Kidney transplantation in people living with human immunodeficiency virus: An overview of the Australian experience.

Kidney transplantation in people living with HIV (PLWHIV) is occurring with increasing frequency. Limited international data suggest comparable patient and graft survival in kidney transplant recipients with and without HIV. All PLWHIV aged ≥18 years who received a kidney transplant between 2000 and 2020 were identified by retrospective data initially extracted from Australia and New Zealand Dialysis and Transplant Registry (ANZDATA), with additional HIV-specific clinical data extracted from linked local health-care records. Twenty-five PLWHIV and kidney failure received their first kidney transplant in Australia between January 2000 and December 2020. Majority were male (85%), with median age 54 years (interquartile range, IQR 43-57). Focal segmental glomerulosclerosis was the most common primary kidney disease (20%), followed by polycystic kidney disease (16%). 80% of patients underwent induction with basiliximab and none with anti-thymocyte globulin (ATG). Participants were followed for median time of 3.5 years (IQR 2.0-6.5). Acute rejection occurred in 24% of patients. Two patients lost their allografts and three died. Virological escape occurred in 28% of patients, with a maximum viral load of 190 copies/mL. In conclusion, kidney transplantation in PLWHIV in Australia is occurring with increasing frequency. Acute rejection is more common than in Australia's general transplant population, but this does not appear to be associated with higher rates of graft failure or mortality out to four years.

Human immunodeficiency virus and solid organ transplantation: a 15-year retrospective audit at a tertiary Australian transplant centre.

BACKGROUND: The incidence of end-stage organ disease in people living with human immunodeficiency virus (HIV) (PLWH) is increasing, as people live longer due to potent, tolerable antiretroviral therapy (ART). Consequently, the number of PLWH who would benefit from solid organ transplant (SOT) is rising. The SOT experience in PLWH in Australia remains limited. Aim To retrospectively review the outcomes for SOT in PLWH at our service, in Victoria, Australia. METHODS: A retrospective cohort study of PLWH undergoing SOT over a 15-year period was performed. Adult PLWH age >18 years were eligible and identified from the Victorian HIV Service database. Descriptive statistics were used to summarise baseline demographics and clinical data, and outcomes following SOT. RESULTS: Nine virologically suppressed PLWH underwent SOT from HIV-negative donors (five kidneys, two livers and two bilateral sequential lung transplants). All patients were male, with a median age of 57.3 years (interquartile range (IQR) = 54.3-60.1) and CD4 count of 485 (IQR = 342-835) at transplantation, and comorbidities were common at baseline. After a median follow up of 3.9 years (IQR = 2.7-7.6), 8 (89%) patents were alive, 7 (78%) had functioning grafts, although 5 (56%) experienced organ rejection. Infections were common. Two patients required modification to their ART due to significant drug-drug interactions prior to transplant, while 5 (56%) had modifications post-SOT. No patients experienced HIV virologic failure. CONCLUSION: PLWH with end-stage organ disease experience good clinical and functional outcomes and should be considered for SOT where indicated. However, multidisciplinary planning and care is essential to optimise care in this patient group.

Treatment of invasive IMP-4 Enterobacter cloacae infection in transplant recipients using ceftazidime/avibactam with aztreonam: A case series and literature review.

Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) are an emerging threat in both solid organ and stem cell transplant recipients. Invasive CPE infections in transplant recipients are associated with a high mortality, often due to limited therapeutic options and antibacterial toxicities. One of the most therapeutically challenging group of CPE are the metallo-ß-lactamase (MBL)-producing Gram-negative bacteria, which are now found worldwide, and often need treatment with older, highly toxic antimicrobial regimens. Newer ß-lactamase inhibitors such as avibactam have well-established activity against certain carbapenemases such as Klebsiella pneumoniae carbapenemases (KPC), but have no activity against MBL-producing organisms. Conversely, aztreonam has activity against MBL-producing organisms but is often inactivated by other co-existing ß-lactamases. Here, we report four cases of invasive MBL-CPE infections in transplant recipients caused by IMP-4-producing Enterobacter cloacae who were successfully treated with a new, mechanism-driven antimicrobial combination of ceftazidime/avibactam with aztreonam. This novel antimicrobial combination offers a useful treatment option for high-risk patients with CPE infection, with reduced drug interactions and toxicity.

Post-transplant complications, patient, and graft survival in pediatric and adolescent kidney transplant recipients at a tropical tertiary care center across two immunosuppression eras.

BACKGROUND: We report pediatric PAKT patient and graft outcomes at a large tropical tertiary center spanning two transplant eras. METHODS: In this retrospective cohort study, all children ≤18 years who underwent kidney transplantation at our center between 1991 and 2016 were included. Data pertaining to their baseline characteristics, post-transplant events, and outcome were retrieved from transplant records and compared between transplant eras (1991-2005 and 2006-2016). RESULTS: A total of 139 children (mean age 15.2 ± 2.9 years) underwent PAKT during this period. The incidence of UTIs, CMV disease, BKVN, invasive fungal infections, new-onset diabetes after transplant, leucopenia, and recurrent NKD was higher in the 2006-2016 era (P < .001 for all), while 1-year cumulative BPAR was comparable (P = .100). Five-year graft and patient survival in the two eras were 89.9% and 94.2% (P = .365) and 92.1% and 95.3% (P = .739), respectively. Incidence of CMV disease, BKVN, graft loss, and death was lower in the calcineurin withdrawal group. Non-adherence accounted for 36% of graft loss; infections caused 43.7% of deaths. On multivariate Cox proportional hazards analysis, independent predictors for graft loss were UTIs and blood transfusion naïve status and for death were serious infections and glomerular NKD. CONCLUSIONS: PAKT in India has excellent long-term graft outcomes, though patient outcomes remain suboptimal owing to a high burden of infections. Current immunosuppression protocols need to be re-examined to balance infection risk, graft, and patient survival.

Safety and utility of kidney biopsy in patients with estimated glomerular filtration rate < 30 ml/min/1.73 m2.

AIM: Kidney biopsy (KBx) is the gold standard for evaluation of kidney disease, but is associated with a higher risk of complications in patients with reduced glomerular filtration rate (GFR). We studied the safety and utility of KBx in patients with eGFR <30 ml/min/1.73 m2 . METHODS: Consecutive adult patients with eGFR <30 ml/min/1.73 m2 , who were planned for a KBx and consented to participate were prospectively enrolled. Patients with solitary/transplant kidney or acute kidney injury were excluded. Haemoglobin was checked on the day of KBx and repeated 18-24 h later along with a screening ultrasound. Post-KBx complications were noted and their risk-factors analysed. The utility of the KBx was graded as effecting significant, some, or no change to subsequent management. RESULTS: Of the 126 patients included, 75% were male, 27.7% were diabetic, and the median eGFR was 13.5 ml/min/1.73m2 . Major complications occurred in 5.6%. Peri-renal haematomas were detected in 37.3%, and haematomas ≥2 cm were significantly more frequent in those with eGFR <15 ml/min/1.73 m2 (29.2% vs. 13%, p = .032). Dialysis was a risk factor, while pre KBx blood transfusion, diabetes and higher serum albumin were protective against any complication. KBx was more likely to make a significant difference in management in those with eGFR 15-29 ml/min/1.73m2 (44.1% vs. 11.1%, p < .001). Increasing age, lower serum creatinine and albumin were independently associated with KBx utility. CONCLUSION: KBx is relatively safe in severe kidney disease but its risk to benefit balance needs to be carefully considered when eGFR is <15 ml/min/1.73m2 .

Developing nephrology services in low income countries: a case of Tanzania.

BACKGROUND: The burden of kidney diseases is reported to be higher in lower- and middle-income countries as compared to developed countries, and countries in sub-Saharan Africa are reported to be most affected. Health systems in most sub-Sahara African countries have limited capacity in the form of trained and skilled health care providers, diagnostic support, equipment and policies to provide nephrology services. Several initiatives have been implemented to support establishment of these services. METHODS: This is a situation analysis to examine the nephrology services in Tanzania. It was conducted by interviewing key personnel in institutions providing nephrology services aiming at describing available services and international collaborators supporting nephrology services. RESULTS: Tanzania is a low-income country in Sub-Saharan Africa with a population of more than 55 million that has seen remarkable improvement in the provision of nephrology services and these include increase in the number of nephrologists to 14 in 2018 from one in 2006, increase in number of dialysis units from one unit (0.03 unit per million) before 2007 to 28 units (0.5 units per million) in 2018 and improved diagnostic services with introduction of nephropathology services. Government of Tanzania has been providing kidney transplantation services by funding referral of donor and recipients abroad and has now introduced local transplantation services in two hospitals. There have been strong international collaborators who have supported nephrology services and establishment of nephrology training in Tanzania. CONCLUSION: Tanzania has seen remarkable achievement in provision of nephrology services and provides an interesting model to be used in supporting nephrology services in low income countries.

Spectrum of biopsy proven renal disease in South Asian children: Two decades at a tropical tertiary care centre.

AIM: We report findings from a large single centre paediatric renal biopsy cohort in South Asia. METHODS: We analyzed all renal biopsies performed on children aged ≤18 years between 1996 and 2015 at our centre. The clinical characteristics and histological diagnosis pertaining to each case, distribution of renal diseases in children with various clinical presentations, and changes in the pattern of kidney disease during the study period were analyzed. RESULTS: A total of 1740 paediatric kidney biopsies were performed during the study period. The mean age was 12.8 ± 4.9 years (8 months to 18 years) and the male: female ratio was 1.5:1. The most common indication for renal biopsy was nephrotic syndrome (63.2%) followed by acute nephritic syndrome (13%). Minimal change disease was the most common cause of nephrotic syndrome while endocapillary proliferative glomerulonephritis (65.7% infection related), remained the commonest cause of acute nephritic syndrome. IgA nephropathy was the commonest cause of chronic kidney disease. Contrary to trends in European paediatric cohorts, the frequency of lupus nephritis increased over the two decades of the study, while that of endocapillary proliferative glomerulonephritis did not show any appreciable decline. CONCLUSION: This study provides the largest data on biopsy proven renal disease in children from South Asia published till date and highlights important differences in the spectrum and trends of kidney disease compared to data from other regions.

Leflunomide with low-dose everolimus for treatment of Kaposi's sarcoma in a renal allograft recipient.

Current treatment of Kaposi's sarcoma is reduction of immunosuppression with or without addition of mammalian target of rapamycin inhibitors (mTORi). Akt signalling plays a central role in oncogenesis of Kaposi's sarcoma. We describe a case of multifocal Kaposi's sarcoma in a renal allograft recipient, which showed unsatisfactory early response to immunosuppression reduction along with everolimus therapy but completely resolved after adding leflunomide. mTORi impair Kaposi's sarcoma oncogenesis by inhibiting mTOR downstream from the Akt signalling. Leflunomide inhibits Akt phosphorylation. This synergistic effect may be beneficial in treatment of Kaposi sarcoma and needs to be explored in trials.

Acute kidney injury in tropical acute febrile illness in a tertiary care centre--RIFLE criteria validation.

BACKGROUND: Acute febrile illnesses are a common cause of tropical acute kidney injury (AKI). The incidence and severity of AKI in tropical febrile illnesses and validity of RIFLE classification are unclear. METHODS: Consecutive adult inpatients of a tertiary hospital in southern India with tropical acute febrile illness between January 2007 and January 2008 were prospectively studied for the incidence and severity of AKI based on RIFLE classification and its association with mortality and dialysis requirement. RESULTS: The 367 patients (mean age 39.7±16.9 years; 60% males) with tropical acute febrile illness due to scrub typhus (51.2%), falciparum malaria (10.4%), enteric fever (8.7%), dengue (7.6%), mixed malaria (6.5%), leptospirosis (3.3%), undifferentiated acute febrile illness (8.4%) and others (3.8%) (spotted fever, vivax malaria and Hantaan virus infection) had an overall mortality rate of 12.3%. The incidence of AKI was 41.1%; of which, 17.4%, 9.3% and 14.4% were in the Risk, Injury and Failure classes, respectively. Of the patients, 7.9% required dialysis. Among the Risk, Injury and Failure groups, there was an incremental risk of mortality (OR 6.9, 20.2 and 25.6; P<0.001) and dialysis requirement (OR 3.4, 28.8 and 178.8; P<0.001). CONCLUSIONS: The incidence of AKI in the common tropical acute febrile illnesses in our study such as scrub typhus, falciparum malaria, enteric fever, dengue and leptospirosis is 41.1%. RIFLE classification is valid and applicable in AKI related to tropical acute febrile illnesses, with an incremental risk of mortality and dialysis requirement.

Successful Implementation of an Increased Viral Risk Donor Waiting List for Preconsented Kidney Transplant Candidates in Victoria, Australia.

Increased viral risk donors (IVRDs) with increased risk behaviors for blood-borne virus infection and negative nucleic acid testing have a low absolute risk of "window period" infection. Utilization and allocation of IVRD organs differ between jurisdictions. METHODS: We examined the characteristics and utilization of deceased donor IVRD kidneys and recipient outcomes within a 2-y period (July 31, 2018-July 31, 2020) postimplementation of a new opt-in allocation pathway for preconsented recipients in Victoria, Australia. RESULTS: Fifty-six kidneys from 31 IVRDs were utilized, comprising 13% of donors. Preconsent rate to accept IVRD kidneys increased to 41% of the waitlist in the 2 y postimplementation, and IVRDs having no kidneys utilized reduced to 0%. Compared with non-IVRD kidneys, kidney offer declines >10 per donor were less likely from IVRDs (3% vs 19%; P < 0.05). IVRDs were younger (median age 36 [IQR 30-44] vs 51 [35-60] y; P < 0.0001), with lower kidney donor profile index (25% [13-40%] vs 57% [29-75%]; P < 0.0001), and less hypertension (0% vs 22%; P < 0.01). Estimated glomerular filtration rate 3 mo post-transplant was superior (P < 0.01). Injecting drug use (61%) was the most common increased risk behavior. 29% of IVRDs were hepatitis C antibody positive but nucleic acid testing negative. No active infection was detected in any recipient post-transplant. CONCLUSIONS: The described opt-in system permits efficient allocation and utilization of kidneys from IVRDs, with superior quality and graft function. Education is crucial to facilitate informed consent and equity of access to this donor pool.

Can mycophenolic acid dose requirement during the first transplant help predict dosing for the second transplant?

We describe the pharmacokinetic profile of mycophenolic acid (MPA) in a patient receiving Mycophenolate mofetil (MMF) during her first and second renal transplantations. The MMF dose required to achieve a therapeutic range of MPA-AUC(0)(-)(12)(h) early following the second transplantation was 10 times greater than that required late following the first transplantation. Her MMF requirement then declined and continued to decrease even beyond 1 year. Intra-individual variability in MPA profiles precluded the ability to predict MMF dosing for the second transplant based on that during the first. Therapeutic drug monitoring of MMF should be continued beyond 1 year of transplantation.

Mycophenolic acid estimation by pooled sampling: a novel strategy.

The aim of the study was to determine the reliability of estimating area under the curve from 0 to 6 hours (AUC0-6) of mycophenolic acid (MPA) by pooling the blood samples from different sampling time points. Eighty 6-hour concentration-time profiles were obtained from 68 patients on mycophenolate mofetil and the MPA AUC0-6 was calculated. In the pooled strategy, each of the equally spaced time point samples was pooled into two samples. Two rectangles were created instead of multiple trapezoids and the sum of their areas equal to the MPA AUC0-6. The linear correlation (r), intraclass correlation, bias, and precision were calculated between the pooled MPA AUC0-6 and the MPA AUC0-6 derived from measurements at different time points. Pharmacokinetic profiles of an additional 20 patients were obtained to study the possibility of using fewer time points to create a single pooled sample to obtain MPA AUC0-6. The linear correlation (r) and intraclass correlation between pooled and measured MPA AUC0-6 was 0.982 and 0.979, respectively. There was a highly significant correlation (r) of 0.978 between the pooled versus measured for both MPA AUC0-3 and MPA AUC3-6. The mean bias and precision (95% confidence interval) for pooled with total measured MPA AUC0-6 was -6.4% (-7.8% to -4.94%) and 7.37% (6.21%-8.54%), respectively. The pooled sample approach using only five time points to estimate MPA AUC0-6 had an unacceptable bias and precision. Pooling 10 samples to a set of two samples gave a highly accurate measure of MPA AUC0-6. The advantages for a central laboratory are the high throughput of samples and the transportation of only two specimens from other centers, all of which leads to a reduction in cost. This approach is extremely useful for studies aimed at examining the bioavailability of mycophenolate mofetil in different ethnic populations within India.

Disseminated cysticercosis.

Cysticercosis is a common public health problem in the Tropics. However, disseminated cysticercosis is rare. We report a patient with chronic liver disease and seizures, in whom a simple plain radiographic examination helped in narrowing down the differential diagnosis to disseminated cysticercosis. The diagnosis was confirmed by serum cysticercal antibody enzyme-linked immunosorbent assay (ELISA) and computerized tomography of the brain.

A model for human leukocyte antigen-matched donor-swap transplantation in India.

BACKGROUND: In developing countries such as India, extending donor-swap transplantation (DSTx) to human leukocyte antigen (HLA)-mismatched patient-donor pairs would increase well-matched living donor kidney transplantation rates, resulting in use of less immunosuppression and less expenses, lower infective morbidity, and better survival. A model for DSTx based on HLA matching is presented. METHODS: Consecutive HLA class 1 antigen (A, B) tests of prospective renal allograft recipients and their related donors, performed at a single center in India was analyzed retrospectively using an HLA matching program to determine the proportion of prospective recipients with poorly matched related donors who could have benefited by DSTx based on HLA matching. RESULTS: Over the past 17.5 years, 2,129 prospective renal allograft recipients and 2,890 donors were tested for HLA class I (A and B) antigens. Of the prospective recipients, 33% did not have well-matched donors (defined as blood group compatible and sharing > or =2 of 4 HLA class I antigens). Among such recipients, 19.2% could have found a well-matched donor-swap pair within a year at a single center. This number would increase to 38% if four major national centers were involved with a shared HLA registry. CONCLUSIONS: Nearly 40% of prospective recipients without well-matched donors would find a donor-swap pair based on HLA matching within a year, with coordination among four national centers and a shared HLA registry, increasing the well-matched living donor renal transplant rates and improving transplant outcomes. This finding is relevant in the context of Indian government amending the Transplantation of Human Organs Act to encourage DSTx.

Denosumab-Induced Severe Hypocalcaemia in Chronic Kidney Disease.

BACKGROUND: Hypocalcaemia is increasingly recognized as a complication of denosumab use in Chronic Kidney Disease (CKD) patients with osteoporosis. Despite Therapeutic Goods Administration (TGA) notifications in 2013, we have subsequently encountered several cases of denosumab-induced hypocalcaemia, raising concern about lack of widespread awareness among prescribing practitioners. AIMS: We reviewed the morbidity and healthcare intervention needs of CKD patients with hypocalcaemia attributed to denosumab. METHODS: A retrospective case series of CKD patients with clinically significant hypocalcaemia after exposure to denosumab, encountered at the tertiary care referral hospital from December 2013 to February 2017, was undertaken. RESULTS: Eight patients (52-85 years of age) with stage 4-5 CKD developed clinically significant hypocalcaemia (corrected calcium 1.45±0.21mmol/L) following denosumab therapy for osteoporosis. Seven of the eight patients required inpatient management with three patients requiring intravenous calcium replacement and cardiac monitoring in a high dependency unit. Our study also identified additional factors that could potentially contribute to hypocalcaemia such as lack of calcium supplementation, use of noncalcium based phosphate binders, absence of or use of lower doses of calcitriol supplementation, low vitamin D levels, concomitant treatment with loop diuretics, history of parathyroidectomy, or presence of acute medical illness. CONCLUSION: Multiple cases of severe hypocalcaemia in CKD patients following denosumab exposure were encountered after TGA warnings, resulting in considerable morbidity and intensive healthcare interventions in CKD patients. We advocate greater awareness amongst the medical profession, careful consideration before using denosumab in CKD patients, and close follow-up after administration to prevent morbidity.