Progression of graft fibrosis under mammalian target of rapamycin inhibitor-based regimen

Aim: Nephrotoxic potential of mammalian target of rapamycin inhibitors (mTORi) is different from calcineurin inhibitors (CNI). The aim of this study is to investigate the interstitial fibrosis (ci) and tubular atrophy (ct) progression from the baseline to first year under a mTORi‐based, CNI‐free regimen. Methods: Thirty‐five kidney transplant recipients who had to have adequate baseline and first year protocol biopsy were enrolled. Exclusion criteria were: the replacement of CNI at any time; acute deterioration in allograft functions; and serum creatinine level above 3 mg/dL at 12 months. Banff criteria were used for histopathological classification. Progression was defined as delta ci + ct ≥ 2 (difference between 12th month and baseline). Results: Mean age of patients and donors were 34 ± 11 and 49 ± 10 years. Twelve patients had delayed graft function (DGF). The maintenance regimen consisted of sirolimus (n = 24) and everolimus (n = 11) with mycophenolate mofetil and steroids. Incidence of acute rejection was 25.7%. At baseline, the incidence of nil and mild fibrosis were 80% and 20%, respectively. At 12 months, 17.1% of patients had moderate, 40% had mild and 42.9% had nil fibrosis. Histological progression from baseline to first year was present in 34% of patients. In multivariate analysis the presence of DGF (P = 0.018) and deceased donor type (P = 0.011) were the most important predictors for fibrosis progression. Conclusion: Progression of graft fibrosis may be seen in one‐third of patients under a mTORi‐based regimen particularly manifested in deceased donor recipients with subsequent DGF.     

Assessment of renal allograft fibrosis by transient elastography

Transient elastography (TE, Fibroscan) has been established as a noninvasive assessment tool of liver fibrosis. We evaluated potentials and limitations of TE for identifying renal allograft fibrosis. The technical possibility of kidney examination by TE was assessed in two 10‐week‐old German landrace pigs and kidney stiffness (KS) was evaluated in 164 renal transplant patients. KS could be determined in all animals at the pole and pars media (29 ± 10 kPa vs. 31 ± 17 kPa). In human renal allografts KS was successfully performed in 94.5% of the test series with reliable results in 72% of the measurements. Mean KS at the pole or pars media were comparable (35.0 ± 19.9 kPa vs. 33.2 ± 18.6 kPa). Significantly higher KS was detected in renal allografts with histologically confirmed advanced fibrosis. Body‐mass‐index, skin‐allograft distance, and peri or intrarenal fluid accumulation were important confounders of successful KS measurements (BMI: r = ?0.31; P < 0.001; distance: r = ?0.50; P < 0.001). Notably, KS did not correlate with renal function. TE represents a noninvasive approach in selected transplant recipients to identify allografts with severe fibrosis. The heterogeneous kidney morphology and several other confounding factors negatively affect measurability of KS by TE. Further technical modifications are required to improve applicability of TE for kidney assessment.     

Experience with belatacept rescue therapy in kidney transplant recipients

In kidney transplant recipients with chronic graft dysfunction, long‐term immunosuppression with calcineurin inhibitors (CNIs) or mTOR inhibitors (mTORi) can be challenging due to adverse effects, such as nephrotoxicity and proteinuria. Seventy‐nine kidney transplant recipients treated with CNI‐based or mTORi‐based maintenance immunosuppression who had CNI‐induced nephrotoxicity or severe adverse events were switched to belatacept. Mean time from transplantation to belatacept conversion was 69.0 months. Mean estimated glomerular filtration rate (eGFR) ± standard deviation at baseline was 26.1 ± 15.0 ml/min/1.73 m², increasing to 34.0 ± 15.2 ml/min/1.73 m² at 12 months postconversion (P < 0.0005). Renal function improvements were also seen in patients with low eGFR (<25 ml/min/1.73 m²) or high proteinuria (>500 mg/l) at conversion. The Kaplan–Meier estimates for patient and graft survival at 12 months were 95.0% and 85.6%, respectively. The discontinuation rate due to adverse events was 7.9%. One case of post‐transplant lymphoproliferative disorder occurred at 17 months postconversion. For comparison, a historical control group of 41 patients converted to mTORi‐based immunosuppression because of biopsy‐confirmed CNI‐induced toxicity was examined; eGFR increased from 27.6 ± 7.2 ml/min/1.73 m² at baseline to 31.1 ± 11.9 ml/min/1.73 m² at 12 months (P = 0.018). Belatacept‐based immunosuppression may be an alternative regimen for kidney transplant recipients with CNI‐ or mTORi‐induced toxicity.     

Noninvasive evaluation of renal allograft fibrosis by transient elastography – a pilot study

Chronic allograft injury (CAI) is the most common cause of graft failure after the first year of transplantation. To date, only protocol biopsies can reveal subclinical disease. Transient elastography (TE) is a novel noninvasive technique that has demonstrated high reliability in the assessment of liver fibrosis. This study evaluates the feasibility of TE for the assessment of renal allograft fibrosis. Fifty‐seven patients underwent TE by the FibroScan® device. Biopsies were performed in 20 patients. Measurement of parenchymal stiffness by TE was successful in 55 of 57 patients (96.5%). Stiffness was significantly correlated to the extent of interstitial fibrosis (Pearson r: 0.67, P: 0.002, R²: 0.45) and inversely related to estimated glomerular filtration rate (eGFR) (Pearson r: ?0.47, P: 0.0003, R²: 0.22). Stiffness values of patients with an eGFR >50 ml/min were significantly lower than in patients with an eGFR ≤50 ml/min (22.2 ± 11.0 vs. 37.1 ± 14.2 kPa, P: 0.0005). The stiffness values of CAI Banff grades 0–1 differed significantly from grade 2 (P: 0.008) and grade 3 (P: 0.046). Parenchymal stiffness measured by TE reflects interstitial fibrosis in kidney allografts. A longitudinal assessment of parenchymal stiffness might be a powerful tool to identify patients with CAI who benefit from biopsy and consequent adaptation of the immunosuppressive regime.     

Correlation analysis of the progesterone‐induced sperm acrosome reaction rate and the fertilisation rate in vitro

In this study, we aimed to investigate whether progesterone‐induced acrosome reaction (AR) rate could be an indicator for fertilisation rate in vitro. Twenty‐six couples with unexplained infertility and undergoing in vitro fertilisation (IVF) treatment were involved. On the oocytes retrieval day after routine IVF, residual sperm samples were collected to receive progesterone induction (progesterone group) or not (control group). AR rate was calculated and fertilisation rate was recorded. The correlation between progesterone‐induced AR and fertilisation rate and between sperm normal morphology and 3PN (tripronuclear) were analysed using the Spearman correlation analysis. The AR rate of progesterone group was statistically higher than that of the control group (15.6 ± 5.88% versus 9.66 ± 5.771%, P < 0.05), but not significantly correlated with fertilisation rate (r = ?0.053, P > 0.01) or rate of high‐quality embryo development (r = ?0.055, P > 0.01). Normal sperm morphology also showed no significant correlation with the amount of 3PN zygotes (r = 0.029, P > 0.01), rate of 3PN zygotes production (r = 0.20, P > 0.01), rate of 3PN embryo development (r = ?0.406, P > 0.01), fertilisation rate (r = ?0.148, P > 0.01) or progesterone‐induced AR rate (r = 0.214, P > 0.01). Progesterone can induce AR in vitro significantly; however, the progesterone‐induced AR may not be used to indicate fertilisation rate.     

Effect of mammalian target of rapamycin inhibitors on cytomegalovirus infection in kidney transplant recipients receiving polyclonal antilymphocyte globulins: a propensity score‐matching analysis

Mammalian target of rapamycin inhibitors (mTORi) prevents cytomegalovirus (CMV) infection in kidney transplant (KT) patients. From May 2010 to December 2013, all KT recipients were retrospectively analysed. Maintenance immunosuppression regimen was divided into mTORi or calcineurin inhibitors (CNI)‐based regimen. Since June 2011, CMV‐seropositive recipients (R+) treated with high‐intensity immunosuppression and mTORi did not receive anti‐CMV prophylaxis. We analysed 350 consecutive patients, of which 95 (27%) received mTORi and 255 (73%) CNI‐based immunosuppression. A Cox‐regression multivariate analysis showed that the use of mTORi‐based immunosuppression during all follow‐up reduced the risk of CMV infection (HR 0.36, 95% CI 0.15–0.89, P = 0.028) and confirmed in a propensity score‐matched cohort (HR 0.4, 95% CI 0.1–0.9, P = 0.047). Early discontinuation of mTORi increased the risk of CMV infection (HR 3.2; 95% CI 1.7–6.0) in univariate analysis. The incidence of CMV infection was not higher among CMV R+ patients on mTORi and requiring high‐intensity immunosuppression when CMV prophylaxis was not given. The use of mTORi protected for CMV infection in KT patients, allowing to avoid antiviral prophylaxis for R+ patients receiving high‐intensity immunosuppression. The increased risk of CMV infection after early discontinuation of mTORi warrants further research.     

Short‐term adverse effects of early subclinical allograft inflammation in kidney transplant recipients with a rapid steroid withdrawal protocol

The impact of subclinical inflammation (SCI) noted on early kidney allograft biopsies remains unclear. This study evaluated the outcome of SCI noted on 3‐month biopsy. A total of 273/363 (75%) kidney transplant recipients with a functioning kidney underwent allograft biopsies 3‐months posttransplant. Among those with stable allograft function at 3 months, 200 biopsies that did not meet the Banff criteria for acute rejection were identified. These were Group I: No Inflammation (NI, n = 71) and Group II: Subclinical Inflammation (SCI, n = 129). We evaluated differences in kidney function at 24‐months and allograft histology score at 12‐month biopsy. SCI patients had a higher serum creatinine (1.6 ± 0.7 vs 1.38 ± 0.45; P = .02) at 24‐months posttransplant, and at last follow‐up at a mean of 42.5 months (1.69 ± 0.9 vs 1.46 ± 0.5 mg/dL; P = .027). The allograft chronicity score (ci + ct + cg + cv) at 12‐months posttransplant was higher in the SCI group (2.4 ± 1.35 vs 1.9 ± 1.2; P = .02). The incidence of subsequent rejections within the first year in SCI and NI groups was 24% vs 10%, respectively (P = .015). De novo donor‐specific antibody within 12 months was more prevalent in the SCI group (12/129 vs 1/71, P = .03). SCI is likely not a benign finding and may have long‐term implications for kidney allograft function.     

C1q binding is not an independent risk factor for kidney allograft loss after an acute antibody‐mediated rejection episode: a retrospective cohort study

After kidney transplantation, C4d is an incomplete marker of acute antibody‐mediated rejection (AMR) and C1q‐binding donor‐specific antibodies (DSA) have been associated with allograft survival. However, the impact on allograft survival of C1q+ DSA after clinical AMR has not been studied yet. We analysed retrospectively in clinical AMR C4d staining and C1q‐binding impact on allograft survival. We compared clinical, histological and serological features of C4d− and C4d+ AMR, C1q+ and C1q− DSA AMR and analysed C4d and C1q‐binding impact on allograft survival. Among 500 for‐cause kidney allograft biopsies, 48 fulfilled AMR criteria. C4d+ AMR [N = 18 (37.5%)] have significantly higher number class I DSA (P = 0.02), higher microvascular score (P = 0.02) and more transplant glomerulopathy (P = 0.04). C1q+ AMR [N = 20 (44%)] presented with significantly more class I and class II DSA (P = 0.005 and 0.04) and C4d+ staining (P = 0.01). Graft losses were significantly higher in the C4d+ group (P = 0.04) but similar in C1q groups. C4d+ but not C1q+ binding was an independent risk factor for graft loss [HR = 2.65; (1.11–6.34); P = 0.028]. In our cohort of clinical AMR, C4d+ staining but not C1q+ binding is an independent risk factor for graft loss. Allograft loss and patient survival were similar in C1q+ and C1q− AMR.     

Influence of epidemiology,immunosuppressive regimens,clinical presentation,and treatment on kidney transplant outcomes of patients diagnosed with tuberculosis: A retrospective cohort analysis

Tuberculosis (TB) mortality is high among kidney transplant (KT) recipients. Although local epidemiology is an important factor, diagnostic/therapeutic challenges and immunosuppressive therapy (ISS) may influence outcomes. We analyzed the cumulative incidence (CumI) of TB in KT recipients receiving a variety of ISS with long‐term follow‐up. Our retrospective single‐center cohort study included all KT procedures performed between January 1, 1998, and August 31, 2014, with follow‐up until August 31, 2014. Induction therapy was based on perceived immunological risk; maintenance ISS included prednisone and calcineurin inhibitor (CNI) plus azathioprine (AZA), and mycophenolic acid (MPA) or mechanistic target of rapamycin inhibitor (mTORi). Thirty‐four patients received belatacept/MPA. KT was performed on 11 453 patients and followed for 1989 (IQR 932 to 3632) days. Among these, 152 patients were diagnosed with TB (CumI 1.32%). Median time from KT to TB was 18.8 (IQR 7.2 to 60) months, with 59% of patients diagnosed after the first year. Unadjusted analysis revealed an increasing confidence interval (CI) of TB (0.94% CNI/AZA vs 1.6% CNI/MPA [HR = 1.62, 95% CI = 1.13 to 2.34, P = .009] vs 2.85% CNI/mTORi [HR = 2.45, 95% CI = 1.49 to 4.32, P < .001] vs 14.7% belatacept/MPA [HR = 13.14, 95% CI = 5.27 to 32.79, P < .001]). Thirty‐seven (24%) patients died, and 39 (25.6%) patients experienced graft loss. Cytomegalovirus infection (P = .02) and definitive ISS discontinuation (P < .001) were associated with death. Rejection (P = .018) and ISS discontinuation (P = .005) occurred with graft loss. TB occurred at any time after KT and was influenced by ISS.     

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

Introduction

Thrombotic microangiopathy (TMA) is characterized by endothelial cell injury and formation of fibrin thrombi within capillary and arterioles. In renal allograft recipients, TMA mainly presents as hemolytic uremic syndrome. Its occurrence is rare, and diagnosis requires a high degree of suspicion. Drug toxicity, in particular from calcineurin inhibitors (CNIs) and mTOR inhibitors (mTORi), is the most common cause posttransplant and has recently been emphasized in the setting of lung transplantation.

Objective

The goal of this study was to investigate the role of mTORi as an added risk factor in the development of TMA to propose strategies for modulation of immunosuppressive (IS) therapy.

Patients and Methods

From a database of 496 renal graft recipients, we analyzed 350 renal graft biopsy specimens gathered at our center from 1998 to 2012. In patients undergoing combined therapy with mTORi and CNI, we compared drugs levels in TMA-affected and TMA-free groups, using mTORi and CNI TLC and the summation of [everolimus TLC + (cyclosporine C2/100)] (Σ) as a surrogate marker of combined exposition to 2 drugs. Receiver-operating characteristic analysis of association of EVL TLC + (C2/100) was performed for patients exposed to mTORi.

Results

Histologic features of TMA were found in 36 patients (prevalence of 7.3%). The caseload was divided into 2 groups: not drug-related TMA (n = 19) and drug-related TMA (n = 17). Despite the prevalence of TMA in patients exposed to mTORi being greater (8 of 153; prevalence, 5.3%) compared with therapies without mTORi (9 of 324; prevalence, 2.8%), statistical difference was not reached. Patients treated with mTORi who developed de novo drug-related TMA had higher blood levels of IS drugs compared with those who did not develop TMA. Receiver-operating characteristic analysis found a significant threshold of 12.5 ng/mL (area under the curve, 0.803; P = .006).

Conclusions

Results confirm the pivotal role of IS drugs in the onset of de novo TMA. On the basis of literature, we could speculate a sequence of endothelial damage by CNI, on which everolimus fits hindering the repair of endothelial injury. Therefore, high blood levels of CNI and mTORi seem to predispose patients to posttransplant TMA. Combined monitoring of these 2 drugs might be used to prevent the complication. Σ [everolimus TLC + (cyclosporine C2/100)] >12.5 ng/mL should be avoided as a surrogate risk factor for adverse effects.     

Circulating Angiopoietin‐2 levels predict mortality in kidney transplant recipients: a 4‐year prospective case–cohort study

Angiopoietin 2 (Angpt2) impairs endothelial function by preventing angiopoietin 1 from binding to their common endothelial‐specific receptor Tie2. Here, we examined whether circulating Angpt2 predicts outcome in kidney transplant recipients. For this case–cohort study, we selected 130 kidney transplant recipients who had died or returned to dialysis within the first 2 years of follow‐up of our cohort study, as well as 130 age‐ and gender‐matched kidney transplant recipients without an event (controls) from a total of 993 kidney transplant recipients. The total of 260 selected patients were followed in median 4 years. Serum Angpt2 at baseline was measured using an in‐house immunoluminometric assay. Median Angpt2 concentrations were significantly higher in patients who died [median (interquartile range – IQR) 3.6 (2.8–5.9) ng/ml] as compared to patients who did not die during the study period [2.8 (2.1–4.1) ng/ml; P < 0.001]. Ln (natural log) Angpt2 levels correlated positively with C‐reactive protein levels (r = 0.315, P < 0.001) and the Charlson Comorbidity Index (r = 0.188, P = 0.002) and were inversely associated with eGFR (r = ?0.301, P < 0.001) hemoglobin (r = ?0.269, P < 0.001), and serum albumin concentrations (r = ‐0.382, P < 0.001). On multivariate analyses, baseline Angpt2 levels independently predicted all‐cause mortality (multivariable‐adjusted hazard ratio associated with one natural log unit higher Angpt2 level: 1.70 (95% confidence interval: 1.10–2.61)). In our analysis, circulating Angpt2 was an independent predictor of all‐cause mortality in stable, prevalent kidney transplant recipients.     

Clinical significance of isolated v lesions in paediatric renal transplant biopsies: muscular arteries required to refute the diagnosis of acute rejection

Intimal vascular lesions are considered features of acute T‐cell‐mediated rejection yet can occur in the absence of tubulointerstitial inflammation, termed isolated ‘v’ lesions. The clinical significance of these lesions is unclear. The diagnosis requires a biopsy with the presence of arteries. The frequency of adequate biopsies was analysed in 89 renal transplant biopsies from 57 paediatric renal allograft recipients, and the incidence of isolated endarteritis was determined. 60 (67%) biopsies contained an artery and of these, isolated ‘v’ lesions occurred in 6 (10%). 5 (83%) biopsies with isolated ‘v’ lesions were associated with positive DSA, suggesting that these lesions may represent acute antibody‐mediated rejection. Patients with vessel‐negative biopsies had an increased decline in eGFR (median ?20.5, IQR ?24.4 to 1.2 ml/min/1.73 m² vs. ?9.6, IQR ?78.7 to ?6.8 ml/min/1.73 m²; P = 0.01). Patients with vessel‐negative biopsies were more likely to have repeat biopsy for ongoing allograft dysfunction, (25.0% vs. 2.4%; P < 0.01). The data suggest that isolated ‘v’ lesions are more common than previously thought. A significant proportion of biopsies classified as ‘normal’ or ‘borderline change’ in the absence of a large vessel may represent undiagnosed acute rejection. This may result in suboptimal therapy with possible adverse effects on renal outcome.     

Correlation between circulating endothelial progenitor cell function and allograft rejection in heart transplant patients

Endothelial progenitor cells (EPCs) may contribute to rejection and cardiac allograft vasculopathy (CAV) by being intrinsically involved in the rejection process and causing neointimal hyperplasia. The mammalian target of rapamycin inhibitors (mTORi), sirolimus and everolimus, have been demonstrated to attenuate the progression of CAV and are cytotoxic to EPC. Thus, one mechanism by which mTORi may protect against CAV is by altering EPC function. Our study measured circulating EPC function and correlated this assessment with rejection episodes in heart transplant (HT) recipients. In addition, we examined the effect of mTORi on EPCs. Patients who received HT at our institution between 1995 and 2007 were included and stratified by International Society for Heart and Lung Transplantation (ISHLT) rejection grade. Group A (n = 13) consisted of patients with at least one moderate/severe rejection episode (grade ≥ 2). Group B (n = 28) patients had no moderate/severe episodes (grade < 2). Patients were also independently stratified based on exposure as mTORi (n = 21) vs. non mTORi (n = 20). To assess EPC functional capacity, we counted the number of colony‐forming units (CFU) of EPCs in peripheral blood samples from HT recipients. There were no significant differences in baseline characteristics between groups. The mean EPC‐CFU counts/plate for group A (rejecting) were 30 ± 6 vs.16 ± 3 for group B (nonrejecting) (P = 0.03). The EPC‐CFU counts/plate in the mTORi group (15 ± 3) were lower compared to the non mTORi (27 ± 5) group (P = 0.04). We found that EPC colony‐forming capacity was higher in HT patients who experienced moderate/severe rejection episodes. Patients on mTORi showed a reduced EPC colony count consistent with our previous findings of EPC cytotoxicity. Detection of circulating EPC function post‐transplant may reliably identify patient risk level for subsequent allograft rejection and allow for appropriate adjustments to immunosuppression. Converting to mTORi therapy may reduce EPC function and provide a novel mechanism to prevent rejection and possibly attenuate the development of CAV.     

T cell–mediated rejection is a major determinant of inflammation in scarred areas in kidney allografts

Inflammation in fibrosis areas (i‐IF/TA) of kidney allografts is associated with allograft loss; however, its diagnostic significance remains to be determined. We investigated the clinicohistologic phenotype and determinants of i‐IF/TA in a prospective cohort of 1539 kidney recipients undergoing evaluation of i‐IF/TA and tubulitis in atrophic tubules (t‐IF/TA) on protocol allograft biopsies performed at 1 year posttransplantation. We considered donor, recipient, and transplant characteristics, immunosuppression, and histological diagnoses in 2260 indication biopsies performed within the first year posttransplantation. Nine hundred forty‐six (61.5%) patients presented interstitial fibrosis/tubular atrophy (IF/TA Banff grade > 0) at 1 year posttransplant, among whom 394 (41.6%) showed i‐IF/TA. i‐IF/TA correlated with concurrent t‐IF/TA (P < .001), interstitial inflammation (P < .001), tubulitis (P < .001), total inflammation (P < .001), peritubular capillaritis (P < .001), interstitial fibrosis (P < .001), and tubular atrophy (P = .02). The independent determinants of i‐IF/TA were previous T cell–mediated rejection (TCMR) (P < .001), BK virus nephropathy (P = .007), steroid therapy (P = .039), calcineurin inhibitor therapy (P = .011), inosine‐5′‐monophosphate dehydrogenase inhibitor therapy (P = .011), HLA‐B mismatches (P = .012), and HLA‐DR mismatches (P = .044). TCMR patients with i‐IF/TA on posttreatment biopsy (N = 83/136, 61.0%) exhibited accelerated progression of IF/TA over time (P = .01) and decreased 8‐year allograft survival (70.8% vs 83.5%, P = .038) compared to those without posttreatment i‐IF/TA. Our results support that i‐IF/TA may represent a manifestation of chronic active TCMR.     

Renal function three years after early conversion from a calcineurin inhibitor to everolimus: results from a randomized trial in kidney transplantation

In a 36‐month, open‐label, multicenter trial, 202 kidney transplant recipients were randomized at week 7 post‐transplant to convert to everolimus or remain on cyclosporine: 182 were analyzed to month 36 (92 everolimus, 90 controls). Mean (SD) change in measured GFR (mGFR) from randomization to month 36 was 1.3 (14.0) ml/min with everolimus versus ?1.7 (15.4) ml/min in controls (P = 0.210). In patients who remained on treatment, mean mGFR improved from randomization to month 36 by 7.9 (11.5) ml/min with everolimus (n = 37) but decreased by 1.4 (14.7) ml/min in controls (n = 62) (P = 0.001). During months 12–36, death‐censored graft survival was 100%, patient survival was 98.9% and 96.7% in the everolimus and control groups, respectively, and 13.0% and 11.1% of everolimus and control patients, respectively, experienced mild biopsy‐proven acute rejection (BPAR). Protocol biopsies in a limited number of on‐treatment patients showed similar interstitial fibrosis progression. Donor‐specific antibodies were present at month 36 in 6.3% (2/32) and 18.0% (9/50) of on‐treatment everolimus and control patients with available data (P = 0.281). During months 12‐36, adverse events were comparable, but discontinuation was more frequent with everolimus (33.7% vs. 10.0%). Conversion from cyclosporine to everolimus at 7 weeks post‐transplant was associated with a significant benefit in renal function at 3 years when everolimus was continued.     

Transient elastography: a new noninvasive diagnostic tool for assessment of chronic allograft nephropathy

Purpose

Chronic allograft nephropathy (CAN) is the most common cause of kidney allograft failure. Protocol biopsies remain the “gold standard” in CAN recognition. However, renal allograft biopsies have numerous limitations. It is an invasive procedure connected with risk of complications, patient discomfort, and sampling errors. The aim of our study was to investigate the usefulness of transient elastography (TE) for the assessment of kidney allograft fibrosis in renal transplant recipients (RTRs).

Methods

In this cross-sectional study, we involved 52 RTRs. Renal allograft stiffness was used to assess its fibrosis by using transient elastography (Fibroscan^®, Echosense, Paris, France). In 23 patients with a deterioration of graft function, percutaneous renal allograft biopsy was performed closely around the time of TE.

Results

We have found that the renal allograft stiffness was highly negatively correlated with estimated glomerular filtration rate (eGFR) (r = ?0.640; p < 0.0001). However, renal allograft stiffness showed a statistically significant difference between patients who had an eGFR > 50 ml/min per 1.73 m² and patients with eGFR < 50 ml/min per 1.73 m² (28 ± 2.7 vs. 33.9 ± 5.5 kPa; p = 0.0003). Also, there was a highly positive correlation between renal allograft stiffness and extent of interstitial fibrosis on renal biopsy (r = 0.727; p = 0.0001).

Conclusion

According to our results, parenchymal stiffness obtained by TE reflects interstitial fibrosis. Therefore, TE provides the opportunity for noninvasive screening of CAN.     

Antibiotics and observation have a similar impact on asymptomatic patients with a raised PSA

Study Type – Therapy (case series)
Level of Evidence 4 What's known on the subject? and What does the study add? As PSA exhibits suboptimal specificity, different strategies have been proposed in order to decrease the number of negative biopsies. An empirical course of antibiotics has been proposed as a cost‐saving strategy to differentiate patients with benign cancer as it could potentially avoid unnecessary biopsies. Despite being limited by its non‐randomized open‐label design, our data suggest that no specific PSA reduction threshold can accurately discriminate prostate cancer. The empirical use of antibiotics for asymptomatic patients with elevated PSA levels should be discouraged.

OBJECTIVES

• ? To compare the influence of a 4‐week course of empirical antimicrobial therapy or observation on the prostate‐specific antigen (PSA) levels of asymptomatic patients with a raised baseline PSA.
• ? To identify whether a decrease in PSA can predict the risk of prostate cancer (PCa) detection on prostate biopsy.

PATIENTS AND METHODS

• ? Patients were referred to our ambulatory centre because of a raised PSA level (>2.5 ng/mL) with a normal digital rectal examination. A 12‐core prostate biopsy was indicated in these patients and they were offered antibiotic treatment with levofloxacin 500 mg daily for 30 days.
• ? Patients who did not agree to use antibiotics but who still showed interest in participating underwent simple observation, serving as controls.
• ? Total and free PSA levels at baseline and after 45 days were measured. Variation in PSA level was calculated.
• ? All patients underwent a 12‐core prostate biopsy 6 weeks after the initial visit.

RESULTS

• ? In all, 245 men were enrolled, but 43 were lost due to follow‐up. A total of 145 patients who used antibiotics and 57 controls were included in the analysis.
• ? The median baseline PSA levels were 7.6 and 7.7 ng/mL in the antibiotic and control groups, respectively, with median follow‐up levels of 6.8 and 7.0 ng/mL. The follow‐up PSA level was significantly lower than the initial PSA level (P = 0.009).
• ? Mean absolute and percentage variation in PSA level were similar in both groups (P = 0.828 and 0.128, respectively).
• ? The overall PCa detection rate was 15.8%, and did not differ among the groups (P = 0.203). Regarding the percentage variation in PSA level, patients diagnosed with PCa tended to have their PSA level increased (22.4 vs –5.3%; P = 0.001). Indeed, a decrease of 20% in PSA was not predictive of a negative prostate biopsy (P = 0.41).
• ? The area under the receiver operating characteristic curve for percentage PSA variation as a predictor of PCa was 0.660.

CONCLUSIONS

• ? PSA levels tend to fall when repeated after 45 days, regardless of antibiotic use.
• ? Despite being associated with the chance of PCa, no percentage PSA variation threshold value exhibits satisfactory discriminatory properties.

     

Contrast-enhanced ultrasonography of the prostate: various imaging findings that indicate prostate cancer

Study Type – Diagnostic (non‐consecutive case series)
Level of Evidence 3b What’s known on the subject? and What does the study add? Contrast‐enhanced ultrasonography (CEUS) can visualize some prostate cancer lesions. Findings suggestive of cancer have been defined as rapid contrast enhancement; increased contrast enhancement. CEUS could be useful for targeted biopsy in patients with a PSA level <10 ng/mL. The CEUS findings suggestive of prostate cancer are more varied than previously reported. Low‐echogenicity areas containing abnormal blood vessels were also found to represent cancer.

OBJECTIVES

• ? To perform transrectal ultrasonography (TRUS) with an ultrasonography (US) contrast agent to visualize prostate cancer.
• ? To explore the possibility of targeted biopsy by studying the findings obtained by different cancerous tissue imaging modalities and evaluating needle biopsies from prostate cancer using contrast‐enhanced ultrasonography (CEUS).

PATIENTS AND METHODS

• ? In all, 41 patients undergoing prostate biopsy and 13 patients undergoing prostatectomy received i.v. injection of the US contrast agent (Sonazoid®).
• ? We evaluated pre‐contrast and contrast‐enhanced US images, and then compared ultrasonographic images and the pathological findings.

RESULTS

• ? Cancer was significantly more frequent at the sites of targeted biopsy where CEUS findings suggested cancer (36.3%) than at sites of systematic biopsy (17.7%, odds ratio = 2.7, P = 0.0026).
• ? In cases with prostate‐specific antigen (PSA) level <10 ng/mL, in particular, prostate cancer was detected at a significantly higher rate by targeted biopsy than by systematic biopsy (27.3 vs 9.5%, odds ratio = 3.4, P = 0.013).
• ? Pathological examination found 26 tumours in prostatectomy specimens. The diameters of the 10 CEUS‐identified tumours were significantly greater than those of the 16 lesions missed by US (mean 18.7 vs 5.9 mm).
• ? CEUS findings suggestive of cancer varied widely: strong contrast enhancement, rapid contrast enhancement, vessels with abnormal perfusion and low contrast enhancement.

CONCLUSIONS

• ? CEUS could be useful for targeted biopsy in patients with a PSA level <10 ng/mL.
• ? The CEUS findings suggestive of prostate cancer are more varied than previously reported.
• ? Detailed examination of CEUS images and application of the data to prostate biopsy could lead to more efficient diagnosis.

     

Effects of smoking on fatty acid composition of phospholipid sperm membrane and the malondialdehyde levels in human seminal plasma

The aim of this study was to investigate fatty acids composition of sperm phospholipids, level of lipoperoxidation represented by malondialdehyde and to examine differences between recent smokers and nonsmokers. The levels of malondialdehyde were in the group of all patients 1.51 ± 0.56 μmol l^?1, in smokers 1.36 ± 0.59 μmol l^?1 and in nonsmokers 1.53 ± 0.55 μmol l^?1. Total sperm membrane phospholipid fatty acids were profiled into several groups, saturated acids (in smokers 61.86 ± 9.02%, in nonsmokers 61.20 ± 11.66%), polyunsaturated acids n‐3 (in smokers 12.62 ± 8.18%, in nonsmokers 14.28 ± 13.65%), polyunsaturated acids n‐6 (in smokers 9.13 ± 4.37%, in nonsmokers 10.10 ± 3.79%) and other acids (in smokers 14.36 ± 3.94%, in nonsmokers 13.88 ± 2.31%). Significant correlations were found between the level of malondialdehyde (MDA) and total sperm motility in all patients (r = ?0.358, P = 0.013), between both the level of MDA and progressive motility (r = ?0.465, P = 0.001) and between the level of MDA and total motility (r = ?0.382, P = 0.037) in nonsmokers. There were no statistically significant differences between composition of sperm phospholipid important fatty acids in smokers and nonsmokers. Significant correlations between selected sperm fatty acids and sperm motility and morphology in smokers and nonsmokers were not observed.     

Does repeat biopsy affect the prognosis of patients with prostate cancer treated with radical prostatectomy? Analysis by the number of cores taken at initial biopsy

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? To date, studies to evaluate clinical significance of prostate cancer detected on repeat biopsy in patients who underwent radical prostatectomy have yielded inconsistent results. The present study confirms that prostate cancer diagnosed after repeat biopsies is related to better pathological outcomes after radical prostatectomy, but not predictive of biochemical recurrence. Additionally, we find that the number of cores taken at initial biopsy do not affect the association between the number of previous biopsies and the prognosis.

OBJECTIVE

• ? To determine whether repeat prostate biopsies are associated with more favourable prognoses compared with diagnosis at initial biopsy in patients who undergo radical prostatectomy for prostate cancer and to determine if this association is affected by the number of cores taken at initial biopsy.

PATIENTS AND METHODS

• ? We reviewed 1147 patients with prostate cancer from 1991 to 2008.
• ? Patients were stratified into two groups by the number of biopsies before diagnosis (initial biopsy vs repeat biopsy: at least two biopsies).
• ? The effects of several variables on pathological outcomes and biochemical recurrence‐free and systemic progression‐free survivals were assessed.

RESULTS

• ? Of the 1147 patients, 1064 (92.8%) were diagnosed with cancer at first biopsy and 83 (7.2%) at repeat biopsy.
• ? Compared with patients diagnosed at initial biopsy, those diagnosed at repeat biopsies were more likely to have a lower clinical stage (cT1c: 79.5% vs 55.5%, P < 0.001) and organ‐confined tumours (78.3% vs 61.3%, P= 0.003), but there was no significant difference in initial biopsy core number (8.3 vs 8.7, P= 0.373).
• ? Five‐year biochemical recurrence‐free and progression‐free survival rates did not show significant differences between the two groups (88.8% vs 82.2%, P= 0.078; 100.0% vs 96.5%, P= 0.105, respectively), and these results were not affected by the number of cores taken at initial biopsy.

CONCLUSIONS

• ? Although prostate cancer diagnosed after repeat biopsies was related to better pathological outcomes after radical prostatectomy, the number of previous biopsies did not predict disease recurrence.
• ? Moreover, the number of cores taken at initial biopsy did not affect these associations.