Lillian W. Gaber

Donor-specific HLA-DQ antibodies may contribute to poor graft outcome after renal transplantation

Increasing evidence suggests a detrimental effect of donor-specific antibodies directed against the human leukocyte antigen (HLA)-A, -B, and -DR loci on renal allograft outcomes. Limited data exist on the impact of de novo HLA-DQ antibodies. Over a 3-year period, we prospectively monitored 347 renal transplant recipients without pre-transplant donor-specific antibodies for their development de novo. After 26 months of follow-up, 62 patients developed donor-specific antibodies, of which 48 had a HLA-DQ antibody either alone (33 patients) or in combination with an HLA-A, -B, or -DR antibody (15 patients). Only 14 patients developed a donor-specific HLA-A, -B, or -DR antibody without a HLA-DQ antibody present. Acute rejection occurred in 21% of the HLA-DQ-only patients, insignificant when compared with 11% of patients without donor-specific antibodies. At the last follow-up, the mean serum creatinine and the fraction of patients with proteinuria were significantly higher in those that developed only HLA-DQ than those without antibodies. The 3-year graft survival was significantly worse when HLA-DQ antibodies were combined with non-DQ antibodies (52%) compared with HLA-DQ alone, non-DQ antibodies alone, or no antibodies (92-94%). Thus, our prospective monitoring study found that donor-specific HLA-DQ antibodies were the most common type detected and these antibodies may contribute to inferior graft outcomes. Ongoing surveillance is necessary to determine the long-term outcome of patients developing HLA-DQ donor-specific antibodies.

A Review of the Evidence for Use of Thymoglobulin Induction in Renal Transplantation

Depleting antilymphocyte, or antithymocyte antibodies, have long been an integral part of induction regimens and continue today to be used in the management of patients at risk of early rejection or those in whom the introduction of calcineurins or other immune suppressants must be delayed. Registry data demonstrate that the most commonly used depleting antibody, rabbit anti-human thymocyte globulin (rATG), is associated with improved outcomes following renal transplantation in high-risk patients, particularly in conjunction with steroid-avoidance regimens. Two prospective randomized trials in high-risk renal allograft patients have also demonstrated an advantage of r-ATG induction compared to the nondepleting interleukin receptor (IL2RA) antibodies. In low-immunologic-risk patients, however, r-ATG induction and IL2RA induction appear to be equivalent in terms of rejection prophylaxis and long-term function. Other studies have shown that sequential rATG-containing regimens were superior to no induction and allowed for successful late introduction of calcineurin inhibitors. The side effect profile of the depleting antibody included increased incidence of fever, hematologic abnormalities, cytomegalovirus infections when prophylaxis was not employed, and in some studies, increased incidence of posttransplant lymphoproliferative disease. This review describes the evidence supporting the use of depleting ATGs in kidney transplantation.

Osteocalcin protects against nonalcoholic steatohepatitis in a mouse model of metabolic syndrome.

Nonalcoholic fatty liver disease, particularly its more aggressive form, nonalcoholic steatohepatitis (NASH), is associated with hepatic insulin resistance. Osteocalcin, a protein secreted by osteoblast cells in bone, has recently emerged as an important metabolic regulator with insulin-sensitizing properties. In humans, osteocalcin levels are inversely associated with liver disease. We thus hypothesized that osteocalcin may attenuate NASH and examined the effects of osteocalcin treatment in middle-aged (12-mo-old) male Ldlr(-/-) mice, which were fed a Western-style high-fat, high-cholesterol diet for 12 weeks to induce metabolic syndrome and NASH. Mice were treated with osteocalcin (4.5 ng/h) or vehicle for the diet duration. Osteocalcin treatment not only protected against Western-style high-fat, high-cholesterol diet-induced insulin resistance but substantially reduced multiple NASH components, including steatosis, ballooning degeneration, and fibrosis, with an overall reduction in nonalcoholic fatty liver disease activity scores. Further, osteocalcin robustly reduced expression of proinflammatory and profibrotic genes (Cd68, Mcp1, Spp1, and Col1a2) in liver and suppressed inflammatory gene expression in white adipose tissue. In conclusion, these results suggest osteocalcin inhibits NASH development by targeting inflammatory and fibrotic processes.

Observations on the use of cidofovir for BK virus infection in renal transplantation

In renal transplantation, BK virus infection can result in significant graft nephropathy and loss. While reduction in immunosuppression (IS) is considered standard therapy, adjunct agents may be warranted. Data are suggestive of a possible role of cidofovir for the management of BK. This study aims to describe the course of BK viremia (BKV) in a large cohort of renal transplant patients receiving adjunct cidofovir.

Considerations in sirolimus use in the early and late post-transplant periods

Sirolimus is an antiproliferative immunosuppressive agent that inhibits the mammalian target of rapamycin. It is highly effective in preventing acute renal allograft rejection and can be used with either calcineurin inhibitors, antimetabolites or corticosteroids. Early studies in renal transplantation have provided insight into optimal dosing strategies of sirolimus and of concomitant immunosuppressive agents. Familiarity with the adverse effect profile of sirolimus and pharmacokinetic and dynamic interactions with other immunosuppressive agents allows for earlier recognition and better management of sirolimus-related complications. The role of sirolimus in preserving long-term renal function, post-transplant malignancies and in prevention of atherosclerosis is currently being considered.

Tubulointerstitial nephritis in systemic lupus erythematosus: innocent bystander or ominous presage.

SLE-associated tubulointerstitial injury (SLE TIN) is increasingly recognized in two forms, i.e., secondary and primary. The secondary form coexists with lupus glomerulonephritis, whereas the primary form develops against the background of no or mild glomerular or vascular involvement. Secondary SLE TIN is frequent, but its frequency and severity correlate with the class of the associated lupus glomerulonephritis (GN), being almost universal in Class IV lupus GN and less frequent in GN of other classes. Although the presence of underlying GN may mask its clinical manifestation, secondary SLE TIN has a major prognostic implication for the renal outcome. Yet, SLE TIN is not factored in the current therapy-focused International Society of Nephrology/Renal Pathology Society schema of renal lupus classification, and its management remains to be elucidated. The pathogenesis of secondary SLE TIN is either immunologic, i.e., the tubulointerstitial injury being mediated by SLE-related immunologic mechanisms akin to those responsible for lupus GN; or non-immunologic, i.e., a nonspecific tubulointerstitial injury secondary to any type of advanced glomerular lesion, regardless of etiology. Primary SLE TIN is rare with about 15 reported cases. It has a rather uniform and distinctive clinical manifestation including acute kidney injury with no or mild proteinuria. It responds well to steroid and usually carries a good prognosis. Its pathogenesis is almost certain immunologic, with immunoglobulin/complement deposits along the tubular basement membrane in each reported case. In spite of these profound clinical implications, the current review underlies a limited knowledge on the pathobiology of SLE TIN.

Outcomes of living donor renal transplants with a negative cross-match and pretransplant donor-specific antibody

INTRODUCTIONnManagement of renal transplant recipients with a negative complement-dependent cytotoxicity-antihuman globulin (CDC-AHG) cross-match and pretransplant donor-specific antibody (DSA) is controversial. We sought to compare outcomes of immunologically high-risk living donor (LD) renal transplant recipients with and without DSA.nnnMETHODSnWe conducted a single-center, retrospective review of all high immune-risk LD renal transplant recipients with a negative CDC-AHG cross-match performed between January 2008 and December 2010. Pretransplant desensitization for DSA was not utilized. Immunosuppression consisted of thymoglobulin induction, followed by tacrolimus, myeophenolate mofetil, and prednisone. DSA was assessed pretransplant and at 1, 3, 6, 9, and 12 months, and every 6 months thereafter.nnnRESULTSnBetween January 2008 and December 2010, 44 LD renal transplants were performed in high immune-risk recipients with a negative CDC-AHG cross-match. Outcomes of 14 recipients with pretransplant DSA were compared with 30 recipients with no DSA. After a median follow-up of 26 months (range, 12-40), overall death-censored graft survival was 100%, with no acute rejection episodes in the DSA group and 1 antibody-mediated rejection in the non-DSA cohort. Mean serum creatinines of the DSA and non-DSA groups at 1 year post-transplant were 1.0 ± 0.4 and 1.2 ± 0.6 mg/dL (P = NS), respectively. Among the pretransplant DSA cohort, 5 of the 14 (36%) developed persistent post-transplant DSA at a median of 9 months (range, 3-24) versus 2 of 30 (7%; P = .025) at a median of 12 months post-transplant in the non-DSA cohort. All recipients in the pretransplant DSA group underwent renal biopsy for persistent post-transplant DSA. Three of 5 biopsies showed C4D deposition in peritubular capillaries without glomerulopathy or arteriopathy.nnnCONCLUSIONSnEarly post-transplant outcomes for LD recipients with a negative cross-match and pretransplant DSA were excellent. In recipients with good and stable renal function, the significance of persistent post-transplant DSA in combination with C4D deposition on biopsy is unclear at this time.

A Surgeons' Guide to Renal Transplant Immunopathology, Immunology, and Immunosuppression

The response to allografting involves adaptive and innate immune mechanisms. In the adaptive system, activated T cells differentiate to cytotoxic effectors that attack the graft and trigger B cells to differentiation to plasma cells that produce anti-HLA antibodies. The innate immune system recognizes antigens in a non-specific manner and recruits immune cells to the graft through the productions of chemotactic factors, and activation of cytokines and the complement cascade. In the kidney the tubules and the endothelium are the targets of the rejection response. Immune suppression is effective in modulating the adaptive immune system effect on graft histology.

Profound nephrotic syndrome in a patient with ovarian teratoma

The nephrotic syndrome (NS) has been associated with a variety of malignancies in a number of reports in the literature, but has been reported in only nine cases associated with ovarian neoplasms. Membranous nephropathy is the most common glomerular pathology causing the NS in patients with solid tumors. There has been only one report of an ovarian neoplasm associated with minimal change disease (MCD). We describe the case of a 36-year-old woman who presented with the NS secondary to biopsy-proven MCD, likely secondary to mature ovarian teratoma. Treatment by tumor removal and prednisone led to remission of the NS. To the best of our knowledge, this is the first report of an ovarian teratoma and the second report of an ovarian neoplasm associated with MCD.