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The immune system normally functions to mitigate infectious and neoplastic risk. In the absence of immunosuppression, the transplantation of allogeneic tissue constitutes a challenge as allorecognition triggers injurious effector mechanisms culminating in allograft destruction. This chapter will focus on the basic mechanisms of allorecognition, costimulation, T cell amplication, effector mechanisms, innate immunity and antibody production.

Postoperative pain is an outcome of importance to potential living kidney donors (LKDs). We prospectively characterized the prevalence, severity, and patterns of acute or chronic postoperative pain in 193 LKDs at six transplant programs. Three pain measurements were obtained from donors on postoperative Day (POD) 1, 3, 7, 14, 21, 28, 35, 41, 49, and 56. The median pain rating total was highest on POD1 and declined from each assessment to the next until reaching a median pain-free score of 0 on POD49. In generalized linear mixed-model analysis, the mean pain score decreased at each pain assessment compared to the POD3 assessment. Pre-donation history of mood disorder (adjusted ratio of means [95% confidence interval (CI)]: 1.40 [0.99, 1.98]), reporting "severe" on any POD1 pain descriptors (adjusted ratio of means [95% CI]: 1.47 [1.12, 1.93]) and open nephrectomy (adjusted ratio of means [95% CI]: 2.61 [1.03, 6.62]) were associated with higher pain scores across time. Of the 179 LKDs who completed the final pain assessment, 74 (41%) met criteria for chronic postsurgical pain (CPSP), that is, any donation-related pain on POD56. Study findings have potential implications for LKD education, surgical consent, postdonation care, and outcome measurements.

Prior studies demonstrate that most living kidney donors (LKDs) report no adverse psychosocial outcomes; however, changes in psychosocial functioning at the individual donor level have not been routinely captured. We studied psychosocial outcomes predonation and at 1, 6, 12, and 24 months postdonation in 193 LKDs and 20 healthy controls (HCs). There was minimal to no mood disturbance, body image concerns, fear of kidney failure, or life dissatisfaction, indicating no incremental changes in these outcomes over time and no significant differences between LKDs and HCs. The incidence of any new-onset adverse outcomes postdonation was as follows: mood disturbance (16%), fear of kidney failure (21%), body image concerns (13%), and life dissatisfaction (10%). Multivariable analyses demonstrated that LKDs with more mood disturbance symptoms, higher anxiety about future kidney health, low body image, and low life satisfaction prior to surgery were at highest risk of these same outcomes postdonation. It is important to note that some LKDs showed improvement in psychosocial functioning from pre- to postdonation. Findings support the balanced presentation of psychosocial risks to potential donors as well as the development of a donor registry to capture psychosocial outcomes beyond the mandatory 2-year follow-up period in the United States.

This study sought to identify the prevalence, pattern, and predictors of clinical fatigue in 193 living kidney donors (LKDs) and 20 healthy controls (HCs) assessed at predonation and 1, 6, 12, and 24 months postdonation. Relative to HCs, LKDs had significantly higher fatigue severity (P = .01), interference (P = .03), frequency (P = .002), and intensity (P = .01), and lower vitality (P < .001), at 1-month postdonation. Using published criteria, significantly more LKDs experienced clinical fatigue at 1 month postdonation, compared to HCs, on both the Fatigue Symptom Inventory (60% vs. 37%, P < .001) and SF-36 Vitality scale (67% vs. 16%, P < .001). No differences in fatigue scores or clinical prevalence were observed at other time points. Nearly half (47%) reported persistent clinical fatigue from 1 to 6 months postdonation. Multivariable analyses demonstrated that LKDs presenting for evaluation with a history of affective disorder and low vitality, those with clinical mood disturbance and anxiety about future kidney failure after donation, and those with less physical activity engagement were at highest risk for persistent clinical fatigue 6 months postdonation. Findings confirm inclusion of fatigue risk in existing OPTN informed consent requirements, have important clinical implications in the care of LKDs, and underscore the need for further scientific examination in this population.

After transplantation of nonrenal solid organs, an acute decline in kidney function develops in the majority of patients. In addition, a significant number of nonrenal solid organ transplant recipients develop chronic kidney disease, and some develop end-stage renal disease, requiring renal replacement therapy. The incidence varies depending on the transplanted organ. Acute kidney injury after nonrenal solid organ transplantation is associated with prolonged length of stay, cost, increased risk of death, de novo chronic kidney disease, and end-stage renal disease. This overview focuses on the risk factors for posttransplant acute kidney injury after liver and heart transplantation, integrating discussion of proteinuria and chronic kidney disease with emphasis on pathogenesis, histopathology, and management including the use of mechanistic target of rapamycin inhibition and costimulatory blockade.

Limited information exists on the predonation costs incurred by eventual living kidney donors (LKDs). Expenses related to completion of the donation evaluation were collected from 194 LKDs participating in the multi-center, prospective Kidney Donor Outcomes Cohort (KDOC) Study. Most LKDs (n = 187, 96%) reported one or more direct costs, including ground transportation (80%), healthcare (24%), lodging (17%) and air transportation (14%), totaling $101 484 (USD; mean = $523 ± 942). Excluding paid vacation or sick leave, donor and companion lost wages totaled $35 918 (mean = $187 ± 556) and $14 378 (mean = $76 ± 311), respectively. One-third of LKDs used paid vacation or sick leave to avoid incurring lost wages. Few LKDs reported receiving financial support from the transplant candidate (6%), transplant candidate’s family (3%), a nonprofit organization (3%), the National Living Donor Assistance Center (7%), or transplant center (3%). Higher total costs were significantly associated with longer distance traveled to the transplant center (p < 0.001); however, total costs were not associated with age, sex, race/ethnicity, household income, marital status, insurance status, or transplant center. Moderate predonation direct and indirect costs are common for adults who complete the donation evaluation. Potential LKDs should be advised of these possible costs, and the transplant community should examine additional strategies to reimburse donors for them.

Background. Rabbit antithymocyte globulin (rATG) is the most widely used kidney transplant induction immunotherapy in the United States. It was recently Food and Drug Administration approved for this indication with typical dose recommendations of 1.5 mg/kg for up to 7 days given via a central line. Methods. We theorized that reduced rATG dosing when compared with conventional dosing (6-10.5 mg/kg) is safe and effective, leading to development of a risk-stratified treatment protocol. Five-year data from a retrospective cohort of 224 adult kidney transplants (2008-2013) with follow-up through 2015 is presented. Cumulative rATG doses of 3 mg/kg were administered peripherally to nonsensitized living donor recipients, 4.5 mg/kg to nonsensitized deceased donor recipients. A subset of higher immunologic risk recipients (defined as history of prior transplant, panel reactive antibody greater than 20%, or flow cytometry crossmatch positivity) received 6 mg/kg. Results. There were no differences in patient or graft survival between the 3 groups. One-year rejection rates in the first 2 groups were 8.3% and 8.8%, respectively, comparable to contemporaneous rates reported to the Scientific Registry of Transplant Recipients. Dose tailoring permitted substantial cost savings estimated at US $1 091 502. Mean length of stay fell by almost 3 days as the protocol was refined. There were no episodes of phlebitis. Infection rates were comparable with those reported to the Scientific Registry of Transplant Recipients. Conclusions. The novel findings of the current study include peripheral administration, reduced dosing, favorable safety, excellent allograft outcomes, and clear associative data regarding reduced costs and length of stay.

Living kidney donors (LKDs) may feel more anxious about kidney failure now that they have only one kidney and the security of a second kidney is gone. The aim of this cross-sectional study was to develop and empirically validate a self-report scale for assessing fear of kidney failure in former LKDs. Participants were 364 former LKDs within the past 10 years at five US transplant centers and 219 healthy nondonor controls recruited through Mechanical Turk who completed several questionnaires. Analyses revealed a unidimensional factor structure, excellent internal consistency (α = 0.88), and good convergent validity for the Fear of Kidney Failure questionnaire. Only 13% of former donors reported moderate to high fear of kidney failure. Nonwhite race (OR = 2.9, P = 0.01), genetic relationship with the recipient (OR = 2.46, P = 0.04), and low satisfaction with the donation experience (OR = 0.49, P = 0.002) were significant predictors of higher fear of kidney failure. We conclude that while mild anxiety about kidney failure is common, high anxiety about future renal failure among former LKDs is uncommon. The Fear of Kidney Failure questionnaire is reliable, valid, and easy to use in the clinical setting.

Hypertension in kidney transplant recipients is a major "traditional" risk factor for atherosclerotic cardiovascular disease. Importantly, atherosclerotic cardiovascular disease is the leading cause of premature death and a major factor in death-censored graft failure in transplant recipients. The blood pressure achieved after transplant is related inversely to postoperative glomerular filtration rate (GFR), with many patients experiencing a significant improvement in blood pressure control with fewer medications within months of surgery. However, the benefits of improved GFR and fluid status may be affected by the immunosuppression regimen. Immunosuppressive agents affect hypertension through a variety of mechanisms, including catechol- and endothelin-induced vasoconstriction, abrogation of nitric oxide-induced vasodilatation, and sodium retention. Most notable is the role of calcineurin inhibitors in promoting hypertension, cyclosporine more so than tacrolimus. Additionally, the combination of calcineurin- and mammalian target of rapamycin (mTOR)-inhibitor therapy is synergistically nephrotoxic and promotes hypertension, whereas steroid withdrawal and minimization strategies seem to have little or no impact on hypertension. Other important causes of hypertension after transplant, beyond a progressive decrease in GFR, include transplant renal artery stenosis and sequelae of antibody-mediated rejection. Calcium channel blockers may be the most useful medication for mitigating calcineurin inhibitor-induced vasoconstriction, and use of such agents may be associated with improvements in GFR. Use of inhibitors of the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, remains an attractive strategy for many transplant recipients, although some recipients may have significant adverse effects associated with these medications, including decreased GFR, hyperkalemia, and anemia. In conclusion, hypertension control affects both patient and long-term transplant survival, and its best management requires careful analysis of causes and close monitoring of therapies.

A deceased-donor kidney transplant recipient developed purulent pericarditis caused by Nocardia despite trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis for Pneumocystis jirovecii. She was treated empirically with ceftriaxone and amikacin and subsequently underwent sternotomy with drainage of an intrapericardial abscess. Culture and susceptibility data demonstrated Nocardia farcinica, which was susceptible to SMX and amikacin, although resistant to ceftriaxone. Nocardia asteroides, the more common human pathogen, is generally susceptible to third-generation cephalosporins and TMP-SMX. N. farcinica is rare in the United States, more virulent and resistant than N. asteroides, and is more likely to cause disseminated disease. Successful therapy of disseminated Nocardia infections is dependent upon choice of appropriate empiric antibiotics in addition to surgical drainage of purulent fluid collections. TMP-SMX prophylaxis may not be sufficient to prevent infections due to Nocardia species in all immunosuppressed transplant recipients. Here, a rare complication of this unusual pathogen is discussed.

While studies in animal models have linked Toll-like receptor (TLR) 4 signaling to kidney injury induced by ischemia and reperfusion, the relevance of TLR4 activation to allograft injury in human kidney transplants is unknown. Here we show that TLR4 is constitutively expressed within all donor kidneys but is significantly higher in deceased-, compared with living-donor organs. Tubules from deceased- but not living-donor kidneys also stained positively for high-mobility group box-1 (HMGB1), a known endogenous TLR4 ligand. In vitro stimulation of human tubular cells with HMGB1, in a TLR4-dependent system, confirmed that HMGB1 can stimulate proinflammatory responses through TLR4. To assess the functional significance of TLR4 in human kidney transplantation, we determined whether TLR4 mutations that confer diminished affinity for HMGB1 influence intragraft gene-expression profiles and immediate graft function. Compared with kidneys expressing WT alleles, kidneys with a TLR4 loss-of-function allele contained less TNFα, MCP-1, and more heme oxygenase 1 (HO-1), and exhibited a higher rate of immediate graft function. These results represent previously undetected evidence that donor TLR4 contributes to graft inflammation and sterile injury following cold preservation and transplantation in humans. Targeting TLR4 signaling may have value in preventing or treating postischemic acute kidney injury after transplantation.

Oral tolerance is an important physiological mechanism of immune hyporesponsiveness to dietary antigens and the commensal flora of the gastrointestinal tract. Feeding of alloantigens, therefore, has the potential to suppress undesirable immune responses after transplantation. To date, there are no published reports on the effects of such an approach in human transplant recipients. In the present pilot study, we demonstrate complete suppression of baseline indirect alloreactivity in patients with chronic renal allograft dysfunction following the oral feeding of low (0.5 mg/d) but not higher (1.0 and 5.0 mg/d) doses of donor major histocompatibility complex (MHC) class II peptides. The regimen was well tolerated with no evidence for sensitization to the donor antigen. Our results indicate that oral feeding of low dose donor MHC peptide may represent a safe and effective therapy to suppress indirect alloreactivity in renal transplant recipients with chronic allograft dysfunction and warrants further clinical investigation.

Hypertension is a prevalent problem in kidney transplant recipients that is known to be a “traditional” risk factor for ASCVD leading to premature allograft failure and death. Donor, transplant and recipient factors impact hypertension risk. Blood pressure control after transplantation is inversely associated with GFR. Calcineurin inhibitors, the most commonly used class of immunosuppressives, cause endothelial dysfunction, increase vascular tone, and sodium retention via the reninangiotensin-aldosterone system resulting in systemic hypertension. Steroid withdrawal seems to have little impact on blood pressure control. Newer agents like belatacept appear to be associated with less hypertension. Transplant renal artery stenosis is an important, potentially treatable cause of hypertension. Dihydropyridine calcium channel blockers mitigate calcineurin inhibitor nephrotoxicity and may be associated with improved eGFR. ACE inhibitors and angiotensin receptor blockers are not recommended in the first 3-6 months given their effects on reduced eGFR, anemia and hyperkalemia. The use of sblockers may be associated with improved patient survival, even for patients with no history of cardiovascular disease.

Some living kidney donors (LKDs) incur costs associated with donation, although these costs are not well characterized in the United States. We collected cost data in the 12 mo following donation from 182 LKDs participating in the multicenter prospective Kidney Donor Outcomes Cohort (KDOC) Study. Most LKDs (n = 167, 92%) had one direct cost or more following donation, including ground transportation (86%), health care (41%), meals (53%), medications (36%), lodging (23%), and air transportation (12%). LKDs missed 33 072 total work hours, 40% of which were unpaid and led to $302 175 in lost wages (mean $1660). Caregivers lost $68 655 in wages (mean $377). Although some donors received financial assistance, 89% had a net financial loss in the 12-mo period, with one-third (33%) reporting a loss exceeding $2500. Financial burden was higher for those with greater travel distance to the transplant center (Spearman's ρ = 0.26, p

Postpartum atypical hemolytic uremic syndrome (aHUS) is a rare disorder associated with poor maternal and fetal outcomes. We describe a case of severe postpartum aHUS with recurrence in a kidney allograft after a second pregnancy. The patient had initially presented age 28 years with aHUS that developed after her first delivery. In spite of treatment with plasma exchange, she developed end-stage renal disease (ESRD) requiring years of hemodialysis before receiving a kidney transplant from a living unrelated donor. Two years later, she became pregnant again and at 26 weeks gestation she presented to our hospital with hypertension and proteinuria. Within 48 hours of delivery she developed hemolytic anemia, thrombocytopenia, and oliguric acute kidney injury (AKI) culminating in the need for dialysis. There was no response to therapeutic plasma exchange (TPE). However, treatment with eculizumab led to prompt, successful resolution of hemolysis, thrombocytopenia, and AKI. Three months after therapy was stopped, her disease relapsed causing renal failure again requiring dialysis. At that time, an allograft biopsy revealed severe thrombotic microangiopathy (TMA). Eculizumab was resumed without plasma exchange leading to resolution of aHUS and return of kidney function. Now, her baby is nearly 2 years old. She remains on maintenance eculizumab therapy 1,200 mg every 2 weeks without dialysis. She has excellent renal function with creatinine of 1.2 mg/dL, eGFR 52 mL/min/1.73 m, and proteinuria 0.35 g/day. She will likely be on eculizumab for the remainder of her life.

Introduction To investigate the role and mechanisms of indirect allorecognition in allograft rejection, we studied whether priming T cells with donor-derived MHC allopeptides could accelerate rejection in a vascularized allograft model. Methods Lewis recipients of fully mismatched Wistar Furth cardiac allografts were immunized before transplantation with donor MHC allopeptides. Results Animals immunized with immunogenic class II MHC allopeptides rejected their grafts in a significantly accelerated fashion compared with controls. Additional studies demonstrated that a single immunodominant RT1.D (HLA-DR like) allopeptide was responsible for accelerating the rejection process. Histological analysis of rejected allografts revealed marked vascular rejection in the accelerated, although not the control, group as well as severe cellular rejection. Peak production of IgM and IgG donor-specific alloantibodies was detected by flow cytometry 1 week earlier in the sera of the accelerated group compared with the control group. Immunohistological analysis of grafts from the accelerated compared with the control group showed increased endothelial deposition of IgG2b, C3, and fibrin, and up-regulation of class II MHC molecule expression. Increased intragraft expression of interferon-y and the interferon-gamma-induced chemokines, inducible protein-10 and Mig, and infiltration by activated mononuclear cells expressing CXCR3, the receptor for inducible protein-10 and Mig, was also seen. Conclusion These novel data provide evidence of a definitive link between indirect allorecognition of donor-derived MHC class II peptides and the cellular and humoral mechanisms of vascularized allograft rejection.

Autosomal dominant periodic fever syndromes are characterized by unexplained episodes of fever and severe localized inflammation. In seven affected families, we found six different missense mutations of the 55 kDa tumor necrosis factor receptor (TNFR1), five of which disrupt conserved extracellular disulfide bonds. Soluble plasma TNFR1 levels in patients were approximately half normal. Leukocytes bearing a C52F mutation showed increased membrane TNFR1 and reduced receptor cleavage following stimulation. We propose that the autoinflammatory phenotype results from impaired downregulation of membrane TNFR1 and diminished shedding of potentially antagonistic soluble receptor. TNFR1-associated periodic syndromes (TRAPS) establish an important class of mutations in TNF receptors. Detailed analysis of one such mutation suggests impaired cytokine receptor clearance as a novel mechanism of disease.

The interaction of the T-cell receptor with the major histocomatibility complex (MHC)-peptide complex is central to T-cell activation. Variation in the nature of the peptide bound within the groove of the MHC molecule may result in an altered T-cell response. Because some naturally processed peptides bound within the groove of the class II MHC molecule are derived from the MHC molecules themselves, we studied the inhibitory effects of synthetic class II MHC peptides on alloimmune responses in vitro. Three peptides derived from a highly conserved region of the class II MHC alpha chains inhibited the rat mixed lymphocyte response (MLR) in a dose-dependent manner, with the human HLA-DQA1 peptide also inhibiting the human and mouse MLR. No effect was seen on mitogen-induced T-cell proliferation. HLA-DQA1 inhibited cytolytic T lymphocyte (CTL) generation in a dose-response fashion, with no reduction in preformed CTL killing, suggesting that the inhibitory effect is targeted at CD4(+) T-cell function. Cell-cycle analysis by flow cytometry showed that restimulation of primed T cells in the presence of HLA-DQA1 resulted in increased apoptosis, whereas unstimulated cells were not affected. These data demonstrate that synthetic peptides derived from highly conserved regions of the class II MHC alpha chain can alter CD4(+) T-lymphocyte alloimmune responses in vitro, and this effect is mediated by the induction of apoptosis in activated T cells.

INTRODUCTION Antibodies directed against human leukocyte antigens (HLAs) impact adversely on renal transplantation. Measures aimed at preventing such antibody formation are thus important. The introduction of recombinant human erythropoietin (rHuEpo) has permitted the reduction of blood transfusion in patients with chronic renal failure. The impact of rHuEpo on the incidence of sensitization in patients awaiting transplantation was therefore studied. METHODS A retrospective analysis of the patients awaiting transplantation before (group A) and 4 years after (group B) the introduction of rHuEpo was performed in order to ascertain changing patterns in the use of blood transfusion and causes of sensitization. RESULTS The total number of transfusions administered to haemodialysis patients decreased by 34% during the study period. This was accompanied by a significant reduction in the ratio of blood transfusion to haemodialysis treatment episodes (0.095 in group A to 0.06 in group B, P = 0.001). The number of patients sensitized as a consequence of blood transfusion decreased from 63% in group A to 28% in group B (P = 0.0004). The overall incidence of sensitization decreased from 50% in group A to 36.5% in group B (P = 0.008). This decrement was associated with a significant reduction in the mean waiting time for transplantation (42.1 +/- 1.1 vs 15.4 +/- 2.4 months, P < 0.0001). The incidence of sensitization due to previous transplantation increased during the study period from 41% in group A to 77% in group B, (P = 0.0004). There was no change in the number of patients sensitized due to pregnancy. CONCLUSION The introduction of rHuEpo has resulted in a significant decrease in the requirements for blood transfusion among patients awaiting transplantation and is associated with a significant reduction in transfusion-related sensitization and mean waiting time for transplantation.

Blocking CD28-B7 T cell costimulatory activation by the fusion protein CTLA4Ig prevents rejection and induces long-term graft acceptance in various experimental transplant models. There are reported differences in the efficacy of CTLA4Ig in renal and cardiac rodent allograft models, but it is not clear whether these are due to the strain or species differences investigated in the different studies reported. This study investigates the effect of blocking CD28-B7 T cell costimulation with murine CTLA4Ig in rat models of acute renal and cardiac allograft rejection models, using the same complete major histocompatibility complex-incompatible strain combination. A single injection of murine CTLA4Ig 2 d after engraftment was able to induce long-term graft acceptance (> 100 d) in 54% of Lewis rat recipients of Wistar-Furth kidneys. Transferring this protocol into the acute Wistar-Furth to Lewis heart allograft model resulted in a mean graft survival time of 24.7+/-16.9 d, and all grafts were ultimately rejected. Only concomitant injection of donor cells (4 x 10(7) splenocytes) plus a single injection of CTLA4Ig on the day of transplant could induce long-term graft acceptance in 50% of animals. In both the cardiac and renal transplant models, the thymus and spleen were required for induction of tolerance. The maintenance phase of tolerance, however, did not require an intact thymus but did require the presence of a spleen. These data have important clinical applicability because human studies with T cell costimulatory blockade are being planned.

Background: Late acute rejection affects up to 28% of renal allograft recipients and remains a major risk factor for late graft loss. As donor-origin antigen-presenting cells are depleted with time, T-cell recognition of donor-derived alloantigenic peptides presented by self antigen-presenting cells (the indirect pathway of allorecognition) may play a key role in the initiation of late acute rejection episodes. Methods. To test this hypothesis, we developed a clinically relevant experimental model in the rat (Wistar-Furth/Lewis) in which allograft recipients received cyclosporine for 1 month after transplantation and were then allowed to reject the graft upon discontinuation of immunosuppression. Lymphocyte proliferation assays to synthetic class II MHC allopeptides of donor origin and also to intact donor (Wistar-Furth) cells were performed at this time. The effector mechanisms studied included delayed-type hypersensitivity (DTH) responses, lymphocyte-mediated cytotoxicity, and alloantibody production. Results. Lymphocytes from recipients undergoing late acute rejection had marked suppression of mixed lymphocyte reaction proliferation to intact donor cells. Significant proliferation to donor-derived 25-mer polymorphic class II MHC allopeptides was elicited, however. In vivo, significant DTH responses were observed to both MHC allopeptides and intact Wistar-Furth cells. Recipient lymphocytes also exhibited significant killing of donor cells, although not third-party cells, and anti-donor alloantibodies were detected by flow cytometry. Conclusion. Our results indicate that T cells primed via the indirect pathway are present during acute rejection that occurs after discontinuation of cyclosporine. Mixed lymphocyte reactivity is markedly reduced at this time. Furthermore, there is an association between such allopeptide-primed T cells and the elicitation of specific DTH responses and provision of help to B cells to produce alloantibodies and activation of CD8+ T cells to become effector cytotoxic cells.

Background. It has been suggested that T cells primed by processed donor major histocompatibility complex antigen (the indirect pathway of allorecognition) may be responsible for mediating chronic allograft rejection. The purpose of this study was to develop a clinically useful assay to study the occurrence of indirect allorecognition during chronic rejection in humans. Methods. A panel of 20 mer peptides corresponding to the hypervariable regions of HLA-DRB1 * 0101, DRB1 * 1501, and DRB1 * 0301 were synthesized. Lymphocytes obtained from renal allograft recipients were cocultured with these peptides. Proliferation was assayed by DNA incorporation of [ 3 H]thymidine, and positive proliferation was defined by a statistically significant increase in counts per minute over background with a minimum stimulation index of 2. The precursor frequency of allopeptide reactive T cells was determined by limiting dilution analysis. Results. Lymphocytes from 82% of patients who were mismatched for at least one of the three DR molecules and had chronic allograft dysfunction specifically proliferated to the mismatched allopeptides (n=11). Proliferation was seen in only 6% of control subjects (2/33, P

Familial Mediterranean fever (fMf) is an inherited condition characterized by polyserositis and is sometimes complicated by AA renal amyloidosis leading to nephrotic syndrome and renal failure. We present a case of a man with fMf who presented with rapidly progressive renal failure caused by light chain deposition disease. This disease association has not previously been described in the medical literature.

BACKGROUND While improved health of the recipient may serve as a primary motivating factor, living kidney donors (LDs) also may expect to accrue some personal benefit following donation. This study sought to identify trajectories of perceived benefit over the first 2 years after donation. METHODS Prospective questionnaire data were collected from 133 LDs from three kidney transplant programs in the United States. Before surgery, LDs completed the Living Donation Expectancies Questionnaire to assess their expectations of personal growth, interpersonal benefits, and spiritual benefits from the donation experience. This report then assessed the degree to which these expectations were met at 1, 6, 12, and 24 months post-donation. RESULTS Analyses revealed four (Interpersonal Benefit) and five (Personal Growth, Spiritual Benefit) distinct trajectories over time. For some LDs, pre-donation expectancies about benefit were met or exceeded over the 2 years, while for others the anticipated benefits were either short-lived or not met at all. Trajectory group assignment was associated with some donor characteristics (e.g., age, gender, and relationship to recipient). Also, LDs whose recipients had functioning grafts and who reported improved health status following transplantation were more likely to have their pre-donation personal growth and interpersonal benefit expectations consistently met or exceeded. CONCLUSIONS Longitudinal trajectory analysis can help to identify different outcomes patterns for LDs and factors associated with them. The relevance of these findings is discussed in the context of LD education, follow-up care, and future research on donation benefits.

It is generally accepted that transplantation is the treatment of choice for selected patients with end-stage kidney disease as patient survival is improved when compared with dialysis. Transplant recipients experience an improvement in quality of life as well as reduced long-term health care costs. Unfortunately, for most individuals, the success of transplantation is based on an absolute requirement for immunotherapy from which most complications derive. Much of the medical care of the transplant patient involves assessing the risks of over- and under-immunosuppression, striving to minimize immunosuppression while avoiding the risks of rejection. Complications range from those that are minor in severity to those that are graft or life threatening. All complications need to be evaluated and managed appropriately in order to minimize nonadherence with medications, premature graft failure, and death.

Background: Clinical Practice guidelines recommend that patients be observed overnight after kidney biopsy based upon data that 1/3 of bleeding complications occur 12 hours post-procedure. Retrospective studies of same day discharge after kidney allograft biopsy suggest this practice may be safe, but no prospective studies to date have examined time to bleeding complications. Methods: We conducted a single center, prospective, observational study of adult outpatient kidney allograft recipients undergoing elective percutaneous allograft biopsy who were observed for 8 hours post-procedure before discharge home. Bleeding complications were characterized as minor or major and tracked by time post-biopsy. Baseline demographics were assessed for correlation with complications. Results: 8/124 (6.4%) of patients had a bleeding complication and 7/8 (87.5%) of complications occurred within the observation window. 3.2 % were minor and 3.2% were major complications with one major complication occurring after the 8-hour period. Neither the baseline demographics nor drop in serum hemoglobin of > 1 g/dl 6 hours after biopsy predicted a bleeding complication. However, a drop of > 1.5 g/dl correlate with a significant bleeding event (p = 0.006). Conclusions: An 8-hour observation window captures the majority of bleeding complications after adult kidney transplant biopsy.

Injured epithelial cells of the proximal tubule upregulate the glycoprotein kidney injury molecule 1 (KIM-1), suggesting its potential as a biomarker of incipient kidney allograft injury. It is unknown whether KIM-1 expression changes in kidney allografts with delayed graft function (DGF), which often follows ischemia-reperfusion injury. Here, we prospectively measured KIM-1 RNA and protein expression in preperfusion biopsies of 30 living- and 85 deceased-donor kidneys and correlated the results with histologic and clinical outcomes after transplantation. We detected KIM-1 expression in 62% of deceased-donor kidneys and only 13% of living-donor kidneys (P < 0.0001). The level of KIM-1 expression before reperfusion correlated inversely with renal function at the time of procurement and correlated directly with the degree of interstitial fibrosis. Surprising, however, we did not detect a significant correlation between KIM-1 staining intensity and the occurrence of DGF. Our findings are consistent with a role for KIM-1 as an early indicator of tubular injury but do not support tissue KIM-1 measurement before transplantation to identify kidneys at risk for DGF.

Oral tolerance is an important physiological mechanism of immune hyporesponsiveness to dietary antigens and the commensal flora of the gastrointestinal tract. Feeding of alloantigens, therefore, has the potential to suppress undesirable immune responses after transplantation. To date, there are no published reports on the effects of such an approach in human transplant recipients. In the present pilot study, we demonstrate complete suppression of baseline indirect alloreactivity in patients with chronic renal allograft dysfunction following the oral feeding of low (0.5 mg/d) but not higher (1.0 and 5.0 mg/d) doses of donor major histocompatibility complex (MHC) class II peptides. The regimen was well tolerated with no evidence for sensitization to the donor antigen. Our results indicate that oral feeding of low dose donor MHC peptide may represent a safe and effective therapy to suppress indirect alloreactivity in renal transplant recipients with chronic allograft dysfunction and warrants further clinical investigation.

Background Chronic kidney disease patients have a high prevalence of inflammation and oxidative stress, and this has been associated with the excess cardiovascular morbidity and mortality observed in this population. Because maintenance hemodialysis is ineffective in controlling these factors, we hypothesized that restoration of kidney function by transplantation would be required to improve uremic inflammation and oxidative stress. Methods This was a prospective cohort study evaluating time-dependent changes in biomarkers of inflammation and oxidative stress before and after renal transplantation. Nineteen end-stage renal disease (ESRD) patients (age 38.3+/-13.7 years, 58% male, 95% white, 21% diabetic) undergoing living-donor renal transplantation were enrolled. C-reactive protein (CRP), interleukin (IL)-6, IL-10, tumor necrosis factor (TNF)-alpha, protein-associated carbonyl content, and F2-isoprostanes were assessed at 1 week pretransplantation and at 1 week and 2 months posttransplantation. Results Pretransplant levels of the pro-inflammatory proteins IL-6, TNF-alpha, and CRP, as well as the oxidative stress markers plasma protein carbonyls and F2-isoprostanes, were significantly elevated in ESRD patients compared with healthy control subjects. We observed rapid and significant declines in all of these biomarkers after transplantation that persisted for 2 months. Conclusions Our findings indicate that restoration of renal function by transplantation improves the chronic inflammation and increased oxidative stress associated with uremia, which may contribute to the improved survival afforded to ESRD patients by renal transplantation.