Edward J. Filippone

Humoral Immune Response and Allograft Function in Kidney Transplantation

HLA antibodies can damage a kidney transplant. In January 2013, consensus guidelines from The Transplantation Society were published regarding technical aspects of HLA antibody determination, as well as their potential significance in the pre- and posttransplantation periods. During the past 2 years, new studies have been reported, but controversies remain. In this article, these new data related to HLA antibodies in kidney transplantation are reviewed and compared to relevant prior research. Pretransplantation sensitization issues are discussed, including the new more sensitive assays (flow cytometry and solid-phase immunoassays such as Luminex single-antigen bead assays). A positive complement-dependent cytotoxicity crossmatch remains an absolute contraindication to transplantation, although a positive flow cytometry crossmatch is only a relative contraindication. Positivity only by solid-phase assays increases the risk for acute rejection and transplant loss, but acceptable cutoffs are not defined. The sensitizing effect of red blood cell transfusions is substantiated. Following allograft failure, continued immunosuppression decreases the risk of sensitization, whereas overall, the effect of nephrectomy remains uncertain. Regarding the posttransplantation period, new data are available concerning the timing and significance of donor-specific antibodies (DSA). Whereas some centers report DSA appearance after years, others detect DSA within months. The prominence of class II DSA, especially DQ, in the posttransplantation period is noted. The relevance of non-HLA antibodies is discussed, including anti-endothelial cell antibodies, major histocompatibility complex class I chain-related protein A antibodies, and angiotensin II type 1 receptor autoantibodies.

Segmental Arterial Mediolysis: Report of 2 Cases and Review of the Literature

Segmental arterial mediolysis (SAM) is an idiopathic noninflammatory vasculopathy involving small to medium arteries, usually in the abdomen, although arteries in the cerebral and coronary circulations also may be affected. Some cases present as abdominal apoplexy due to aneurysmal rupture, but ischemia and infarction also occur. Not uncommonly, SAM may be misdiagnosed as a systemic necrotizing vasculitis. We present 2 patients with bilateral renal infarctions, cerebral arterial dissections, and visceral artery microaneurysms. Both were diagnosed initially as polyarteritis nodosa. The diagnosis was changed to SAM, in one case based on clinical and radiologic features, and in the other, on an open wedge kidney biopsy. We discuss the differential diagnosis and review the literature on SAM.

Sensitization trends after renal allograft failure: the role of DQ eplet mismatches in becoming highly sensitized.

Sensitization following renal allograft failure (AF) is highly variable. Some patients remain non‐sensitized (NS), while others become highly sensitized (HS). We studied 66 NS patients who experienced AF after initial kidney transplantation. Post‐failure, two main groups of NS panel reactive antibody (PRA) class I and II <10% and HS patients (PRA class I or II ≥80%) were identified. The impact of acute rejection (AR), immunosuppression withdrawal (ISW) at AF, allograft nephrectomy, graft intolerance syndrome (GIS), and both standard serologic and eplet‐based mismatches (MM) in inducing HS status after failure was examined. Late PRA testing post‐failure revealed 18 patients remained NS and 34 patients became HS. African American recipients, ISW at AF, DQB1 eplet MM, and presence of GIS were associated with becoming HS. Presence of total zero eplet MM, zero DQA1/B1 eplet MM, continuation of immunosuppression after failure, and a hyporesponsive immune status characterized by recurrent infections were features of NS patients. DQ eplet MM represents a significant risk for becoming HS after AF. Studies comparing ISW vs. continuation in re‐transplant candidates with high baseline DQ eplet MM burden should be performed. This may provide insights if sensitization post‐AF can be lessened.

The Nephrotoxicity of Vancomycin

Vancomycin use is often associated with nephrotoxicity. It remains uncertain, however, to what extent vancomycin is directly responsible, as numerous potential risk factors for acute kidney injury frequently coexist. Herein, we critically examine available data in adult patients pertinent to this question. We review the pharmacokinetics/pharmacodynamics of vancomycin metabolism. Efficacy and safety data are discussed. The pathophysiology of vancomycin nephrotoxicity is considered. Risk factors for nephrotoxicity are enumerated, including the potential synergistic nephrotoxicity of vancomycin and piperacillin‐tazobactam. Suggestions for clinical practice and future research are given.

Humoral immunity in renal transplantation: epitopes, Cw and DP, and complement-activating capability – an update

Humoral immune responses can destroy a renal allograft. In January 2013, Consensus Guidelines were published regarding testing and management concerns with respect to antibodies in transplantation. New studies have been reported over the past two yr and controversies remain. We review here the new data in light of the Consensus Guidelines and the relevant prior research with emphasis on antibody characteristics and potential for pathogenicity. The heart of immune recognition, epitopes, is stressed, including the realization that DQ (and probably DP) epitopes may be determined not only by eplets within a given α‐ or β‐chain, but also by specific α‐ and β‐chain pairings. The significance of Cw and DP loci are discussed. To better understand which donor‐specific antibodies are pathogenic, IgG subclass determination has been studied, and in in vitro complement fixation assays, such as the C4d and C1q assays, have been evaluated.

Goal-directed antihypertensive therapy: lower may not always be better.

At least 16 treatment trials have been done in which patients were randomly assigned different blood pressure goals in an attempt to better define specific target pressures. We critically review the data. At least 16 trials have been done in which patients were randomly assigned different blood pressure goals. Surprisingly, they did not show that a lower target offered significant clinical benefit, and they suggest the potential for harm.

Normoglycemic Diabetic Nephropathy: The Role of Insulin Resistance

The pathophysiology of diabetic nephropathy (DN) is complex and incompletely understood. Whereas hyperglycemia is clearly important, the role of insulin resistance (IR) is increasingly recognized. We present the case of a normotensive non-smoking obese woman with nephrotic syndrome who was found to have DN by biopsy. All measures of glucose metabolism, including fasting glucose, glycosylated hemoglobin, and oral glucose tolerance testing, were repeatedly normal with little exception. IR was documented, however, based on the presence of the metabolic syndrome and an elevated homeostasis model assessment of IR. We posit that this IR is central to the pathogenesis of our patients lesion, and this may explain other cases of DN with normoglycemia. The literature supporting this concept is discussed.

Idiopathic membranous nephropathy and IgG4: an interesting relationship.

Idiopathic membranous nephropathy (iMN) is a single-organ autoimmune disease characterized by subepithelial deposition of immune complexes containing IgG4 resulting in proteinuria, nephrotic syndrome, and, in some, end-stage renal disease. The pathogenesis involves a chronic IgG4 response against specific podocyte antigens which have now been at least partially defined in the neonatal, early childhood, and adult varieties. More has recently been learned about the genetic predisposition as well. This review discusses the pathophysiology of iMN in light of these discoveries and what is known about the genesis and potential clinical ramifications of an antigen-specific IgG4 response.

Tacrolimus-induced thrombotic microangiopathy: natural history of a severe, acute vasculopathy.

Calcineurin inhibitors (CNI) have been clearly associated with posttransplant thrombotic microangiopathy (PTTMA). We report a case of de novo PT-TMA involving predominantly small arteries and arterioles of a renal allograft in a patient receiving tacrolimus. Serial biopsies demonstrate the natural history of this lesion through the chronic nonspecific phase. The case is discussed in the context of a literature review of PT-TMA in general and CNI use in particular.

Membranous nephropathy in the kidney allograft

Membranous nephropathy (MN) may occur in a kidney transplant as recurrence of the original disease (rMN) or as a de novo MN (dnMN). rMN often occurs early, within the first year, and often in a mild or subclinical fashion. Recurrence cannot be predicted by clinical features at the time of transplantation. The natural history is increasing proteinuria over time, with less chance for spontaneous remission compared to primary MN (pMN). Antiphospholipase A2 receptor (PLA2R) antibodies should be evaluated in all patients with pMN at the time of transplantation and serially. If titers persist or rise, biopsy is indicated. Irrespective of PLA2R status, any case with proteinuria reaching 1 g/day should be biopsied. No randomized controlled trials have been published regarding treatment of rMN. Observational data support use of rituximab. Given the progressive nature of rMN and lack of spontaneous remissions, a period of observation does not seem justifiable. dnMN occurs with about equal frequency as rMN and shares features of secondary MN in native kidneys. Causes include viral infections (e.g., hepatitis B or C), which should be treated. In some cases, dnMN may represent an atypical alloimmune response. The role of rituximab in dnMN is undefined.