Kidney donor outcomes ≥ 50 years after donation.

Many living kidney donors (LDs) are young at donation; yet there are little data on long-term LD follow-up. We report on 66 LDs who donated ≥50 years ago: 22 (33.3%) are still alive (current age, 78.5 ± 7.25 years); 39 (59%) died (mean age at death, 74.2 ± 12.3 years); and 5 are lost to follow-up (mean age at last contact, 68.7 ± 4.6 years). Those who died were older at donation (P < .001). Causes of death included 12 (30.8% of deaths) cardiovascular diseases, 9 (23.0%) respiratory failures, 5 (12.8%) malignancies and 4 (10.3%) infections, and 9 (23%) were unknown or miscellaneous. Forty-nine living donors (74%) developed hypertension at a mean age of 59.9 ± 14.0 years; 12 (18%) developed diabetes at a mean age of 62 ± 19.4 years; and 11 (16.7%) developed proteinuria at a mean age of 60.6 ± 18.2 years-each at a similar incidence as seen in the age-matched general population. At last follow-up, the eGFR by CKD-EPI (mean ± SD) for donors currently alive was 60.2 ± 13.4 mL/min/1.73 m2 ; for those that died, 54.0 ± 21.5 mL/min/1.73 m2 ; for those lost to follow-up, 55.6 ± 7.5 mL/min/1.73 m2 . ESRD developed in 2 (3.3%). SF-36 quality of life health survey scores (n = 21) were similar to the age-matched general population.

Inhibition of autophagy increases apoptosis during re-warming after cold storage in renal tubular epithelial cells.

Prolonged cold storage and re-warming (CS/REW) of kidneys are risk factors for delayed graft function (DGF). Studies in renal tubular epithelial cells (RTECs) have determined apoptosis and autophagy in models of either cold storage (CS) or re-warming alone. The effect of both cold storage and re-warming on apoptosis and autophagy, in RTECS is not known and is relevant to DGF as the kidney is subjected to both CS and re-warming. We hypothesized that CS/REW of RTECs would induce autophagy that protects against apoptosis. In CS/REW, there was increased autophagic flux of RTECs. Autophagy inhibition using an Atg5 siRNA resulted in increased cleaved caspase-3 and increased apoptotic cells (on both morphology and annexin V staining) during CS/REW. The effect of autophagy inhibition on necrosis in RTECs is unknown. There were increased necrosis and caspase-1, a mediator of necrosis, during CS/REW, and the Atg5 siRNA had no effect on necrosis and caspase-1. In a kidney transplant model, there was an increase in LC3 II, a marker of autophagy, in kidneys transplanted after cold storage. In summary, autophagic flux is increased during CS/REW. Autophagy inhibition resulted in increased cleaved caspase-3 and increased apoptosis during CS/REW without an effect on necrosis or caspase-1. In conclusion, autophagy inhibition in RTECs after CS/REW induces apoptotic cell death and may be deleterious as a therapy to decrease DGF.

Renal adaptation during hibernation.

Hibernators periodically undergo profound physiological changes including dramatic reductions in metabolic, heart, and respiratory rates and core body temperature. This review discusses the effect of hypoperfusion and hypothermia observed during hibernation on glomerular filtration and renal plasma flow, as well as specific adaptations in renal architecture, vasculature, the renin-angiotensin system, and upregulation of possible protective mechanisms during the extreme conditions endured by hibernating mammals. Understanding the mechanisms of protection against organ injury during hibernation may provide insights into potential therapies for organ injury during cold storage and reimplantation during transplantation.

NLRP3 inflammasome knockout mice are protected against ischemic but not cisplatin-induced acute kidney injury.

We have demonstrated that caspase-1 is a mediator of both cisplatin-induced acute kidney injury (AKI) and ischemic AKI. As caspase-1 is activated in the inflammasome, we investigated the inflammasome in cisplatin-induced and ischemic AKI. Mice were injected with cisplatin or subjected to bilateral renal pedicle clamping. Immunoblot analysis of whole kidney after cisplatin-induced AKI revealed: 1) an increase in apoptosis-associated Speck-like protein containing a caspase recruitment domain (ASC), the major protein that complexes with nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing proteins (NLRP) 1 or 3 to form the inflammasome; 2) an increase in caspase-1 activity, caspase-5, and NLRP1, components of the NLRP1 inflammasome; and 3) a trend toward increased NLRP3. To determine whether the NLRP3 inflammasome plays an injurious role in cisplatin-induced AKI, we studied NLRP knockout (NLRP3(-/-)) mice. In cisplatin-induced AKI, the blood urea nitrogen, serum creatinine, acute tubular necrosis score, and tubular apoptosis score were not significantly decreased in NALP3(-/-) mice compared with wild-type mice. We have previously demonstrated the injurious role of caspase-1 in ischemic AKI. NLRP3, but not ASC or NLRP1, is increased in ischemic AKI. NLRP3(-/-) mice with ischemic AKI had significantly lower blood urea nitrogen, serum creatinine, and acute tubular necrosis and apoptosis scores than the wild-type controls. The difference in protection against cisplatin-induced AKI compared with ischemic AKI in NLRP3(-/-) mice was not explained by the differences in proinflammatory cytokines interleukin (IL)-1ß, IL-6, chemokine (C-X-C motif) ligand 1, or tumor necrosis factor α. NLRP3 inflammasome is a mediator of ischemic AKI but not cisplatin-induced AKI, and further investigation of the NLRP1 inflammasome in cisplatin-induced AKI should prove interesting.

Solid Organ Transplant Graft-Versus-Host Disease in a Kidney/Pancreas Transplant Patient: Use of Chimerism Testing and a Rare Presentation of Cutaneous GVHD.

Introduction. Solid organ transplant graft-versus-host disease (SOT-GVHD) is a rare phenomenon in which recipients of solid organ transplant develop GVHD due to the presence of donor lymphocytes in the graft. SOT-GVHD most often occurs in patients receiving small bowel or liver transplants. Diagnosis is typically via identification of lymphocytic infiltration on histopathology and molecular demonstration of donor T cell chimerism in the target organ. The gastrointestinal (GI) system is the most common target of SOT-GVHD, and one estimate places long-term survival of patients with SOT-GVHD at 20% at 5 years. In this report, we present the case of a patient with sequential kidney and pancreas transplant who developed SOT-GVHD targeting host lymphocytes, skin, and liver, with a long period of stability before treatment with antithymocyte globulin. Peripheral blood chimerism testing was used to track response to therapy. Remarkably, he survived 1.5 years despite recurrent infections before dying of unrelated causes.

Enteric Conversion of Bladder-drained Pancreas as a Predictor of Outcomes in Almost 600 Recipients at a Single Center.

Complications associated with bladder-drained pancreata necessitating enteric conversion are common. Data on the outcomes after enteric conversion are conflicting. We studied the association between enteric conversion and the pancreas graft rejection, loss, and mortality. METHODS: At our center, 1117 pancreas transplants were performed between 2000 and 2016. We analyzed 593 recipients with bladder-drained pancreata, of which 523 received solitary transplants and 70 received simultaneous pancreas-kidney transplants. Kaplan-Meier function was used to estimate time to conversion by transplant type. Cox proportional hazards models were utilized to evaluate patient survival, death-censored graft survival, and acute rejection-free survival while treating conversion as a time-dependent covariate. Subsequently, we examined the association between timing of conversion and the same outcomes in the conversion cohort. RESULTS: At 10 y posttransplant, 48.8% of the solitary pancreas recipients and 44.3% of simultaneous pancreas-kidney transplant recipients had undergone enteric conversion. The enteric conversion was associated with 85% increased risk of acute rejection (hazard ratio [HR] = 1.85; 95% confidence interval [CI] = 1.37-2.49; P < 0.001). However, the conversion was not associated with graft loss or mortality. In the conversion cohort, a longer interval from engraftment to conversion was associated with an 18% lower rejection rate (HR = 0.82; 95% CI = 0.708-0.960; P = 0.013) and a 22% better graft survival (HR = 0.78; 95% CI = 0.646-0.946; P = 0.01). CONCLUSIONS: Enteric conversion was associated with increased risk of rejection, but not increased risks of graft loss or mortality. The decision to convert should consider the increased rejection risk. A longer interval from engraftment to conversion appears favorable.

Protection From Apoptotic Cell Death During Cold Storage Followed by Rewarming in 13-Lined Ground Squirrel Tubular Cells: The Role of Prosurvival Factors X-Linked Inhibitor of Apoptosis and PhosphoAkt.

BACKGROUND: Hibernators, such as the 13-lined ground squirrel, endure severe hypothermia during torpor followed by periodic rewarming (REW) during interbout arousal (IBA), proapoptotic conditions that are lethal to nonhibernating mammals. We have previously shown that 13-lined ground squirrel tubular cells are protected from apoptotic cell death during IBA. To understand the mechanism of protection, we developed an in vitro model of prolonged cold storage (CS) followed by REW, which is akin to the in vivo changes of hypothermia followed by REW observed during IBA. We hypothesized that renal tubular epithelial cells (RTECs) isolated from hibernating ground squirrels would be protected against apoptosis during CS/REW versus nonhibernating mouse RTECs. METHODS: Isolated hibernating ground squirrel and mouse RTECs were subjected to CS at 4°C for 24 hours followed by REW to 37°C for 24 hours (CS/REW). RESULTS: Ground squirrel RTECs had significantly less apoptosis compared to mouse RTECs when subjected to CS/REW. Next, we hypothesized that the mechanism of protection was related to the antiapoptotic proteins X-linked inhibitor of apoptosis (XIAP), phospho-Akt (pAkt), and phospho-BAD. There was a significantly increased pAkt and pBAD expression in ground squirrel versus mouse RTECs subjected to CS/REW. The XIAP expression was maintained in ground squirrel RTECs but was significantly decreased in mouse RTECs after CS/REW. Ground squirrel RTECs in which gene expression of Akt1 and XIAP was silenced lost their protection and demonstrated increased apoptosis and cleaved caspase-3 expression after CS/REW. CONCLUSIONS: Our findings suggest that ground squirrel RTECs are protected against apoptosis during prolonged CS/REW by the "prosurvival" factors XIAP and pAkt.

Protection Against Cold Storage-Induced Renal Tubular Cell Apoptosis.

BACKGROUND: Prolonged cold storage (CS) of donor kidneys is associated with tubular cell apoptosis and caspase-3 activation. We have previously shown that pancaspase inhibition prevents CS-associated tubular apoptosis. Because of the nonspecific nature of pancaspase inhibitors, which block all caspases including proinflammatory caspase-1, the effect of specific caspase-3 inhibition during CS is unknown. X-linked inhibitor of apoptosis (XIAP) is the most potent naturally occurring specific inhibitor of caspase-3. We hypothesized that prolonged CS would decrease XIAP, whereas upregulation of XIAP with the novel compound UCF-101 would protect against caspase-3 activation and tubular cell apoptosis. METHODS: LLC-PK1 tubular cells and whole kidneys from C57BL/6 mice were subjected to prolonged CS with or without UCF-101, and examined for XIAP, caspase-3, and tubular apoptosis. RESULTS: Tubular cells subjected to prolonged CS in vitro demonstrated significantly decreased XIAP and significantly increased apoptosis, caspase-3 protein and activity. UCF-101 treatment significantly increased XIAP, significantly decreased capsase-3 protein and activity, and protected against apoptosis. To determine the therapeutic significance, whole kidneys were subjected to prolonged CS with UCF-101. UCF-101 significantly increased XIAP in donor kidneys and protected against apoptosis. CONCLUSIONS: Prolonged CS of tubular cells in vitro and whole mouse kidneys ex vivo is associated with loss of XIAP and subsequent tubular cell apoptosis. UCF-101 protects against the loss of XIAP during prolonged CS both in vitro and ex vivo, and is associated with significantly reduced tubular cell apoptosis. UCF-101 may represent an attractive approach to improve organ preservation.

"Leaky" Rationality: How Research on Behavioral Decision Making Challenges Normative Standards of Rationality.

For more than 30 years, decision-making research has documented that people often violate various principles of rationality, some of which are so fundamental that theorists of rationality rarely bother to state them. We take these characteristics of decision making as a given but argue that it is problematic to conclude that they typically represent departures from rationality. The very psychological processes that lead to "irrational" decisions (e.g., framing, mental accounting) continue to exert their influence when one experiences the results of the decisions. That is, psychological processes that affect decisions may be said also to "leak" into one's experience. The implication is that formal principles of rationality do not provide a good enough normative standard against which to assess decision making. Instead, what is needed is a substantive theory of rationality-one that takes subjective experience seriously, considers both direct and indirect consequences of particular decisions, considers how particular decisions fit into life as a whole, and considers the effects of decisions on others. Formal principles may play a role as approximations of the substantive theory that can be used by theorists and decision makers in cases in which the formal principles can capture most of the relevant considerations and leakage into experience is negligible.