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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.

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.

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

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.

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.

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.

We studied T-cell clones generated from grafts of rejecting and tolerant animals and investigated the regulatory function of Th2 clones in vitro and in vivo. To prevent allograft rejection, we treated LEW strain recipient rats of WF strain kidney grafts with CTLA4Ig to block CD28-B7 costimulation. We then isolated epitope-specific T-cell clones from the engrafted tissue, using a donor-derived immunodominant class II MHC allopeptide presented by recipient antigen-presenting cells. Acutely rejected tissue from untreated animals yielded self-restricted, allopeptide-specific T-cell clones that produced IFN-gamma, whereas clones from tolerant animals produced IL-4 and IL-10. Adoptive transfer into naive recipients of Th1 clones, but not Th2 clones, induced alloantigen-specific delayed-type hypersensitivity (DTH) responses. In addition, Th2 clones suppressed DTH responses mediated by Th1 clones in vivo and blocked Th1 cell proliferation and IFN-gamma production in vitro. A pilot human study showed that HLA-DR allopeptide-specific T-cell clones generated from patients with chronic rejection secrete Th1 cytokines, whereas those from patients with stable graft function produce Th2 cytokines in response to donor-specific HLA-DR allopeptides. We suggest that self-restricted alloantigen-specific Th2 clones may regulate the alloimmune responses and promote long-term allograft survival and tolerance.

Renal involvement remains a major complication of multiple myeloma, particularly in advanced disease. A retrospective analysis was performed of the modes of presentation, treatment and outcome of all patients with multiple myeloma treated in our renal unit between 1987 and 1996. Thirty-four patients were identified: in 26 (76%) the diagnosis of myeloma was made only after referral. Light chains were the most common paraprotein in both serum and urine. Twenty-one (62%) patients underwent renal biopsy: myeloma cast nephropathy was the predominant histological finding in 16 cases. Thirty-one (91%) patients had severe renal failure (GFR20 mL/min), with 28 (82%) requiring dialysis within 2 weeks of admission. Despite treatment of presumed precipitaing causes of acute deterioration in renal function, only 1 of these 28 patients subsequently became independent of dialysis. Most had advanced stage myeloma: 29 (85%) were Durie-Salmon stage II or III. Hypercalcemia, sepsis and pathological fractures were the principal complications. Median survival overall was 5 months. The main causes of death were withdrawal of renal replacement therapy (overwhelming myeloma, severe debilitation) and sepsis. Nineteen (56%) patients received long-term (1 month) renal replacement therapy with a median survival of 8 months. However, five of these (26%) have survived for more than 12 months on dialysis and report a good quality of life.

The favorable safety profile of the newer antidepressant drugs recently introduced has lead to their increased use in transplant recipients. These new agents are a chemically diverse group of compounds that have selective serotonin reuptake inhibitory properties. Most of these medications inhibit one or more hepatic microsomal cytochrome p450 isoenzymes. Because cyclosporine is metabolized predominantly by CYP3A3/4 isoenzymes, inhibition of this system can lead to the buildup of toxic levels. Two case reports of cyclosporine toxicity attributable to interactions with the novel antidepressants nefazodone and fluvoxamine are presented. The serum creatinine and whole blood cyclosporine levels were found to be elevated at a routine clinic visit. Although it was subsequently possible to reduce the dose of cyclosporine by between 33% and 50%, the frequency of blood draws and consultations was greatly increased in both patients over several weeks, resulting in considerable patient anxiety. Interestingly, both nefazodone and fluvoxamine are known to potently inhibit the CYP3A3/4 isoenzymes. It is concluded that the introduction of a novel antidepressant to a cyclosporine-treated allograft recipient may be complicated by cyclosporine toxicity. Intensive monitoring of the serum creatinine and cyclosporine level is indicated under such circumstances, with dose reductions performed as indicated.

Severe hypothermia is associated with serious patient morbidity and mortality. The groups most frequently affected are the elderly, the very young and substance abusers. We describe three such cases which were successfully treated using warmed peritoneal dialysis. Two patients recovered completely and were left with no long term deficits. The third patient recovered from the acute event, but succumbed later to an underlying medical condition. Warmed peritoneal lavage is an efficient, cost effective approach which is easily performed without specialist equipment, and involves minimal risk to the patient.