Borderline rejection: To treat or not to treat?

INTRODUCTION: It is unclear whether kidney transplant recipients with a biopsy diagnosis as a "borderline" acute T-cell mediated rejection (TCMR) requires the treatment with intravenous (iv) steroids pulse plus/minus intensification of the maintenance therapy (TRT) in comparison with the simple clinical follow-up (F-UP). METHODS: We retrospectively followed a consecutive series of kidney transplant recipients diagnosed with a borderline acute TCMR at biopsy by surveillance or clinical indication for 12 months and compared TRT and F-UP groups. We evaluated trends in renal function by measuring estimated glomerular filtration rate (eGFR) using multiple regression models. Repeated eGFR measures (REML) were adjusted for potential confounding factors for 12 months. The difference in 12-month eGFR values were observed in the TRT vs F-UP groups, type of biopsy, as well as the surveillance vs. clinical outcomes. RESULTS: Out of 59 included patients, 37% of them were in the TRT group and remaining 63% in the F-UP group. As expected, the TRT group had, at the time of biopsy, lower eGFR value of 39.0 ml/min/m2 [16.5] in comparison to 49.6 [19.6] ml/min/m2 in the F-UP group (P = 0.043), Similarly, the TRT group required more frequent clinical biopsies vs. F-UP group (68% vs. 32%; P = 0.014). However, the TRT group recovered kidney function reaching the eGFR values of the F-UP group at 12 months; the increase being significant only in patients who received indication biopsies (P < 0.001). The estimated adjusted TRT effect on 12-month eGFR change after indication biopsy was improved by +15.8 ml/min/1.73m2 (95%CI: +0.1 to +31.4 ml/min/1.73 m2; P = 0.048 by three-way interaction term) compared to the F-UP group. CONCLUSION: Our preliminary study supports the indication for the treatment of acute borderline TCMR only in cases with biopsies performed by clinical indication.

Long-term immunological outcomes of early subclinical inflammation on surveillance kidney allograft biopsies.

The long-term impact of early subclinical inflammation (SCI) through surveillance biopsy has not been well studied. To do this, we recruited a prospective observational cohort that included 1000 sequential patients who received a kidney transplant from 2013-2017 at our center. A total of 586 patients who underwent a surveillance biopsy in their first year post-transplant were included after excluding those with clinical rejections, and those who were unable to undergo a surveillance biopsy. Patients were classified based on their biopsy findings: 282 with NSI (No Significant Inflammation) and 304 with SCI-T (SCI and Tubulitis) which was further subdivided into 182 with SC-BLR (Subclinical Borderline Changes) and 122 with SC-TCMR (Subclinical T Cell Mediated Rejection, Banff 2019 classification of 1A or more). We followed the clinical and immunological events including Clinical Biopsy Proven Acute Rejection [C-BPAR], long-term kidney function and death-censored graft loss over a median follow-up of five years. Episodes of C-BPAR were noted at a median of two years post-transplant. Adjusted odds of having a subsequent C-BPAR was significantly higher in the SCI-T group [SC-BLR and SC-TCMR] compared to NSI 3.8 (2.1-7.5). The adjusted hazard for death-censored graft loss was significantly higher with SCI-T compared to NSI [1.99 (1.04-3.84)]. Overall, SCI detected through surveillance biopsy within the first year post-transplant is a harbinger for subsequent immunological events and is associated with a significantly greater hazard for subsequent C-BPAR and death-censored graft loss. Thus, our study highlights the need for identifying patients with SCI through surveillance biopsy and develop strategies to prevent further alloimmune injuries.

Focal therapy for prostate cancer with irreversible electroporation: Oncological and functional results of a single institution study.

PURPOSE: Focal irreversible electroporation (IRE) for prostate cancer aims to reduce quality of life complications, however outcomes data remains limited. We aimed to evaluate histological in-field clearance of prostate cancer at ≥12 months post-IRE. MATERIALS AND METHODS: Retrospective review of prospectively acquired data of consecutive patients treated between August 2018 and August 2021. Significant recurrence was defined as a ≥6 mm core Gleason 3+3, or ≥Gleason 3+4 with ≥4 mm tumour length. A second definition of any focus of International Society of Urological Pathology (ISUP) ≥2 was also analysed. RESULTS: The median follow-up of the entire cohort is 23 months (range 3-39 mo). For 64 primary IRE procedures, surveillance biopsy was performed in 40/50 (80.0%) with ≥12 months follow-up. Significant in-field recurrence occurred in 3/40 (7.5%), or 4/40 (10.0%) with any focus of ISUP >2. Significant out-of-field recurrence occurred in 5/40 (12.5%). In salvage IRE, three patients (3/6, 50.0%) have undetectable prostate-specific antigen levels, two have no residual cancer on biopsy and one patient had out-of-field recurrence. For sexually active men, erectile function was maintained in 24/28 (85.7%) of primary IRE. No incontinence developed in primary IRE (0/64). CONCLUSIONS: Focal primary IRE for prostate cancer is associated with 90% infield ablation of any ISUP grade >2 cancer with a low risk of urinary incontinence or impotence. Surveillance prostate biopsies are required to exclude progression despite a normal post-IRE multiparametric magnetic resonance imaging (mpMRI). Salvage IRE is a promising option for localised recurrence after prostate radiotherapy with low morbidity.

Diagnostic Accuracy and Prognostic Value of Serial Prostate Multiparametric Magnetic Resonance Imaging in Men on Active Surveillance for Prostate Cancer.

BACKGROUND: Multiparametric magnetic resonance imaging (MRI) is increasingly utilized to improve the detection of clinically significant prostate cancer. Evidence for serial MRI in men on active surveillance (AS) is lacking. OBJECTIVE: To evaluate the role of MRI in detecting Gleason grade group (GG) ≥2 disease in confirmatory and subsequent surveillance biopsies for men on AS. DESIGN, SETTING, AND PARTICIPANTS: This was a single-center study of men with low-risk prostate cancer enrolled in an AS cohort between 2006 and 2018. All men were diagnosed by systematic biopsy and underwent MRI prior to confirmatory ("MRI1") and subsequent surveillance ("MRI2") biopsies. MRI lesions were scored with Prostate Imaging Reporting and Data System (PI-RADS) version 2. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was biopsy upgrade to GG ≥ 2 prostate cancer, and the secondary outcome was definitive treatment. Test characteristics for PI-RADS score were calculated. Multivariable logistic and Cox proportional hazard regression models were used to determine the associations between PI-RADS score change and outcomes, on a per-examination basis. RESULTS AND LIMITATIONS: Of 125 men with a median follow-up of 78 mo, 38% experienced an increase in PI-RADS scores. The sensitivity and positive predictive value of PI-RADS ≥3 for GG ≥ 2 disease improved from MRI1 to MRI2 (from 85% to 91% and from 26% to 49%, respectively). An increase in PI-RADS scores from MRI1 to MRI2 was associated with GG ≥ 2 (odds ratio [OR] 4.8, 95% confidence interval [CI] 1.7-13.2) compared with PI-RADS 1-3 on both MRI scans. Men with PI-RADS 4-5 lesions on both MRI scans had a higher likelihood of GG ≥ 2 than patients with PI-RADS 1-3 lesions on both (OR 3.3, 95% CI 1.3-8.6). Importantly, any increase in PI-RADS scores was independently associated with definitive treatment (hazard ratio 3.9, 95% CI 1.3-11.9). This study was limited by its retrospective, single-center design. CONCLUSIONS: The prognostic value of MRI improves with serial examination and provides additional risk stratification. Validation in other cohorts is needed. PATIENT SUMMARY: We looked at the role of serial prostate magnetic resonance imaging in men with low-risk prostate cancer on active surveillance at the University of California, San Francisco. We found that both consistently visible and increasingly suspicious lesions were associated with biopsy upgrade and definitive treatment.

Donation after circulatory death is associated with increased fibrosis on 1-year post-transplant kidney allograft surveillance biopsy.

AIM: The use of kidneys donated after circulatory death (DCD) provides an invaluable expansion of the organ supply for transplantation. Here, we investigated the effect of DCD on fibrotic changes on 1 1-year post 1-transplant surveillance kidney allograft biopsy. METHODS: Recipients of a deceased donor kidney transplant between 2013 and 2017 at a single institution, who survived 1 year and underwent surveillance biopsy, were included in the analysis (n = 333: 87 DCD kidneys, 246 kidneys donated after brain death [DBD]). Banff scores for interstitial fibrosis and tubular atrophy were summed as IFTA and compared between the groups. RESULTS: DCD and DBD groups were comparable for baseline characteristics. Delayed graft function was 39% in DCD versus 19% in DBD, P = .0002. Patient and graft survival were comparable for DCD and DBD cohorts. IFTA scores were higher in DCD compared to DBD (2.43±..13 vs. 2.01±..08, P = .0054). On multivariate analysis, the odds of IFTA > 2 in the DCD group was 2.5× higher (95%CI: 1.354.63) than in the DBD group. Within the DCD group, kidneys with IFTA > 2 had inferior 5-year graft survival (P = .037). CONCLUSION: Compared to DBD kidneys, DCD kidneys developed a greater degree of fibrotic changes on 1-year post-transplant surveillance biopsy, which affected graft longevity within the DCD cohort.

Avoiding surveillance biopsy: Use of a noninvasive biomarker assay in a real-life scenario.

PURPOSE: TruGraf™ blood test measures a specific gene expression signature in peripheral blood mononuclear cells for noninvasive assessment of kidney transplant recipients (KTRs) with stable renal function, excluding subclinical acute rejection (subAR) with high degree of confidence. Study objective was to correlate TruGraf™ test with 6-month surveillance biopsy (SBx). METHODS: Prospective, single-center study of 116 consecutive KTRs with SBx performed at 6 months post-transplant..TruGraf™ done at time of SBx; results compared with histology (Banff 2017) for concordance. RESULTS: Of 116 enrollees, 26 excluded, absent biopsy (n = 17), test quality control issues (n = 9), leaving 90 KTRs-66% deceased donor kidneys, 58% African American, and 59% male. TruGraf™ result negative in 67 subjects; 54 had normal biopsy, indicating SBx could have been avoided. Eight subjects had true positive result where biopsy justified. Unnecessary biopsy would have been performed in 15 subjects with false-positive TruGraf™, and subAR missed in 13 subjects with false-negative test. In overall population of 90 patients, SBx would have been avoided in 54 (60%). CONCLUSIONS: Implementation of TruGraf™ testing in a "real-world" cohort at the time of SBx identified a significant proportion of KTRs that could have avoided SBx.

Maintaining the Health of the Renal Allograft: Laboratory and Histologic Monitoring After Kidney Transplantation.

Advances in posttransplant care, including new immunosuppressive medications have led to excellent short-term renal allograft survival. However, there is a small therapeutic window within which the patient and the clinician must balance the risk of rejection, with side effects such as infection, malignancy, and toxicity. Laboratory testing plays a key role in this ongoing monitoring, which includes relatively simple tests, such as serum creatinine, to complex tests, such as solid-phase assays, used to monitor for donor-specific antibody and surveillance allograft biopsies. This article reviews the role of the laboratory tests and surveillance biopsies in posttransplant monitoring.

The 1-year Renal Biopsy Index: a scoring system to drive biopsy indication at 1-year post-kidney transplantation.

Surveillance biopsies after renal transplantation remain debatable. To drive the decision of such intervention, we propose a predictive score of abnormal histology at 1-year post-transplantation, named 1-year Renal Biopsy Index (1-RBI). We studied 466 kidney recipients from the DIVAT cohort alive with a functioning graft and a surveillance biopsy at 1-year post-transplantation. Patients displaying abnormal histology (49%) (borderline, acute rejection, interstitial fibrosis and tubular atrophy [IFTA] grade 2 or 3, glomerulonephritis) were compared to the normal or subnormal (IFTA grade 1) histology group. Obtained from a lasso penalized logistic regression, the 1-RBI was composed of recipient gender, serum creatinine at 3, 6, and 12 month post-transplantation and anticlass II immunization at transplantation (internal validation: AUC = 0.71, 95% CI [0.53-0.83]; external validation: AUC = 0.62, 95% CI [0.58-0.66]). While we could not determinate a threshold able to identify patients at high chance of normal or subnormal histology, we estimated and validated a discriminating threshold capable of identifying a subgroup of 15% of the patients with a risk of abnormal histology higher than 80%. The 1-RBI is computable online at www.divat.fr. The 1-RBI could be a useful tool to standardize 1-year biopsy proposal and may for instance help to indicate one in case of high risk of abnormal histology.

Safety and utility of surveillance biopsies in pediatric kidney transplant patients.

There is currently no way to diagnose a rejection before a change in serum creatinine. This had led some to start doing SB, but little data exist on the utility and safety of SB in pediatric patients. There is also little known on practice patterns of pediatric nephrologists. A retrospective review of pediatric kidney transplant SB between January 2013 and January 2017 at a single center was performed. A survey went to the PedNeph email list. There were 47 SB; 15 at 6 months, 12 at 1 year, 13 at 2 years, and 7 at 3 years. There were 3 minor (1 gross hematuria and 2 hematomas) and no major complications. On 6-month SB, 1 had SC 1A ACR (6.7%) with no BR ACR. On the 12-month SB, there were 5 with SCBR ACR (41.7%) and 1 with SC AMR (8.3%). On the 2-year SB, there were 4 that had SCBR ACR (30.8%), and 1 with SC AMR (7.7%). On the 3-year SB, 1 had chronic transplant glomerulitis (14.3%). The survey showed that 34.3% of pediatric nephrologists perform SB. SB can be performed safely. By early identification of histological lesions, SB gives us an opportunity for individualized immunosuppressive regimens that may prevent chronic allograft dysfunction and improve long-term graft outcome.

Macrophage density in early surveillance biopsies predicts future renal transplant function.

Inflammation impairs renal allograft survival but is difficult to quantify by eye at low densities. Here we measured leukocyte abundance in early surveillance biopsies by digital image analysis to test for a role of chemokine receptor genotypes and analyze the predictive value of leukocyte subsets to allograft function. In six-week surveillance biopsies, T-cell (CD3), B-cell (CD20), macrophage (CD68), and dendritic cell (CD209) densities were assessed in whole slide scans. Renal cortical CD3, CD20, and CD68 were significantly higher in histologic rejection. The CCR2 V64I genotype was associated with lower CD3 and CD209 densities. Above-median CD68 density was significantly associated with lower combined patient and graft survival with a hazard ratio of 3.5 (95% confidence interval 1.1-11.0). Both CD20 and CD68 densities inversely correlated with estimated glomerular filtration rate (eGFR) four years after transplantation. Additionally, CD68 correlated with eGFR loss. Among histological measurements including a complete Banff classification, only CD68 density was a significant predictor of an eGFR under 30ml/min after four years (odds ratio 7.4, 1.8-31.0) and part of the best eGFR prediction set in a multivariable linear regression analysis of multiple clinical and pathologic parameters. In a second independent cohort, the original CD68 median maintained its discriminative power for survival and eGFR. Thus, digital high-resolution assessment of CD68+ leukocyte infiltration significantly improves prognostic value of early renal transplant biopsies.

Single center experience of subclinical rejections and BK nephropathies by kidney allografts' surveillance biopsies.

PURPOSE: Acute rejection of the kidney allograft remains the most important factor affecting the long-term graft outcome and is a major predictor of development of chronic damage and graft loss. Several studies have shown that early detection and treatment of subclinical rejection episodes may be beneficial for the graft outcome. The role of protocol (surveillance) biopsies and the value of donor specific antibodies (DSA) monitoring are still debatable. METHODS: This is a prospective observational study involving seventeen kidney recipients transplanted in north-eastern part of Poland who underwent "zero", 3-month and 12-month allograft biopsies as well as DSA assessment. RESULTS: Histologic analysis of the biopsies showed subclinical acute cellular rejection in 17.6% of patients (two tubulointerstitial, one vascular) at 3-months post transplantation, and additional case of borderline rejection at the 12-month point. Moreover, two cases (11.8%) of polyomavirus BK nephropathy were diagnosed (one at 3 and one at 12 month point). None of the patients developed de novo DSA. CONCLUSIONS: Our protocol biopsies allowed us to detect significant proportion of patients with subclinical, but histologically relevant acute cellular rejection and BK nephropathy. Early therapeutic intervention had beneficial effects in a 4-year follow up.

Utility of Ultrasound in the Diagnosis, Treatment, and Follow-up of Prostate Cancer: State of the Art.

Prostate cancer screening currently consists of serum prostate-specific antigen and digital rectal examination, followed by transrectal ultrasound-guided biopsy for diagnostic confirmation. Although the current paradigm of prostate cancer screening has led to a decrease in advanced disease and cancer-related mortality, these techniques have limitations in terms of sensitivity and specificity, resulting in missed cancers that are clinically significant and the overdetection of clinically insignificant cancers. New imaging techniques and technologies are required to improve the detection of prostate cancer. This article summarizes the use of novel ultrasound techniques and technologies in the detection, biopsy, and treatment of prostate cancer.

Pancreas transplantation: The Wake Forest experience in the new millennium.

AIM: To investigate the Wake Forest experience with pancreas transplantation in the new millennium with attention to surgical techniques and immunosuppression. METHODS: A monocentric, retrospective review of outcomes in simultaneous kidney-pancreas transplant (SKPT) and solitary pancreas transplant (SPT) recipients was performed. All patients underwent pancreas transplantation as intent-to-treat with portal venous and enteric exocrine drainage and received depleting antibody induction; maintenance therapy included tapered steroids or early steroid elimination with mycophenolate and tacrolimus. Recipient selection was based on clinical judgment whether or not the patient exhibited measureable levels of C-peptide. RESULTS: Over an 11.25 year period, 202 pancreas transplants were performed in 192 patients including 162 SKPTs and 40 SPTs. A total of 186 (92%) were primary and 16 (8%) pancreas retransplants; portal-enteric drainage was performed in 179 cases. A total of 39 pancreas transplants were performed in African American (AA) patients; of the 162 SKPTs, 30 were performed in patients with pretransplant C-peptide levels > 2.0 ng/mL. In addition, from 2005-2008, 46 SKPT patients were enrolled in a prospective study of single dose alemtuzumab vs 3-5 doses of rabbit anti-thymocyte globulin induction therapy. With a mean follow-up of 5.7 in SKPT vs 7.7 years in SPT recipients, overall patient (86% SKPT vs 87% SPT) and kidney (74% SKPT vs 80% SPT) graft survival rates as well as insulin-free rates (both 65%) were similar (P = NS). Although mortality rates were nearly identical in SKPT compared to SPT recipients, patterns and timing of death were different as no early mortality occurred in SPT recipients whereas the rates of mortality following SKPT were 4%, 9% and 12%, at 1-, 3- and 5-years follow-up, respectively (P < 0.05). The primary cause of graft loss in SKPT recipients was death with a functioning graft whereas the major cause of graft loss following SPT was acute and chronic rejection. The overall incidence of acute rejection was 29% in SKPT and 27.5% in SPT recipients (P = NS). Lower rates of acute rejection and major infection were evidenced in SKPT patients receiving alemtuzumab induction therapy. Comparable kidney and pancreas graft survival rates were observed in AA and non-AA recipients despite a higher prevalence of a "type 2 diabetes" phenotype in AA. Results comparable to those achieved in insulinopenic diabetics were found in the transplantation of type 2 diabetics with detectable C-peptide levels. CONCLUSION: In the new millennium, acceptable medium-term outcomes can be achieved in SKPT and SPTs as nearly 2/3rds of patients are insulin independent following pancreas transplantation.

Steroid withdrawal in kidney allograft recipients.

This review highlights the aggregate of knowledge obtained from the temporal trend of kidney transplant immune suppression. We will discuss the burden of steroid side effects and their impact on quality of life in kidney allograft recipients, which have led to minimizing steroid exposure. Issues arising since the inception of the concept of steroid withdrawal will be discussed, along with how they have continually led to a shift in research focus on this subject matter. The usefulness of surveillance biopsies and how further elucidation of the pathophysiology of interstitial fibrosis and tubular atrophy could contribute to improving long-term allograft outcomes will also be discussed. We will elaborate on the role of calcineurin inhibitor minimization alongside steroid withdrawal in improving long-term graft survival. Future expectations of subsequent studies with a view to improving overall kidney allograft outcomes by eliminating attendant problems associated with steroids will also be covered.