Background. The biological effects of SARS-CoV-2 infection in transplanted kidneys are uncertain with little pathological information. Methods. This single-center, prospective observational study evaluated kidney transplant biopsies from recipients of deceased donors with COVID-19, current recipients contracting SARS-CoV-2 Omicron variant in 2022, against prior BK virus (BKV) infection and uninfected (without SARS-CoV-2 or BKV) samples, as respective positive and negative comparators (n = 503 samples). Results. We demonstrated nonvirus tubular injury in implanted tissue from infected donors and prevalent recipients with mild acute COVID-19 and acute kidney injury, excluding direct viral infection as a cause of kidney damage. COVID particles were absent in 4116 ultrastructural images of 295 renal tubules from 4 patients with acute COVID-19. No viral cytopathic effect, viral allograft nephropathy, or SARS-CoV-2 RNA was detected in acute tissues, nor in 128 sequential samples from infected donors or recipients with COVID-19. Following recipient COVID-19 (mean 16.8 ± 12.0 wk post-infection), the biopsy-prevalence of rejection was 33.0% (n = 100 biopsies) versus 13.4% for contemporaneous uninfected controls (n = 337; P < 0.001). Prior COVID-19 was an independent risk factor for incident rejection using multivariable generalized estimating equation adjusted for competing risks (odds ratio, 2.195; 95% confidence interval, 1.189-4.052; P = 0.012). Landmark and matched-pair analyses confirmed an association of SARS-CoV-2 with subsequent transplant rejection, with a similar pattern following BKV infection. Conclusions. Transplantation from COVID-19+ deceased donors yielded good recipient outcomes without evidence of viral tissue transmission. Acute kidney injury during COVID-19 was mediated by archetypical tubular injury and infection correlated with an increased risk of subsequent rejection.

Background. Since November 2021, a new variant of concern (VOC), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) lineage B.1.1.529 (Omicron) has emerged as the dominant coronavirus disease 2019 (COVID-19) infection worldwide. We describe the clinical presentation, risk factors, and outcomes in a cohort of kidney and kidney pancreas transplant recipients with COVID-19 caused by Omicron infection. Methods. We included all kidney and kidney pancreas transplant recipients diagnosed with SARS-CoV-2 Omicron infections between December 26, 2021, and January 14, 2022, in a single transplant center in Australia. Identification of the VOC Omicron was confirmed using phylogenetic analysis of SARS-CoV-2 sequences. Results. Forty-one patients with kidney (6 living and 33 deceased) and kidney pancreas transplants were diagnosed with the VOC Omicron (lineage B.1.1.529/BA.1) infection during the study period. The mean age (SD) at the time of diagnosis was 52 (11.1) y; 40 (out of 41) (98%) had received at least 2 doses of COVID-19 vaccine. Cough was the most frequent symptom (80.5%), followed by myalgia (70.7%), sore throat (63.4%), and fever (58.5%). After a follow-up time of 30 d, 1 (2.4%) patient died, 2 (4.9%) experienced multiorgan failure, and 5 (12.2%) had respiratory failure; 11 (26.8%) patients developed other superimposed infections. Compared with recipients who did not receive sotrovimab antibody therapy, the odds ratio (95% confidence interval) for hospitalization among patients who received sotrovimab was 0.05 (0.005-0.4). Conclusions. Despite double or triple dose vaccination, VOC Omicron infections in kidney and kidney pancreas transplant recipients are not necessarily mild. Hospitalization rates remained high (around 56%), and sotrovimab use may prevent hospitalization.

Polyomavirus BK virus (BKPyV) infection is an important complication of kidney transplantation and allograft failure. The prevalence of viremia is 10%–15%, compared with BK-associated nephropathy (BKPyVAN) at 3%–5%. Given that there are no effective antiviral prophylaxis or treatment strategies for BKPyVAN, active screening to detect BKPyV viremia is recommended, particularly during the early posttransplant period. Immunosuppression reduction to allow viral clearance may avoid progression to severe and irreversible allograft damage. The frequency and duration of screening are highly variable between transplant centers because the evidence is reliant largely on observational data. While the primary treatment goals center on achieving viral clearance through immunosuppression reduction, prevention of subsequent acute rejection, premature graft loss, and return to dialysis remain as major challenges. Treatment strategies for BKPyV infection should be individualized to the recipient’s underlying immunological risk and severity of the allograft infection. Efficacy data for adjuvant therapies including intravenous immunoglobulin and cidofovir are sparse. Future well-powered and high-quality randomized controlled trials are needed to inform evidence-based clinical practice for the management of BKPy infection.

Background: Simultaneous pancreas-kidney transplantation (SPK) remains the gold standard treatment for patients with type I diabetes mellitus and end-stage renal failure. Enteric drainage is utilised to handle exocrine secretions from the graft, with enteric leaks being the most challenging of complications. There remains a lack of published research regarding risk factors for enteric leaks. Methods: As such we undertook a retrospective cohort study of SPK transplants performed at Westmead Hospital over twenty years (between 1998-2017, n=425) to identify the occurrence of enteric leaks as well as donor, recipient and transplantation procedure risk factors. Descriptive statistics were generated using SPSS version 22.0 (IBM SPSS Statistics for Windows, Armonk, NY, USA). The student’s t-test and/or Mann-Whitney U test was used to detect significance. All tests were two tailed and any statistically significant difference was considered at the P <0.05 level. Results: Of the 425 patients, 16 (3.5%) experienced an enteric leak. Of these, 12 (80%) had significant vascular disease, defined as coronary artery disease, cerebrovascular disease, retinopathy, peripheral neuropathy or peripheral vascular disease requiring surgical intervention. The risk of an enteric leak increased in recipients with significant vascular disease. Conclusion: The rates at Westmead Hospital were lower than those published in the literature. We demonstrated that the presence of significant vascular disease predisposed recipients to enteric leak. These findings highlight the importance of careful donor and recipient selection to optimise patient outcomes.

Liver transplantation (LT) is a life-saving operation but, with a limited donor pool, especially in Australia and New Zealand, patient selection for the waitlist remains crucial. The indication for LT should be assessed independent of the aetiology. Whilst there have been challenges in justifying LT for patients with acute alcoholic hepatitis (AH) and unresectable colorectal cancer liver metastases (CRLM) owing to previous reports of poor survival rates, the evidence landscape is changing. The aim of this manuscript is to review these specific, and evolving, indications for LT, namely AH and CRLM.

For patients with type 1 diabetes mellitus who progress to the point of requiring renal replacement therapy, the relative benefits of simultaneous pancreas and kidney transplantation (SPK) and deceased donor kidney transplantation across different age categories compared to dialysis are uncertain. Using Australian and New Zealand registry data from 2006 to 2016, a probabilistic Markov model (n = 10 000) was built comparing patient survival between SPK and deceased donor kidney transplantation with dialysis. Compared to dialysis, the average life years saved (LYS) and quality-adjusted life years (QALY) for SPK and deceased donor kidney transplantation were 5.48 [95% CI 5.47, 5.49] LYS and 6.48 [6.47, 6.49] QALY, and 3.38 [3.36, 3.40] LYS and 2.46 [2.45, 2.47] QALY, respectively. For recipients aged 50 years or younger, receiving a deceased donor kidney, the average incremental gains compared to dialysis were 4.13 [4.10, 4.16] LYS and 2.99 [2.97, 3.01] QALY, and for recipients older than 50 years, 3.05 [3.02, 3.08] LYS and 2.25 [2.23, 2.27] QALY. Compared to dialysis, SPK transplantation incurs the greatest benefits in LYS and QALY for patients with type 1 diabetes requiring renal replacement therapy. Patients older than 50 years still experience survival benefits from deceased donor kidney transplantation compared to dialysis.

Adenine phosphoribosyltransferase (APRT) enzyme deficiency is an important and potentially reversible cause of progressive chronic kidney disease. It is a rare, autosomal recessive disorder that was first described in 19741Simmonds H.A. Van Acker K.J. Cameron J.S. Snedden W. The identification of 2,8-dihydroxyadenine, a new component of urinary stones.Biochem J. 1976; 157: 485-487Crossref PubMed Scopus (52) Google Scholar with more than 40 known mutations2Runolfsdottir H.L. Palsson R. Agustsdottir I.M. et al.Kidney disease in adenine phosphoribosyltransferase deficiency.Am J Kidney Dis. 2016; 67: 431-438Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 3Bollée G. Dollinger C. Boutaud L. et al.Phenotype and genotype characterization of adenine phosphoribosyltransferase deficiency.J Am Soc Nephrol. 2010; 21: 679-688Crossref PubMed Scopus (85) Google Scholar and estimated prevalence of 1 in 50,000 to 100,000 persons.2Runolfsdottir H.L. Palsson R. Agustsdottir I.M. et al.Kidney disease in adenine phosphoribosyltransferase deficiency.Am J Kidney Dis. 2016; 67: 431-438Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 4Zaidan M. Palsson R. Meriequ E. et al.Recurrent 2,8-dihydroxyadenine nephropathy: a rare but preventable cause of renal allograft failure.Am J Transplant. 2014; 14: 2623-2632Crossref PubMed Scopus (37) Google Scholar, 5Bollée G. Harambat J. Bensman A. et al.Adenine phosphoribosyltransferase deficiency.Clin J Am Soc Nephrol. 2012; 7: 1521-1527Crossref PubMed Scopus (64) Google Scholar The APRT enzyme is important for the conversion of adenine to adenosine monophosphate in the salvage purine pathway. Deficiency of this enzyme results in the metabolism of adenine into 2,8-dihydroxyadenine (DHA) by xanthine oxidase (xanthine dehydrogenase) (Figure 1a). DHA is highly insoluble in urine and will precipitate to cause either urolithiasis or crystal nephropathy. There are no known extrarenal manifestations and reasons for this remains unclear given the extensive tissue distribution of this enzyme. The typical appearances of DHA crystals on renal biopsy are of yellow-brown needle-shaped crystals, which are arranged in spherical, radial, or irregular aggregates and are birefringent under polarized light. Tubular injury, deposition, and obstruction can occur, and foreign body reaction with histiocytes can be seen surrounding some of the crystals. Left untreated, chronic crystal deposition in the kidney can lead to irreversible tubular atrophy and interstitial fibrosis. Crystalluria is characterized by birefringent yellow-brown crystals that are round in appearance and display a Maltese cross pattern on polarized light microscopy. Although it can present in any age group and stage of disease, it is most commonly diagnosed in adults (median age 36 years2Runolfsdottir H.L. Palsson R. Agustsdottir I.M. et al.Kidney disease in adenine phosphoribosyltransferase deficiency.Am J Kidney Dis. 2016; 67: 431-438Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar), with up to 15% of patients diagnosed either in end-stage renal failure or following kidney transplantation.3Bollée G. Dollinger C. Boutaud L. et al.Phenotype and genotype characterization of adenine phosphoribosyltransferase deficiency.J Am Soc Nephrol. 2010; 21: 679-688Crossref PubMed Scopus (85) Google Scholar, 4Zaidan M. Palsson R. Meriequ E. et al.Recurrent 2,8-dihydroxyadenine nephropathy: a rare but preventable cause of renal allograft failure.Am J Transplant. 2014; 14: 2623-2632Crossref PubMed Scopus (37) Google Scholar APRT deficiency also may be misdiagnosed, as other forms of renal stone disease, crystal nephropathy, or chronic kidney disease of unknown etiology.2Runolfsdottir H.L. Palsson R. Agustsdottir I.M. et al.Kidney disease in adenine phosphoribosyltransferase deficiency.Am J Kidney Dis. 2016; 67: 431-438Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar The diagnosis of APRT deficiency in patients with urolithiasis or crystal nephropathy is based on the following: (i) genetic mutation testing; (ii) absent or reduced APRT enzyme activity in red cell lysates; or (iii) confirmation of DHA crystal composition by infrared spectroscopy (Figure 1b). Reducing DHA production by xanthine oxidase inhibition is the cornerstone of pharmacological therapy for APRT deficiency. Allopurinol is the most used drug in this instance, whereas the addition or switch to febuxostat has been used in several cases.2Runolfsdottir H.L. Palsson R. Agustsdottir I.M. et al.Kidney disease in adenine phosphoribosyltransferase deficiency.Am J Kidney Dis. 2016; 67: 431-438Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar, 6Nanmoku K. Kurwosawa A. Shinzato T. et al.Febuxostat for the prevention of recurrent 2,8-dihydroxyadenine nephropathy due to adenine phosphoribosyltransferase deficiency following kidney transplantation.Intern Med. 2017; 56: 1387-1391Crossref PubMed Scopus (8) Google Scholar Supportive therapy includes low purine diet and high fluid intake. Urinary alkalinization is ineffective, as DHA remains insoluble at physiological urine pH ranges.5Bollée G. Harambat J. Bensman A. et al.Adenine phosphoribosyltransferase deficiency.Clin J Am Soc Nephrol. 2012; 7: 1521-1527Crossref PubMed Scopus (64) Google Scholar We present 3 cases (Tables 1 and 2) that highlight the diagnostic pitfalls and challenges in management, particularly in the transplantation setting. For further details to this article, please refer to the Supplementary Methods and Supplementary References.Table 1Baseline characteristics of the 3 patients, before transplantation in cases 1 and 2Patient characteristicsCase 1Case 2Case 3Age, yr, at diagnosis475223GenderMaleFemaleMaleRaceCaucasianLebaneseLebaneseComorbiditiesObesity, hypertension, atrial fibrillationGraves diseaseObesity, atrial flutterUrolithiasisNoNoYesFamily history of kidney diseaseNoNoNoCreatinine at presentation, μmol/l3562681020Proteinuria, g/24 h0.921.090.23Microscopic hematuriaNoNoNoNative kidney biopsyLM: 15/18 globally sclerosed glomeruli; tubular, epithelial and interstitial birefringent, brown crystal deposition with diffuse interstitial inflammation and fibrosis.IF: nondiagnosticEM: Needle-shaped crystals in some tubulesLM: 6 of 10 globally sclerosed glomeruli; golden brown, birefringent tubular crystals with associated diffuse interstitial fibrosis and inflammation.IF: nondiagnosticEM: nondiagnosticLM: 5 of 17 globally sclerosed glomeruli; yellow- brown, birefringent tubular crystals with associated diffuse interstitial fibrosis.IF: nondiagnosticEM: nondiagnosticProvisional diagnosisAPRT deficiencyChronic interstitial nephritisOxalate nephropathyTime from presentation to dialysis (modality)2 mo (hemodialysis)3 yr (peritoneal dialysis)<1 wk (hemodialysis)Time from native biopsy to APRT diagnosis10 wk6 yr10 moGenetic testingNot doneHomozygous c.188G>A (p.Gly63Asp)Homozygous c.188G>A (p.Gly63Asp)APRT enzyme activity, nmol/min per mg0.10.110.09Urine stone analysisNANAOrganic materialUrine 2,8-DHA28 mmol/molNot availableNot availableUrine biochemistryHypocitraturiaHypocitraturiaHyperoxaluriaUrine microscopyYes, but assessed only posttransplantBirefringent crystalsAPRT, adenine phosphoribosyltransferase; EM, electron microscopy; IF, immunofluorescence; LM, light microscopy; mo, month; NA, not applicable; wk, week; y, yr.Normal APRT enzyme activity > 0.15 nmol/min per mg and spot urine 2,8-DHA <13 mmol/mol. Open table in a new tab Table 2Post–kidney transplant course for patients 1 and 2Case 1Case 2TransplantationJanuary 2018May 2017APRT diagnosis before transplantationYesNoAllopurinol dose pretransplant150 mg (for 4.5 yr)NoDelayed graft functionYesYesImplantation biopsyAcute tubular injuryAcute tubular injuryTime from transplant to crystal detection, d1024Maximal allopurinol dose, mg600300Oxypurinol trough, mg/l21–3230–36Drug reaction with eosinophilia and systemic symptoms or ocular involvementNilNilFebuxostat40 mgNilCrystalluria posttransplantDetected 4 mo postNot detected 12 mo postTreatment for rejectionYes, pulse methylprednisoloneYes, methylprednisolone and 6 mg/kg antithymocyte globulin (day 24 for Banff grade 2A rejection: i1, t1, v1, ptc2, c4d-ve)Other complicationsInvasive CMV disease (graft CMV nephritis; colitis)BK virus–associated nephropathyShingles (reactivation of varicella zoster)CMV viremiaUrinary tract infectionsThree-mo posttransplant biopsyInvolved 15% of biopsy (less)No rejection: ci2, ct2, cv1, ah1No rejection: 15% crystals ci3, ct3, cv1, ah0Three-mo posttransplant GFR/DTPA, ml/min per 1.73 m25242Twelve-mo posttransplant biopsyNot availableNo rejection: 15% crystals ci3, ct3, cv1, ah0Last available creatinine level, μmol/l164 (6 mo post)145 (12 mo post)Maintenance immunosuppressionTacrolimus, mycophenolate, prednisoloneTacrolimus, mycophenolate, prednisoloneAPRT, adenine phosphoribosyltransferase; CMV, cytomegalovirus; DTPA, technetium-99m diethylene-triamine-pentaacetic acid; GFR, glomerular filtration rate; mo, month; yr, year. Open table in a new tab APRT, adenine phosphoribosyltransferase; EM, electron microscopy; IF, immunofluorescence; LM, light microscopy; mo, month; NA, not applicable; wk, week; y, yr. Normal APRT enzyme activity > 0.15 nmol/min per mg and spot urine 2,8-DHA <13 mmol/mol. APRT, adenine phosphoribosyltransferase; CMV, cytomegalovirus; DTPA, technetium-99m diethylene-triamine-pentaacetic acid; GFR, glomerular filtration rate; mo, month; yr, year. A 47-year-old Caucasian gentleman presented in 2013 for evaluation of renal impairment on a background of obesity, hypertension and atrial fibrillation. At the time of presentation, the serum creatinine (SCr) was 356 μmol/l (estimated glomerular filtration rate 17 ml/min per 1.73 m2) and subnephrotic proteinuria of 0.92 g/d without microscopic hematuria. This is compared with baseline SCr 119 μmol/l measured 5 years previously. The hemoglobin A1c, autoimmune, and myeloma serology were all unremarkable. Computed tomography scan showed 8.5 cm kidneys without evidence of calculi or hydronephrosis. A native renal biopsy revealed global sclerosis in 15 of 18 glomeruli and multiple, yellow-brown tinged crystals in the tubular lumen, epithelial cytoplasm, interstitium, with associated giant cells, marked tubular atrophy, and diffuse interstitial fibrosis. The crystals ranged from needle to rod to rhomboid in shape and were birefringent under polarized light. Congo red was negative and immunofluorescence was nondiagnostic. Electron microscopy revealed unremarkable glomerular features, no evidence of electron-dense deposits, but noted needle-shaped crystals in some tubules. A 24-hour urine collection was unremarkable except for hypocitraturia (0.4 mmol/d). Given the unusual crystal appearance, APRT deficiency was suspected and subsequent testing confirmed this diagnosis with reduced APRT enzyme activity (0.1 nmol/min per mg; normal >0.15 nmol/min per mg) and elevated urinary 2,8-dihydroxyadenine (28 mmol/mol; normal < 13 mmol/mol). Despite treatment with allopurinol (100 mg/d), he progressed to be dialysis dependent 2 months after presentation. His allopurinol was increased to 150 mg daily when he received a deceased renal transplant in January 2018. He had delayed graft function and the implant biopsy showed acute tubular injury, and a repeat biopsy at day 10 demonstrated recurrence of crystal nephropathy with borderline rejection with interstitial inflammation and tubulitis. He received intravenous methylprednisolone (total of 1500 mg), and allopurinol was increased to 400 mg daily. Subsequent biopsy on day 21 showed similar findings (crystal nephropathy, borderline rejection) and he received further pulse methylprednisolone. His renal function improved, no longer needing dialysis at 3 weeks posttransplant, and reached a trough SCr 180 μmol/l. His allopurinol was up-titrated to a maximum tolerated dose of 600 mg daily (limited by diarrhea) and trough oxypurinol levels varied between 21 and 32 mg/l. Surveillance urine microscopy (Figure 2e and f) showed persistent crystalluria and 20 mg of feboxustat was introduced, in addition to allopurinol 600 mg daily. Four-months after transplantation, he developed invasive cytomegalovirus (CMV) disease and a repeat biopsy (Figure 2a–d) with SCr 270 μmol/l showed acute tubular injury, crystalline nephropathy, and CMV inclusions. His renal function improved to SCr 164 μmol/l following treatment of CMV disease and up-titration of feboxustat to 60 mg daily. He developed a facial rash, which was diagnosed as rosacea and resolved with a short course of doxycycline. Baseline characteristics of all 3 cases and the posttransplant course are summarized in Tables 1 and 2. A 52-year-old Lebanese woman was investigated for progressive kidney disease with SCr 97 μmol/l rising to 268 μmol/l (estimated glomerular filtration rate 54 and 17 ml/min per 1.73 m2, respectively) over 4 months. She had subnephrotic proteinuria (1.09 g/24 hours) without microscopic hematuria, and the renal ultrasound showed atrophic left kidney and 12.5 cm right kidney. The renal biopsy showed diffuse interstitial inflammation and fibrosis with the occasional golden brown, birefringent intratubular crystals, and this was attributed to ciprofloxacin-associated chronic interstitial disease, and she progressed onto peritoneal dialysis 3 years later. She received a deceased renal transplant and required 2 sessions of hemodialysis for delayed graft function. A biopsy day 3 posttransplant showed acute tubular injury and borderline rejection, which was treated with methylprednisolone. Her renal function improved to SCr 220 μmol/l but then deteriorated to SCr 262 μmol/l after a period of subtherapeutic tacrolimus levels. A biopsy at day 24 showed Banff grade 2A T-cell–mediated rejection (Banff scores: i1, t1, v1, ptc2), positive simian virus (SV40) stain, and tubular and interstitial crystal deposition.7Haas M. Loupy A. Lefaucheur C. et al.The Banff 2017 Kidney Meeting Report: revised diagnostic criteria for chronic active T cell–mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials.Am J Transplant. 2017; 18: 293-307Crossref Scopus (634) Google Scholar She received antithymocyte globulin (total 6 mg/kg) with improvement from peak SCr 327 μmol/l to SCr 243 μmol/l. Oxalate nephropathy was suspected, but 24-hour urine metabolic screen was unremarkable except for hypocitraturia (<2 mmol/d). With the experience in case 1, we tested for and confirmed APRT deficiency with reduced APRT enzyme activity (0.11 nmol/min per mg). Genetic testing confirmed homozygous c.188G>A; p.Gly63Asp mutation (an identified pathogenic APRT gene mutation). Urine DHA testing was now unavailable. The patient was commenced on allopurinol at 5 weeks posttransplant, tolerating 300 mg/d (corresponding trough oxypurinol levels 35–36 mg/l), again, limited by diarrheal symptoms. Despite the positive SV40 stain, both blood and urine polymerase chain reaction testing for polyoma and BK virus were negative and hence not initially treated. A repeat biopsy 2 weeks later showed persistent crystals and positive SV40 in 2 nuclei and despite repeatedly negative blood and urine polyoma virus on polymerase chain reaction, so she was treated with intravenous immunoglobulin (IV.Ig) with improvement of SCr to 130 to 150 μmol/l. The 3-month protocol glomerular filtration rate of 42 ml/min per 1.73 m2 (technetium-99m diethylene-triamine-pentaacetic acid) and protocol biopsy was clear from rejection, SV40 staining but had persistence of tubular crystal deposition (associated with detectable crystalluria). Over the next 9 months, she developed CMV viremia, reactivation of varicella zoster infection, and recurrent urinary tract infections. Her 1-year protocol biopsy (SCr 136 μmol/l, no detectable crystalluria on polarized light microscopy) showed no evidence of rejection or SV40 staining, but persistently detectable birefringent crystals on the biopsy. These were predominantly distributed in the tubular epithelial cells and interstitium; and associated with significant tubular atrophy and interstitial fibrosis. She also developed a mild facial rash around this time, hence the allopurinol was reduced to 200 mg daily (corresponding oxypurinol level 24 ng/ml) with the introduction of feboxustat 40 mg daily. The results of the serum creatinine, crystal load, and tissue distribution at time of transplant (indication and protocol) biopsy of both cases 1 and 2 are presented in Figure 3. The biopsies of both patients showed similar pattern: early in the disease course, during maximal DHA excretion and crystal formation, most crystals are seen in the luminal space. On maximal allopurinol (and/or feboxustat) therapy, there was a progressive decline in the number of crystals seen in the luminal space, with more found in the epithelial layer and interstitial space. A 23-year-old man of Lebanese descent, who experienced 1 episode of urolithiasis in childhood, presented with oliguric acute kidney injury with SCr 1020 μmol/l (12 months prior with SCr 92 μmol/l). The patient commenced acute hemodialysis given no reversible factors were identified and the renal biopsy showed global sclerosis in 5 of 17 glomeruli, ischemic changes in the viable glomeruli, and birefringent tubular crystals with associated tubular atrophy and severe interstitial fibrosis. The patient’s mother had kept this stone and analysis of this revealed “organic” material. Twenty-four hour urine testing revealed 0.23 g/24 hours proteinuria, no hematuria, and borderline elevated urine oxalate 532 μmol/d (normal < 500 μmol/d). Primary hyperoxaluria was ruled out (negative genetic testing of AGXT, GRHPR, and DHDPSL genes) and no obvious secondary causes were detected on further clinical interrogation. Unexpectedly, this patient coincidentally had the same surname as Case 2 (but not immediately related) and the pathologist suspected APRT deficiency. The diagnosis was confirmed with low enzyme activity (0.09 nmol/min per mg) and a homozygous genetic mutation was confirmed (c.188G>A; p.Gly63Asp). Crystalluria also was detected in this patient on polarized light microscopy. These cases highlight challenging aspects in management of APRT deficiency, particularly given the lack of clinical suspicion, limited access to confirmatory testing, and difficulties in defining target levels of monitoring of disease and response to treatment. The condition was initially misdiagnosed in cases 2 and 3, as chronic interstitial nephritis and oxalate nephropathy. In case 2, the diagnosis was made only after detection of recurrence of crystals in the allograft biopsy; and again, this was initially thought to be oxalate nephropathy. This highlights 2 difficulties with histological diagnosis: (i) native renal biopsies in the late stages of disease may be nonspecific due to long-term scarring; and (ii) it may be misdiagnosed as other forms of crystal nephropathy and requires close examination of the features to differentiate between the causes. Owing to the rare nature of the disease, there is a low index of clinical suspicion. Clues that should alert the clinician to consider APRT deficiency include histological findings of tubular and/or interstitial deposits of crystalline material, crystalluria, and negative screening (and unresponsiveness to treatment) for other more common causes of crystalline nephropathy.8Nasr S.H. Sethi S. Cornell L.D. et al.Crystalline nephropathy due to 2,8-dihydroxyadeninuria: an under-recognized cause of irreversible renal failure.Nephrol Dial Transplant. 2010; 25: 1909-1915Crossref PubMed Scopus (55) Google Scholar Access to confirmatory testing also may be a limiting factor. Testing for urinary DHA was not available after the first case (5 years ago). Crystal and stone analysis with infrared mass spectroscopy is also not widely available and would have been useful particularly for case 3, where stone analysis was inconclusive as “organic material.” APRT enzyme activity measured in red cell lysates are usually absent or reduced, but there exist a number of rare pathogenic variants that confer disease but do not lower red cell lysate APRT enzyme activity.9Deng L. Yang M. Frund S. et al.2,8-Dihydroxyadenine urolithiasis in a patient with considerable residual adenine phosphoribosyltransferase activity in cell extracts but with mutations in both copies of APRT.Mol Genet Metabol. 2001; 72: 260-264Crossref PubMed Scopus (13) Google Scholar Cornerstone of therapy is to reduce systemic DHA production by reducing purine intake (although most production is via salvage pathway); and inhibition of xanthine oxidase (or xanthine dehydrogenase) with allopurinol or febuxostat (a nonpurine selective inhibitor). There currently is no effective intervention for removal of DHA metabolite, or increasing its urinary solubility. Dialysis is ineffective in preventing DHA, as it is usually protein bound, and any removal on dialysis would be unable to keep up with the high rate of production given the ubiquitous nature of the purine salvage pathway. The dosing of allopurinol is not straightforward. High doses of allopurinol2Runolfsdottir H.L. Palsson R. Agustsdottir I.M. et al.Kidney disease in adenine phosphoribosyltransferase deficiency.Am J Kidney Dis. 2016; 67: 431-438Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar,4Zaidan M. Palsson R. Meriequ E. et al.Recurrent 2,8-dihydroxyadenine nephropathy: a rare but preventable cause of renal allograft failure.Am J Transplant. 2014; 14: 2623-2632Crossref PubMed Scopus (37) Google Scholar,8Nasr S.H. Sethi S. Cornell L.D. et al.Crystalline nephropathy due to 2,8-dihydroxyadeninuria: an under-recognized cause of irreversible renal failure.Nephrol Dial Transplant. 2010; 25: 1909-1915Crossref PubMed Scopus (55) Google Scholar,S1 (up to 600 mg) and febuxostat (80 mg)6Nanmoku K. Kurwosawa A. Shinzato T. et al.Febuxostat for the prevention of recurrent 2,8-dihydroxyadenine nephropathy due to adenine phosphoribosyltransferase deficiency following kidney transplantation.Intern Med. 2017; 56: 1387-1391Crossref PubMed Scopus (8) Google Scholar have been required to achieve effective inhibition of DHA crystalluria. Icelandic nephrologists at Landspitali Hospital (who also run the Rare Stone Group Consortium APRT registry) also have used a combination of high-dose 800 mg allopurinol and 80 mg febuxostat in some cases. These doses are much higher than the recommended dose for patients with significant renal impairment or on dialysis, often leading to concerns of allopurinol hypersensitivity or drug reaction with eosinophilia and systemic symptoms. This limitation also applies in the use of febuxostat, although there have been examples of febuxostat being safely used in patients with chronic kidney diseaseS5 stage 5 (up to 80 mg daily)S2–S4 and transplant patients in the management of gout. With these concerns in mind, close monitoring is required for high-dose therapy of either agent, with particular attention to drug reaction with eosinophilia and systemic symptoms/rash, liver dysfunction, or gastrointestinal side effects. Oxypurinol is the active metabolite of allopurinol and is renally excreted (minimal excretion when creatinine clearance is <10 ml/min, but dialyzable). Oxypurinol levels have been used to help guide the management of gout (recommended trough levels 5–10 mg), but no target levels exist for APRT deficiency.S6,S7 We believe this can be a useful measure to assess therapeutic dosing in future patients, particularly to account for variability with compliance, absorption, metabolism, and renal function rather than a target or weight-based allopurinol dose alone. We measured oxypurinol levels in both transplant patients and found high levels in both despite the different doses: case 1 on 600 mg daily with trough levels 21 to 32 mg/l; and case 2 on 300 mg daily with trough levels above 30 mg/l; the maximum allopurinol dose in both patients was limited by diarrhea. Both patients described mild, erythematous, nonpruritic, nonpalpable facial rash while on long-term therapy. Case 1 was treated for rosacea without change in therapy otherwise; and in case 2, the mild rash resolved with small reduction of allopurinol therapy. Histological analysis on renal biopsy is the gold standard to assess therapeutic response, although this is limited by the invasiveness, sample error, and the kinetics of crystal formation (new crystal deposition vs. excretion/removal of existing crystals). Urine microscopy and DHA metabolites are the only noninvasive methods to monitor therapy. Absence of crystals under conventional and polarized microscopy (and if possible, confirmation with infrared microscopy) has been used as a marker for adequate therapy. Measurement of urine DHA metabolites is an attractive option, as it is more sensitive (before formation of crystals) and can be used with allopurinol or feboxustat (no therapeutic level monitoring), but this is measured only through select laboratories. A recent study of 10 patients with APRT deficiency demonstrated marked reduction of urine DHA (24-hour sample and DHA:creatitine ratio) when treated with allopurinol or febuxostat and will be a promising area once validated and more accessible.S8 The same group is also conducting research into measurement of DHA metabolites in blood, which will be useful in the setting of anuric patients. Uric acid levels are not useful for APRT deficiency (urate levels < 0.25 mmol/l in our patients). Recurrence of disease after transplantation is a major issue, and there have been relatively poor outcomes reported to date for patients with APRT deficiency. In the largest case series (by Zaidan et al.4Zaidan M. Palsson R. Meriequ E. et al.Recurrent 2,8-dihydroxyadenine nephropathy: a rare but preventable cause of renal allograft failure.Am J Transplant. 2014; 14: 2623-2632Crossref PubMed Scopus (37) Google Scholar) involving 9 patients with renal transplantation, the median delay to diagnosis was 5 weeks after transplantation; and despite allopurinol or feboxustat therapy, 7 of 9 patients developed chronic allograft nephropathy or graft loss. One case series (by Nasr et al.8Nasr S.H. Sethi S. Cornell L.D. et al.Crystalline nephropathy due to 2,8-dihydroxyadeninuria: an under-recognized cause of irreversible renal failure.Nephrol Dial Transplant. 2010; 25: 1909-1915Crossref PubMed Scopus (55) Google Scholar) reported a patient treated with combination prednisolone and allopurinol (400 mg/d) before transplantation, with no evidence of recurrence, but unfortunately died with multiorgan failure from unrelated reasons; and another patient treated with allopurinol (200 mg/d) who suffered from recurrence of disease. As described earlier, the optimal dosing of allopurinol or feboxustat is unclear and clearly poses a challenge in future renal transplant candidates given the risk of early recurrence, chronic graft dysfunction, and loss. Although our patient in case 1 was already on allopurinol before transplantation, he was probably underdosed for his weight; and likely needed additional postdialysis dosing, given the active metabolite (oxypurinol) was dialyzable. In the early posttransplant setting, there is high risk of acute graft dysfunction from a “dumping” phenomenon, with vast amounts of accumulated systemic DHA excreted into the urine by the new allograft kidney. The risk of tubular crystal formation is higher in the setting of oliguric or low flow states; and both our patients were found to have hypocitraturia. Early crystal formation and deposition is associated with acute tubular injury, tubular obstruction, foreign body reaction, and tubulitis. It was difficult to distinguish if inflammation on the biopsies was due to crystalline disease or if there was concurrent early or “borderline rejection” (tubulitis and interstitial infiltrates but not meeting Banff Criteria for type 1A rejection). Given they both suffered from delayed graft function, inflammation on the early biopsies was treated with intravenous methylprednisolone, and 1 patient progressed to develop unequivocal Banff grade 2A rejection. This dilemma is not a benign problem, and the clinical assessment will need to be individualized to balance the risk of long-term adverse graft outcomes of borderline/subclinical rejection or tubulitis secondary to crystalline disease versus the well-established complications of overimmunosuppression.S10,S11 Both patients suffered infectious complications: case 1 with invasive CMV; and case 2 with BK nephropathy, varicella zoster reactivation, CMV viremia, and recurrent urinary tract infections. We reviewed the posttransplant biopsies of our patients and found that early in the disease course, crystals were almost exclusively seen in the proximal tubules. With the initiation of allopurinol therapy, there was at least no further increase in overall crystal burden, with very slow, small decrement over several months for both cases. Sequential biopsies in both our transplant patients (on maximal tolerated allopurinol) showed changes to the distribution of crystal load. We hypothesize based on the results presented in Figures 2a and b and 3e and f, following early luminal deposition, the crystals are then also incorporated into the tubular epithelial layer by either endocytosis, or encapsulation (formation of new layer of epithelial cells).S9 This is then followed by atrophy or rupture of the tubular basement membrane and deposition of crystals into the interstitial compartment (Figure 4). Interstitial crystal deposition sustains an ongoing inflammatory response, leading to chronic tubular atrophy and interstitial fibrosis and is an important contributor to the progressive chronic tubular and interstitial Banff scores in our patients (Figure 3g and h).S9 Genetic testing in family members of a patient diagnosed with APRT deficiency relies on pathogenic variants being found in the proband. The large majority of probands will have mutations detectable by sequencing, although rare individuals may have pathogenic deletions that may be missed by Sanger sequencing or exome capture–based techniques. Diagnosis in other family members, particularly at-risk siblings, may then proceed using the known mutations. Alternatively, APRT enzyme activity or urinary purine metabolite analysis might be more appropriate dependent on cost and availability. Genetic counseling should be offered to family members. Management of patients with asymptomatic APRT deficiency found on either genetic or enzymatic testing in unclear. There is a risk of silent disease, as some cases manifest in childhood,2Runolfsdottir H.L. Palsson R. Agustsdottir I.M. et al.Kidney disease in adenine phosphoribosyltransferase deficiency.Am J Kidney Dis. 2016; 67: 431-438Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar,S12 whereas some are detected only when patients are found to have late-stage chronic kidney disease in adulthood. It is tempting to treat all patients regardless of symptoms, particularly because allopurinol is a relatively inexpensive drug, but it may be useful to consider renal function and urinary screening (crystalluria or DHA metabolites) to decide whether long-term exposure to high-dose allopurinol is warranted. APRT deficiency is an important differential to consider in patients with undetermined crystal nephropathy or nephrolithiasis. It is potentially reversible, but the current treatment strategies are far from satisfactory, and this has implications on long-term graft survival in transplant recipients.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare, autosomal recessive disorder which results in increased production of 2,8-dihydroxyadenine (DHA) viathe purine salvage pathway. Excess DHA is excreted in the urine, where it forms highly insoluble crystals and manifests as either urolithiasis or crystalline nephropathy. The onset and presentation of disease is variable and may present as chronic kidney disease of unknown aetiology; renal calculi; misdiagnosed oxalate nephropathy; graft dysfunction following renal transplantation; or through family screening.

We report the first case of a simultaneous pancreas and renal transplantation, in Australia, in a 45 year old male with long standing human immunodeficiency virus infection, type 1 diabetes mellitus and diabetic nephropathy requiring haemodialysis. This patient experienced previous virological failure and subsequent resistance to most nucleoside and non-nucleoside reverse transcriptase inhibitors. However, using novel combinations of anti-retroviral agents, along with careful monitoring, successful outcomes were achieved during the peri and post transplantation period, with excellent pancreas and renal graft function at one year.

Introduction Pancreas-kidney transplantation remains the gold standard treatment for patients with Type I Diabetes Mellitus and End-Stage Renal Failure as it is the only one that treats renal failure whilst also restoring normoglycaemia. The technique of choice for handling the exocrine component is enteric drainage, with published 5-year patient and graft survival rates being 85% and 75% respectively. Despite its long term success, it is a highly morbid procedure. An enteric leak (EL) of the duodenal stump is one of the more challenging complications specific to Pancreas Transplantation, with an incidence of 4-10%. Interestingly, recent research has demonstrated that the rates of ELs might be lower than previously thought. The objective of our study was to explore if this was true and to determine if there were additional factors that increased the risk of ELs. Methods All pancreas transplants at Westmead Hospital performed between January 2008 and August 2017 (n = 234) were analysed in order to identify ELs that occurred at any stage post-operatively. Risk factors for ELs including donor (age, gender, BMI, hypertension, diabetes, smoking status, vascular disease), patient (age, gender, BMI, hypertension, diabetes, smoking status, alcohol use, vascular disease, lowest blood pressure during admission) and transplantation procedure characteristics (vasopressor use, antibiotics administered, blood pressure, ischaemic time, anastomotic time, fluid boluses and graft types) were collected and analysed. Adjusting for possible confounders, a multivariate logistic regression model was used to assess the risk and predictors of enteric leaks using SPSS v. 22.0. Results and Discussion Of the 234 recipients, 12 (5%) experienced an EL. Of these, 9 (75%) recipients had vascular disease, 6 (50%) recipients were ex-smokers, 1 (8%) recipient a current smoker and 3 (25%) recipients were obese with a BMI >30kg/m2. Six (50%) donors were overweight with a BMI >25kg/m2. All 12 patients were returned to theatre and converted to bladder drainage. At time of publication, no patients had experienced graft failure. The risk of EL increases by as much as 4.4 fold in recipients with vascular disease (OR: 4.4; 95% CI: 0.80-24.21; P=0.088). Although the association was weaker, other factors such as recipient BMI >24.2kg/m2 increased the risk of EL by as much as 1.8 fold (OR: 1.8; 95% CI: 0.4-9.3; P=0.46). The risk of EL increases by more than 3 fold in donors aged between 23 to 32 years compared to <22 years (OR: 3.1; 95% CI: 0.3-32.8; P=0.34). These odds increase by as much as 5 fold for donors ≥33 years (OR: 5.0; 95% CI: 0.5-52.5; P=0.180). The risk of EL increases 1.3 times in male recipients (OR: 1.3; 95% CI: 0.2-8.0; P=0.77) and when the donor was female (OR: 1.3; 95% CI: 0.3-6.9; P=0.75). Finally, the risk of EL increases by as much as two fold for a donor with a BMI >25.4kg/m2 (OR: 2.1; 95% CI: 0.3-15.3; P=0.463) and is 1.3 times higher for a donor with a BMI between 22.5-25.4kg/m2 (OR: 1.3; 95% CI: 0.2-10.9; P=0.80) compared to a donor with a BMI of <22.5kg/m2. Conclusions At Westmead in our patients over the past 10 years, the rate of enteric leaks is in agreement with the rates previously described in the literature. When controlling for all variables, there was weak evidence of an association between vascular disease and ELs. These findings identify possible risk factors for ELs, the need for further research in this area and careful donor selection.

Introduction Simultaneous pancreas-kidney (SPK) transplant remains the gold standard treatment renal failure secondary to Type 1 diabetes. Thrombosis in the early post-transplant period is an early complication with devastating outcomes, including multiple procedures, return to the operating theatre and in many cases graft loss. This is the first study to comprehensively examine the potential role of numerous risk factors for thrombosis in SPK transplant recipients. Materials and Methods We reviewed all simultaneous pancreas-kidney transplants (SPK) performed at our institution over the past 10 years (2008-2017) including 235 patients. Risk factors for thrombosis including donor factors (age, gender, BMI, smoking status, hypoxia in cause of death), recipient factors (age, gender, BMI, hypertension, diabetes, vascular disease and smoking status) and operative factors (vasopressor use, blood pressure, ischemic time, anastomotic time, fluid boluses, arterial or venous grafts) were examined. Adjusting for possible confounders, a multivariate logistic regression model was used to assess the risk and predictors of thrombosis using SPSS v. 22.0. Results and Discussion Of the 235 patients, 41 (17.4%) experienced thrombosis of the pancreas graft. Of the total patients, 16 (6.8%) lost the pancreas graft as a consequence of the thrombosis. The risks of thrombosis increases by 25.6 fold in male donors (compared to females) (OR: 25.6; 95% CI: 2.2-303.1; P=0.01). The presence of hypoxia increases the odds of thrombosis by as much as 4.0 fold (OR: 4.0; 95% CI: 0.8-21.4; P=0.102). The age of the donor plays a significant role. Patients between 26 to 35 years have a 2.7 fold increased risk compared to those less than 20 years (OR: 2.7; 95% CI: 0.4-18.7; P=0.32). This risk almost doubles in donors >36 years (OR: 5.3; 95% CI: 0.6-47.3; P=0.14). A recipient between the age of 37 to 42 years is at 10.6 times greater risk of thrombosis compared to those <36 years (OR: 10.6; 95% CI: 1.4-79.2; P=0.02). Conclusions Results of this work suggest that careful selection of donors for pancreas transplantation is paramount to reducing the risk of thrombosis. Donor gender, age, and cause of death can be used to decide which donors are at highest risk. Female donors, younger donors and those with a cause of death that does not involve hypoxia can be considered the lowest risk donors. In higher risk donors, the use of interventions that reduce the risk of thrombosis or more careful vigilance may aid prevention of graft loss due to this challenging complication.

Kidney donors who have attained sustained virologic response at 12 or more weeks (SVR 12) after treatment with direct-acting antiviral (DAA) therapy for hepatitis C virus (HCV) are now being used at our transplant units. We report 3 HCV seronegative recipients who developed HCV antibody (anti-HCV) without evidence of viral transmission after receiving organs from such donors. Two recipients, A and B, received a kidney each from a 55-year-old male deceased donor who had a history of noncirrhotic HCV (genotype 1a) and had achieved SVR 12 with ledipasvir/sofosbuvir 1 month before donation. The donor was anti-HCV positive and HCV RNA negative at the time of transplantation. Recipient C received a living donor kidney from her 60-year-old brother, who had also been treated with ledipasvir/sofosbuvir for noncirrhotic HCV (genotype 1a). He donated 2 months after achieving SVR 12, and subsequent annual testing of the donor has demonstrated ongoing SVR. Both donors were deemed low risk for HCV reinfection/exposure. All recipients were HCV RNA and anti–HCV-negative pretransplant and received standard immunosuppression with IL-2 receptor blocker, prednisolone, tacrolimus, and mycophenolate mofetil. Anti-HCV was confirmed using various methods at days 32 (recipient A), 99 (recipient B), and 72 (recipient C) without evidence of viral transmission (HCV RNA undetectable). Ten months posttransplant, recipients A and C have had excellent graft function, no episodes of rejection, no proteinuria, and normal liver function tests (Table 1). At 7 months posttransplant, recipient B had 1 episode of acute tubular necrosis in the context of sepsis. At 10 months posttransplant, all recipients have persistent anti-HCV detected (Table 1). There were also no changes in pretransplant and posttransplant antibody response to other antigens including rubella, toxoplasma, tetanus toxoid, and hepatitis B.TABLE 1: Renal function and hepatitis C serology in all recipients over timeTo our knowledge, this is the first case series reporting persistent detection of anti-HCV without evidence of viral transmission in seronegative recipients who received kidneys from HCV-positive donors who had achieved SVR with a DAA. We hypothesize that HCV proteins1 may have been present in the donor kidney and presented via class I major histocompatibility complex to elicit an antibody response. In the same way, experimental HCV vaccine trials using nonstructural proteins have demonstrated the induction of neutralizing antibody responses.2 This phenomenon has not been demonstrated in recipients who received kidneys from donors who had spontaneously cleared HCV3 or who had been treated with interferon.4 The persistent and specific presence of anti-HCV makes the hypothesis that passive transfer of antibodies being responsible for these findings unlikely. The short duration between donor SVR 12 and kidney donation raises the possibility that there may have been donor-derived HCV proteins present. Donors with successfully treated HCV are being used in kidney transplantation. A trial is currently underway using viremic HCV-positive donors with successful treatment of the recipient in the early posttransplant period with DAAs.5 Detection of de novo anti-HCV in recipients of recently cleared HCV donors is likely not to indicate HCV infection and appears unlikely to exert deleterious impact on graft or patient outcomes. Further studies are required to determine the mechanism and significance of antibody expression posttransplant and the duration of positivity.

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.

Verruconis gallopava is an uncommon cause of phaeohyphomycosis. We describe an unusual case of disseminated V. gallopava infection in a renal transplant recipient involving the endocardium but without endocarditis, associated with fungaemia and infection in the skin, oral cavity, brain and lung. The isolate was first detected from blood cultures which is rare. Surgical resection of cardiac fungal mass was not possible. The patient died despite resolution of fungaemia and combination antifungal therapy.

Background Reactivation of BK polyoma virus causes a destructive virus allograft nephropathy (BKVAN) with graft loss in 46%. Treatment options are limited to reduced immunosuppression and largely ineffective antiviral agents. Some studies suggest benefit from intravenous immunoglobulin (IVIG). Methods We evaluated effectiveness of adjuvant IVIG to eliminate virus from blood and tissue, in a retrospective, single-center cohort study, against standard-of-care controls. Both groups underwent reduced immunosuppression; conversion of tacrolimus to cyclosporine; and mycophenolate to leflunomide, oral ciprofloxacin, and intravenous cidofovir. Results Biopsy-proven BKVAN occurred in 50 kidneys at 7 (median interquartile range, 3-12) months after transplantation, predominantly as histological stage B (92%), diagnosed following by dysfunction in 46%, screening viremia in 20%, and protocol biopsy in 34%. After treatment, mean viral loads fell from 1581 ± 4220 × 103 copies at diagnosis to 1434 ± 70 639 midtreatment, and 0.138 ± 0.331 after 3 months (P < 0.001). IVIG at 1.01 ± 0.18 g/kg was given to 22 (44%) patients. The IVIG group more effectively cleared viremia (hazard ratio, 3.68; 95% confidence interval, 1.56-8.68; P = 0.003) and BK immunohistochemistry from repeated tissue sampling (hazard ratio, 2.24; 95% confidence interval, 1.09-4.58; P = 0.028), and resulted in faster (11.3 ± 10.4 months vs 29.1 ± 31.8 months, P = 0.015) and more complete resolution of viremia (33.3% vs 77.3%, P = 0.044). Numerically, fewer graft losses occurred with IVIG (27.3% vs 53.6% for control, P = 0.06), although graft and patient survivals were not statistically different. Acute renal dysfunction requiring pulse corticosteroid was common (59.1% vs 78.6%, P = 0.09), respectively, after immunosuppression reduction. Conclusions Combination treatment incorporating adjuvant IVIG was more effective eliminating virus from BKVAN, compared with conventional therapy. Validation by multicenter randomized trial is needed.

Introduction The routine culture of organ donor transport media (ODTM) is yet to become standard policy at all transplant centers. This is possibly due to most previous studies finding it is characterized by low culture rates and unclear clinical utility. Our aim was to review our data from bacterial cultures of all ODTM to identify key factors that may contribute to potential infections in transplant recipients. Methods We reviewed 457 recipients of kidney, pancreas or SPK transplants, of which 286 had cultures performed on ODTM, using sterile technique. 208 samples were transferred into standard culture pots and 95 into BACTEC culture pots. Culture results were reviewed and organisms classified by likely source (skin flora, enteric flora or respiratory/oral flora). We then reviewed the presence of any clinically significant infection at the transplant site in all recipients and characterized the organisms by likely source. Analysis with SPSS statistical package was performed to assess the rate of contamination by source for kidney or SPK transplants and ascertain the likelihood of correspondence in infection source. Results The sensitivity of BACTEC culture was significantly superior to standard culture (X2(1, 286) =74.06, p<0.001), detecting contamination in 62.1% of samples. This was relative to 15.9% of samples in the standard culture. The increased rate of contamination in the kidney for SPK group over the kidney for kidney alone group was driven by the high rate of enteric flora contamination in the SPK group (26.5%, N=9/34), over kidney for kidney alone transplant (9.8%, N=6/61). This is particularly relevant given 38.5% (10/26) of recipients with enteric flora contamination of transport media had an infection of the transplant site caused by enteric flora. Only 25% (65/260) of recipients who did not have contamination with enteric flora had an infection of the transplant site caused by enteric flora. Conclusions BACTEC culture is significantly superior and should be adopted as the standard of culture at all transplant centers, to improve the utility of routine testing of ODTM. Evidence suggests transmissibility of enteric contamination of ODTM, and the SPK transplant group is particularly vulnerable in this regard.