ABO Incompatible Kidney Transplantation Without B-cell Depletion is Associated With Increased Early Acute Rejection: A Single-Center Australian Experience.

We performed a single-center retrospective cohort study of 66 consecutive ABO incompatible kidney transplants (ABOiKT) performed without B-cell depleting therapy. Outcomes were compared to an earlier era performed with rituximab (n = 18) and a contemporaneous cohort of ABO compatible live donor transplants (ABOcKT). Acute rejection within 3 months of transplant was significantly more common after rituximab-free ABOiKT compared to ABOiKT with rituximab (OR 8.8, p = 0.04) and ABOcKT (OR 2.9, p = 0.005) in adjusted analyses. Six recipients of rituximab-free ABOiKT experienced refractory antibody mediated rejection requiring splenectomy, and a further two incurred early graft loss with no such episodes amongst ABOiKT with rituximab or ABOcKT cohorts. Patient and graft survival were similar between groups over a median follow-up of 3.1 years. This observational evidence lends strong support to the continued inclusion of rituximab in desensitization protocols for ABOiKT.

Notifiable Infectious Diseases Among Organ Transplant Recipients: A Data-Linked Cohort Study, 2000-2015.

Background: Infections, including common communicable infections such as influenza, frequently cause disease after organ transplantation, although the quantitative extent of infection and disease remains uncertain. Methods: A cohort study was conducted to define the burden of notifiable infectious diseases among all solid organ recipients transplanted in New South Wales, Australia, 2000-2015. Data linkage was used to connect transplant registers to hospital admissions, notifiable diseases, and the death register. Standardized incidence ratios (SIRs) were calculated relative to general population notification rates, accounting for age, sex, and calendar year. Infection-related hospitalizations and deaths were identified. Results: Among 4858 solid organ recipients followed for 39 183 person-years (PY), there were 792 notifications. Influenza was the most common infection (532 cases; incidence, 1358 [95% CI, 1247-1478] per 100 000 PY), highest within 3 months posttransplant. Next most common was salmonellosis (46 cases; incidence, 117 [95% CI, 87-156] per 100 000 PY), then pertussis (38 cases; incidence, 97 [95% CI, 71-133] per 100 000 PY). Influenza and invasive pneumococcal disease (IPD) showed significant excess cases compared with the general population (influenza SIR, 8.5 [95% CI, 7.8-9.2]; IPD SIR, 9.8 [95% CI, 6.9-13.9]), with high hospitalization rates (47% influenza cases, 68% IPD cases) and some mortality (4 influenza and 1 IPD deaths). By 10 years posttransplant, cumulative incidence of any vaccine-preventable disease was 12%, generally similar by transplanted organ, except higher among lung recipients. Gastrointestinal diseases, tuberculosis, and legionellosis had excess cases among transplant recipients, although there were few sexually transmitted infections and vector-borne diseases. Conclusions: There is potential to avoid preventable infections among transplant recipients with improved vaccination programs, health education, and pretransplant donor and recipient screening.

Dialysis Disequilibrium: Is Acidosis More Important than Urea?

Dialysis disequilibrium syndrome is a severe complication associated with dialysis treatment. Manifestations may range from mild such as headache to severe such as seizures and coma. Risk factors for development include initial dialysis treatment, uraemia, metabolic acidosis, and extremes of age. We report a case of dialysis disequilibrium in a patient with a failing kidney transplant secondary to the recurrence of IgA nephropathy. Disturbance in cognition and neurologic functioning occurred six hours after the completion of initiation of intermittent haemodialysis. During two sessions of intermittent haemodialysis of 3 and 4 hours, urea was reduced by 21.9 and 17.2 mmol/L and measured serum osmolality was reduced by 25 and 14 mOsm/kg, respectively. Subsequent admission to the intensive care unit and initiation of continuous renal replacement therapy for 48 hours resulted in complete resolution of symptoms. In this case report, we discuss atypical clinical and radiologic features of dialysis disequilibrium occurring with modest reductions in urea and serum osmolality.

Characteristics and Donation Outcomes of Potential Organ Donors Perceived to Be at Increased Risk for Blood-borne Virus Transmission: An Australian Cohort Study 2010-2018.

BACKGROUND: Safely increasing organ donation to meet need is a priority. Potential donors may be declined because of perceived blood-borne virus (BBV) transmission risk. With hepatitis C (HCV) curative therapy, more potential donors may now be suitable. We sought to describe potential deceased donors with increased BBV transmission risk. METHODS: We conducted a cohort study of all potential organ donors referred in NSW, Australia, 2010-2018. We compared baseline risk potential donors to potential donors with increased BBV transmission risk, due to history of HIV, HCV or hepatitis B, and/or behavioral risk factors. RESULTS: There were 624 of 5749 potential donors (10.9%) perceived to have increased BBV transmission risk. This included 298 of 5749 (5.2%) with HCV (including HBV coinfections) and 239 of 5749 (4.2%) with increased risk behaviors (no known BBV). Potential donors with HCV and those with increased risk behaviors were younger and had fewer comorbidities than baseline risk potential donors (P < 0.001). Many potential donors (82 with HCV, 38 with risk behaviors) were declined for donation purely because of perceived BBV transmission risk. Most were excluded before BBV testing. When potential donors with HCV did donate, they donated fewer organs than baseline risk donors (median 1 versus 3, P < 0.01), especially kidneys (odds ratio 0.08, P < 0.001) and lungs (odds ratio 0.11, P = 0.006). CONCLUSIONS: Many potential donors were not accepted because of perceived increased BBV transmission risk, without viral testing, and despite otherwise favorable characteristics. Transplantation could be increased from potential donors with HCV and/or increased risk behaviors.

New blood-borne virus infections among organ transplant recipients: An Australian data-linked cohort study examining donor transmissions and other HIV, hepatitis C and hepatitis B notifications, 2000-2015.

BACKGROUND: Blood-borne viral infections can complicate organ transplantation. Systematic monitoring to distinguish donor-transmitted infections from other new infections post transplant is challenging. Administrative health data can be informative. We aimed to quantify post-transplant viral infections, specifically those transmitted by donors and those reactivating or arising new in recipients. METHODS: We linked transplant registries with administrative health data for all solid organ donor-recipient pairs in New South Wales, Australia, 2000-2015. All new recipient notifications of hepatitis B (HBV), C (HCV), or human immunodeficiency virus (HIV) after transplant were identified. Proven/probable donor transmissions within 12 months of transplant were classified using an international algorithm. RESULTS: Of 2120 organ donors, there were 72 with a viral infection (9/72 active, 63/72 past). These 72 donors donated to 173 recipients, of whom 24/173 already had the same infection as their donor, and 149/173 did not, so were at risk of donor transmission. Among those at risk, 3/149 recipients had proven/probable viral transmissions (1 HCV, 2 HBV); none were unrecognized by donation services. There were no deaths from transmissions. There were no donor transmissions from donors without known blood-borne viruses. An additional 68 recipients had new virus notifications, of whom 2/68 died, due to HBV infection. CONCLUSION: This work confirms the safety of organ donation in an Australian cohort, with no unrecognized viral transmissions and most donors with viral infections not transmitting the virus. This may support targeted increases in donation from donors with viral infections. However, other new virus notifications post transplant were substantial and are preventable. Data linkage can enhance current biovigilance systems.

Effect of language and country of birth on the consent process and medical suitability of potential organ donors; a linked-data cohort study 2010-2015.

PURPOSE: Australia has unmet need for transplantation. We sought to assess the impact of cultural and linguistic diversity (CALD) on family consent and medical suitability for organ donation. METHOD: Cohort study of New South Wales donor referrals, 2010-2015. Logistic regression estimated effects of primary language other than English and birthplace outside Australia (odds ratios OR, with 95% confidence intervals, 95%CI). Outcomes were whether families were asked for consent to donation, provided consent for donation, and whether the referral was medically suitable for donation. RESULTS: Of 2977 organ donor referrals, a similar proportion of families had consent for donation was sought between non-English speakers and English speakers (p = .07), and between overseas-born compared to Australian-born referrals (p = .3). However, consent was less likely to be given for both non-English speakers than English speakers (OR 0.44, 95%CI:0.29-0.67), and those overseas-born than Australian-born (OR 0.54, 95%CI:0.41-0.72). For referrals both overseas-born and non-English speaking, families were both less likely to be asked for consent (OR 0.67; 95%CI:0.49-0.91) or give consent (OR 0.24; 95%CI0.16-0.37). There was no difference in medical suitability between English speakers and non-English speakers (p = .6), or between Australian-born and overseas-born referrals (p = .6). CONCLUSION: Intervention to improve consent rates from CALD families may increase donation.

Residual risk of infection with blood-borne viruses in potential organ donors at increased risk of infection: systematic review and meta-analysis.

OBJECTIVE: To estimate the prevalence and incidence of human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) among people at increased risk of infection in Australia; to estimate the residual risk of infection among potential solid organ donors in these groups when their antibody and nucleic acid test results are negative. STUDY DESIGN: Systematic review and meta-analysis of reports of the incidence and prevalence of HIV, HCV, and HBV in groups at increased risk of infection in Australia. DATA SOURCES: MEDLINE, government and agency reports, Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine conference abstracts, the Australian New Zealand Clinical Trial Registry, and National Health and Medical Research Council grants published 1 January 2000 - 14 February 2019; personal communications. DATA SYNTHESIS: Residual risk of HIV infection was highest among men who have sex with men (4.8 [95% CI, 2.7-6.9] per 10 000 antibody-negative persons; 1.5 [95% CI, 0.9-2.2] per 10 000 persons who are both antibody- and nucleic acid-negative). Residual risk of HCV infection was highest among injecting drug users (289 [95% CI, 191-385] per 10 000 antibody-negative persons; 20.9 [95% CI, 13.8-28.0] per 10 000 antibody- and nucleic acid-negative persons). Residual risk for HBV infection was highest among injecting drug users (98.6 [95% CI, 36.4-213] per 10 000 antibody-negative people; 49.4 [95% CI, 18.2-107] per 10 000 persons who were also nucleic acid-negative). CONCLUSIONS: Absolute risks of window period viral infections are low in people from Australian groups at increased risk but with negative viral test results. Accepting organ donations by people at increased risk of infection but with negative viral test results could be considered as a strategy for expanding the donor pool. REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO), CRD42017069820.

Evolution of Glycemic Control and Variability After Kidney Transplant.

BACKGROUND: The evolution of glycemic changes after kidney transplantation has not been described. We prospectively examined glycemic control and variability over time from transplantation using continuous glucose monitoring (CGM). METHOD: Continuous glucose monitoring devices were fitted for 3 to 5 days at time of transplant, month 3, and month 6 posttransplant. Indices of glucose control (mean glucose, percent time in hyperglycemic range, and Glycemic Risk Assessment Diabetes Equation score) and variability were calculated. An oral glucose tolerance test was performed at month 3. RESULTS: Twenty-eight patients (mean age, 45 ± 15 years) were enrolled, 64% male, 75% white, receiving tacrolimus, mycophenolate, and prednisolone (93%). Of 24 patients with complete CGM data at month 0, 3 had prior diabetes and 6 (25%) developed new-onset diabetes after transplant (NODAT). Hyperglycemia (>11.1 mM) was evident in 79% during days 0 to 3 posttransplant, particularly between 1 and 9 PM. Compared with recipients without diabetes, recipients with prior diabetes had higher mean glucose (7.8 mM; 95% confidence interval [CI], 7.4-8.2 vs 9.9 mM; 95% CI, 8.9-10.8; P < 0.001), Glycemic Risk Assessment Diabetes Equation (GRADE) score (4.5; 95% CI, 3.7-5.4 vs 7.8; 95% CI, 5.6-10.4; P = 0.003) and percent time with hyperglycemia. Glycemic control was also inferior in those that subsequently developed NODAT (mean glucose, 8.8 mM; 95% CI, 8.2-9.4; P = 0.004, GRADE: 6.2, 95% CI, 5.2-7.7; P = 0.04 vs no diabetes). Glucose variability was increased in patients with prior diabetes (glucose standard deviation, 1.99; 95% CI, 1.72-2.27 vs 2.97; 95% CI, 2.27-3.67; P = 0.006) but not in NODAT. All measures of glucose control and variability significantly improved over time after transplantation (P < 0.001). CONCLUSIONS: Dysglycemia is very common after renal transplantation, exhibiting a distinct diurnal pattern of afternoon and evening hyperglycemia. The magnitude of hyperglycemia and variability are maximal in recipients with preexisting diabetes and significant in those who go on to develop NODAT. Dysglycemia improves with time.

Hepatitis Transmission Risk in Kidney Transplantation (the HINT study): A Cross-Sectional Survey of Transplant Clinicians in Australia and New Zealand.

BACKGROUND: Interpreting hepatitis serology and virus transmission risk in transplantation can be challenging. Decisions must balance opportunity to transplant against potential infection transmission. We aimed to survey understanding among the Australian and New Zealand medical transplant workforce of hepatitis risk in kidney donors and recipients. METHODS: An anonymous, self-completed, cross-sectional survey was distributed via electronic mailing lists to Australian and New Zealand clinicians involved in kidney transplantation (2014-2015). We compared interpretation of clinical scenarios with paired donor and recipient hepatitis B virus and hepatitis C virus serology to recommendations in clinical practice guidelines. We used logistic regression modeling to investigate characteristics associated with decisions on transplant suitability in scenarios with poor (<50%) guideline concordance (odds ratios [OR]). RESULTS: One hundred ten respondents had representative workforce demographics: most were male (63%) nephrologists (74%) aged 40 to 49 years. Although donor and recipient hepatitis status was largely well understood, transplant suitability responses varied among respondents. For a hepatitis B virus surface antigen-positive donor and vaccinated recipient, 44% suggested this was unsuitable for transplant (guideline concordant) but 35% suggested this was suitable with prophylaxis (guideline divergent). In 4 scenarios with transplant suitability guideline concordance less than 50%, acute transplant care involvement predicted guideline concordant responses (OR, 1.69; P = 0.04). Guideline concordant responses were chosen less by hepatologists, intensive care doctors (OR, 0.23, 0.35, respectively; P = 0.01), and New Zealanders (guideline concordant responses OR, 0.17; P < 0.01; alternative responses OR, 4.31; P < 0.01). CONCLUSIONS: Despite broadly consistent interpretations of hepatitis serology, transplant suitability decisions varied and often diverged from guidelines. Improved decision support may reduce clinician variability.

Interleukin-18 binding protein therapy is protective in adriamycin nephropathy.

Adriamycin nephropathy (AN) is an experimental model of focal segmental glomerulosclerosis (FSGS) in which macrophages are considered to play a pathogenic role. We hypothesize that interleukin-18 (IL-18), largely derived from macrophages, is a key contributor to kidney injury in AN and a potential therapeutic target. In this study, BALB/c mice received adriamycin (9.6 mg/kg) via tail vein injection and subsequently were treated with either neutralizing IL-18 binding protein (IL-18BP; 250 µg) or normal saline (control). At 5 wk, IL-18 was upregulated in AN, and IL-18BP therapy afforded significant protection against the development of AN, resulting in less proteinuria (P < 0.01), kidney dysfunction (P < 0.01), glomerulosclerosis (P < 0.001), and interstitial accumulation of macrophages and T cells (P < 0.001). Gene expression of IL-18 downstream inflammatory molecules, including inducible nitric oxide synthase (P < 0.001), TNF-α (P < 0.001), and IFN-γ (P < 0.01); IL-17 (P < 0.001) and the chemokines CCL2 (P < 0.01) and CCL5 (P < 0.005), was reduced. We demonstrate that IL-18 plays a significant role in the pathogenesis of AN. The protective effect of IL-18BP therapy illustrates the importance of immune mediators in chronic proteinuric kidney disease and highlights the potential of IL-18BP therapy.

HMGB1 contributes to kidney ischemia reperfusion injury.

High-mobility group box 1 (HMGB1), a nuclear factor released extracellularly as an inflammatory cytokine, is an endogenous ligand for Toll-like receptor 4 (TLR4). TLR4 activation mediates kidney ischemia-reperfusion injury (IRI), but whether HMGB1 contributes to IRI is unknown. Here, treating wild-type mice with neutralizing anti-HMGB1 antibody protected them against kidney IRI, evidenced by lower serum creatinine and less tubular damage than untreated mice. Mice treated with anti-HMGB1 had significantly less tubulointerstitial infiltration by neutrophils (day 1) and macrophages (day 5) and markedly reduced apoptosis of tubular epithelial cells. Furthermore, anti-HMGB1 antibody-treated IRI kidneys had significantly lower levels of IL-6, TNFα, and monocyte chemoattractant protein 1 (MCP1). mRNA, which are downstream of HMGB1. Conversely, administration of rHMGB1 after reperfusion exacerbated kidney IRI in wild-type mice. TLR4 deficient (TLR4(-/-)) mice were protected against kidney IRI; administration of neither anti-HMGB1 antibody nor rHMGB1 affected this renoprotection. In conclusion, endogenous HMGB1 promotes kidney damage after IRI, possibly through the TLR4 pathway. Administration of a neutralizing antibody to HMGB1 either before or soon after ischemia-reperfusion affords significant protection, suggesting therapeutic potential for acute kidney injury.

Photopheresis therapy for problematic renal allograft rejection.

BACKGROUND: Photopheresis is an immunomodulatory therapy for the treatment of T cell-mediated disorders. It has been used for rejection prophylaxis in cardiac transplantation, adjuvant treatment of bronchiolitis obliterans in lung transplantation, treatment of graft verse host disease, and in a small number of cases, for treatment of acute rejection in renal transplantation. Little is known of long-term outcomes following the use of photopheresis in solid organ transplantation. METHODS: We report prospective follow-up of our consecutive experience of the use of photopheresis as adjuvant/salvage therapy for problematic rejection in patients undergoing renal transplantation. Transplant graft survival, infective and malignant outcomes were reported. RESULTS: A cohort of 10 renal transplants recipients received photopheresis therapy for therapy-resistant rejection. Conventional therapy included an average of 6.2 g pulse methyl-prednisolone and 17.1 days antilymphocyte therapy. The cohort received additional photopheresis therapy when the unresponsive nature of their rejections raised concerns of graft loss. Median follow-up censored for patient loss was 66.7 months following photopheresis commencement. Rejection resolved in association with photopheresis use in all 10 patients. Six patients continued to have stable graft function (median serum creatinine: 191.5 micromol/L) at a median follow-up of 71.0 months. There has been one patient death from sepsis and two from malignancy with functioning grafts while one graft has been lost to disease recurrence. CONCLUSION: Photopheresis may have a role as an adjuvant or salvage antirejection therapy in solid organ transplantation. Furthermore, evaluation in randomized controlled clinical trials is required to evaluate its potential.

IL-18 contributes to renal damage after ischemia-reperfusion.

IL-18 is a proinflammatory cytokine produced by macrophages and other cell types present in the kidney during ischemia-reperfusion injury (IRI), but its role in this injury is unknown. Here, compared with wild-type mice, IL-18(-/-) mice subjected to kidney IRI demonstrated better kidney function, less tubular damage, reduced accumulation of neutrophils and macrophages, and decreased expression of proinflammatory molecules that are downstream of IL-18. For determination of the relative contributions of leukocytes and parenchymal cells to IL-18 production and subsequent kidney damage during IRI, bone marrow-chimeric mice were generated. Wild-type mice engrafted with IL-18(-/-) hemopoietic cells showed less kidney dysfunction and tubular damage than IL-18(-/-) mice engrafted with wild-type bone marrow. In vitro, macrophages produced IL-18 mRNA and protein in response to ischemia. These data suggest bone marrow-derived cells are the key contributors to IL-18-mediated effects of renal IRI. Finally, similar to IL-18(-/-) mice, pretreatment of wild-type mice with IL-18-binding protein was renoprotective in this model of IRI. In conclusion, IL-18, derived primarily from cells of bone marrow origin, contributes to the renal damage observed during IRI. IL-18-binding protein may have potential as a renoprotective therapy.

TLR4 activation mediates kidney ischemia/reperfusion injury.

Ischemia/reperfusion injury (IRI) may activate innate immunity through the engagement of TLRs by endogenous ligands. TLR4 expressed within the kidney is a potential mediator of innate activation and inflammation. Using a mouse model of kidney IRI, we demonstrated a significant increase in TLR4 expression by tubular epithelial cells (TECs) and infiltrating leukocytes within the kidney following ischemia. TLR4 signaling through the MyD88-dependent pathway was required for the full development of kidney IRI, as both TLR4(-/-) and MyD88(-/-) mice were protected against kidney dysfunction, tubular damage, neutrophil and macrophage accumulation, and expression of proinflammatory cytokines and chemokines. In vitro, WT kidney TECs produced proinflammatory cytokines and chemokines and underwent apoptosis after ischemia. These effects were attenuated in TLR4(-/-) and MyD88(-/-) TECs. In addition, we demonstrated upregulation of the endogenous ligands high-mobility group box 1 (HMGB1), hyaluronan, and biglycan, providing circumstantial evidence that one or more of these ligands may be the source of TLR4 activation. To determine the relative contribution of TLR4 expression by parenchymal cells or leukocytes to kidney damage during IRI, we generated chimeric mice. TLR4(-/-) mice engrafted with WT hematopoietic cells had significantly lower serum creatinine and less tubular damage than WT mice reconstituted with TLR4(-/-) BM, suggesting that TLR4 signaling in intrinsic kidney cells plays the dominant role in mediating kidney damage.

The role of macrophages in allograft rejection.

Macrophage accumulation has long been recognized as a feature of allograft rejection, yet the role of macrophages in rejection remains underappreciated. Macrophages contribute to both the innate and acquired arms of the alloimmune response and thus may be involved in all aspects of acute and chronic allograft rejection. Recent advances in macrophage biology have allowed a better understanding of the mechanisms of macrophage accumulation, their state of activation and the pleuripotent roles they play in allograft rejection. Therapeutic attention to macrophages, in addition to T lymphocytes, may lead to improved outcomes in organ transplantation.