Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand.

Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. Although TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4-8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 (a disintegrin and metalloprotease thrombospondin, number 13) activity. A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin-associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC-HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC-HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. Although early confirmation of aHUS is often not possible, except in the minority of patients in whom auto-antibodies against factor H are identified, genetic testing ultimately reveals a complement-related mutation in a significant proportion of aHUS cases. The presence of other TMA-associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA.

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand.

Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. While TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4-8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 activity (a disintegrin and metalloprotease thrombospondin, number 13). A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin-associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC-HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC-HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. While early confirmation of aHUS is often not possible, except in the minority of patients in whom autoantibodies against factor H are identified, genetic testing ultimately reveals a complement-related mutation in a significant proportion of aHUS cases. The presence of other TMA-associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA.

Divided dosing reduces prednisolone-induced hyperglycaemia and glycaemic variability: a randomized trial after kidney transplantation.

BACKGROUND: Prednisolone is a major risk factor for hyperglycaemia and new-onset diabetes after transplantation. Uncontrolled observational data suggest that divided dosing may reduce requirements for hypoglycaemic agents. This study aims to compare the glycaemic effects of divided twice daily (BD) and once daily (QD) prednisolone. METHODS: Twenty-two kidney transplant recipients without diabetes were randomized to BD or QD prednisolone. Three weeks post-transplant, a continuous glucose monitor (iPro2(®) Medtronic) was applied for 5 days with subjects continuing their initial prednisolone regimen (Days 1-2) before crossover to the alternative regimen. Mean glucose, peak glucose, nadir glucose, exposure to hyperglycaemia (glucose ≥7.8 mmol/L) and glycaemic variability were assessed. RESULTS: The mean ± standard deviation (SD) age of subjects was 50 ± 10 years and 77% were male. Median (interquartile range) daily prednisolone dose was 25 (20, 25) mg. BD prednisolone was associated with decreased mean glucose (mean 7.9 ± 1.7 versus 8.1 ± 2.3 mmol/L, P < 0.001), peak glucose [median 10.4 (9.5, 11.4) versus 11.4 (10.3, 13.4) mmol/L, P< 0.001] and exposure to hyperglycaemia [median 25.5 (14.6, 30.3) versus 40.4 (33.2, 51.2) mmol/L/h, P = 0.003]. Median glucose peaked between 14:55-15.05 h with BD and 15:25-15:30 h with QD. Median glycaemic variability scores were decreased with BD: SD (1.1 versus 1.9, P < 0.001), mean amplitude of glycaemic excursion (1.5 versus 2.2, P = 0.001), continuous overlapping net glycaemic action-1 (CONGA-1; 1.0 versus 1.2, P = 0.039), CONGA-2 (1.2 versus 1.4, P = 0.008) and J-index (25 versus 31, P = 0.003). CONCLUSIONS: Split prednisolone dosing reduces glycaemic variability and hyperglycaemia early post-kidney transplant.

A practical limited sampling strategy to predict free prednisolone exposure and glycemia in kidney transplant recipients.

BACKGROUND: Despite significant interindividual variability in prednisolone pharmacokinetics and potentially serious consequences with inadequate or excessive exposure, monitoring of prednisolone levels is not employed to guide therapy. As ultrahigh-performance liquid chromatography-tandem mass spectrometry methods can now measure the active free fraction of prednisolone, this study aimed to evaluate the performance of 15 published limited sampling strategies (LSSs) for predicting free prednisolone exposure in adult kidney transplant recipients and to examine the relationship between free/total prednisolone exposure and plasma glucose. METHODS: The study was performed in 11 subjects without diabetes 3-4 weeks postkidney transplantation. Area under the concentration time curve profiles of total and free prednisolone from 0 to 12 hours postdose (AUC0₋12) were determined and compared with predicted AUC0₋12 values calculated from published LSSs. Venous glucose was measured concurrently with the 13 sampling time points. RESULTS: The mean (±SD) age of subjects was 52 ± 12 years, 5 were men and the median (interquartile range) daily prednisolone dose was 20.0 mg (20.0-22.5). Interindividual variation in dose-adjusted free and total prednisolone exposure was 1.9- and 3.2-fold, respectively. All 15 free prednisolone LSSs exhibited good correlation (r ≥ 0.83), with bias and imprecision less than 15%. An LSS incorporating 1.25- and 3-hour samples had the highest predictive power (r = 0.97, bias 1.2%, imprecision 5.6%). Free prednisolone AUC0₋12 correlated with peak glucose levels (r = 0.65, P = 0.037), as did predicted AUC0₋12 from 14/15 LSSs. CONCLUSIONS: Biologically active free prednisolone exposure can be accurately predicted postkidney transplantation by LSSs incorporating 2-point concentration sampling. Peak plasma glucose concentration correlated well with prednisolone exposure.

Antiphospholipid syndrome in renal transplantation.

Antiphospholipid syndrome (APS) may occur in isolation or in association with systemic lupus erythematosus (SLE), with the potential to cause renal failure via several distinct pathologies. Renal transplantation in the presence of APS carries a risk of early graft loss from arterial or venous thrombosis, or thrombotic microangiopathy (TMA). Whilst perioperative anticoagulation reduces the risk of large vessel thrombosis, it may result in significant haemorrhage, and its efficacy in preventing post-transplant TMA is uncertain. Here, we report a patient with end-stage kidney disease (ESKD) due to lupus nephritis and APS, in whom allograft TMA developed soon after transplantation despite partial anticoagulation. TMA resolved with plasma exchange-based therapy albeit with some irreversible graft damage and renal impairment. We discuss the differential diagnosis of post-transplant TMA, and current treatment options.

Low-dose valaciclovir and cytomegalovirus immunoglobulin to prevent cytomegalovirus disease in high-risk renal transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) remains an important cause of disease in renal transplant recipients. Prophylaxis is effective in reducing disease; however, the optimal regimen remains uncertain. We assessed the efficacy of low-dose valaciclovir (3 months) and intravenous CMV immunoglobulin in the prevention of CMV disease in CMV-negative recipients of kidneys from CMV-positive donors (D+/R-). METHODS: A single-centre, retrospective study examining the incidence of CMV disease and patient and graft survival in all patients transplanted between October 2000 and November 2004. RESULTS: Among 203 renal transplant recipients, 46 were D+/R- (22.7%) and received prophylaxis. Of the 203 recipients, 21 (10.3%) developed CMV disease over a four-year follow-up period. Within the D+/R- group, CMV disease occurred in 15.2% of patients at 6 months (7/46), and 21.7% at 4 years (10/46). Of the 10 D+/R- patients who developed CMV disease, six were inadvertently on a dose of valaciclovir below that dictated by protocol arising from a failure to increase dosage in parallel with improving recipient renal function. In the D+/R- recipients where the protocol was adhered to, the incidence of CMV disease was 5% (2/40) at 6 months, and 10% (4/40) at 4 years. CONCLUSION: Low-dose valaciclovir with CMV immunoglobulin was as efficacious in preventing CMV disease as other published regimens, including those with full-dose valaciclovir and valganciclovir. There was a low incidence of CMV disease beyond 6 months. Outcomes could be improved by ensuring appropriate dose adjustment following changes in renal function.

Modifiers of complement activation for prevention of antibody-mediated injury to allografts.

PURPOSE OF REVIEW: Improvements in prevention and management of cellular rejection of solid organ transplants, coupled with increasing numbers of sensitized patients, have focused attention on antibody-mediated rejection (AbMR). Complement is a critical component of AbMR, in addition to interfacing between innate and adaptive immunity and the coagulation cascade. This article reviews complement biology and strategies to overcome complement in AbMR, cognisant that antibody can act independently of complement. RECENT FINDINGS: The past decade has witnessed an improvement in the prevention and treatment of AbMR as a result of solid-phase assays to determine antibody specificity, definition of histopathological criteria, and use of plasmapheresis and/or intravenous immunoglobulin (IVIG). Nonetheless, AbMR continues to impact adversely on short- and long-term graft survival. Use of B and/or T-lymphocyte-depleting therapies has not shown measurable benefit, and the need remains for therapies that deplete antibody, or provide better protection from complement-mediated damage. Disordered complement activity in human diseases such as paroxysmal nocturnal haemoglobinuria, has provided additional impetus to pursuing therapeutic complement inhibition. Preliminary data from C5 inhibition with eculizumab in the treatment and prevention of AbMR have shown promise. Trials with recombinant human inhibitors of C1 (effective in angioedema) to prevent or treat AbMR are beginning. SUMMARY: Despite current limitations, 'protection' of the transplant through plasmapheresis and/or IVIG enables many allografts to survive in sensitized recipients. Elucidating the pathways mediating graft acceptance, by constitutive antibody deletion, or 'accommodation' (wherein donor organ remains uninjured despite antibody binding), or other local protective mechanism(s), is an equally important challenge in the quest to overcome AbMR.

Histological and Extended Clinical Outcomes After ABO-Incompatible Renal Transplantation Without Splenectomy or Rituximab.

BACKGROUND: Excellent short-term results have been reported in ABO-incompatible (ABOi) renal transplant recipients managed solely with antibody removal and conventional immunosuppression. However, long-term clinical outcomes with this regimen and predictive information from protocol biopsies are lacking. METHODS: We compared outcome data in ABOi and ABO-compatible (ABOc) recipients receiving this regimen approximately 4 years posttransplant, and histology from biopsies approximately 12 months posttransplant. RESULTS: Patient and graft survivals among 54 ABOi recipients were 98.1% and 90.7%, respectively, at 4 years. Graft function was similar between ABOi (creatinine, 140.3 µmol/L) and ABOc recipients (creatinine, 140.2 µmol/L) (P = 0.99), with no significant change over the study period in either group (Δcreatinine, -0.83 vs 6.6 µmol/L) (P = 0.59). There was no transplant glomerulopathy in biopsies from either group. Interstitial fibrosis (IF) and tubular atrophy (TA) was present in 7 (28%) of 25 ABOi compared with 7 (20.6%) of 34 ABOc (P = 0.52). Progression of IF/TA from implantation was noted in 6 (24%) of 25 ABOi and 6 (17.6%) of 34 ABOc, respectively. C4d staining without antibody-mediated rejection was present in 13 (52%) 25 early posttransplant biopsies from ABOi recipients by immunohistochemistry, but in only 4 (16%) of 25 at 12 months. CONCLUSIONS: ABO-incompatible renal transplant performed with antibody removal and conventional immunosuppression continues to provide excellent patient and graft survival, and stable renal function over 4 years. Coupled with absent transplant glomerulopathy and low rates of progressive IF/TA on earlier biopsies, this suggests that ABOi with conventional immunosuppression and antibody removal, without rituximab or splenectomy, can achieve long-term outcomes comparable to ABO-compatible transplantation.

Prediction and diagnosis of post transplant diabetes.

The identification of at-risk individuals prior to transplantation may enable implementation of measures to prevent or delay PTDM development, while early detection facilitates prompt management and may prevent acute and chronic complications. Thus, in this review, we examine proposed tools for the prediction of PTDM for use prior to and following solid organ transplantation. This includes PTDM prediction models based on biochemical assessments of glycaemia and other indices, in addition to those solely based on clinical parameters. We also examine the available methods for diagnosis of PTDM early and late post-transplant, including the advantages and limitations of fasting plasma glucose (FPG), OGTT, random plasma glucose and HbA1c assessment. Key findings are that OGTT should remain the gold standard diagnostic method for PTDM, however, there is emerging data to support a role for HbA1c beyond 3 months posttransplant. FPG has low sensitivity during the first year post-transplant. Improved prediction and diagnosis of PTDM may lead to improvements in patient survival, quality of life and health care costs in future.

Screening for new-onset diabetes after kidney transplantation: limitations of fasting glucose and advantages of afternoon glucose and glycated hemoglobin.

BACKGROUND: The sensitivity of fasting plasma glucose (FPG) in screening for new-onset diabetes after transplantation (NODAT) has been questioned, particularly in the presence of moderate-dose prednisolone, where peak plasma glucose occurs 7 to 8 hr after administration. Oral glucose tolerance testing (OGTT) has been mooted as an alternative but is inconvenient for patients. METHODS: We compared sensitivity of screening tests for NODAT at 6 weeks, 3 months, and 12 months after kidney transplantation in recipients receiving prednisolone, mycophenolate, and tacrolimus. RESULTS: At 6 weeks, NODAT (capillary blood glucose [CapBG] ≥11.1 mmol/L, FPG ≥7.0 mmol/L, 2-hr plasma glucose ≥11.1 mmol/L, or glycated hemoglobin [HbA1c] ≥6.5%) was detected in 46% with CapBG versus 12% with OGTT (P=0.013), 4% with HbA1c (P<0.001), and 0% with FPG (P<0.001; n=26). At 3 months, NODAT was present in 14% with HbA1c versus 20% with OGTT (P=0.600) and 2% with FPG (P=0.059; n=50), whereas, at 12 months, NODAT was found in 4% with HbA1c versus 6% with OGTT (P=1.00) and 2% with FPG (P=0.618; n=51). Combining 3- and 12-month data, OGTT recorded NODAT in 14% and impaired glucose tolerance in 28%, whereas HbA1c detected NODAT in 10% and impaired glucose tolerance (from ≥5.7 to <6.5%) in 51%. Employing HbA1c as a screening test and reserving OGTT for those with impaired glucose tolerance would detect NODAT with a sensitivity more than 94%, avoiding the need for OGTT in 49% of patients. CONCLUSIONS: This study confirms the inadequacy of FPG screening for NODAT in the first 6 weeks after transplantation, at which time 4 p.m. CapBG also outperformed OGTT. From 3 months, HbA1c had similar sensitivity to OGTT and represents a convenient alternative.

ABO-incompatible matching significantly enhances transplant rates in kidney paired donation.

BACKGROUND: Although preformed donor-specific anti-human leukocyte antigen antibodies (DSA) can be overcome by plasmapheresis-based strategies with some success in renal transplantation, kidney paired donation (KPD) is a more effective strategy to avoid DSA. In contrast, ABO incompatibility can be crossed with outcomes equivalent to ABO-compatible transplantation. Here, we report the ability of accepting human leukocyte antigen-compatible but ABO-incompatible donors to increase the number of exchanges in a KPD program. METHODS: In the Australian KPD program, virtual crossmatch is used to allocate suitable donors to recipients. Acceptance of ABO-incompatible donors is allowed in cases where anti-blood group antibody titres are deemed amenable to removal by apheresis or immunoabsorption. The number of matched recipients, identified chains, and transplants performed with and without acceptance of ABO incompatibility was analyzed. RESULTS: In 2 years, 115 pairs were included in nine quarterly match runs. Incompatibility due to DSA accounted for 86% of the listed pairs and 52% were also blood group incompatible to their coregistered donor. Median calculated panel-reactive antibody in registered recipients was 83% (mean, 67%±37%). ABO-incompatible donors were accepted for 36 patients. Two waitlist recipients and 48 KPD candidates were matched and transplanted. Ten recipients (20%) of an ABO-incompatible donor kidney were distributed across 8 chains that resulted in 21 recipients being transplanted. Thus, without ABO-incompatible matching, only 27 recipients in 12 chains would have been transplanted. CONCLUSION: Acceptance of blood group-incompatible donors for patients with low to moderate anti-blood group antibody significantly increases transplant rates for highly sensitized recipients.