Adam McLean

Microcirculation Inflammation Associates With Outcome in Renal Transplant Patients With De Novo Donor‐Specific Antibodies

In renal transplant patients with de novo donor‐specific antibodies (dnDSA) we studied the value of microcirculation inflammation (MI; defined by the addition of glomerulitis (g) and peritubular capillaritis (ptc) scores) to assess long‐term graft survival in a retrospective cohort study. Out of all transplant patients with standard immunological risk (n = 638), 79 (12.4%) developed dnDSA and 58/79 (73%) had an indication biopsy at or after dnDSA development. Based on the MI score on that indication biopsy patients were categorized, MI0 (n = 26), MI1u2009+u20092 (n = 21) and MIu2009≥u20093 (n = 11). The MI groups did not differ significantly pretransplantation, whereas posttransplantation higher MI scores developed more anti‐HLA class Iu2009+u2009II DSA (pu2009= 0.011), showed more TCMR (pu2009<u20090.001) and showed a trend to C4d‐positive staining (p = 0.059). Four‐year graft survival estimates from time of indication biopsy were MI0 96.1%, MI1u2009+u20092 76.1% and MIu2009≥u20093 17.1%; resulting in a 24‐fold increased risk of graft failure in the MIu2009≥u20093 compared to the MI0 group (p = 0.003; 95% CI [3.0–196.0]). When adjusted for C4d, MIu2009≥u20093 still had a 21‐fold increased risk of graft failure (p = 0.005; 95% CI [2.5–180.0]), while C4d positivity on indication biopsy lost significance. In renal transplant patients with de novo DSA, microcirculation inflammation, defined by gu2009+u2009ptc, associates with graft survival.

Long-term survival of chronic dialysis patients following survival from an episode of multiple-organ failure

IntroductionThis study aimed to examine the long-term outcome for patients with end-stage renal failure (ESRF) who survived multiple-organ failure.MethodsWe performed a review of databases from the renal medicine service and intensive care units (ICU) of the participating hospitals within Imperial College Healthcare NHS Trust, London, UK. Patients with ESRF admitted to ICU who required support of two or more organ systems or were ventilated for more than 36 hours were included. To provide a comparison we examined the survival of a comparator group of ESRF patients in the general population with similar demographic and disease characteristics to our study group. We also examined the outcome for ESRF patients admitted to ICU who died prior to discharge.ResultsSurvival data for two years following discharge from ICU were examined for the impact of age, prior dialysis history, Acute Physiology and Chronic Health Evaluation (APACHE) II scores and medical or surgical status. Of the 199 patients who met the inclusion criteria, 111 (56%) survived their ICU stay. Sixty-two (56%) of the survivors remained alive two years following discharge. There was no group difference in survival with regards to age, dialysis history or APACHE II scores. Those admitted with a medical rather than surgical diagnosis were less likely to survive two years (P < 0.01). Patients who died in ICU had higher APACHE II scores (P < 0.0001) and were more likely to have a medical diagnosis. By log rank analysis two-year mortality was significantly higher (P = 0.003) in the ICU survivors than the comparator group with ESRF. This difference was lost when patients who died within a month of discharge were excluded.ConclusionsESRF patients with multiple-organ failure have a high mortality, with the increased risk of death continuing into the early post-ICU period. Those with non-surgical diagnoses have the highest risk. Survival within the group who live beyond the early post-ICU period appears similar to the background population of ESRF patients.

Circulating complement factor H-related proteins 1 and 5 correlate with disease activity in IgA nephropathy

IgA nephropathy (IgAN) is a common cause of chronic kidney disease and end-stage renal failure, especially in young people. Due to a wide range of clinical outcomes and difficulty in predicting response to immunosuppression, we need to understand why and identify which patients with IgAN will develop progressive renal impairment. A deletion polymorphism affecting the genes encoding the complement factor H-related protein (FHR)-1 and FHR-3 is robustly associated with protection against IgAN. Some FHR proteins, including FHR-1 and FHR-5, antagonize the ability of complement factor H (fH), the major negative regulator of the complement alternative pathway, to inhibit complement activation on surfaces, a process termed fH deregulation. From a large cohort of patients, we demonstrated that plasma FHR-1 and the FHR-1/fH ratio were elevated in IgAN and associated with progressive disease. Plasma FHR-1 negatively correlated with eGFR but remained elevated in patients with IgAN with normal eGFR. Serum FHR5 was slightly elevated in IgAN but did not correlate with eGFR. Neither FHR5 levels nor the FHR-5/fH ratio was associated with progressive disease. However, higher serum FHR-5 levels were associated with a lack of response to immunosuppression, the presence of endocapillary hypercellularity, and histology scores of disease severity (the Oxford Classification MEST score). Thus, FHR-1 and FHR-5 have a role in IgAN disease progression.

Renal allograft recipients fail to increase interferon-γ during invasive fungal diseases.

Invasive fungal diseases are a major cause of death in renal allograft recipients. We previously reported that adjunctive recombinant human interferon‐γ therapy has clinical utility for invasive fungal diseases after renal transplantation. We have now developed a rapid peripheral blood‐based quantitative real‐time PCR assay that enables accurate profiling of cytokine imbalances. Our preliminary studies in renal transplant patients with invasive fungal diseases suggest that they fail to mount an adequate interferon‐γ response to the fungal infection. In addition, they have reduced IL‐10 and increased TNF‐α when compared to stable renal transplant patients. These preliminary cytokine profiling‐based observations provide a possible explanation for the therapeutic benefit of adjunctive human interferon‐γ therapy in renal allograft recipients with invasive fungal diseases.

What goes around (in kidney transplant rejection) does not necessarily come around (in the blood).

The report by Simon et al. in the current issue of this journal continues a recent strand in this large corpus of work by looking at the CD8 cytotoxic mediators perforin and granzyme. Using real-time PCR (with a fixed volume of peripheral blood as the implicit denominator) they found that elevated levels of perforin on days 8–10 gave a specificity of 90% and a sensitivity of 82% in identifying rejectors. Results for granzyme B were slightly less good (specificity 87% and sensitivity 72%). These data are similar to those reported recently from Memphis (3), although this group found that Granzyme B was the more specific marker. Both these reports follow Li et al.’s finding of elevated perforin and granzyme-B levels in the urine of rejecting kidney transplants (4). The work of Simon et al. is to be commended in that they have presented their primary data. From this it is clear that however great the p-values, there is far too much overlap between rejectors and nonrejectors for this test to be used to determine clinical decisions.

Long‐ and short‐term outcomes in renal allografts with deceased donors: A large recipient and donor genome‐wide association study

Improvements in immunosuppression have modified short‐term survival of deceased‐donor allografts, but not their rate of long‐term failure. Mismatches between donor and recipient HLA play an important role in the acute and chronic allogeneic immune response against the graft. Perfect matching at clinically relevant HLA loci does not obviate the need for immunosuppression, suggesting that additional genetic variation plays a critical role in both short‐ and long‐term graft outcomes. By combining patient data and samples from supranational cohorts across the United Kingdom and European Union, we performed the first large‐scale genome‐wide association study analyzing both donor and recipient DNA in 2094 complete renal transplant‐pairs with replication in 5866 complete pairs. We studied deceased‐donor grafts allocated on the basis of preferential HLA matching, which provided some control for HLA genetic effects. No strong donor or recipient genetic effects contributing to long‐ or short‐term allograft survival were found outside the HLA region. We discuss the implications for future research and clinical application.

Molecular Assessment of C4d-Positive Renal Transplant Biopsies Without Evidence of Rejection

Introduction Immunohistochemical staining for C4d in peritubular capillaries has been part of antibody-mediated rejection (AbMR) definition in the Banff Classification for Allograft Pathology since 2003. However, it has limited sensitivity and specificity, therefore the clinical significance of C4d-positive biopsies without evidence of rejection (C4d+ WER) is unknown. We investigated the transcript levels of genes associated with AbMR in C4d+ WER biopsies from both ABO-compatible and incompatible renal transplant patients. Methods RNA was extracted from formalin-fixed paraffin-embedded renal transplant biopsies (n = 125) and gene expression analysis of 35 AbMR-associated transcripts carried out using the NanoString nCounter system. Results AbMR-associated transcripts were significantly increased in samples with AbMR or suspicious AbMR. A subgroup of 17 of 35 transcripts that best distinguished AbMR from C4d-negative biopsies without evidence of rejection was used to study C4d+ WER samples. There was no differential expression between C4d-negative and C4d+ WER from both ABO-incompatible and -compatible transplants. The geometric mean of 17 differentially expressed genes was used to assign the C4d+ WER biopsies a high- or low-AbMR transcript score. Follow-up biopsies showed AbMR within 1 year of initial biopsy in 5 of 7 high-AbMR transcript patients but only 2 of 46 low-AbMR transcript patients. In multivariate logistic regression analysis, elevated transcript levels in a C4d+ WER biopsy were associated with increased odds for biopsy-proven AbMR on follow-up (P = 0.032, odds ratio 16.318), whereas factors including donor-specific antibody (DSA) status and time since transplantation were not. Conclusion Gene expression analysis in C4d+ WER samples has the potential to identify patients at higher risk of developing AbMR.

Management of the Acute Transplant

In only a little over a single working lifetime from the late 1950s, kidney transplantation has moved from a startlingly novel, exciting, and dangerous new therapy for the then-terminal diagnosis of end-stage renal failure to become a routine and common operation throughout the developed world and in many developing countries. The charismatic surgical pioneers of the early decades have given way, as the health and economic benefits of successful transplantation have become apparent, to a dense superstratum of protocols, guidelines, and legal requirements constraining activity within the highly ethically complex landscape of deceased donor organ retrieval and allocation and live donor directed (and undirected altruistic) kidney donation.