Association of Serum Levels and Immunohistochemical Labelling of Des-Gamma-Carboxy-Prothrombin in Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma.

Hepatocellular cancer (HCC) is one of the main reasons for liver transplantation (LT). Biomarkers, such as alpha-foetoprotein (AFP) and Des-gamma-carboxy-prothrombin (DCP), can be helpful in defining the recurrence risk post LT. This study aims to evaluate the association between the intensity of DCP immunohistochemical labelling and serum DCP levels in patients undergoing LT for HCC. We carried out a prospective monocentric study including patients who all underwent LT for cirrhosis between 2016 and 2018 and all fell under the Milan criteria. The accepted diagnostic criteria for HCC were contrast-enhanced imaging and histology. Thirty-nine patients were followed for a median of 21 months, with HCC lesions categorized into negative, focally positive, and diffusely positive groups based on DCP immunohistochemistry. The serum DCP levels were significantly higher in the positive groups (258 mAU/mL for the focally and 257 mAU/mL for the diffusely positive) than in the negative group (48 mAU/mL) (p = 0.005) at diagnosis and at the time of liver transplantation (220 mAU/mL for the diffuse positive group). Microvascular invasion (58.8% vs. 19.0% for the diffusely positive and negative groups, respectively, p < 0.001) and lesion size (20 mm in the diffusely labelled group versus 12 mm in the other groups, p = 0.002) were significantly correlated with DCP labelling. Late recurrence occurred only in the positive groups; in the negative group, it occurred within the first 3 months after transplantation. DCP labelling in liver lesions correlates with serum levels and a more aggressive tumour profile. Further investigation is needed to determine if highly DCP-labelled tumours allow for the better selection of high-risk patients before LT.

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.

Tacrolimus-Associated Terminal Ileitis After Kidney Transplantation, Mimicking Crohn Disease: A Case Report.

The onset of gastroduodenal ulcers is a frequent complication after transplantation, whereas cases of intestinal ulcers are sporadic and poorly described in the literature. A patient on immunosuppressive therapy with tacrolimus and mycophenolate mofetil after kidney transplant for immunoglobulin A-related glomerulonephritis developed symptoms compatible with Crohn disease 7 months after the transplant. The patient was hospitalized for abdominal pain, diarrhea, fever, and weight loss. Imaging and a colonoscopy showed signs of idiopathic inflammatory bowel disease (IBD) affecting the terminal ileum. Behcet's disease, post-transplant lymphoma, cytomegalovirus, Epstein-Barr virus, or mycobacteria infection were excluded. Mycophenolate mofetil was suspended, and steroid therapy was increased without clinical improvement. Eleven units of blood were required for severe anemia. A further colonoscopy revealed ulcerations involving the cecal fundus, ileocecal valve, and distal ileum with bowel stenosis and suspected ischemia. The patient, therefore, underwent an emergency laparoscopic ileocolic resection. The histologic examination did not reveal clear signs of IBD, ischemia, or viral infection of the ileum. The findings seemed indicative of iatrogenic damage from immunosuppressive therapy. The postoperative course was regular, and after 12 months, the patient was asymptomatic, on low-dose tacrolimus and prednisone therapy. During immunosuppressive therapy, the onset of isolated ileal ulcers, which can mimic IBD, may be a sporadic complication.

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.

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.

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.

The Enhanced Recovery after Surgery (ERAS) Pathway Is a Safe Journey for Kidney Transplant Recipients during the "Extended Criteria Donor" Era.

Enhanced recovery after surgery (ERAS) protocols are still underused in kidney transplantation (KT) due to recipients' "frailty" and risk of postoperative complications. We aimed to evaluate the feasibility and safety of ERAS in KT during the "extended-criteria donor" era, and to identify the predictive factors of prolonged hospitalization. In 2010−2019, all patients receiving KT were included in ERAS program targeting a discharge home within 5 days of surgery. Recipient, transplant, and outcomes data were analyzed. Of 454 KT [male: 280, 63.9%; age: 57 (19−77) years], 212 (46.7%) recipients were discharged within the ERAS target (≤5 days), while 242 (53.3%) were discharged later. Patients within the ERAS target (≤5 days) had comparable recipient and transplant characteristics to those with longer hospital stays, and they had similar post-operative complications, readmission rates, and 5 year graft/patient survival. In the multivariate analysis, DGF (HR: 2.16, 95% CI: 1.08−4.34, p < 0.030) and in-hospital dialysis (HR: 3.68, 95% CI: 1.73−7.85, p < 0.001) were the only predictive factors for late discharge. The ERAS approach is feasible and safe in all KT candidates, and its failure is primarily related to the postoperative graft function, rather than the recipient's clinical status. ERAS pathways, integrated with strict collaboration with local nephrologists, allow early discharge after KT, with clinical benefits.

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.

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.

Adipose-Derived Stem/Stromal Cells in Kidney Transplantation: Status Quo and Future Perspectives.

Kidney transplantation (KT) is the gold standard treatment of end-stage renal disease. Despite progressive advances in organ preservation, surgical technique, intensive care, and immunosuppression, long-term allograft survival has not significantly improved. Among the many peri-operative complications that can jeopardize transplant outcomes, ischemia-reperfusion injury (IRI) deserves special consideration as it is associated with delayed graft function, acute rejection, and premature transplant loss. Over the years, several strategies have been proposed to mitigate the impact of IRI and favor tolerance, with rather disappointing results. There is mounting evidence that adipose stem/stromal cells (ASCs) possess specific characteristics that could help prevent, reduce, or reverse IRI. Immunomodulating and tolerogenic properties have also been suggested, thus leading to the development of ASC-based prophylactic and therapeutic strategies in pre-clinical and clinical models of renal IRI and allograft rejection. ASCs are copious, easy to harvest, and readily expandable in culture. Furthermore, ASCs can secrete extracellular vesicles (EV) which may act as powerful mediators of tissue repair and tolerance. In the present review, we discuss the current knowledge on the mechanisms of action and therapeutic opportunities offered by ASCs and ASC-derived EVs in the KT setting. Most relevant pre-clinical and clinical studies as well as actual limitations and future perspective are highlighted.

Physical Inactivity: A Modifiable Risk Factor for Morbidity and Mortality in Kidney Transplantation.

In patients with chronic kidney disease, sedentary behavior is widely recognized as a significant risk factor for cardiovascular disease, diabetes, obesity, osteoporosis, cancer, and depression. Nevertheless, the real impact of physical inactivity on the health of kidney transplant (KT) recipients remains uncertain. Over the last decade, there has been a renewed interest in exploring the effects of regular physical exercise on transplant-related outcomes. There is now mounting evidence that physical activity may reduce the burden of cardiovascular risk factors, preserve allograft function, minimize immunosuppression requirement, and ameliorate the quality of life of KT recipients. Many positive feedbacks can be detected in the early stages of the interventions and with a minimal exercise load. Despite these encouraging results, the perceived role of physical activity in the management of KT candidates and recipients is often underrated. The majority of trials on exercise training are small, relatively short, and focused on surrogate outcomes. While waiting for larger studies with longer follow-up, these statistical limitations should not discourage patients and doctors from initiating exercise and progressively increasing intensity and duration. This narrative review summarizes current knowledge about the deleterious effects of physical inactivity after KT. The benefits of regular physical exercise are also outlined.

Human Endogenous Retroviruses Long Terminal Repeat Methylation, Transcription, and Protein Expression in Human Colon Cancer.

Colon cancer is the fourth most common malignancy in both incidence and mortality in developed countries. Infectious agents are among the risk factors for colon cancer. Variations in human endogenous retrovirus (HERV) transcript and protein levels are associated with several types of cancers, but few studies address HERV expression in colon cancer. Fifty-eight patients with advanced-stage colon cancer were enrolled in this study. HERV-H, -K (HML-2), -P LTRs, Alu, and LINE-1 methylation levels and transcription of HERV-H, -K (HML-2), and -P env and HERV-K pol genes in normal adjacent and tumor tissues were investigated by pyrosequencing and RT-qPCR, respectively. Expression of the HERV-K (HML-2) Pol and Env proteins in selected tissues was examined by Western blotting. Associations between HERV transcript expression and methylation levels and between clinical characteristics and HERV expression were evaluated. Compared to adjacent normal tissues, LINE-1 was hypomethylated in tumor tissues (p < 0.05), whereas Alu, HERV-K (HML-2), and -H LTRs showed a decreasing trend in tumor tissue compared to normal tissue, though without a significant difference. The transcription levels of HERV env and pol genes were similar. However, the HERV-K (HML-2) Pol protein was more highly expressed (p < 0.01) in surrounding normal tissues, but the HERV-K (HML-2) Env protein was only expressed in tumor tissues. Although HERV LTR methylation and gene expression did not show significant differences between tumor and normal tissues, HERV protein expression differed greatly. Pol protein expression in normal cells may induce reverse transcription and subsequent integration into the host genome, likely favoring cell transformation; in contrast, the Env protein in tumor tissue may contribute to cancer progression through cell-to-cell fusion.

Viral Genomic Characterization and Replication Pattern of Human Polyomaviruses in Kidney Transplant Recipients.

Human Polyomavirus (HPyV) infections are common, ranging from 60% to 100%. In kidney transplant (KTx) recipients, HPyVs have been associated with allograft nephropathy, progressive multifocal leukoencephalopathy, and skin cancer. Whether such complications are caused by viral reactivation or primary infection transmitted by the donor remains debated. This study aimed to investigate the replication pattern and genomic characterization of BK Polyomavirus (BKPyV), JC Polyomavirus (JCPyV), and Merkel Cell Polyomavirus (MCPyV) infections in KTx. Urine samples from 57 KTx donor/recipient pairs were collected immediately before organ retrieval/transplant and periodically up to post-operative day 540. Specimens were tested for the presence of BKPyV, JCPyV, and MCPyV genome by virus-specific Real-Time PCR and molecularly characterized. HPyVs genome was detected in 49.1% of donors and 77.2% of recipients. Sequences analysis revealed the archetypal strain for JCPyV, TU and Dunlop strains for BKPyV, and IIa-2 strain for MCPyV. VP1 genotyping showed a high frequency for JCPyV genotype 1 and BKPyV genotype I. Our experience demonstrates that after KTx, HPyVs genome remains stable over time with no emergence of quasi-species. HPyVs strains isolated in donor/recipient pairs are mostly identical, suggesting that viruses detected in the recipient may be transmitted by the allograft.

Outcomes and surgical complications following living-donor renal transplantation using kidneys retrieved with trans-peritoneal or retro-peritoneal hand-assisted laparoscopic nephrectomy.

The best minimally invasive procedure for living-donor kidney retrieval remains debated. Our objective was to assess trans-peritoneal (TP) and retro-peritoneal (RP) hand-assisted laparoscopic donor nephrectomy (HALDN). In this single-center retrospective study, we analyzed results from 317 living-donor renal transplants (RT) performed between 2008 and 2016. Donor and recipient outcomes were compared between TP-HALDN (n = 235) and RP-HALDN (n = 82). Conversion to open nephrectomy (0.4% vs 0%; P = 1.000), intra-operative complications (1.7% vs 1.2%; P = 1.000), and 1-year overall post-operative complications (11.9% vs 17.1%; P = .258) rates were similar in TP-HALDN and RP-HALDN. Overall surgical site infections were higher in RP-HALDN (6.1% vs 1.7%; P = .053), whereas incisional hernias were only recorded following TP-HALDN (3.4% vs 0%; P = .118). The duration of the procedure was 11-minute shorter for TP-HALDN than RP-HALDN (P < .001) but extraction time was equivalent (2, IQR 1.5-2.5 minutes; P = 1.000). RT following TP-HALDN and RP-HALDN showed comparable one-year death-censored allograft survival (97% vs 98.8%; P = .685), primary non-function (0.4% vs 0%; P = .290), delayed graft function (1.3% vs 4.9%; P = .077), and urological complications (2.6% vs 4.9%; P = .290) rates. In our series, donor and recipient outcomes were not substantially affected by the approach used for donor nephrectomy. TP-HALDN and RP-HALDN were both safe and effective.

Treatment options for localised renal cell carcinoma of the transplanted kidney.

Currently, there is no consensus among the transplant community about the treatment of renal cell carcinoma (RCC) of the transplanted kidney. Until recently, graftectomy was universally considered the golden standard, regardless of the characteristics of the neoplasm. Due to the encouraging results observed in native kidneys, conservative options such as nephron-sparing surgery (NSS) (enucleation and partial nephrectomy) and ablative therapy (radiofrequency ablation, cryoablation, microwave ablation, high-intensity focused ultrasound, and irreversible electroporation) have been progressively used in carefully selected recipients with early-stage allograft RCC. Available reports show excellent patient survival, optimal oncological outcome, and preserved renal function with acceptable complication rates. Nevertheless, the rarity and the heterogeneity of the disease, the number of options available, and the lack of long-term follow-up data do not allow to adequately define treatment-specific advantages and limitations. The role of active surveillance and immunosuppression management remain also debated. In order to offer a better insight into this difficult topic and to help clinicians choose the best therapy for their patients, we performed and extensive review of the literature. We focused on epidemiology, clinical presentation, diagnostic work up, staging strategies, tumour characteristics, treatment modalities, and follow-up protocols. Our research confirms that both NSS and focal ablation represent a valuable alternative to graftectomy for kidney transplant recipients with American Joint Committee on Cancer stage T1aN0M0 RCC. Data on T1bN0M0 lesions are scarce but suggest extra caution. Properly designed multi-centre prospective clinical trials are warranted.

Allograft artery mycotic aneurysm after kidney transplantation: A case report and review of literature.

BACKGROUND: Allograft artery mycotic aneurysm (MA) represents a rare but life-threatening complication of kidney transplantation. Graftectomy is widely considered the safest option. Due to the rarity of the disease and the substantial risk of fatal consequences, experience with conservative strategies is limited. To date, only a few reports on surgical repair have been published. We describe a case of true MA successfully managed by aneurysm resection and arterial re-anastomosis. CASE SUMMARY: An 18-year-old gentleman, on post-operative day 70 after deceased donor kidney transplantation, presented with malaise, low urinary output, and worsening renal function. Screening organ preservation fluid cultures, collected at the time of surgery, were positive for Candida albicans. Doppler ultrasound and contrast-enhanced computer tomography showed a 4-cm-sized, saccular aneurysm of the iuxta-anastomotic segment of the allograft artery, suspicious for MA. The lesion was wide-necked and extended to the distal bifurcation of the main arterial branch, thus preventing endovascular stenting and embolization. After multidisciplinary discussion, the patient underwent surgical exploration, aneurysm excision, and re-anastomosis between the stump of the allograft artery and the internal iliac artery. The procedure was uneventful. Histology and microbiology evaluation of the surgical specimen confirmed the diagnosis of MA caused by Candida infection. Three years after the operation, the patient is doing very well with excellent allograft function and no signs of recurrent disease. CONCLUSION: Surgical repair represents a feasible option in carefully selected patients with allograft artery MA. Anti-fungal prophylaxis is advised when preservation fluid cultures are positive.

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.

Systematic review of ablative therapy for the treatment of renal allograft neoplasms.

BACKGROUND: To date, there are no guidelines on the treatment of solid neoplasms in the transplanted kidney. Historically, allograft nephrectomy has been considered the only reasonable option. More recently, nephron-sparing surgery (NSS) and ablative therapy (AT) have been proposed as alternative procedures in selected cases. AIM: To review outcomes of AT for the treatment of renal allograft tumours. METHODS: We conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2009 Checklist. PubMed was searched in March 2019 without time restrictions for all papers reporting on radiofrequency ablation (RFA), cryoablation (CA), microwave ablation (MWA), high-intensity focused ultrasound (HIFU), and irreversible electroporation (IRE) of solid tumours of the kidney allograft. Only original manuscripts describing actual cases and edited in English were considered. All relevant articles were accessed in full text. Additional searches included all pertinent references. Selected studies were also assessed for methodological quality using a tool based on a modification of the Newcastle Ottawa scale. Data on recipient characteristics, transplant characteristics, disease characteristics, treatment protocols, and treatment outcomes were extracted and analysed. Given the nature and the quality of the studies available (mostly retrospective case reports and small retrospective uncontrolled case series), a descriptive summary was provided. RESULTS: Twenty-eight relevant studies were selected describing a total of 100 AT procedures in 92 patients. Recipient age at diagnosis ranged from 21 to 71 years whereas time from transplant to diagnosis ranged from 0.1 to 312 mo. Most of the neoplasms were asymptomatic and diagnosed incidentally during imaging carried out for screening purposes or for other clinical reasons. Preferred diagnostic modality was Doppler-ultrasound scan followed by computed tomography scan, and magnetic resonance imaging. Main tumour types were: papillary renal cell carcinoma (RCC) and clear cell RCC. Maximal tumour diameter ranged from 5 to 55 mm. The vast majority of neoplasms were T1a N0 M0 with only 2 lesions staged T1b N0 M0. Neoplasms were managed by RFA (n = 78), CA (n = 15), MWA (n = 3), HIFU (n = 3), and IRE (n = 1). Overall, 3 episodes of primary treatment failure were reported. A single case of recurrence was identified. Follow-up ranged from 1 to 81 mo. No cancer-related deaths were observed. Complication rate was extremely low (mostly < 10%). Graft function remained stable in the majority of recipients. Due to the limited sample size, no clear benefit of a single procedure over the other ones could be demonstrated. CONCLUSION: AT for renal allograft neoplasms represents a promising alternative to radical nephrectomy and NSS in carefully selected patients. Properly designed clinical trials are needed to validate this therapeutic approach.

Microwave Ablation of Renal Cell Carcinoma of the Transplanted Kidney: Two Cases.

Thermal ablative techniques have been increasingly recognized as a valuable alternative to graftectomy and nephron-sparing surgery for the treatment of small neoplasms arising in the transplanted kidney. However, long-term efficacy and safety data are still lacking. In particular, current experience with microwave ablation is limited to a very recent single-centre series of three cases. We herein report two microwave ablations of renal cell carcinoma of the kidney allograft. The procedures were successfully performed under ultrasound guidance with complete tumour necrosis, no peri-operative complications, and preserved renal function. No recurrences were observed after 3 years of follow-up.

Causes of late transplant failure in cyclosporine-treated kidney allograft recipients.

BACKGROUND: There is little information about very long-term outcomes of kidney allograft recipients exposed to calcineurin inhibitors. METHODS: In this single-centre retrospective study with 20-year follow-up, we analyzed data from 644 patients who underwent primary renal transplantation between 1983 and 1993. Participants were treated with a cyclosporine-based immunosuppressive scheme and had allograft function at 1 year. RESULTS: After 20 years, 15.2% patients died, 39.7% experienced allograft loss, 26.8% were alive with a functioning transplant, and 18.2% were lost to follow-up. Cardiovascular disease (30.8%), malignancy (26.6%) and infection (17.0%) were the main causes of death. Age, new-onset proteinuria > 1 g/day, major acute cardiovascular event (MACE), and malignancy were independent predictors of mortality at time-dependent multivariate analysis. Chronic rejection (63.3%), recurrent glomerulonephritis (14.0%), and nonspecific interstitial fibrosis/tubular atrophy (13.2%) were the leading cause of allograft loss. Basal disease, hepatitis C, difference between 1 year and nadir serum creatinine, new-onset proteinuria > 1 g/day, and MACE were independent predictors of transplant failure. Among patients with 20-year allograft function, we recorded the following complications: hypertension (85%), malignancy (13%), diabetes (9%), and cardiovascular disease (9%). Median serum creatinine and proteinuria were 1.4 mg/dL and 0.6 g/day, respectively. CONCLUSIONS: Prolonged use of cyclosporine may expose to several dose-related adverse events and may contribute to the development of allograft dysfunction but it does not necessarily cause relentless, progressive transplant failure if patients are carefully and consistently monitored during the follow-up.