Kathy Kable

Antiviral medications to prevent cytomegalovirus disease and early death in recipients of solid-organ transplants: a systematic review of randomised controlled trials

BACKGROUND Antiviral prophylaxis is commonly used in recipients of solid-organ transplants with the aim of preventing the clinical syndrome associated with cytomegalovirus infection. We undertook a systematic review to investigate whether this approach affects risks of cytomegalovirus disease and death. METHODS Randomised controlled trials of prophylaxis with antiviral medications for cytomegalovirus disease in solid-organ-transplant recipients were identified. Data were combined in meta-analyses by a random-effects model. FINDINGS Compared with placebo or no treatment, prophylaxis with aciclovir, ganciclovir, or valaciclovir significantly reduced the risks of cytomegalovirus disease (19 trials, 1981 patients; relative risk 0.42 [95% CI 0.34-0.52]), cytomegalovirus infection (17 trials, 1786 patients; 0.61 [0.48-0.77]), and all-cause mortality (17 trials, 1838 patients; 0.63 [0.43-0.92]), mainly owing to lower mortality from cytomegalovirus disease (seven trials, 1300 patients; 0.26 [0.08-0.78]). Prophylaxis also lowered the risks of disease caused by herpes simplex or zoster virus, bacterial infections, and protozoal infections, but not fungal infection, acute rejection, or graft loss. Meta-regression showed no significant difference in the risk of cytomegalovirus disease or all-cause mortality by organ transplanted or cytomegalovirus serostatus; no conclusions were possible for cytomegalovirus-negative recipients of negative organs. In trials of direct comparisons, ganciclovir was more effective than aciclovir in preventing cytomegalovirus disease. Valganciclovir and intravenous ganciclovir were as effective as oral ganciclovir. INTERPRETATION Prophylaxis with antiviral medications reduces the risk of cytomegalovirus disease and associated mortality in recipients of solid-organ transplants. This approach should be used routinely in cytomegalovirus-positive recipients and in cytomegalovirus-negative recipients of organs positive for the virus.

Treatment of subclinical rejection diagnosed by protocol biopsy of kidney transplants.

Background. Subclinical rejection (SCR) causes chronic allograft damage, which may be prevented by antirejection therapy. Methods. A pilot study of the effect of routine treatment of SCR was performed in 88 recipients of either a kidney (n=59) or combined kidney-pancreas transplant (n=29) undergoing protocol biopsy (PBX) surveillance at 1 and 3 months, using calcineurin inhibitors, mycophenolate mofetil, and corticosteroid therapy. Results. SCR was seen in 46.6% (41/88 patients), as 30 borderline and 11 acute SCR. From 279 transplant biopsies, the prevalence of SCR was 25% (22/88) at 1 month, 10.2% (9/88) at 3 months, and 8.3% (2/24) at 12 months PBX. Treatment included bolus intravenous or oral corticosteroids (n=20) and augmented immunosuppression, either by conversion to tacrolimus (n=6) or increased doses of maintenance therapy (n=14), whereas OKT3 was used in one case of subclinical vascular rejection. Borderline episodes were not treated in 12 patients. In biopsies taken to assess therapeutic response, persistent SCR was present in 46.1% (6/13). Treatment of SCR at 1 month was followed by lower acute Banff sum scores at 3 months PBX (P<0.01–0.0001). Early chronic damage was already present in the 1 month PBX, associated with SCR (P<0.0005 versus without SCR), although by 3 months these differences were lost. Rates of opportunistic infections and BK nephropathy were not increased by SCR treatment. Conclusion. Early chronic allograft damage was associated with SCR and therapy appeared to ameliorate further immune-mediated injury, although the efficacy of corticosteroids alone may be inadequate. A controlled trial of therapy for SCR is warranted.

Nosocomial Pneumocystis jirovecii pneumonia: lessons from a cluster in kidney transplant recipients.

Background. Pneumocystis jirovecii pneumonia (PJP) is an important infection-related complication, whose mode of transmission remains uncertain. Methods. We investigated a nosocomial cluster of 14 PJP cases (11 confirmed and 3 probable) in kidney transplant recipients using epidemiological and genotyping methods. Results. Poisson regression calculated an incidence density ratio of 42.8 (95% confidence interval [CI], 14.1–129.3) versus background 0.64 cases of 1000 patient-years (P<0.001). All patients presented with respiratory failure, 10 required ventilation, two died, and six transplants failed, costing

Tests for Latent Tuberculosis in People With ESRD: A Systematic Review.

31,854 (±SD

Clinical Utility of Urinary Cytology to Detect BK Viral Nephropathy.

26,048) per patient. Four-locus multilocus sequence typing analysis using DNA extracts from 11 confirmed cases identified two closely related genotypes, with 9 of 11 sharing an identical composite multilocus sequence typing genotype. Contact tracing found colocalization of cases within clinic waiting areas, suggesting person-to-person transmission. Minimal and maximal PJP incubation periods were 124±83 to 172±71 days, respectively. Oropharyngeal washes from outpatient staff and ambient air samples were negative for P. jirovecii DNA. Cohort analysis (14 cases vs. 324 unaffected clinic control patients) identified independent risk factors including previous cytomegalovirus infection (odds ratio [OR], 65.9; 95% CI, 7.9–550; P<0.001), underlying pulmonary disease (OR, 10.1; 95% CI, 2.3–45.0; P=0.002), and transplant dysfunction (OR=1.61 per 10 mL/min/1.73 m2, 95% CI, 1.15–2.25, P=0.006). The outbreak was controlled by reintroduction of trimethoprim/sulfamethoxazole prophylaxis to all potentially exposed clinic patients and its extension to 12 months in recent recipients. Conclusions. Nosocomial PJP clusters are likely due to interhuman transmission by airborne droplets to susceptible hosts. Prompt recognition and a strategy of early preemptive blanket PJP prophylaxis to all exposed transplant clinic recipients from the third confirmed case are recommended to limit outbreak escalation.

Molecular Epidemiology Linking Multihospital Clusters of Opportunistic Pneumocystis jirovecii Pneumonia

BACKGROUND The relative diagnostic accuracy of interferon γ release assays (IGRAs; based on ELISA [enzyme-linked immunosorbent assay] or ELISPOT [enzyme-linked immunosorbent spot], ie, the QuantiFERON and T-SPOT.TB tests, respectively) and the tuberculin skin test (TST) for latent tuberculosis (TB) infection in people with end-stage kidney disease is uncertain and national guidelines for their use are inconsistent. STUDY DESIGN Systematic review. SELECTION CRITERIA FOR STUDIES Evaluated performance of tests for latent TB with clinical risk-factor assessment. SETTING & POPULATION People with end-stage kidney disease (chronic kidney disease stage 5 [eGFR <15] or kidney transplant recipients). No limits on setting. INDEX TESTS ELISA- or ELISPOT-based IGRAs, TST, assays to detect antimycobacterial antibodies, and flow cytometry-based tests. OUTCOMES Odds of test positivity with clinical risk factor for latent TB, expressed as ORs and relative ORs (RORs). RESULTS 47 studies (6,828 participants) were included, but only 30 studies (4,546 participants) contained sufficient data to contribute to meta-analysis. Studies were predominately in the dialysis population (23/30; 3,700 participants) in countries with low to moderate TB prevalence (0.0-50.0 cases/10(5) persons). BCG vaccination rate was variable (2.7%-100.0%). 9 studies compared IGRAs with the TST directly, 17 studies evaluated the TST only, and the other 4 studies evaluated other tests. Compared to a positive TST result, a positive ELISA-based IGRA result was associated more strongly with radiologic evidence of past TB (ROR, 4.29; 95% CI, 1.83-10.3; P = 0.001) and contact with active TB (ROR, 3.36; 95% CI, 1.61-7.01; P = 0.001). Compared to a negative TST result, a negative ELISA-based IGRA result was associated more strongly with BCG vaccination (ROR, 0.30; 95% CI, 0.14-0.63; P = 0.002). There were insufficient data to compare performance of the ELISPOT-based IGRA with the TST or ELISA-based IGRA. LIMITATIONS 17 of 47 included studies (36.2%) did not contain sufficient data to contribute to meta-analysis. CONCLUSIONS Compared to the TST, the ELISA-based IGRA was associated more strongly with risk factors for latent TB in end-stage kidney disease.

BK Virus Nephropathy: Histological Evolution by Sequential Pathology

Background Reactivation of BK polyoma virus can result in destructive viral allograft nephropathy (BKVAN) with limited treatment options. Screening programs using surrogate markers of viral replication are important preventive strategies, guiding immunosuppression reduction. Methods We prospectively evaluated the diagnostic test performance of urinary decoy cells and urinary SV40T immunochemistry of exfoliated cells, to screen for BKVAN, (defined by reference histology with SV40 immunohistochemistry, n = 704 samples), compared with quantitative viremia, from 211 kidney and 141 kidney-pancreas transplant recipients. Results The disease prevalence of BKVAN was 2.6%. Decoy cells occurred in 95 of 704 (13.5%) samples, with a sensitivity of 66.7%, specificity of 88.6%, positive predictive value (PPV) of 11.7%, and negative predictive value of 98.5% to predict histologically proven BKVAN. Quantification of decoy cells improved the PPV to 32.1% (10 ≥ cells threshold). Immunohistochemical staining of urinary exfoliated cells for SV40T improved sensitivity to 85.7%, detecting atypical or degenerate infected cells (specificity of 92.3% and PPV of 33.3%), but was hampered by technical failures. Viremia occurred in 90 of 704 (12.8%) with sensitivity of 96.3%, specificity of 90.3%, PPV of 31.5%, and negative predictive value of 99.8%. The receiver-operator curve performance of quantitative viremia surpassed decoy cells (area under the curve of 0.95 and 0.79, respectively, P = 0.0018 for differences). Combining decoy cell and BK viremia in a diagnostic matrix improved prediction of BKVAN and diagnostic risk stratification, especially for high-level positive results. Conclusions Although quantified decoy cells are acceptable surrogate markers of BK viral replication with unexceptional test performances, quantitative viremia displayed superior test characteristics and is suggested as the screening test of choice.

Excellent outcomes of simultaneous pancreas kidney transplantation in patients from rural and urban Australia: a national service experience.

TO THE EDITOR—Pneumocystis jirovecii is responsible for severe inflammatory pneumonia in transplant recipients [1–6]. We encountered a cluster of fulminant P. jirovecii pneumonia (PJP) in 14 transplant recipients occurring a mean of 6.3 years (SD, 5.3 years) after transplant, beyond our 6-month trimethoprimsulfamethoxazole (TMP-SMZ) prophylaxis period [4]. Additional clusters emerged in 7 other Sydney hospitals (n = 30 patients), 3 regional hospitals (n = 8), 4 large interjurisdictional transplant units (n = 24), and 7 other interstate hospitals (n = 13) over 2 years, eventually controlled by reintroduction of universal TMP-SMZ prophylaxis for 12 months. Eight further patients presented (2 hospitals) following discontinuation of long-term prophylaxis, which was restarted after sites were disease-free for 14 months. In total, 97 PJP infections occurred in kidney (n = 87), liver (n = 4), liver-kidney (n = 1), and kidney-pancreas (n = 3) transplant recipients and 1 lupus patient and 1 hematology patient in 23 hospitals; there were 14 deaths and 10 kidney allograft failures. Four-loci multilocus sequence typing of known variable regions within the P. jirovecii genome was undertaken [4] to define the outbreak’s molecular epidemiology. We evaluated the concatenated sequences of 4 genetic loci (β-tub, DHPS, mtLSU, and ITS1/2) [5] from 48 patients with PJP and 11 unrelated controls; phylogenetic relationships were established using PAUP* 4.0b10 software (Sinauer Associates, Sunderland, Massachusetts). Genetic analysis of DNA sequences revealed an initial outbreak genotype (sequence type 1 [ST1]), and 2 closely related genotypes differing only by a single-nucleotide polymorphism in either the mtLSU (ST2) or ITS1/2 region (ST9), whereas the β-tub and DHPS sequences were identical. The last identified genotype (ST10), which emerged 52 months after the index case, differed by 6 nucleotides. Meticulous contact tracing found colocalization of asymptomatic prodromal PJP patients within our clinic waiting areas, and interhospital transmission facilitated by travel of infected patients with local cross-infection in distant locations. Patient-to-patient transmission mediated by airborne droplets best explains the epidemiology, supported by molecular tracing evidence and individual exposure histories. A common environmental source is unlikely given multiple distinct clusters within disparate geographical locations, which infers the evolution of strains with greater virulence or persistence. The epidemiology of early opportunistic PJP in modern organ transplantation was fundamentally altered by routine TMP-SMZ prophylaxis, with presentations now occurring increasingly later or within clusters

Clearance of BK Virus Nephropathy by Combination Antiviral Therapy With Intravenous Immunoglobulin.

Reactivation of BK virus in renal allografts causes a destructive chronic infection. This single‐center retrospective cohort study describes the evolution of BK virus allograft nephropathy (BKVAN) from 63 kidneys (from 61 patients) using sequential histopathology (454 biopsies, averaging 7.8 ± 2.6 per kidney) followed for 60.1 mo. Uninfected protocol biopsies formulated time‐matched control Banff scores (n = 975). Interstitial inflammation occurred in 73% at diagnosis, correlating with viral histopathology (r = 0.413, p = 0.008) and amplifying early injury with accelerated interstitial fibrosis and tubular atrophy (IF/TA, p = 0.017) by 3 mo. Prodromal simian virus 40 large T antigen (SV40T)–negative inflammation with viremia preceded the histological diagnosis in 23.8%. Persistent subacute injury from viral cytopathic effect was associated with acute tubular necrosis and ongoing interstitial inflammation, culminating in IF/TA in 86.9%. Overall, cellular interstitial infiltration mitigated the intensity of subsequent tubular injury, SV40T, and tissue viral load, assessed by sequential paired histology (p < 0.001). Graft loss was predicted by high‐level viremia (hazard ratio [HR] 4.996, 95% CI 2.19–11.396, p < 0.001), deceased donor (HR 3.201, 95% CI 1.149–8.915, p = 0.026), and late acute rejection (HR 3.124, 95% CI 1.037–9.413, p = 0.043). Transplant failure occurred in 38.1%, with uncontrolled infection (58.3%) and SV40T‐negative chronic rejection (41.7%) causing losses. BKVAN is characterized by subacute virus‐induced tubular injury, inflammation, and progressive nephron destruction. Effective antiviral therapy remains an unmet clinical need.

Bortezomib in ABO‐incompatible kidney transplant desensitization: A case report

Background Simultaneous pancreas and kidney (SPK) transplantation is performed to restore normoglycemia and renal function in patients with type 1 diabetes mellitus and end-stage renal failure. The National Pancreas Transplant Unit (NPTU) in Sydney provides a service to a population spread across 7.4 million km2. We aimed to see if SPK transplantation outcomes differed between recipients from metropolitan (M) centers and those from nonmetropolitan (NM) regions. Methods Using a prospectively collected database, patient and graft survival were analyzed. Patients were categorized according to region of residence and by distance from the NPTU. Results Between January 2001 and May 2010, 165 patients underwent first-time SPK transplantation at the NPTU. There were 126 M and 39 NM recipients. Median distance from the NPTU was 732 km for donors (range, 0–3930 km) and 887 km for recipients (range, 1–4114 km). Median follow-up was 5.2 years (range, 1.1–10.3 years). Actuarial 5-year patient survival was 94% in M and 95% in NM groups. At 5 years, non–death-censored pancreas graft survival was 75% and 82% among M and NM patients, respectively, while kidney allograft survival was 88% in M and 92% in NM groups. There was no significant difference in patient and graft survival between groups. Distance of donor and recipient from the NPTU did not influence graft or patient survival. Conclusions SPK transplantation can be performed with excellent outcomes at a national center with a vast catchment area, irrespective of donor or recipient location.