T2), 30 (T3), 60 (T4), 90 (T5), 180 (T6), 270 (T7), 360 (T8), and 540 (T9) days after transplant. Specimens were tested for JC (JCPyV) and BK (BKPyV), by quantitative Real-Time PCR. The course of post-KTx HPyVs viruria, and the association between JCPyV viruria in recipients and donors, were evaluated. RESULTS: HPyVs were detected in 3/58 (5.2%) allograft biopsies. HPyVs viruria was present in 29/58 (50%) donors and 41/58 (70.7%) recipients. JCPyV DNA was detected in 26/58 (44.8%) donors and 25/58 recipients (43.1%), 19 of whom received kidney from JCPyV positive donor, whereas BKPyV genome was detected in 3 (5.2%) donors and 22 (37.9%) recipients. The median time of JCPyV, and BKPyV first episode of replication was 1, and 171 days post KTx, respectively. At T0, JCPyV viruria of donors was associated with increased risk of JCPyV replication post-KTx; recipients with JCPyV positive donors showed lower risk of BKPyV replication post-KTx. CONCLUSIONS: The results suggested that JCPyV may be transmitted by allograft, and that its replication post KTx might prevent BKPyV reactivation. Future investigation regarding correlation between chronic exposure to immunosuppressive agents and HPyVs urinary replication are warranted.

A review on JC virus infection in kidney transplant recipients.

The polyomavirus (PyV), JC virus (JCV), is a small nonenveloped DNA virus that asymptomatically infects about 80% of healthy adults and establishes latency in the kidney tissue. In case of immunodeficient hosts, JCV can lytically infect the oligodendrocytes, causing a fatal demyelinating disease, known as progressive multifocal leukoencephalopathy (PML). Although the reactivation of another human PyV, BK virus (BKV), is relatively common and its association with the polyomavirus associated nephropathy (PyVAN) following renal transplantation is proven, JCV replication and its impact on graft function and survival are less well studied. Here we describe the biology of JCV and its pathological features and we review the literature regarding the JCV infection analyzed in the setting of transplantations.

Investigation of polyomaviruses replication in pediatric patients with nephropathy receiving rituximab.

Rituximab is a chimeric monoclonal antibody reacting with the CD20 antigen on B cells. It has been proposed as treatment for the idiopathic nephrotic syndrome, recurrent idiopathic nephropathy, and focal segmental glomerulosclerosis refractory to steroids. Rituximab influences T-cell immunity and may predispose the patients to opportunistic infections, such as progressive multifocal leukoencephalopathy caused by the polyomavirus JC (JCV). The risk of latent viruses infections/reactivations in pediatric patients receiving monoclonal antibodies is not well known yet. In this longitudinal 6-month study, the effects of rituximab on JCV and BK virus (BKV) replication have been investigated. Blood, serum, and urine samples have been collected monthly from 11 pediatric patients (mean age: 11 years) with the idiopathic nephrotic syndrome and recurrent idiopathic nephropathy, under rituximab therapy. JCV and BKV real-time PCRs and sequencing of the viral protein 1 and the non-coding control region have been conducted. The same investigations have been undertaken on samples collected from eight pediatric patients (controls, mean age: 6 years), with idiopathic nephrotic syndrome or focal segmental glomerulosclerosis, treated with conventional chemotherapy. JCV was detected in the urine of one patient (9%), and one control (12.5%); BKV was found in the urine of 7/11 patients (63.6%) and 2/8 controls (25%) and in blood samples from four patients. No significant difference was found in the mean viral loads and in the viral molecular characterizations between the two groups. The polyomaviruses replication was not associated with rituximab therapy in children.

The potential of steroids and xenobiotic receptor polymorphisms in forecasting cyclosporine pharmacokinetic variability in young kidney transplant recipients.

The steroids and xenobiotics receptor (SXR) up-regulates the expression and the synthesis of key enzymes in CyA metabolism. In this study, we examined the possible interactions between CyA exposure and SXR polymorphisms during the first year after renal transplantation. The study involved 66 pediatric renal transplant recipients (25 women and 41 men, mean age 13.9 ± 7.4 yr). All patients were genotyped for two sequence variations in the NR1I2 gene: g.-205_-200delGAGAAG and 7635 A>G. CyA trough levels and CyA weight-adjusted daily dose were recorded at 30, 90, 180, and 360 days after transplantation and compared between the different genotypes. A third newly discovered SXR polymorphism was characterized and also included in the study. CyA trough levels and CyA weight-adjusted daily dose were comparable on four time points throughout the first year post-transplant in all three groups. GEE showed a significant reduction in weight-adjusted CyA daily dose in patients carrying the deletion of 6 bp in SXR with a significant group-by-time effect that persisted also when analysis was corrected for age, prednisone dose, and acute rejection episodes. In our group of patients, only the g.-205_-200delGAGAAG SXR polymorphism was able to influence the metabolism of CyA continuously, during the first year after transplantation.

Case report: Eculizumab plus obinutuzumab induction in a deceased donor kidney transplant recipient with DEAP-HUS.

The wide-spread use of the anti-complement component 5 monoclonal antibody (moAb) eculizumab has greatly reduced the incidence of relapsing atypical hemolytic uremic syndrome (aHUS) after kidney transplantation (KT). However, the optimal management of aHUS transplant candidates with anti-Complement Factor H (CFH) antibodies remains debated. In these patients, the benefits of chronic eculizumab administration should be weighed against the risk of fatal infections, repeated hospital admissions, and excessive costs. We report the case of a 45-year-old female patient with CFHR1/CFHR3 homozygous deletion-associated aHUS who underwent deceased-donor KT despite persistently elevated anti-CFH antibody titers. As induction and aHUS prophylaxis, she received a combination of eculizumab and obinutuzumab, a humanized type 2 anti-CD20 moAb. The post-operative course was uneventful. After 1-year of follow-up, she is doing well with excellent allograft function, undetectable anti-CFH antibodies, sustained B-cell depletion, and no signs of aHUS activity. A brief review summarizing current literature on the topic is also included. Although anecdotal, our experience suggests that peri-operative obinutuzumab administration can block anti-CFH antibodies production safely and effectively, thus ensuring long-lasting protection from post-transplant aHUS relapse, at a reasonable cost. For the first time, we have demonstrated in vivo that obinutuzumab B-cell depleting properties are not significantly affected by eculizumab-induced complement inhibition.

Epidemiology, Clinical Characteristics, Diagnostic Work Up, and Treatment Options of Leishmania Infection in Kidney Transplant Recipients: A Systematic Review.

Current knowledge on Leishmania infection after kidney transplantation (KT) is limited. In order to offer a comprehensive guide for the management of post-transplant Leishmaniasis, we performed a systematic review following the latest PRISMA Checklist and using PubMed, Scopus, and Embase as databases. No time restrictions were applied, including all English-edited articles on Leishmaniasis in KT recipients. Selected items were assessed for methodological quality using a modified Newcastle-Ottawa Scale. Given the nature and quality of the studies (case reports and retrospective uncontrolled case series), data could not be meta-analyzed. A descriptive summary was therefore provided. Eventually, we selected 70 studies, describing a total of 159 cases of Leishmaniasis. Most of the patients were adult, male, and Caucasian. Furthermore, they were frequently living or travelling to endemic regions. The onset of the disease was variable, but more often in the late transplant course. The clinical features were basically similar to those reported in the general population. However, a generalized delay in diagnosis and treatment could be detected. Bone marrow aspiration was the preferred diagnostic modality. The main treatment options included pentavalent antimonial and liposomal amphotericin B, both showing mixed results. Overall, the outcomes appeared as concerning, with several patients dying or losing their transplant.

In Vitro Study Evaluating the Effect of Different Immunosuppressive Agents on Human Polyomavirus BK Replication.

BACKGROUND: Human polyomavirus BK (BKPyV) is the etiologic agent of polyomavirus-associated nephropathy, a leading cause of kidney transplant dysfunction. Because of the lack of antiviral therapies, immunosuppression minimization is the recommended treatment. This strategy offers suboptimal outcomes and entails a significant risk of rejection. Our aim was to evaluate the effect of different immunosuppressive drugs (leflunomide, tacrolimus, mycophenolic acid, sirolimus, and everolimus) and their combinations in an in vitro model of BKPyV infection. METHODS: Human renal tubular epithelial cells were infected with BKPyV and treated with leflunomide, tacrolimus, mycophenolic acid, sirolimus, and everolimus, administered alone or in some combination thereof. Viral replication was assessed every 24 hours (up to 72 hours) by BKPyV-specific quantitative real-time polymerized chain reaction for the VIRAL PROTEIN 1 sequence in cell supernatants and by western blot analysis targeting the viral protein 1 and the glyceraldehyde 3-phosphate dehydrogenase on total protein lysates. Results were described as viral copies/mL and compared between treatments at any prespecified time point of the study. RESULTS: The highest inhibitory effects were observed using leflunomide or everolimus plus mycophenolic acid (mean BKPyV replication log reduction 0.28). The antiviral effect of everolimus persisted when it was used in combination with tacrolimus (mean BKPyV replication log reduction 0.27). CONCLUSIONS: Our experience confirms that everolimus has anti-BKPyV properties and prompts future research to investigate possible mechanisms of action. It also provides a rational basis for targeted clinical trials evaluating alternative immunosuppressive modification strategies.

Outcomes of Patients Receiving a Kidney Transplant or Remaining on the Transplant Waiting List at the Epicentre of the COVID-19 Pandemic in Europe: An Observational Comparative Study.

Since the declaration of the COVID-19 pandemic, the number of kidney transplants (KT) performed worldwide has plummeted. Besides the generalised healthcare crisis, this unprecedented drop has multiple explanations such as the risk of viral transmission through the allograft, the perceived increase in SARS-CoV-2-related morbidity and mortality in immunocompromised hosts, and the virtual "safety" of dialysis while awaiting effective antiviral prophylaxis or treatment. Our institution, operating at the epicentre of the COVID-19 pandemic in Italy, has continued the KT programme without pre-set limitations. In this single-centre retrospective observational study with one-year follow-up, we assessed the outcomes of patients who had undergone KT (KTR) or remained on the transplant waiting list (TWL), before (Pre-COV) or during (COV) the pandemic. The main demographic and clinical characteristics of the patients on the TWL or receiving a KT were very similar in the two periods. The pandemic did not affect post-transplant recipient and allograft loss rates. On the contrary, there was a trend toward higher mortality among COV-TWL patients compared to Pre-COV-TWL subjects. Such a discrepancy was primarily due to SARS-CoV-2 infections. Chronic exposure to immunosuppression, incidence of delayed allograft function, and rejection rates were comparable. However, after one year, COV-KTR showed significantly higher median serum creatinine than Pre-COV-KTR. Our data confirm that KT practice could be safely maintained during the COVID-19 pandemic, with excellent patient- and allograft-related outcomes. Strict infection control strategies, aggressive follow-up monitoring, and preservation of dedicated personnel and resources are key factors for the optimisation of the results in case of future pandemics.

Percutaneous cutting balloon angioplasty for the treatment of renovascular hypertension in children and adolescents.

OBJECTIVE: Percutaneous transluminal renal angioplasty (PTRA), the recommended treatment in children with renovascular hypertension (RVH), often has unsatisfactory outcomes. Cutting balloons may improve the results of angioplasty in different vascular beds with complex and resistant lesions. We retrospectively analysed the effects of percutaneous cutting balloon angioplasty (PCBA) on blood pressure, cardiac mass and renal artery acceleration time in children/adolescents referred to our centre for RVH. PATIENTS AND METHODS: Thirteen patients (aged 9-19 years) with renal artery stenosis (RAS) and severe hypertension were identified. RASs were focal fibromuscular (FMD) or FMD-like dysplasia (in six cases bilateral, in five associated with mid aortic syndrome). Ten patients had uncontrolled hypertension, in nine cases associated with left ventricular hypertrophy (LVH). Acceleration time was abnormal in all stenotic arteries. Eighteen PCBA were performed, in three arteries associated with stent implantation. RESULTS: PCBA was technically successful in all individuals without major complications. In one patient, an intra-stent restenosis occurred, successfully redilated with conventional angioplasty without recurrence at 4 years distance. One year after PCBA, mean SBP and DBPs were markedly reduced from 146 ±â€Š25 to 121 ±â€Š10 mmHg and from 87 ±â€Š11 to 65 ±â€Š12 mmHg, respectively ( P  < 0.001 for both). At that time, hypertension was cured in seven children and controlled in five individuals. This favourable outcome was confirmed with ambulatory blood pressure measurement in four patients. At the latest follow-up, left ventricular mass and acceleration time were normal in all patients. CONCLUSION: PCBA proved to be a well tolerated and effective procedure that can be considered as an alternative to PTRA to treat hypertensive children/adolescents with recurrent or resistant RAS.

Association between CYP3A5 polymorphisms and blood pressure in kidney transplant recipients receiving calcineurin inhibitors.

Abstract Renal cytochrome P450 3A5 (CYP3A5) has been associated with blood pressure (BP) control in humans. We investigated whether CYP3A5 polymorphisms are associated with post- transplant hypertension in a selected population of kidney recipients receiving calcineurin inhibitors. Ninety-two kidney transplant recipients receiving cyclosporine (CyA) or tacrolimus (Tac) were genotyped for CYP3A5 polymorphisms, and the association between the CYP3A5 alleles (*1,*3) and hypertension on post-operative day (POD) 6 and POD 180 was verified, with multiple regression being used to identify the putative co-variates that may predict the extent and severity of hypertension in transplant recipients at different post-transplant times. The CYP3A5*1 carriers had higher systolic (SBP) and diastolic blood pressure (DBP) in both the immediate and delayed post-transplant period when adjusted for anti-hypertensive medication (POD 6: SBP = 161 ± 23 vs. 140 ± 23 mmHg; DBP = 120 ± 15 vs. 87 ± 14 mmHg, p < 0.05. POD 180: SBP = 136 ± 16 vs. 129 ± 14 mmHg; DBP = 89 ± 15 vs. 80 ± 15 mmHg, p < 0.05). The severity of hypertension between the CYP3A5*1 carriers and noncarriers on POD 6 was documented by the significantly different distribution of hypertension classes, but this was not confirmed on POD 180. The CYP3A5 genotype was the only independent variable affecting mean arterial pressure. The results of this study show that CYP3A5 polymorphisms are associated with the severity and degree of hypertension in kidney transplant recipients receiving calcineurin inhibitors regardless of the time of recording. However, the role of concomitant medications such as steroids with strong CYP3A5 inducing activity, should be taken into account.