The Histological Spectrum and Clinical Significance of T Cell-mediated Rejection of Kidney Allografts.

T cell-mediated rejection (TCMR) remains a significant cause of long-term kidney allograft loss, either indirectly through induction of donor-specific anti-HLA alloantibodies or directly through chronic active TCMR. Whether found by indication or protocol biopsy, Banff defined acute TCMR should be treated with antirejection therapy and maximized maintenance immunosuppression. Neither isolated interstitial inflammation in the absence of tubulitis nor isolated tubulitis in the absence of interstitial inflammation results in adverse outcomes, and neither requires antirejection treatment. RNA gene expression analysis of biopsy material may supplement conventional histology, especially in ambiguous cases. Lesser degrees of tubular and interstitial inflammation (Banff borderline) may portend adverse outcomes and should be treated when found on an indication biopsy. Borderline lesions on protocol biopsies may resolve spontaneously but require close follow-up if untreated. Following antirejection therapy of acute TCMR, surveillance protocol biopsies should be considered. Minimally invasive blood-borne assays (donor-derived cell-free DNA and gene expression profiling) are being increasingly studied as a means of following stable patients in lieu of biopsy. The clinical benefit and cost-effectiveness require confirmation in randomized controlled trials. Treatment of acute TCMR is not standardized but involves bolus corticosteroids with lymphocyte depleting antibodies for severe, refractory, or relapsing cases. Arteritis may be found with acute TCMR, active antibody-mediated rejection, or mixed rejections and should be treated accordingly. The optimal treatment ofchronic active TCMR is uncertain. Randomized controlled trials are necessary to optimally define therapy.

Histologic Antibody-mediated Kidney Allograft Rejection in the Absence of Donor-specific HLA Antibodies.

Histologic antibody-mediated rejection (hAMR) is defined as a kidney allograft biopsy satisfying the first 2 Banff criteria for diagnosing AMR: tissue injury and evidence of current/recent antibody interaction with the endothelium. In approximately one-half of such cases, circulating human leukocyte antigen (HLA) donor-specific antibodies (DSA) are not detectable by current methodology at the time of biopsy. Some studies indicated a better prognosis for HLA-DSA-negative cases of hAMR compared to those with detectable HLA-DSA, whereas others found equally poor survival compared to hAMR-negative cases. We reviewed the literature regarding the pathophysiology of HLA-DSA-negative hAMR. We find 3 nonmutually exclusive possibilities: (1) HLA-DSA are involved, but just not detected; (2) non-HLA-DSA (allo or autoantibodies) are pathogenically involved; and/or (3) antibody-independent NK cell activation is mediating the process through "missing-self" or other activating mechanisms. These possibilities are discussed in detail. Recommendations regarding the approach to such patients are made. Clearly, more research is necessary regarding the measurement of non-HLA antibodies, recipient/donor NK cell genotyping, and the use of antibody reduction therapy or other immunosuppression in any subset of patients with HLA-DSA-negative hAMR.

The Monitoring of Donor-derived Cell-free DNA in Kidney Transplantation.

Cell-free DNA (cfDNA) exists in plasma and can be measured by several techniques. It is now possible to differentiate donor-derived cfDNA (ddcfDNA) from recipient cfDNA in the plasma or urine of solid organ transplant recipients in the absence of donor and recipient genotyping. The assessment of ddcfDNA is being increasingly studied as a noninvasive means of identifying acute rejection (AR) in solid organ transplants, including subclinical AR. We herein review the literature on the correlation of ddcfDNA with AR in kidney transplantation. There have been at least 15 observational studies that have assessed ddcfDNA in urine or plasma using various methodologies with various thresholds for abnormality. Overall, elevated ddcfDNA indicates allograft injury as may occur with AR, infection, or acute tubular injury but may also be found in clinically stable patients with normal histology. Sensitivity is greater for antibody-mediated AR than for cell-mediated AR, and normal levels do not preclude significant cell-mediated rejection. Measurement of ddcfDNA is not a replacement for biopsy that remains the gold standard for diagnosing AR. Serial monitoring of stable patients may allow earlier detection of subclinical AR, but the efficacy of this approach remains to be established. Normal levels should not preclude planned protocol biopsies. There may be roles for following ddcfDNA levels to assess the adequacy of treatment of AR and to guide the intensity of immunosuppression in the individual patient. Randomized controlled trials are necessary to validate the benefit and cost-effectiveness for these various uses. No firm recommendations can be made at this time.

The Problem of Subclinical Antibody-mediated Rejection in Kidney Transplantation.

Defined as histologic evidence of rejection on a protocol biopsy in the absence of kidney dysfunction, subclinical rejection has garnered attention since the 1990s. The major focus of much of this research, however, has been subclinical T cell-mediated rejection (TCMR). Herein, we review the literature on subclinical antibody-mediated rejection (AMR), which may occur with either preexisting donor-specific antibodies (DSA) or upon the development of de novo DSA (dnDSA). In both situations, subsequent kidney function and graft survival are compromised. Thus, we recommend protocol biopsy routinely within the first year with preexisting DSA and at the initial detection of dnDSA. In those with positive biopsies, baseline immunosuppression should be maximized, any associated TCMR treated, and adherence stressed, but it remains uncertain if antibody-reduction treatment should be initiated. Less invasive testing of blood for donor DNA or gene profiling may have a role in follow-up of those with negative initial biopsies. If a protocol biopsy is positive in the absence of detectable HLA-DSA, it also remains to be determined whether non-HLA-DSA should be screened for either in particular or on a genome-wide basis and how these patients should be treated. Randomized controlled trials are clearly needed.

The Implications of B-lineage Cells in Kidney Allografts.

The majority of cells comprising the inflammatory infiltrates in kidney allografts undergoing acute and/or chronic rejection are typically T cells and monocyte/macrophages with B cells, plasma cells, and eosinophils accounting for <5%. In a significant minority of biopsies, B lineage cells (B cells and/or plasma cells) may be found more abundantly. Although plasma cell infiltrates tend to be more diffuse, B cells tend to aggregate into nodules that may mature into tertiary lymphoid organs. Given the ability to target B cells with anti-CD20 monoclonal antibodies and plasma cells with proteasome inhibitors and anti-CD38 monoclonal antibodies, it is increasingly important to determine the significance of such infiltrates. Both cell types are potential effectors of rejection, but both also have a tolerizing potential. B cell infiltrates have been associated with steroid resistance and reduced graft survival in some studies but not in others, and their presence should not prompt automatic depletional therapy. Plasma cell-rich infiltrates tend to occur later, may be associated with cell-mediated and/or antibody-mediated rejection, and portend an adverse outcome. Viral infection and malignancy must be ruled out. Randomized controlled trials are needed to determine the appropriateness of specific therapy when B cells and/or plasma cells are found. No strong therapeutic recommendations can be made at this time.

Venous cystic adventitial disease of the common femoral vein.

Venous adventitial cystic disease is a rare condition with few reports previously described. We report the case of a 39-year-old female who presented with left lower extremity edema, acutely exacerbated by exercise. Imaging revealed a hypoechoic mass posterior to her left common femoral vein. Open surgical excision and evacuation was performed with resolution of symptoms within 24 hours. A review of the literature is discussed, along with presentation, diagnosis, treatment, and pathology of this intriguing condition.