The authors describe the findings of Wiebe et al (page 1157) that de novo donor-specific HLA antibodies have adverse prognostic implications for long-term renal transplant survival and discuss how these findings may impact individual patient care and direct future research. The authors describe the findings of Wiebe et al (page 1157) that de novo donor-specific HLA antibodies have adverse prognostic implications for long-term renal transplant survival and discuss how these findings may impact individual patient care and direct future research. Advances in immunosuppression have dramatically lowered rates of acute cellular rejection but have impacted less on rates of long-term renal allograft survival (1Lodhi SA Lamb KE Meier-Kriesche HU Solid organ allograft survival improvement in the United States: The long-term does not mirror the dramatic short-term success.Am J Transplant. 2011; 11: 1226-1235Abstract Full Text Full Text PDF PubMed Scopus (284) Google Scholar). This could be because of (1) late immunoreactivity against the allograft, (2Wiebe C Gibson IW Blydt-Hansen TD et al.Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant.Am J Transplant. 2012; 12: 1157-1167Abstract Full Text Full Text PDF PubMed Scopus (742) Google Scholar) the nephrotoxicity of calcineurin inhibitors and/or (3) the development of opportunistic infections. In this issue, Dr. Wiebe and coinvestigators from the University of Manitoba provide strong evidence for the importance of the first possibility by a longitudinal analysis of circulating HLA antibodies, renal histology and clinical outcome (2Wiebe C Gibson IW Blydt-Hansen TD et al.Evolution and clinical pathologic correlations of de novo donor-specific HLA antibody post kidney transplant.Am J Transplant. 2012; 12: 1157-1167Abstract Full Text Full Text PDF PubMed Scopus (742) Google Scholar). Advances in solid phase multiplex assays have provided transplant physicians with an unprecedented ability to detect donor-specific HLA antibodies (DSAs). However, it has not been clear whether these ultrasensitive techniques to detect DSAs have any pathologic significance or clinical utility posttransplantation. Furthermore, the risk factors that predispose one patient to develop DSAs as compared to another have not been clearly defined. The paper by Wiebe et al. sheds light on the pathologic significance of de novo DSA (dnDSA) and discusses potential risk factors for their development. The paper demonstrates that the detection of dnDSAs by sensitive solid-phase assays has adverse prognostic implications and raises several new questions. A major finding of the paper is that in a low-risk population on a modern immunosuppressive regimen (i.e. mainly Caucasian, primary transplant recipients with low panel reactive antibody levels) dnDSAs as detected by solid phase assays develop at a surprisingly high rate of 15% over a mean period of 6 years. Furthermore, the 10-year survival rate of patients with dnDSAs is inferior (59%) compared to patients that do not develop dnDSAs (96%). An obvious conclusion from these data is that the development of dnDSAs has poor prognostic implications and although this may be true, the challenge is to use this information. Should the development of dnDSAs be used as a standard endpoint in clinical immunomodulation trials as a potential marker of long-term dysfunction of an allograft? Although this may be a helpful approach to determine if one immunomodulatory approach may be more beneficial than another for a group of people, it is more difficult to know what to do when faced with a patient who has developed dnDSA. From the data in the paper, it is unclear whether every dnDSA has equal pathogenicity. The authors acknowledge that there seem to be groups of patients with different pathologic responses to the development of a dnDSA. Some patients experience acute allograft dysfunction and these patients seem to have higher rates of mixed cellular and antibody rejection as compared to a group of patients with stable allograft function and no dnDSA. Other patients have more indolent damage and these seem to have less activation of the complement system as evidenced by lower rates of diffuse C4d deposition and milder histologic evidence of rejection. Finally, some patients seem to have no allograft dysfunction as evidenced by stability of serum creatinine or lack of significant proteinuria and although these patients had no findings of rejection by light microscopy, they did have evidence of activation of the complement system as indicated by C4d staining and presence of mild peritubular capillaritis. The authors argue that although renal function may seem stable in these patients, the histologic changes suggest that progressive damage is occurring that will not remain clinically silent for long, a conclusion also reached in a study on 3-month protocol biopsies in sensitized patients (3Loupy A GS Hill Suberbielle C et al.Significance of C4d Banff scores in early protocol biopsies of kidney transplant recipients with preformed donor-specific antibodies (DSA).Am J Transplant. 2011; 11: 56-65Abstract Full Text Full Text PDF PubMed Scopus (201) Google Scholar). However, it seems that some patients can do quite well even after developing dnDSA. Thus, a future challenge is to identify and determine which antibodies are more pathogenic. Among the current approaches under evaluation to address this issue are tests for complement fixation (C1q) (4Chen G, Sequeira F, Tyan DB. Novel C1q assay reveals a clinically relevant subset of human leukocyte antigen antibodies independent of immunoglobulin G strength on single antigen beads. Human Immunol 2011; 72: 849–858.Google Scholar) and analysis of subclasses of IgG (5Honger G Hopfer H Arnold ML Spriewald BM Schaub S Amico P Pretransplant IgG subclasses of donor-specific human leukocyte antigen antibodies and development of antibody-mediated rejection.Transplantation. 2011; 92: 41-47Crossref PubMed Scopus (83) Google Scholar). One would expect that evidence of tissue injury would be valuable in this assessment either by morphology, immunopathology or gene expression (6Sis B Jhangri GS Bunnag S K Allanach Kaplan B Halloran PF Endothelial gene expression in kidney transplants with alloantibody indicates antibody-mediated damage despite lack of C4d staining.Am J Transplant. 2009; 9: 2312-2323Abstract Full Text Full Text PDF PubMed Scopus (392) Google Scholar). Other questions arise from this paper. How should patients that have developed dnDSA be treated? Randomized controlled clinical trials will be needed to reveal the optimal management and whether new immunosuppressive agents, eculizumab or belatacept, will be useful in treatment or prevention of chronic antibody-mediated rejection. Should allocation strategies be reevaluated in light of lowering rates of dnDSA production by better HLA-DR matching? This paper is an important first step in identifying the issues. Chronic antibody-mediated rejection is a challenge for diagnosis, because the disease evolves slowly (years), has fluctuating pathology (e.g. C4d) and has a variable course. Not all cases have detectable C4d or DSA at any particular time. Despite these limitations, it is clear that dnDSA can be the first sign to damage below the waterline in otherwise stable patients and deserves further attention by the transplant community. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

Introduction: Abdominal compartment syndrome is a phenomenon frequently described in the trauma and critical care literature. Renal allograft compartment syndrome (RACS) has been recognized after renal transplantation, but is not widely reported. The mechanism of RACS is attributed to retroperitoneal hypertension secondary to anatomic restrictions and accompanying edema, resulting in allograft compression, ischemia and dysfunction. Prompt recognition and early open surgical decompression are required to salvage graft function. Methods: We describe a case of RACS, in a patient previously on peritoneal dialysis, which resulted from the accumulation of a large amount of intraperitoneal fluid and was successfully treated without open surgical decompression. Results: After an initial 36-hour period of excellent allograft function and improving serum creatinine, severe oliguria and a rising serum creatinine developed unexpectedly. Doppler ultrasound findings were consistent with RACS, revealing adequate arterial and venous blood flow, but severely decreased diastolic flow within the intrarenal arteries. A significant amount of intraperitoneal fluid was identified in the absence of any perigraft collection or hematoma. A percutaneous kidney transplant biopsy performed on the fourth post-operative day demonstrated normal renal architecture without any evidence of rejection. A focal area of acute interstitial nephritis was noted, as well as focal tubular changes consistent with acute tubular necrosis (ATN) and regeneration. Immediately after the biopsy procedure, the perinephric drain output increased drastically, producing copious amounts of serous fluid drainage with a creatinine identical to the serum creatinine level, and there was a subsequent increase in urine production. A repeat duplex ultrasound revealed marked improvement in diastolic blood flow and almost no residual intraperitoneal fluid. Recovery of renal allograft function was evidenced by sustained urine output and the return of a consistent decline in serum creatinine. Conclusion: We conclude that RACS should be considered when initially well-established allograft function abruptly deteriorates and more common causes of early dysfunction have already been excluded. Doppler ultrasound can assist in making a timely diagnosis. While early intervention is typically required to salvage allograft function before irreversible damage occurs, open surgical decompression may not always be necessary.

For patients with chronic renal and liver diseases, simultaneous liver and kidney transplantation (SLKT) is the best therapeutic option. The role of a pretransplant donor-specific antibody (DSA) in SLKT is unclear. We report the results of a retrospective review from 7/08 to 10/09 of SLKT at our institution. Monitoring of DSA was performed using single antigen bead assay. Between 7/08 and 10/09, there were six SLKT who had preformed DSA and positive XM (four class I and II DSA, one class I DSA only, one class II only). One-year patient and renal graft survival was 83%. Death-censored liver allograft survival was 100%. Acute humoral rejection (AHR) of the kidney occurred in 66% (three with both class I and II DSA and one with only class II DSA) of patients. In those with AHR, class I antibodies were rapidly cleared (p < 0.01) while class II antibodies persisted (p = 0.25). All patients who had humoral rejection of their kidney had preformed anticlass II antibodies. Liver allografts may not be fully protective of the renal allograft, especially with pre-existing MHC class II DSA. Long-term and careful follow-up will be critical to determine the impact of DSA on both allografts.

Kokko, K. E.; Farnon, E.; Butt, F. K.; Hawxby, A. M.; Fratkin, J.; Seawright, A. H.; Shieh, W.; Dasilva, A.; Visvesvara, G.; Zaki, S.; Kuehnert, M. O.B.O. the Balamuthia Transplant Investigation Team Author Information

The Page kidney phenomenon is a well recognized entity where an extrinsically compressed kidney results in hypertension and loss of function. This compression is usually caused by a subcapsular hematoma secondary to blunt abdominal trauma or an invasive procedure such as a renal biopsy. We describe an unusual case involving the spontaneous development of a Page kidney 24 days after renal transplantation without any history of preceding trauma. The subcapsular hematoma was detected by a computerized tomographic scan performed as part of the work-up for acute allograft dysfunction. Prompt recognition and early intervention are essential if renal function is to be restored before irreversible damage occurs.

1Surgery, University of Mississippi Medical Center, Jackson/MS/UNITED STATES OF AMERICA, 2Medicine, University of Mississippi Medical Center, Jackson/MS/UNITED STATES OF AMERICA

In this issue of AJT, Locke et al. (1Locke JE Zachary AA Warren DS et al.Proinflammatory events are associated with significant increases in breadth and strength of HLA –specific antibody.Am J Transplant. 2009; Abstract Full Text Full Text PDF Scopus (101) Google Scholar) report that proinflammatory events, ranging from bacterial infections to myocardial infarctions, are associated with an increase in the breadth and strength of HLA antibodies among patients previously sensitized to HLA antigens. While suspected for years, descriptions of this relationship were all anecdotal. As the first report to assess the data scientifically, Locke et al. have presented reasonable evidence to conclude that the suspicions were true. The question now is what to do with this information. The authors advocate more frequent monitoring of highly sensitized patients, citing that such antibodies in transplant recipients are associated with higher rates of rejection and graft loss compared to unsensitized patients. However, these data were collected prior to the development of sensitive solid phase techniques and likely represent a failure to have detected donor specific antibodies (DSA) pretransplant. More recent data reveals that highly sensitized patients without DSA have graft survival essentially identical to unsensitized patients (2Bray RA Nolen JD Larsen C et al.Transplanting the highly sensitized patient: The Emory algorithm.Am J Transplant. 2006; 6: 2307-2315Crossref PubMed Scopus (176) Google Scholar). Nonetheless, the appearance (or reappearance) of DSA in a transplant recipient may be a reason for concern and an impetus to initiate aggressive therapy to prevent graft rejection (3Burns JM Cornell LD Perry DK et al.Alloantibody levels and acute humoral rejection early after positive crossmatch kidney transplantation.Am J Transplant. 2008; 8: 2684-2694Crossref PubMed Scopus (180) Google Scholar). However, others report that DSA positive patients with stable renal function (4Bartel G Regele H Wahrmann M et al.Posttransplant HLA alloreactivity in stable kidney transplant recipients – Incidences and impact on long-term allograft outcomes.Am J Transplant. 2008; 8: 2652-2660Crossref PubMed Scopus (58) Google Scholar) and no episodes of antibody mediated rejection (5Lefaucheur C Suberbielle-Boissel C Hill GS et al.Clinical relevance of preformed HLA donor specific antibodies in kidney transplantation.Am J Transplant. 2008; 8: 324-331Crossref PubMed Scopus (183) Google Scholar), have excellent graft function/survival and caution not to regard DSA as problematic unless there is graft dysfunction. Currently, the patients most likely to be at risk for early posttransplant development of DSA are those patients who had DSA prior to transplant and underwent desensitization (3Burns JM Cornell LD Perry DK et al.Alloantibody levels and acute humoral rejection early after positive crossmatch kidney transplantation.Am J Transplant. 2008; 8: 2684-2694Crossref PubMed Scopus (180) Google Scholar). Such patients are already being monitored closely since they are known to be at risk for adverse outcomes. Would they benefit from more frequent monitoring if they experience a proinflammatory event posttransplant? Perhaps, although it is unknown whether increase in antibody activity after a proinflammatory event are sustainable and/or clinically relevant. Locke et al. did not indicate whether the 23 patients transplanted across a positive crossmatch who experienced a proinflammatory event and had an increase in the breadth and strength of HLA antibodies had a worse outcome compared to 19 positive crossmatch patients without a documented inflammatory event. Other important groups of patients to consider are those who are unsensitized and those who, while sensitized, are transplanted without any history of DSA. Do these categories of patients need frequent monitoring for de novo DSA anytime they experience an infection or other proinflammatory event? As Locke et al. reported, the increased breadth of HLA activity following an inflammatory event was due to an expansion of antibodies within the same cross reactive group (CREG) as antibodies previously detected in the patient and not to the development of ‘new’ antibodies, As an example, consider two patients with well defined antibodies; one moderately sensitized (current PRA = 47%), the other, highly sensitized (current PRA = 87% PRA). The antibodies identified in the highly sensitized patient have been stable over a three- year period (certainly a time frame when a proinflammatory event is likely to have occurred) and never included specificities (private or CREG) against donor antigens. In contrast, antibodies in the moderately sensitized patient have waxed and waned during that same time frame and while none of the antibodies appeared to be donor directed, they were against the same CREG as one of the mismatched donor antigens. Do both patients require increased antibody monitoring after an inflammatory event? As Locke et al. note, >80% of renal transplant recipients develops an infection during their first posttransplant year. Importantly, the overall rate of antibody-mediated rejection in these patients is less than 5%. Unquestionably, Locke et al. raise an interesting and potentially important association between proinflammatory events and the subsequent expression of HLA antibodies. However, based on the sheer number of inflammatory events that can occur, the diversity of patients receiving transplants (sensitized, unsensitized and desensitized) and the unknown duration, stability and clinical significance of the antibodies that develop are major variables that should be considered. Prospective outcome studies are needed before routine monitoring for HLA antibodies postinflammation can be endorsed.

Shen, L; Agarwal, A; Turgeon, N; Pearson, T; Larsen, C; Bray, R; Gebel, H; Kirk, A; Kokko, K Author Information

Agarwal, A; Metha, A; Turner, A; Kokko, K; Turgeon, N; Tso, P; Newell, K; Larsen, C; Kirk, A Author Information