Protocol Biopsies Research Articles

Complement Activation in Kidneys of Patients With COVID-19.

Most patients who became critically ill following infection with COVID-19 develop severe acute respiratory syndrome (SARS) attributed to a maladaptive or inadequate immune response. The complement system is an important component of the innate immune system that is involved in the opsonization of viruses but also in triggering further immune cell responses. Complement activation was seen in plasma adsorber material that clogged during the treatment of critically ill patients with COVID-19. Apart from the lung, the kidney is the second most common organ affected by COVID-19. Using immunohistochemistry for complement factors C1q, MASP-2, C3c, C3d, C4d, and C5b-9 we investigated the involvement of the complement system in six kidney biopsies with acute kidney failure in different clinical settings and three kidneys from autopsy material of patients with COVID-19. Renal tissue was analyzed for signs of renal injury by detection of thrombus formation using CD61, endothelial cell rarefaction using the marker E-26 transformation specific-related gene (ERG-) and proliferation using proliferating cell nuclear antigen (PCNA)-staining. SARS-CoV-2 was detected by in situ hybridization and immunohistochemistry. Biopsies from patients with hemolytic uremic syndrome (HUS, n = 5), severe acute tubular injury (ATI, n = 7), zero biopsies with disseminated intravascular coagulation (DIC, n = 7) and 1 year protocol biopsies from renal transplants (Ctrl, n = 7) served as controls. In the material clogging plasma adsorbers used for extracorporeal therapy of patients with COVID-19 C3 was the dominant protein but collectin 11 and MASP-2 were also identified. SARS-CoV-2 was sporadically present in varying numbers in some biopsies from patients with COVID-19. The highest frequency of CD61-positive platelets was found in peritubular capillaries and arteries of COVID-19 infected renal specimens as compared to all controls. Apart from COVID-19 specimens, MASP-2 was detected in glomeruli with DIC and ATI. In contrast, the classical pathway (i.e. C1q) was hardly seen in COVID-19 biopsies. Both C3 cleavage products C3c and C3d were strongly detected in renal arteries but also occurs in glomerular capillaries of COVID-19 biopsies, while tubular C3d was stronger than C3c in biopsies from COVID-19 patients. The membrane attack complex C5b-9, demonstrating terminal pathway activation, was predominantly deposited in COVID-19 biopsies in peritubular capillaries, renal arterioles, and tubular basement membrane with similar or even higher frequency compared to controls. In conclusion, various complement pathways were activated in COVID-19 kidneys, the lectin pathway mainly in peritubular capillaries and in part the classical pathway in renal arteries whereas the alternative pathway seem to be crucial for tubular complement activation. Therefore, activation of the complement system might be involved in the worsening of renal injury. Complement inhibition might thus be a promising treatment option to prevent deregulated activation and subsequent collateral tissue injury.

Kidney allograft rejection: Diagnosis and treatment practices in USA- A UNOS survey.

We studied diverse rejection management strategies across centers by conducting a UNOS survey of kidney transplant program directors in 2017. There were 104 total responses from 235 kidney transplant programs representing 88 unique transplant programs (response rate 37%). Information was collected on center-specific management practices. Pertinent center-specific data were obtained from the OPTN database. Of the respondents, 33% were considered large centers (>100 transplants/year). Thymoglobulin was the most commonly used induction agent at 84%, 72% responders do rapid steroid withdrawal, and mycophenolic acid (MPA) is the major antimetabolite (100%). For diagnosing TCMR, 100% used indication biopsy, 28% used protocol biopsy, 2% used serum biomarkers, and none used urine cytokines. For ABMR, 99% used indication biopsy, 34% used protocol biopsy, 72% used DSA, 21% used C1q positive DSA, and none used gene profiling (ENDATS). The treatment of subclinical and clinical TCMR included iv/PO steroids. PP/IVIG were the commonest treatments for ABMR. The use of rituximab, bortezomib, and eculizumab increased from C4D-ABMR to recurrent ABMR. There are diverse management practices for diagnosing and treating rejection. An effort to harmonize these diverse practices for management of TCMR and ABMR will give an opportunity to pool data for evaluating clinical outcomes.

Research Highlights.

Research Highlights.

Molecular Diversity of Clinically Stable Human Kidney Allografts

Clinical decision and immunosuppression dosing in kidney transplantation rely on transplant biopsy tissue histology even though histology has low specificity, sensitivity, and reproducibility for rejection diagnosis. The inclusion of stable allografts in mechanistic and clinical studies is vital to provide a normal, noninjured comparative group for all interrogative studies on understanding allograft injury. To refine the definition of a stable allograft as one that is clinically, histologically, and molecularly quiescent using publicly available transcriptomics data. In this prognostic study, the National Center for Biotechnology Information Gene Expression Omnibus was used to search for microarray gene expression data from kidney transplant tissues, resulting in 38 studies from January 1, 2017, to December 31, 2018. The diagnostic annotations included 510 acute rejection (AR) samples, 1154 histologically stable (hSTA) samples, and 609 normal samples. Raw fluorescence intensity data were downloaded and preprocessed followed by data set merging and batch correction. The primary measure was area under the receiver operating characteristics curve from a set of feature selected genes and cell types for distinguishing AR from normal kidney tissue. Within the 28 data sets, the feature selection procedure identified a set of 6 genes (KLF4, CENPJ, KLF2, PPP1R15A, FOSB, TNFAIP3) (area under the curve [AUC], 0.98) and 5 immune cell types (CD4+ T-cell central memory [Tcm], CD4+ T-cell effector memory [Tem], CD8+ Tem, natural killer [NK] cells, and Type 1 T helper [TH1] cells) (AUC, 0.92) that were combined into 1 composite Instability Score (InstaScore) (AUC, 0.99). The InstaScore was applied to the hSTA samples: 626 of 1154 (54%) were found to be immune quiescent and redefined as histologically and molecularly stable (hSTA/mSTA); 528 of 1154 (46%) were found to have molecular evidence of rejection (hSTA/mAR) and should not have been classified as stable allografts. The validation on an independent cohort of 6 months of protocol biopsy samples in December 2019 showed that hSTA/mAR samples had a significant change in graft function (r = 0.52, P < .001) and graft loss at 5-year follow-up (r = 0.17). A drop by 10 mL/min/1.73m2 in estimated glomerular filtration rate was estimated as a threshold in allograft transitioning from hSTA/mSTA to hSTA/mAR. The results of this prognostic study suggest that the InstaScore could provide an important adjunct for comprehensive and highly quantitative phenotyping of protocol kidney transplant biopsy samples and could be integrated into clinical care for accurate estimation of subsequent patient clinical outcomes.

A single-center experience: Liver biopsy results during a year.

Background and Aim:Liver biopsy is the gold standard method for the diagnosis and treatment of liver diseases. In this study, we aimed to evaluate the results of liver biopsies performed in a year in our clinic. In addition, we also aimed if these liver biopsies could reveal the etiology of liver disease in patients with elevations of transaminases or/and alkaline phosphatase levels or liver masses.Materials and Methods:Patients who had liver biopsies for persistently elevated transaminases or/and alkaline phosphatase levels, protocol biopsies after liver transplantation, or liver masses in our hepatology clinic between 2011 and 2012 were included in the study. Liver biopsy decisions were made by experts during the hepatology council. Liver biopsies were previously performed using classical percutaneous liver biopsy or ultrasonography-guided Sonocan® liver biopsy sets. The pathology results of liver biopsies and clinical data of the matching patients were obtained from the liver biopsy record archives and patient files, respectively.Results:Totally, 479 liver biopsy results (male=252, 52.6%, mean age 49±14.5 years) were evaluated in the study. Of these patients, 432 (male=228) underwent percutaneous liver biopsy and 47 (male=24) underwent Sonocan® needle biopsy. The most common histopathologic diagnoses in the percutaneous liver biopsy group were chronic hepatitis B (n=127, 29.4%), normal histopathological findings (n=50, 11.6% and 32 of them were protocol biopsies after liver transplantation), and nonalcoholic steatohepatitis (NASH, n=41, 9.5%). The most common histopathologic diagnoses in the Sonocan® group were 25 liver metastasis out of 29 liver tumors (n=25, 53.2% of all) chronic hepatitis B (n=5, 10.6%), and NASH (n=3, 6.4%).Conclusion:In this study, diversity in liver biopsy results indicates the importance of histopathological evaluation. The most prevalent pathology in the liver biopsies was chronic hepatitis B, which is the most common chronic liver disease in Turkey. The metastatic liver tumor was the most common among the liver masses.

INCIDENCE OF CYTOMEGALOVIRUS DISEASE IN KIDNEY TRANSPLANT RECIPIENTS RECEIVING EVEROLIMUS AND REDUCED TACROLIMUS DOSES: A COHORT RETROSPECTIVE ANALYSIS

Introduction: Cytomegalovirus (CMV) is the most common viral pathogen occurring in postrenal transplantation. CMV infection usually develops during the first few months after transplantation. The success of CMV prophylaxis with antivirals has resulted in a decrease in the incidence of CMV infection. However, CMV remains a significant pathogen, associated with allograft rejection and loss, mortality, interstitial fibrosis and tubular atrophy (IF/TA) in protocol biopsies, and increased post-transplant costs. Purpose: To determine the incidence of cytomegalovirus disease in kidney transplant recipients receiving Everolimus and reduced Tacrolimus doses. Material and Methods: All low immunological risk patients, >18 years old whom received kidney transplantation at Santa Casa de Misericordia de Juiz de Fora between January 2013 and February 2017 were retrospectively assessed. The first group received induction therapy with Basiliximab, and the post-operative maintenance regimen included Tacrolimus, Mycophenolic acid and Prednisone (BAS/MPS), and the second group received Polyclonal antilymphocyte globulins (2,25mg/kg) as induction therapy, and then low dose of Tacrolimus (2mg/10kg/day), Everolimus and Prednisone as maintenance regimen (r-ATG/EVR). None of the patients received pharmacological prophylaxis or preemptive therapy against CMV. Results: Patients receiving EVR showed a lower incidence of CMV when compared to those receiving MPS (4.2% x 17.5%, p=0.005). There was an important difference in the time of hospitalization to treat CMV disease. Patients of the MPS stayed hospitalized for about 20 days more than the EVR group (p=0.005). There was no difference as to the incidence of rejection, delayed graft function or graft survival. Conclusion: Results from this trial conducted in low immunological risk kidney transplant recipients receiving no CMV prophylaxis demonstrated that EVR was associated to a decrease in CMV disease incidence when compared to MPS. These data suggest that kidney transplant recipients receiving EVR may not need CMV prophylaxis.

Successful Outcomes With Transplanting Kidneys From Deceased Donors With Acute Kidney Injury Necessitating Temporary Renal Replacement Therapy: Avenue for Increase in Organ Utilization

Background: Our aim was to determine outcomes with transplanting kidneys from deceased donors with severe acute kidney injury requiring acute renal replacement therapy. Methods: We included all patients who received deceased donor kidney transplant during 2008 to 2019. We compared the graft survival, estimated glomerular filtration rate (eGFR) and findings on surveillance biopsy in three groups of deceased donor kidneys: Acute Kidney Injury stage 3 (AKIN3) with RRT, AKIN3 without RRT, and <85% Kidney Donor profile Index (KDPI) donors without AKI (AKIN 0). Findings: There were 172 recipients who received a kidney from donors with Acute Kidney injury stage 3 (AKIN3) requiring renal replacement therapy (RRT). We compared the study group to 528 recipients who received a kidney from donors with AKIN stage 3 not on RRT and 463 recipients who received 2 on protocol biopsy at 4 months and 1 year was similar across the three groups. Interpretation: Transplanting selected kidneys from deceased donors with AKIN3 requiring RRT is safe and has excellent outcomes. Funding Statement: None. Declaration of Interests: The authors declare no conflicts of interest. Ethics Approval Statement: This study was approved by the Mayo Clinic Institutional Review Board as a retrospective, single center case control study of patients receiving deceased donor kidney transplantation during 2008 to 2019.

Treatment of Chronic Active Antibody-mediated Rejection With Pulse Steroids, IVIG, With or Without Rituximab is Associated With Increased Risk of Pneumonia.

Background.The risk of infection associated with specific treatments of chronic active antibody-mediated rejection (cAMR) after kidney transplantation remains unknown.Methods.This was a single-center study of kidney transplant recipients treated with pulse steroids, intravenous immunoglobulin (IVIG) ± rituximab for biopsy-confirmed cAMR. The control group consisted of age- and race-matched patients who underwent donor-specific antibody-based protocol biopsies but had no rejection. We collected data on BK virus (BKV), cytomegalovirus (CMV), urinary tract infection (UTI), and pneumonia postbiopsy.Results.There were 49 patients in each group. In those with cAMR, 21 (43%) were treated with steroids, IVIG, and rituximab; the remaining received steroids and IVIG only. The risk of graft failure was greater in the cAMR group [22 (45%) vs. 3 (6%), P < 0.001]. Kaplan-Meier analyses demonstrated a significantly greater risk of pneumonia in the cAMR group (P = 0.02). This was confirmed by multivariable Cox regression analyses [Hazard ratio (HR) = 6.04, P = 0.027, 95% CI, 1.22-29.75]. None of the patients with pneumonia were affected by opportunistic pathogens. Additionally, the risk of CMV, UTI, and BKV was not increased. Rituximab was not independently associated with any of the infections studied.Conclusions.Treatment of cAMR, but not rituximab, was associated with a 6-fold increased risk of pneumonia. Additional studies are needed to determine the safety and efficacy of prolonged antimicrobial prophylaxis and monitoring strategies, including for hypogammaglobulinemia, to reduce the risk of pneumonia following the treatment of cAMR.

Transplantation of Kidneys From Hepatitis C Virus-Infected Donors to Hepatitis C Virus-Negative Recipients: One-Year Kidney Allograft Outcomes

Transplant centers in the United States are increasingly willing to transplant kidneys from hepatitis C virus (HCV)-infected (HCV+) donors into HCV- recipients. We studied the association between donor HCV infection status and kidney allograft function and posttransplantation allograft biopsy findings. Retrospective cohort study. We examined 65 HCV- recipients who received a kidney from a HCV+ donor and 59 HCV- recipients who received a kidney from a HCV- donor during 2018 at a single transplant center. Predictor(s) of donor infection with HCV. Kidney allograft function and allograft biopsy findings during the first year following transplantation. We compared estimated glomerular filtration rate (eGFR), findings on for-cause and surveillance protocol biopsies, development of de novo donor-specific antibodies (DSAs), and patient and allograft outcomes during the first year following transplantation between recipients of HCV+ and HCV- kidneys. We used linear regression to estimate the independent association between allograft function and HCV viremic status of the kidney donor. The mean age of recipients was 52 ± 11 (SD) years, 43% were female, 19% and 80% of recipients were White and Black, respectively. Baseline characteristics were similar between the HCV+ and HCV- groups. There were no statistically significant differences between the HCV+ and HCV- groups in delayed graft function rates (12% vs 8%, respectively); eGFRs at 3, 6, 9, and 12 months post-transplantation; proportions of patients with cellular rejection (6% vs 7%, respectively); and proportions with antibody-mediated rejection (7% vs 10%, respectively) or de novo DSAs (31% vs 20%, respectively). HCV viremic status was not associated with eGFR at 3, 6, 9, or 12 months. Generalizability from a single-center study and small sample size was limited. Recipients of kidneys from donors infected with HCV had similar kidney allograft function and probability of rejection in the first year after transplantation compared to those who received kidneys from donors without HCV infection.

Clinicopathological Analysis of Acute/Active Antibody-Mediated Rejection in Renal Allografts According to the Banff 2013 Classification

Aim: This study evaluated the clinicopathological findings of acute/active antibody-mediated rejection (AABMR) according to the Banff 2013 classification. Methods: We analyzed 345 biopsies of 269 kidney transplant recipients. Pathological AABMR (PAABMR) was defined as histological evidence of acute tissue injury and endothelial injury by light microscopy regardless of donor-specific antibodies (DSAs). Results: Among the 345 biopsies, 29 (8.4%) were diagnosed as PAABMR. The mean g score was 1.17 ± 0.60, the mean ptc score was 1.97 ± 1.32, and DSA positivity was found in 69% of PAABMR. The mean duration after transplantation was 22.9 ± 26.7 months. Among 3 groups (DSA-high, mean fluorescence intensity (MFI) ≥ 5,000; DSA-low, MFI < 5,000 to ≥1,000; below cutoff), ABO incompatibility in DSA-high was significantly lower and second transplantation in DSA-high was significantly higher. We found 83% of PAABMR by the protocol biopsy (subclinical AABMR [SAABMR]). The short-term clinical and light microscopical changes in 8 cases of SAABMR did not show worsening during follow-up period (9–24 months). However, ultrastructural finding, including glomerular endothelial swelling, subendothelial electron-lucent widening, and early glomerular basement duplication, were found by electron microscopy (EM) in the first biopsies, and half of the SAABMR cases developed de novo circular peritubular capillary multilayering in the follow-up biopsies. Conclusion: PAABMR was mainly found by the protocol biopsy. The short-term follow-up of SAABMR patients did not show worsening clinically and light microscopically, but ultrastructural examination by EM was useful to detect early lesions of endothelial injury and progression of glomerular and peritubular capillary basement membrane alterations.

Impact of treatment of subclinical rejection at 2 weeks after kidney transplantation, compared by analysis of 1-year histologic outcomes

Background: Subclinical rejection (SCR) is associated with chronic allograft nephropathy, which is the most common cause of al lograft failure in kidney transplantation (KT). Therefore, early detection and treatment of SCR through protocol biopsy can reduc es the incidence of chronic allograft nephropathy and the improvement of graft survival. This study aims to evaluate the effective early detection role of routine protocol biopsy by comparing the pathologic outcome. Methods: We retrospectively analyzed 914 KT recipients in Samsung Medical Center between August 2012 and December 2018. Of these, pediatric cases, re-transplantations and multi-organ transplantation, cyclosporine and azathioprine users, patients who were not underwent protocol biopsy, and diagnosed rejection but not treated patients were excluded. Finally, a total of 624 adult patients who were underwent protocol biopsy at post KT 2 weeks and 1 year were analyzed. Results: After propensity score matching, patients were divided into two groups, 2-week protocol biopsy proven normal group (n=256) and rejection group (n=96). Before propensity matching, normal group was significant higher recipient age and ABO incompatible KT, rejection group was higher human leukocyte antigen II mismatch and proportion of deceased donor KT, the dif ference was corrected through matching. Rejection group showed no significant difference from normal group in the tendency of graft function (estimated glomerular filtration rate), and Kaplan-Meier curve also shown that in graft survival. In the pathologic outcomes between two groups and two periods, the pathological differences between two groups showed a decrease between two periods. Conclusions: SCR treatment through protocol biopsy can contribute to maintenance of graft function and improvement of patho logic change.

Feasibility and safety of 2-week protocol biopsy after kidney transplantation

Background: Protocol biopsies to detect and treat subclinical rejection early after kidney transplantation are useful for improv ing outcomes. However, there have been few studies on the optimal timing of early protocol biopsy. In this study, the results of 2-week and 1-year biopsies were analyzed in terms of technical feasibility, complications, and outcomes. Methods: Allograft protocol biopsies were performed in 916 adult recipients of kidney transplantation between 2012 and 2019 in our center. Retrospective analysis of complications and clinical outcomes of 880 2-week biopsies and 556 1-year biopsies were performed. Results: There were no significant difference between the median number of biopsy cores and sampled glomeruli of 2-week biopsies and 1-year biopsies. All allograft biopsies were technically successful. Total complication rates of 2-week and 1-year biopsies were 27.5% (242/880) and 15.5% (86/556). Major complication (Clavien-Dindo grading III-IV) rates of 2-week and 1-year biopsies were 0.23% (2/880) and 0.18% (1/556). There were only two major complication cases in 2-week biopsies: bleeding requiring surgical exploration (n=1) and bleeding requiring radiological intervention (n=1), and was only one major complication case in 1-year biopsies: allograft failure (n=1). There was no significant risk factor for major complication, even though immuno logic factors, pre-biopsy laboratory results, basic characteristics are analyzed with univariate and multivariate analysis. Detection rates of subclinical rejection was 16.5% (145/880) for 2-week biopsies and 32.9% (183/556) for 1-year biopsies. Conclusions: The 2-week protocol biopsy is as feasible and safe as the 1-year protocol biopsy in kidney transplant. It contributes to early detection of a significant number of subclinical rejection after kidney transplantation.

The protective role of protocol biopsy against chronic kidney disease progression in kidney transplantation

The protective role of protocol biopsy against chronic kidney disease progression in kidney transplantation

Two‐year protocol biopsy after kidney transplantation in clinically stable recipients – a retrospective study

The idea of protocol biopsy is to detect subclinical pathologies, including rejection, recurrent disease, or infection for early intervention and adjustment of immunosuppressants. Nevertheless, it is not adopted by most clinicians because of its low yield rate and uncertain long-term benefits. This retrospective study evaluated the impact of protocol biopsy on renal function and allograft survival. A two-year protocol biopsy was proposed for 190 stable patients; 68 of them accepted [protocol biopsy (PB) group], while 122 did not [nonprotocol biopsy (NPB) group]. The rejection diagnosis was made in 13 patients by protocol biopsy, and 11 of them had borderline rejection. In the following 5years, graft survival was better in the PB group than in the NPB group (P=0.0143). A total of 4 and 17 patients in the PB and NPB groups, respectively, had rejection events proven by indication biopsy. Renal function was better preserved in the PB group than in the NPB group (P=0.0107) for patients with rejection events. Nevertheless, the survival benefit disappeared by a longer follow-up period (12-year, P=0.2886). In conclusion, 2-year protocol biopsy detects subclinical pathological changes in rejection and preserves renal function by early intervention so as to prolong graft survival within 5years.

Clinicopathological Analysis of Medullary Ray Injury in 1-Year Protocol Paediatric Renal Allograft Biopsies

Aim: Medullary ray injury was recently reported in renal transplant biopsies. This study was performed to clarify the clinicopathological features of medullary ray injury in paediatric living renal transplant recipients. Methods: Paediatric recipients who completed a 5-year follow-up after living renal transplantation were enroled. We evaluated the clinical and pathological parameters of the presence or absence of medullary ray injury in their 1-year protocol biopsies. Results: Of 48 1-year protocol biopsies, 18 (37.5%) showed histological evidence of medullary ray injury. The 48 paediatric recipients were classified as those with medullary ray injury (n = 18; MRI-1Y [+] group) and those without medullary ray injury (n = 30; MRI-1Y [−] group) in the 1-year protocol biopsies. The prevalence of histological evidence of calcineurin inhibitor (CNI) nephrotoxicity, chronic obstruction or reflux nephropathy, and imaging findings of vesicoureteral reflux was 66.7, 22.2, and 7.7% in the MRI-1Y (+) group and 33.3, 13.3, and 15.4% in the MRI-1Y (−) group, respectively. Only the prevalence of CNI nephrotoxicity was significantly different between the 2 groups. There was no significant difference in the mean estimated glomerular filtration rate at 1, 3, or 5 years after transplantation between the 2 groups. Conclusion: In total, 37.5% of 1-year protocol biopsies showed histological evidence of medullary ray injury. This finding suggests that CNI nephrotoxicity might be the main contributor to medullary ray injury in 1-year protocol biopsies. The presence of medullary ray injury had little influence on renal function, at least during the first 5 years after transplantation.

The Problem of Subclinical Antibody-mediated Rejection in Kidney Transplantation.

Defined as histologic evidence of rejection on a protocol biopsy in the absence of kidney dysfunction, subclinical rejection has garnered attention since the 1990s. The major focus of much of this research, however, has been subclinical T cell-mediated rejection (TCMR). Herein, we review the literature on subclinical antibody-mediated rejection (AMR), which may occur with either preexisting donor-specific antibodies (DSA) or upon the development of de novo DSA (dnDSA). In both situations, subsequent kidney function and graft survival are compromised. Thus, we recommend protocol biopsy routinely within the first year with preexisting DSA and at the initial detection of dnDSA. In those with positive biopsies, baseline immunosuppression should be maximized, any associated TCMR treated, and adherence stressed, but it remains uncertain if antibody-reduction treatment should be initiated. Less invasive testing of blood for donor DNA or gene profiling may have a role in follow-up of those with negative initial biopsies. If a protocol biopsy is positive in the absence of detectable HLA-DSA, it also remains to be determined whether non-HLA-DSA should be screened for either in particular or on a genome-wide basis and how these patients should be treated. Randomized controlled trials are clearly needed.

Total nephroureterocystectomy and urethrectomy due to urothelial carcinoma associated with the BK polyomavirus infection after kidney transplantation: a case report with literature review

BackgroundBK polyomavirus (BKPyV) infection after kidney transplantation is an important cause of graft failure among kidney transplant recipient and may cause malignant tumor, although the association between BKPyV infection and malignant tumor has been controversial yet.Case presentationWe report a case of a 39-year-old-male kidney transplantation (KTx) recipient with urine BKPyV replication who developed a graft pelvic tumor with the positive Simian virus 40 large T antigen (SV40 TAg). The patients received a living-related KTx from his 65-year-old mother. A protocol biopsy at 14 months after KTx showed BKPyV-associated nephropathy. Therefore, the dose of immunosuppressants was reduced, resulting in improved BKPyV viremia, but viruria persisted. About 117 months after KTx, urine cytology showed atypical cells suspicious for malignancy. Cystoscopy revealed a tumor on the neck of the bladder. Transurethral resection of the bladder tumor (TUR-BT) was performed; however, the diagnosis of malignancy was not confirmed at that time. Six months after the TUR-BT, urine cytology showed atypical cells definite for malignancy. Computed tomography and retrograde pyelography showed no evidence of urinary tract tumor and metastasis. Subsequently, total nephroureterocystectomy and urethrectomy were performed. Histological examination of the graft ureter revealed a high-grade urothelial carcinoma, with glandular differentiation, pT1. Immunohistochemically, the tumor showed positivities for SV40 TAg and p53, along with increased Ki67 labeling cells were increased. By contrast, nonneoplastic cells were negative for SV40 TAg. At the time of writing the present manuscript, the patient is free from recurrence or residual tumor and being closely monitored without additional therapy, 32 months after the surgery.ConclusionThe relationship between BKPyV infection after KTx and bladder carcinogenesis remains to be elucidated. However, when the KTx recipients who continue to have BKPyV infection for a long time are treated, the possibility of risk factors for renourinary carcinoma should always be carefully considered.

De novo HLA Class II antibodies are associated with the development of chronic but not acute antibody-mediated rejection after liver transplantation - a retrospective study.

Donor-specific antibodies (DSA) cause antibody-mediated rejection (AMR); however, their pathogenic role has not yet been adequately investigated after liver transplantation. The aim of our study was to analyse the clinical significance of DSA and complement-binding DSA for the prediction of AMR after liver transplantation. Our cohort included 120 liver recipients with assessed protocol biopsies one year post-transplant. All patients had defined HLA-specific and complement-binding (C1q+and C3d+) antibodies before and in regular intervals after transplantation. The incidence of DSA was evaluated in relation with clinical and histopathological data in the liver allografts. A higher occurrence of acute AMR was observed in recipients with preformed complement-binding DSA to HLA Class I antigens. Patients who developed chronic AMR had more frequently de novo-produced antibodies against HLA Class II antigens (P=0.0002). A correlation was also found between de novo-formed C1q+and C3d+-binding antibodies to HLA Class II antigens and the development of chronic AMR (P=0.043). Our study implies that preformed complement-binding DSA to HLA Class I antigens are related to increased risk of acute antibody-mediated rejection, while chronic AMR is more frequent in patients with de novo-produced antibodies to HLA Class II antigens after liver transplantation.

What is the value of repeat kidney biopsies in patients with lupus nephritis?

Recent studies with protocol biopsies have shown a mismatch between clinical and histological remission in lupus nephritis (LN). We aimed to evaluate histological changes in repeat kidney biopsies by clinical indication in patients with LN. We analyzed 107 patients with LN in which a kidney biopsy was performed between 2008 and 2018. Of those, we included 26 (24.2%) who had ≥2 kidney biopsies. Classification was done according to the International Society of Nephrology/Renal Pathology Society. Mean time between biopsies was 71.5 ± 10.7 months. 73.1% of patients presented a change of class at repeat biopsy; 38.4% to a higher class and 34.6% to a lower class. A significant increase in glomerulosclerosis (% GS) (3.8% vs 18.7%, p = 0.006), interstitial fibrosis (3.8% vs 26.9%, p = 0.021), tubular atrophy (15.4% vs 57.7%, p = 0.001) and chronicity index (CI) (1 vs 3, p < 0.001) was observed at repeat biopsy. Subjects who developed chronic kidney disease progression had a lower rate of complete remission at 12 months (0% vs 37.5%, p = 0.02), higher % GS at first biopsy (7.9% vs 1.2%, p = 0.02) and higher CI (4 vs 2, p = 0.006), tubular atrophy (90% vs 37.6%, p = 0.008), interstitial fibrosis (50% vs 12.5%, p = 0.036) and vascular lesions (60% vs 18.8%, p = 0.031) at second biopsy. Our major finding was that patients with LN showed a significant increase in % GS, interstitial fibrosis, tubular atrophy and vascular lesions in repeat biopsies performed by clinical indication. This suggest that a second kidney biopsy may provide valuable and useful information regarding kidney disease progression.

Association between obesity after liver transplantation and steatosis, inflammation, and fibrosis of the graft.

Nonalcoholic steatohepatitis has become one of the leading causes of liver transplantation. The development of steatosis, as well as the link to inflammation and fibrosis, after transplantation remain poorly understood. The aim of this analysis was to evaluate the influence of obesity on histopathological changes of the graft during long-term follow-up. A total of 1494 longitudinal liver biopsies of 271 recipients were evaluated during a follow-up period of 5 to 10years. Clinical and laboratory parameters as well as histopathological categories of steatosis, inflammation, and fibrosis were explored by routine protocol biopsies. The BMI and prevalence of diabetes mellitus significantly increased after transplantation (P<.01). Diabetes and de novo obesity were significantly associated with the degree of graft steatosis. There was no correlation between former steatosis and inflammation or fibrosis. Inflammation was a precursor of fibrosis, and fibrosis increased over the first 3years (P<.01). No severe graft dysfunction was observed. Obesity and diabetes mellitus correlated with higher grades of steatosis and de novo steatosis after transplantation. Metabolic syndrome must be considered as a serious post-transplant complication that can cause histopathological alteration. However, the progress from steatosis to steatohepatitis is not as common as expected.