BK polyomavirus-pathogen, paradigm and puzzle.

BK virus is a polyomavirus with seroprevalence rates of 80% in adults. Infection is usually acquired during childhood, and the virus is benign or pathologic depending on immune status. The virus reactivates in immunodeficiency states, mostly among transplant (either kidney or bone marrow) recipients. There are approximately 15 000 renal transplants every year in the USA, of which 5-10% develop BK polyomavirus nephropathy; 50-80% of patients who develop nephropathy go on to develop graft failure. BK virus is associated with BK polyomavirus nephropathy, ureteral stenosis, late-onset hemorrhagic cystitis, bladder cancer and other nonlytic large T-expressing carcinomas. The renal spectrum begins with viruria and can end with graft failure. The clinical spectrum and outcomes vary among transplant patients. New noninvasive diagnostic methods, such as urinary polyomavirus Haufen detected by electron microscopy, are currently under study. Treatment is primarily directed at decreasing immunosuppression but may be associated with graft rejection. Repeat transplantation is encouraged as long as viral clearance in plasma prior to transplant is accomplished. There remain no definitive data regarding the utility of transplant nephrectomy.

Donor-Derived Cell-Free DNA (ddcf-DNA) and Acute Antibody-Mediated Rejection in Kidney Transplantation.

Monitoring kidney transplant recipients for evidence of allograft rejection is essential to lower the risk of graft loss. The traditional method relies on serial checks in serum creatinine with a biopsy of the allograft if dysfunction is suspected. This is invasive, labor-intensive and costly. As such, there is widespread interest in the use of biomarkers to provide a noninvasive approach to detecting allograft rejection. One such biomarker is donor-derived cell-free DNA (ddcf-DNA). Here, we review the methodology for the determination of the amount/fraction of ddcf-DNA, evaluate the available data of its use in kidney transplantation and render an opinion in the clinical decision-making of these patients.

Variability in assessing for BK viremia: whole blood is not reliable and plasma is not above reproach - a retrospective analysis.

Polyomavirus nephropathy (PVN) is a major complication of kidney transplantation. Most reports describe polyomavirus viremia either precedes or is detectable at the time of diagnosis of PVN. This association is the basis of current screening recommendations. We retrospectively reviewed the PCR results of blood and urine samples from 29 kidney transplant recipients with biopsy-proven PVN. Biopsies were performed for a rise in serum creatinine or persistent high-level BK viruria. All biopsies showed polyoma virus large T-antigen expression in tubular epithelium using immunohistochemistry. All had viruria preceding or at the time of biopsy (range, 5.2 × 104 to >25 × 106 BKV DNA copies/ml). Twenty (69%) had viremia ranging from 2.5 × 103 to 4.3 × 106 copies/ml at the time of the biopsy. Via blood BK PCR assay, nine (31%) had no BK viremia detected either preceding or at the time of the biopsy. In five recipients where sufficient specimen permitted, additional plasma BK assessment revealed positive detection of viremia. A comparative analysis of assays from two centres was performed with spiked samples. BK DNA may not be detected in the blood of some kidney transplant recipients with histologically confirmed PVN. This may reflect limitation of whole blood as opposed to plasma-based BK DNA assessment.

Membranous nephropathy transplanted in the donor kidney: observations of resolving glomerulopathy in serial allograft biopsies.

We report a case of idiopathic, PLA2R-negative membranous nephropathy (MN) transplanted via a deceased donor kidney. Changes in glomerular immune deposits were followed in serial biopsies. The allograft recipient had end-stage disease without significant proteinuria from ischemic nephropathy due to chronic heart failure, hypertension, atherosclerosis and presumed diabetic nephropathy. Combined cardiac and renal transplants were performed. Maintenance immunosuppression consisted of prednisone, a calcineurin inhibitor and mycophenolate mofetil. MN was identified in the pre-implantation biopsy of the donor kidney. The recipient never developed significant proteinuria and there was no identifiable impact on graft function. Serial biopsies performed at Days 0, 18, 150, 234 and 812 revealed mild effacement of podocyte foot processes, progressive change from Ehrenreich-Churg Stage III-IV lesions of MN to segmental resolution by electron microscopy, and progressive decrease of IgG staining by immunofluorescence. The findings provide a novel observation of the protracted process of glomerular immune deposit resolution in healing MN transplanted in a neutral host environment.

Impact of transplant pharmacists on length of stay and 30-day hospital readmission rate: a single-centre retrospective cohort study.

OBJECTIVES: Our study was conducted to evaluate the impact of clinical transplant pharmacy services on the kidney transplant programme at our centre, following the introduction of these services in terms of inpatient length of stay (LOS) and all-cause 30-day readmission rates by comparing these data to data from before (and therefore in the absence of) the services. METHODS: This was a single-centre retrospective cohort analysis. Data were collected in two phases: phase I (pre-transplant pharmacist period, that is, transplant pharmacist service was not available) comprised transplant patients between 1 October 2015 and 30 September 2016 and phase II (post-transplant pharmacist period) comprised transplant patients between 1 October 2016 and 30 September 2017. Patients ≥18 years of age, who received a kidney transplant in our centre, and received steroids, tacrolimus and mycophenolate for maintenance immunosuppression, were included. Transplant pharmacy services provided followed the expectations of the Centers for Medicare & Medicaid Services for transplant centres. Primary outcomes were LOS after transplant surgery and all-cause 30-day hospital readmission rate. Secondary outcomes included the number of pharmacy notes, the achievement of therapeutic levels of tacrolimus at day 7 post-surgery and delayed graft function. RESULTS: The two groups (n=101 in phase I and n=104 in phase II) had similar demographics and transplant characteristics at baseline. There was a statistically significant difference in the inpatient LOS (6.58 vs 5.76 days; p=0.041) between phase I and phase II, respectively. However, this did not pan out in the rate of 30-day hospital readmission (36 (35.6%) vs 27 (25.9%); p=0.133) between the two phases. The number of transplant pharmacist notes pre-transplant, post-surgery and on discharge were significantly higher in the post-transplant pharmacist group. There was no significant difference in tacrolimus concentration at day 7 (mean 7.15 ng/mL in phase I vs 6.95 ng/mL in phase II; p=0.673) or delayed graft function. CONCLUSION: Our study showed a favourable inpatient LOS and comparable 30-day hospital readmission rate before and after the implementation of transplant pharmacy services.

Platelet CD61 expression in vascular calcineurin inhibitor toxicity of renal allografts.

Calcineurin inhibitor (CI) toxicity in renal allografts is frequently associated with arteriolar injury. Platelet activation occurs in response to vascular injury associated with CI therapy. Platelets are detectable in tissue sections by immunohistochemistry for CD61. This immunohistochemical study examines patterns of platelet deposition in CI-associated vascular toxicity of renal allografts. Renal allograft biopsies were grouped into (i) CI-associated thrombotic microangiopathy (CITMA, n = 28); (ii) vascular CI toxicity without thrombotic microangiopathy (VTox, n = 43); and (iii) allograft controls with minimal arteriolopathy abnormalities, both with CI exposure (MA, n = 10) and without CI exposure (NCI, n = 15). Two-micrometer paraffin sections were stained using a monoclonal antibody to CD61 by standard immunoperoxidase methods. Mural and luminal CD61 deposits in arterioles were graded from 0 to 3+, and proportions of arteriolar and glomerular profiles with CD61 deposits were determined for each biopsy. Granular CD61 deposits were detected in arterioles in biopsies with CITMA (92.9%) and VTox (81%) and less frequently in MA (30%) and NCI (33%). The proportion of arterioles with CD61 deposits was greater in CITMA than in VTox (46.3% +/- 28.5% vs 21.3% +/- 22.2%, P = .001) and more extensive than in controls (MA, 3.6% +/- 8.9%; NCI, 3.2% +/- 5.5%). Median arteriolar CD61 grades for CITMA exceeded grades for VTox (2 vs 0.5, P = .001), and CD61 grades in VTox were significantly greater than in controls with MA (0) and NCI (0) (P = .0001). In conclusion, arteriolar mural platelet CD61 deposition was observed in vascular CI toxicity and was most extensive and severe in CI-associated thrombotic microangiopathy. Identification of "insudative platelet arteriolopathy" in renal allograft biopsies, by immunohistochemical detection of CD61, may facilitate recognition of vascular CI toxicity.

Histoplasma Peritonitis: An Extremely Rare Complication of Peritoneal Dialysis.

Bacterial peritonitis is a common complication of peritoneal dialysis, but fungal peritonitis is unusual and is mostly due to Candida species. Peritonitis due to Histoplasma capsulatum is rare and we report one such case. A 63-year-old female presented with progressively worsening abdominal pain, fever, and altered mental status. She had end-stage renal disease and had been on peritoneal dialysis for 4 years. She had abdominal tenderness without rebound or guarding. Laboratory studies and CT of abdomen were significant for leukocytosis and peritoneal membrane thickening, respectively. Peritoneal dialysis fluid study was consistent with peritonitis and culture of the fluid grew Histoplasma capsulatum. Treatment recommendations include removal of catheter and initiation of antifungal therapy. With the availability of newer antifungals, medical management without removal of PD catheter is possible, but at the same time if there is no response to treatment within a week, PD catheter should be removed promptly.

Renal replacement therapy in patients with acute respiratory distress syndrome: a single-center retrospective study.

BACKGROUND: Patients with acute respiratory distress syndrome (ARDS) who develop acute kidney injury have increased mortality and frequently require renal replacement therapy (RRT). The optimal timing for initiation of RRT after onset of ARDS to improve survival is not known. METHODS: We retrospectively reviewed clinical data on patients admitted to our health system over a 2-year period. Individual charts were carefully reviewed to ascertain that patients met the Berlin criteria for ARDS and to categorize RRT utilization. The Kaplan-Meier analysis was conducted to compare early (£48 hours postintubation) versus late (>48 hours postintubation) initiation of RRT. Associations between RRT initiation and mortality were evaluated using Cox proportional hazards regression. RESULTS: A total of 75 patients were identified with ARDS, 95% of whom received RRT. Mortality of patients who required RRT was 56%. The main indications for RRT initiation were fluid overload (75%), metabolic acidosis (64%), and hyperkalemia (33%). The Kaplan-Meier analysis comparing early initiation of RRT to late initiation of RRT showed no survival benefit. Cox proportional hazard models testing the association between timing of RRT initiation with survival and adjusting for sex, race, ethnicity, and Acute Physiology and Chronic Health Evaluation II score did not reach statistical significance (HR=0.94, 95% CI=0.48-1.86). CONCLUSION: Timing of RRT initiation was not associated with a survival benefit. Prospective study in the utilization and outcomes of RRT in ARDS could assist in optimizing its usage in this population.

Treatment of renal allograft polyoma BK virus infection with leflunomide.

BACKGROUND: Polyoma BK virus produces an aggressively destructive nephropathy in approximately 3% to 8% of renal allografts, is associated with graft loss within one year in 35% to 67% of those infected and there is no therapy of proven efficacy. Leflunomide is an immune suppressive drug with anti viral activity in vitro and in animals. METHODS: We treated twenty-six patients with biopsy proven NK virus nephropathy (BKN) with either leflunomide alone (n=17) or leflunomide plus a course of cidofovir (n=9) and followed them for six to forty months. Leflunomide was dosed to a targeted blood level of active metabolite, A77 1726, of 50 microg/ml to 100 microg/ml (150 microM to 300 microM). Response to treatment was gauged by serial determinations of viral load in blood and urine (PCR), serum creatinine, and repeat allograft biopsy. RESULTS: In the 22 patients consistently sustaining the targeted blood levels of active drug, blood and urine viral load levels uniformly decreased over time (P<.001). Mean serum creatinine levels stabilized over the first six months of treatment, and with 12 months or more of follow-up in 16 patients the mean serum creatinine has not changed significantly from base line. Four patients who did not consistently have blood levels of active drug (A77 1726) above 40 microg/ml did not clear the virus until these levels were attained or cidofovir was added. CONCLUSIONS: Leflunomide inhibits Polyoma virus replication in vitro and closely monitored leflunomide therapy with specifically targeted blood levels appears to be a safe and effective treatment for Polyoma BK nephropathy.

Nephron segment localization of polyoma virus large T antigen in renal allografts.

This study uses CD10 and epithelial membrane antigen (EMA) as respective proximal and distal tubular segment markers to localize polyoma virus replicative activity, as determined by large T antigen (TAg) expression, in allograft polyoma virus nephropathy (PVN). Sixteen biopsies and 2 nephrectomy specimens with PVN had serial 2-mum paraffin sections stained using monoclonal antibodies to polyoma virus TAg by immunoperoxidase with diaminobenzidine as chromogen. A second immunolabeling step used CD10 as a proximal nephron marker or EMA as a distal tubular marker, and alkaline phosphatase with fast red as chromogen. BK viral DNA was detected in blood in 16 of 18 tested. Fourteen of 16 had cortex and medulla, and 2 had cortex only in the biopsy sample. Fourteen (100%) of 14 had double-positive EMA and TAg expression (EMA+TAg+) in medullary collecting ducts. T antigen was evident in loops of Henle in nephrectomies. Thirteen (81.3%) of 16 had EMA+TAg+, and 10 (62.5%) of 16 had CD10+TAg+ cortical tubular segments. CD10+TAg+ cells were observed in the parietal epithelium of Bowman's capsule in 3 biopsies (18.75%). T antigen was observed in 5.1% of CD10+ tubular profiles compared with 21% of EMA+ profiles in renal cortex (P < .0001). Polyoma virus TAg was observed in medullary collecting ducts, in distal and proximal cortical tubules, and in Bowman's capsule, in decreasing order of frequency. Loops of Henle also had TAg. This distribution suggests potential for an ascending route of infection of allograft tubules in PVN.

Early Posttransplant Isolated v1 Lesion Does Not Need to Be Treated and Does Not Lead to Increased Fibrosis.

Acute vascular rejection (AVR) is characterized by intimal arteritis in addition to tubulitis and interstitial inflammation. It is associated with a poorer prognosis compared to tubulointerstitial rejection (AIR) and AVR is associated with a higher rate of graft loss than AIR. The prognosis and treatment of arteritis without tubulitis and interstitial inflammation (isolated v1 lesion) are still controversial. We report a case of a patient who had a biopsy of the kidney allograft for evaluation of slow graft function. The biopsy revealed an isolated v1 lesion. However, we chose not to augment immunosuppression. The patient's kidney allograft function improved over time with close monitoring. Repeat biopsy a year later showed no evidence of endothelialitis and relatively unchanged fibrosis and no other abnormalities. Although it is suggested that most cases of isolated v1 lesions will respond to corticosteroids or T cell depleting therapies, some cases will improve with conservative management. Further studies are needed to determine which cases could be managed conservatively.

Epidemiology of Glomerular Disease in Southern Arizona: Review of 10-Year Renal Biopsy Data.

Glomerulonephritis stands third in terms of the etiologies for end-stage kidney disease in the USA. The aim of this study was to look at the patterns of biopsy-proven glomerulonephritis based on data from a single center.Kidney biopsy specimens of all patients above the age of 18 years, over a 10-year period, who had diagnosis of nondiabetic glomerular disease, were selected for the study.The most common histopathological diagnosis was focal and segmental glomerulosclerosis (FSGS) (22.25%, 158/710) followed by membranous nephropathy (20.28%, 144/710) and immunoglobulin (Ig)A nephropathy (19.71%, 140/710). There was male preponderance in all histological variants except IgA nephropathy, lupus nephritis, and pauci-immune glomerulonephritis. The race distribution was uneven, and all histological variants, except minimal change disease and lupus nephritis, were more commonly seen in whites. In a separate analysis of the histological pattern in Hispanics, lupus nephritis was the most common pathology (28.70%, 62/216) followed by FSGS (18.05%, 39/216). In American Indian population, the most common pathology was IgA nephropathy (33.33%, 8/24) followed by FSGS (16.67%, 4/24).This study highlights the histopathological patterns of glomerular disease in southern Arizona. The data suggest regional and ethnic variations in glomerular disease that may point towards genetic or environmental influence in the pathogenesis of glomerular diseases.

Implications of immunohistochemical detection of C4d along peritubular capillaries in late acute renal allograft rejection.

BACKGROUND: Immunohistochemical detection of the C4d complement product along peritubular capillaries (PC) may indicate humoral rejection of renal allografts. We examined the frequency of PC C4d expression in renal-allograft biopsies with acute rejection (AR) arising more than 6 months after transplantation and the impact of this finding. METHODS: C4d was detected by immunoperoxidase in 2-micron paraffin sections of consecutive biopsies obtained over a 3-year period. The extent was classified as diffuse (> or =50% PC C4d+), focal (<50% C4d+), and negative (C4d-). Clinical data were obtained by retrospective chart review. Fifty-five AR episodes with Banff 97 types 1A (n = 13), 1B (n = 26), 2A (n = 11), 2B (n = 3), and 3 (n = 2) met inclusion criteria. RESULTS: PC C4d expression was diffuse in 23 (42%), focal in 9 (16%), and negative in 23 (42%) biopsies. AR episodes with focal and diffuse C4d expression had higher proportionate elevation of serum creatinine at biopsy and 4 weeks after diagnosis (P< or =0.05). Biopsies with diffuse PC C4d had interstitial hemorrhage (56.5%) and plasmacytic infiltrates (52%) more frequently than C4d- biopsies (22% and 16%), P = 0.02, but had no other distinctive histologic features. Graft loss was greater in diffuse (65%) compared with focal C4d+ (33%) and C4d- (33%) groups 1 year after diagnosis, P = 0.03. Other clinical and pathologic parameters did not differ significantly, including treatment received for AR. CONCLUSION: Evidence of acute cellular with occult humoral rejection is identified in more than 40% of late AR episodes. Late acute humoral rejection may be associated with interstitial hemorrhage and plasma cells and contributes significantly to graft loss.

Polyoma virus infection of renal allografts: relationships of the distribution of viral infection, tubulointerstitial inflammation, and fibrosis suggesting viral interstitial nephritis in untreated disease.

Whether polyoma virus (PV) infection of renal allografts induces an antiviral or antigraft immune reaction is unclear. By examination of the relationships of tubular PV to graft inflammation and scarring, this study sought histological evidence of viral interstitial nephritis in allograft biopsies with untreated PV infection and compared the inflammatory indices to controls with acute rejection (AR). Morphological features including viral cytopathic changes (VCCs) and modified Banff 97 histological indices were evaluated in sections of 28 diagnostic biopsies from a group of patients receiving prednisone, tacrolimus, and mycophenolate mofetil at constant dosage before biopsy. Two-micrometer paraffin sections were stained for PV large T antigen (TAg) and for C4d, by immunohistochemistry. Tubular profiles with 1 or more nuclei expressing TAg per x200 field were scored using an interval scale (0-10; none to 91-100%) by 2 observers. Controls with AR (n = 38, TAg negative) were matched for time after transplantation and severity of Banff 97 interstitial inflammation (i) and tubulitis (t) scores. Median t scores for tubules with VCC or TAg or both exceeded scores for tubules without VCC or TAg (3 versus 0, P = .001). Tubular TAg score correlated with i score (r = 0.58, P < .01) and sum ct + ci score (r = 0.61, P < .001). Atrophic tubules in scars had persistent VCC and/or TAg. Interstitial plasma cells (75% versus 21%) and neutrophils (32% versus 0%) were more frequent, and interstitial fibrosis was more severe (ci >1 in 54% versus 21%) in polyoma virus nephropathy (PVN) than in the group with AR (P < .01). Intimal arteritis (0% versus 35.7%), peritubular capillary C4d (0% versus 47.4%), and interstitial hemorrhage (4% versus 37%) were almost exclusively found in AR (P < .01). Tubular inflammation in untreated PVN involves infected tubular profiles with greater severity than those without evidence of infection. The extent of tubular PV infection is proportional to interstitial inflammation and scarring. Tubulointerstitial inflammation in PV infection has significant qualitative differences from AR. Observations in these examples of untreated PVN suggest that the allograft inflammatory reaction may exhibit features of viral tubulointerstitial nephritis distinct from AR.

Use of leflunomide in renal transplant recipients with ganciclovir-resistant/refractory cytomegalovirus infection: a case series from the University of Chicago.

INTRODUCTION: Although antiviral prophylaxis for cytomegalovirus (CMV) is widely used, CMV infection remains common in renal transplant recipients with adverse consequences. METHODS: We report 5 cases of renal transplant recipients with resistant CMV infection who were successfully managed with leflunomide at the University of Chicago Medical Center. RESULTS: Five renal transplant recipients (2 simultaneous pancreas/kidney transplants, 3 deceased donor kidney transplants) were diagnosed with GCV-resistant CMV infection from 2003 to 2011. Of the 4 patients who had resistance genotype testing, 3 showed a UL97 mutation and 1 patient had a clinically resistant CMV infection. All patients received CMV prophylaxis with valganciclovir for 3 months. The number of days from the date of transplant to viremia ranged from 38 to 458 days (median 219). All 5 patients received other antiviral agents (e.g. ganciclovir, foscarnet), and in 4 patients, viremia was cleared before leflunomide was initiated as consolidation (or maintenance) therapy. CONCLUSION: Leflunomide was well tolerated and successful in preventing recurrence of viremia in renal transplant recipients with resistant CMV infection. The beneficial effect of leflunomide in this setting warrants further investigation.

Cardiovascular diseases in kidney transplant recipients: the role of anemia.

Cardiovascular diseases are among the leading causes of mortality and death associated graft loss in kidney transplant recipients. Recently, there has been an increased awareness of the potential role of nontraditional risk factors such as anemia in contributing to the increased burden of cardiovascular diseases in kidney transplant recipients. Studies that are primarily based on retrospective data analyses have shown an association between anemia and cardiovascular outcomes. These findings underscore the need for prospective studies to better understand these risks and to implement management strategies that would have a positive impact on patient and graft outcomes. On the basis of the available data, this article reviews the magnitude of cardiovascular diseases and anemia in kidney transplant recipients with a focus on the role of anemia on cardiovascular outcomes in these patients.

Differing tales of two patients after receiving a kidney transplant from a donor with disseminated intravascular coagulation.

In order to decrease the time on the deceased donor kidney wait list and to have more organs available, criteria for acceptable organs for transplant could be made less stringent. There are reports of successful recipient outcomes using kidney donors presenting with disseminated intravascular coagulation (DIC). We report a unique circumstance where two patients received kidneys from the same deceased donor who had DIC; one patient developed thrombotic microangiopathy (TMA) while the other did not. This difference in outcome may indicate that both donor and recipient factors contribute to the development of posttransplant TMA.

Aortocaval fistula: a rare cause of venous hypertension and acute renal failure.

Spontaneous rupture of abdominal aortic aneurysm into the inferior vena cava is rare and is associated with high mortality and morbidity. The clinical presentation can be variable and thus the diagnosis can be difficult. It can present with symptoms and signs of an abdominal emergency, venous hypertension, or systemic hypoperfusion. The traditional method of repair has been open surgery which is associated with high rate of complications. We report a case of aortocaval fistula (ACF) presenting with acute renal failure and heart failure, which was treated successfully with a novel, endovascular approach.