Search

BackgroundMedication non-adherence is a risk factor for acute kidney transplant rejection. The association of non-adherence with short-term allograft loss in patients who develop acute rejection and are subsequently treated with maximal therapy is unknown.MethodsWe conducted a retrospective single center cohort study of adult patients who developed acute rejection from January 2003 to December 2017 and were treated with lymphocyte depletion. Clinicopathologic characteristics including adherence status were collected and descriptive statistics utilized to compare groups. The primary outcome was all-cause graft loss at 6 months after acute rejection treatment. A multivariable logistic regression quantified the association of non-adherence with the outcome.ResultsA total of 182 patients were included in the cohort, of whom 71 (39%) were non-adherent. Compared to adherent patients, non-adherent patients were younger (mean age 37y vs 42y), more likely to be female (51% vs 35%) and developed acute rejection later (median 2.3y vs 0.5y from transplant). There were no differences in estimated glomerular filtration rate or need for dialysis on presentation, Banff grade, or presence of antibody mediated rejection between the 2 groups. Overall, 48 (26%) patients lost their grafts at 6 months after acute rejection treatment. In adjusted analysis, non-adherence was associated with all-cause graft loss at 6 months after acute rejection treatment [OR 2.64 (95% CI 1.23–5.65,p = 0.012].ConclusionsAfter adjusting for common confounders, non-adherent patients were at increased risk for short-term allograft loss after a severe acute rejection despite lymphocyte depletion. This finding may aid clinicians in risk stratifying patients for poor short-term outcomes and treatment futility.

The advent of generic alternatives for transplant immunosuppressant drugs has engendered concern and discussion. The process by which the food and drug administration (FDA) approves generic substitutes is reviewed. A category of medicines defined as narrow therapeutic index (NTI) drugs is defined with evidence that many (but not all) of the commonly used transplant medications fall into this category. It is demonstrated that the current FDA standards are inadequate to vet NTI agents. Outcomes data are presented that show generic switching for NTI drugs can be successfully accomplished with careful blood level monitoring, but clinical and financial negative consequences can flow from unregulated switching. Recommendations are made for provider use of generic immunsuppressants, for recipient education and response to switching, and for pharmacy shandling of generic alternatives.

At a time when the judicious use of a broad range of immunosuppressive drugs has ensured excellent patient and organ survival rates after kidney transplantation, attention is focusing on strategies to minimize their side effects. Almost all immunosuppressive medications are associated with some form

The United States end-stage renal disease (ESRD) population is growing progressively older. As a percentage of the overall ESRD population, the number of patients 65 years of age and older approached 40% by 1989. However, the percentage of ESRD patients with a functioning transplant was only 2.7% in this age group. Success of transplantation in geriatric ESRD patients over the last decade is due to improved patient selection as well as the use of cyclosporine A and lower doses of corticosteroids, with the achievement of 1-year patient and graft survival rates of 85% and 75%, respectively. For patients older than 60 or 65 years, the 5-year "functional" graft survival is 55% to 60%. Although overall results are excellent, the management of transplantation in the elderly requires an understanding of pharmacology, immunology, and physiology peculiar to this age group. Since the elderly have a degree of immune incompetence, they require less aggressive immunotherapy. Elderly patients have decreased hepatic enzyme activity, especially the P450 system, and therefore require a lower cyclosporine dose. Although elderly patients experience less rejection episodes than younger patients, graft loss in the elderly transplant recipient is due mainly to patient death. Most common causes of death in the elderly transplant recipient are cardiovascular disease and infection related to peaks of immunosuppression. Shortage of cadaver kidneys and limited life expectancy of the geriatric ESRD patient make allocation of cadaver kidneys to patients over 70 years (and even 65 years) a controversial issue and an ethical dilemma. Use of elderly cadaver donors (over 55 to 60 years) is associated with inferior success rates and is not an optimal solution to shortage of cadaver kidneys.

Although considerable advances in the field of transplantation have improved short-term outcomes, little impact has been made on the long-term success of transplant allografts. As a result, a substantial proportion of patients will ultimately return to dialysis and the milieu of ESRD. Approximately 20% of all renal patients on the transplant waiting list in the United States have had a previously failed allograft.1 This population has high mortality with 10-yr survival of

Kidney transplantation is well known to increase survival and improve quality of life over conventional dialysis therapies. But are contemporary, intensive dialysis therapies, such as nocturnal home hemodialysis, associated with outcomes as good as those obtained with deceased donor transplantation?

THE RENAL BIOPSY is considered the gold standard method for the diagnosis of the processes that cause graft dysfunction. Complete morphological studies must be systematically applied to these samples to specifically assess the etiology of those processes. The likelihood of a particular etiology largely depends on the interval since transplantation. In the early posttransplantation period, most cases of renal dysfunction are etiology by acute tubular necrosis, reperfusion injury, acute rejection, drug toxicity, obstruction, surgical complications, or infection. Later in the time course, other causes of graft dysfunction include chronic transplant nephropathy, cyclosporine toxicity, and recurrent or de novo glomerular diseases. However, recurrent disease also should be considered in some cases in the immediate posttransplantation period. We present a renal transplant recipient with systemic lupus erythematosus (SLE) and early allograft dysfunction and rapid graft failure. The serial biopsies and complete morphological studies permitted a specific diagnosis in this case.

Specific safeguards to guide the approval process and substitution practices for generic immunosuppressive agents are necessary for the effective delivery of patient care. Currently, the Food and Drug Administration (FDA) requires the demonstration of bioequivalence of generic drugs to innovator drugs in normal healthy subjects, a criterion that may be insufficient for critical-dose drugs. For generic equivalents of critical-dose drugs and for innovator critical-dose drugs, there should be a requirement for replicate studies measuring intrasubject variability and subject-treatment interactions to establish that bioequivalence holds true. Extensive testing of generic drugs in all target patient types is impractical and should not be required. However, when evidence suggests that the bioavailability of a critical-dose drug may vary substantially in certain subgroups, the FDA should require a demonstration of bioequivalence of generic versions to innovator products in these representative target populations. Changes in the approval process for generics should be accompanied by more consistent substitution practices. Pharmacists should notify the prescribing physician and patient whenever a critical-dose drug (generic or brand name) is dispensed in a different formulation from the one the patient has been taking. Therapeutic substitution for such drugs should not be made unless the prescribing physician has granted approval. The health care provider should consider instituting appropriate monitoring whenever patients are switched between generic formulations or between innovator drugs and generic formulations. Patients should be well informed about generic substitutes so that they can participate in treatment choices.

The pathogenesis of Alport syndrome involves type IV collagen molecules containing the α3(IV) chain: Evidence from anti-GBM nephritis after renal transplantation. Mutations in the COL4A5 collagen gene have been implicated as the primary defect in Alport syndrome, a heritable disorder characterized by sensorineural deafness and glomerulonephritis that progresses to end-stage renal failure. In the present study, the molecular nature of the defect in Alport glomerular basement membrane (GBM) was explored using anti-GBM alloantibodies (tissue-bound and circulating) produced in three Alport patients subsequent to renal transplantation. The alloantibodies bound to the α3(IV)NC1 domain of type IV collagen and not to any other basement membrane component. In tissue sections, the alloantibodies bound specifically to peripheral GBM in normal kidney and the affected renal transplant but not to that of Alport kidney. These results establish that: the α3 chain in type IV collagen molecules, the Goodpasture autoantigen, is the target alloantigen in post-transplant anti-GBM nephritis in patients with Alport syndrome, and that a molecular commonality exists in the pathogenesis of anti-GBM nephritis causing loss of renal allografts in patients with Alport syndrome and renal failure in patients with Goodpasture syndrome. These findings implicate: (1) defective assembly of type IV collagen molecules containing the α3(IV) chain in Alport GBM; and (2) the existence of a mechanism linking the assembly of molecules containing the α3(IV) chain with those containing the α5(IV) chain.

This report deals with the clinical application of monoclonal antibody techniques to fine needle aspiration biopsy (FNAB) of the renal transplant. The technique was deemed to be quite helpful in corroborating cell type analysis made by classical cytochemistry (Giemsa staining), and determination of the nature of the lymphoid subset at play in rejection. The role of activation marker analysis and class 2 alloantigen analysis in particular for rejection was also discussed.

Beta 2 -microglobulin (β 2 M) is a low molecular weight (11,800 daltons) globular protein detected on the cell membrane of all nucleated cells, including lymphocytes, where it is associated with the glycoproteins of the major histocompatibility complex. With a small sized Stokes radius, 16 Å, and a sieving coefficient of 0.7 to 1.0, β 2 M diffuses freely between intra- and extravascular space and is freely filtered through the glomerular basement membrane, then reabsorbed (99.9%) and degraded by the proximal tubular cells. The kidney, the major site of the catabolism of β 2 M [1, 2], can extract and metabolize β 2 M even in the absence of glomerular filtration [3, 4]. Under normal circumstances, cellular synthesis, release, and catabolism of this protein varies little in an individual. Although certain inflammatory, immunologic, and neoplastic disorders can produce elevated serum levels in patients with normal renal function, the usual cause of an elevation in serum beta 2 -microglobulin (sβ 2 M) is renal insufficiency. Because of these properties, β 2 M is an excellent indicator of GFR [1]. Moreover, in patients with recent kidney allografts who pass scanty amounts of urine, continued clearance of β 2 M from the plasma may be taken as evidence of graft viability [3, 4]. These properties permit an analysis of the utility of sβ 2 M measurements as a noninvasive laboratory assessment of renal transplant status. At present, serum creatinine (sCr) is the standard, noninvasive test available to evaluate renal function. However, creatinine values can lag behind the histologic changes observed in the rejection process and are of no use during hemodialysis or in the presence of postsurgical acute renal failure. The purpose, then, of this study was to explore the relationship between sCr and β 2 M serum concentrations and to evaluate the utility of monitoring transplant function with sβ 2 M. We found a strong correlation between β 2 M serum concentration and sCr, that a rise in sβ 2 M heralded the diagnosis of transplant rejection, and that continued clearance of sβ 2 M in the absence of excretory renal function supported a diagnosis of postsurgical acute renal failure.

Hepatitis C virus (HCV) infection, the leading cause of posttransplant liver disease, has recently been recognized as one of the major causes of morbidity and mortality in renal transplantation. Most HCV antibody-positive recipients acquire HCV infection before or at the time of transplantation. The prevalence of HCV among patients with end-stage renal disease (ESRD) undergoing dialysis is reported between 12% to 85%, depending on the techniques used such as antibody and RNA assays [1‐ 4]. It has been shown that HCV is transmissible by organ transplantation [5, 6]. In recipients of kidneys from HCV antibody positive donors, 57 to 96% were tested positive for HCV RNA by polymerase chain reaction (PCR) and 0 to 55% developed post-transplantation liver disease [7]. There have been controversial reports on the long-term effects of HCV infection on graft and patient survival in kidney transplant recipients. In this issue of Kidney International, Pereira and colleagues analyze the impact of HCV infection on survival of kidney transplant and ESRD patients [8]. They report that the presence of HCV infection was associated with an increased risk of death in patients referred for renal transplantation, and the effect of transplantation was similar in anti-HCV positive and negative patients. They conclude that anti-HCV positive status is not a contraindication for renal transplantation, which has a beneficial effect on long-term survival in anti-HCV positive patients. The report by Pereira and associates provides new fuel to the controversy as to how HCV infection alters outcomes in ESRD and transplant population [8]. Two important infection-related outcomes are described by the authors: the relationship of infection to chronic liver disease and to transplant outcome. There have been other reports of progressive liver disease in HCVinfected renal allograft recipients. A study by Morales et al demonstrated that more than 50% of HCV positive renal transplant recipients exhibited a severe pattern including cirrhosis, chronic active hepatitis and chronic persistent hepatitis in liver biopsies indicating the seriousness of HCV infection [9]. Older age at transplant, female sex, and morphologic diagnosis of advanced chronic hepatitis were found to be associated with histologic progression to cirrhosis [10]. On the other hand, several other groups have described the absence of dire consequences of HCV infection on patient and graft survival in renal allograft recipients [11, 12]. A group of HCV-infected ESRD patients (N 5 14) was prospectively followed for up to two years with pretransplant liver biopsies, and virologic and biochemical parameters post-transplant [11]. All patients did well with functioning grafts despite enhanced viral replication and mild increase in liver enzymes. Haem and colleagues followed 62 HCV positive renal transplant recipients with liver biopsies for a mean of 72 months (range 36 to 108 months) [12]. Although they found a 42% incidence of chronic active hepatitis, patient and graft survival were not significantly different from HCV negative recipients. At our institution, we found that, despite a predisposition to post-transplant liver disease in recipients with pre-existing HCV infection, overall patient and graft survival were similar in long-term follow up (median follow-up 9 years) in the HCV positive and HCV negative recipients [12]. Irrespective of the antibody status, the outcome was poor in patients with associated liver disease. Less controversial has been the variant impact of HCV infection on patient outcomes related to forms of renal replacement. Similar to the report by Pereira et al, in a study by Knoll and colleagues, HCV-positive renal transplant recipients had a better survival compared with HCV-positive patients who were acceptable candidates for transplantation but were on dialysis [14]. The importance of these studies lies in using a cohort of dialysis patients for outcome comparison very similar to the transplant group as they were on the transplant waiting list, reducing the possibility that differences discerned were merely a consequence of selection bias. The continuing controversy of the impact of HCV infection on the transplant recipient demands further study and analysis by examining such issues as variant viral strains or geographic differences, and improving our understanding of HCV related liver disease. Nevertheless, the report by Pereira and his colleagues supports the conclusion that transplantation is the preferred mode of renal replacement therapy for HCV positive patients with end-stage renal disease [8].

ONOCLONAL ANTIBODIES have ad­ vanced the clinical utility of various forms of renal transplant biopsies. With respect to core needle biopsies of the renal transplant, immuno­ peroxidase studies using monoclonal antibodies to specific cell markers have to date been adjunctive. Standard histochemical and pathologic analysis of the core biopsy permits an accurate clinical diagnosis to be made based on the architecture of the tissue and the presence, position, and nature of immunocompetent cell infiltrates. The role of monoclonal antibodies has been able to delineate the pedigree of the infiltrating lymphocyte respon­ sible for rejection that may be discerned. Because rejection is a heterogenous entity, cells from a wide range of different pedigrees participate in the phenomenon. Little additional diagnostic informa­ tion has so far been gained by analysis of these markers by monoclonal antibodies. In contrast, the presence of activation markers, such as the in­ terleukin 2 (IL-2) receptor, the transferrin recep­ tor, or the appearance of class II antigens on tubu­ lar cells has been instructive as it may confirm the presence of rejection diagnosed by standard technique. Dual markers will in the future improve the role that the surface structures playas diagnos­ tic elements. The most important role for the panel of described monoclonal antibodies at present may be prognosis. In terms of the fine needle aspiration biopsy, monoclonal antibodies may play a greater diagnostic role. The goal of this form of biopsy is to aspirate out of the allograft an array of cells including immunocompetent cells and isolated tubular structures. Morphologic analysis by stand­ ard histochemical techniques permits one to appre­ ciate the stage of maturation of the