Associations of Perfusate Biomarkers and Pump Parameters With Delayed Graft Function and Deceased Donor Kidney Allograft Function.

Hypothermic machine perfusion (HMP) is increasingly used in deceased donor kidney transplantation, but controversy exists regarding the value of perfusion biomarkers and pump parameters for assessing organ quality. We prospectively determined associations between perfusate biomarkers (neutrophil gelatinase-associated lipocalin [NGAL], kidney injury molecule 1, IL-18 and liver-type fatty acid-binding protein [L-FABP]) and pump parameters (resistance and flow) with outcomes of delayed graft function (DGF) and 6-mo estimated GFR (eGFR). DGF occurred in 230 of 671 (34%) recipients. Only 1-h flow was inversely associated with DGF. Higher NGAL or L-FABP concentrations and increased resistance were inversely associated with 6-mo eGFR, whereas higher flow was associated with higher adjusted 6-mo eGFR. Discarded kidneys had consistently higher median resistance and lower median flow than transplanted kidneys, but median perfusate biomarker concentrations were either lower or not significantly different in discarded compared with transplanted kidneys. Notably, most recipients of transplanted kidneys with isolated "undesirable" biomarker levels or HMP parameters experienced acceptable 6-mo allograft function, suggesting these characteristics should not be used in isolation for discard decisions. Additional studies must confirm the utility of combining HMP measurements with other characteristics to assess kidney quality.

Associations of deceased donor kidney injury with kidney discard and function after transplantation.

Deceased donor kidneys with acute kidney injury (AKI) are often discarded due to fear of poor outcomes. We performed a multicenter study to determine associations of AKI (increasing admission-to-terminal serum creatinine by AKI Network stages) with kidney discard, delayed graft function (DGF) and 6-month estimated glomerular filtration rate (eGFR). In 1632 donors, kidney discard risk increased for AKI stages 1, 2 and 3 (compared to no AKI) with adjusted relative risks of 1.28 (1.08-1.52), 1.82 (1.45-2.30) and 2.74 (2.0-3.75), respectively. Adjusted relative risk for DGF also increased by donor AKI stage: 1.27 (1.09-1.49), 1.70 (1.37-2.12) and 2.25 (1.74-2.91), respectively. Six-month eGFR, however, was similar across AKI categories but was lower for recipients with DGF (48 [interquartile range: 31-61] vs. 58 [45-75] ml/min/1.73m(2) for no DGF, p < 0.001). There was significant favorable interaction between donor AKI and DGF such that 6-month eGFR was progressively better for DGF kidneys with increasing donor AKI (46 [29-60], 49 [32-64], 52 [36-59] and 58 [39-71] ml/min/1.73m(2) for no AKI, stage 1, 2 and 3, respectively; interaction p = 0.05). Donor AKI is associated with kidney discard and DGF, but given acceptable 6-month allograft function, clinicians should consider cautious expansion into this donor pool.

Differences in tolerance for health risk to the living donor among potential donors, recipients, and transplant professionals.

In organ donation, the donor, recipient, and transplant team must all accept potential health risks to the donor and any uncertainties. To gauge these risks, we surveyed general altruism and risk-taking behaviors in 112 potential donors, 111 potential recipients, and 51 transplant professionals. Next, participants indicated their risk thresholds for long-term donor hypertension, cardiovascular disease, and kidney failure that would stop them from pursuing living donation and their willingness to proceed when risks were uncertain. The three groups had similar general altruism and risk-taking behaviors. Potential donors were significantly more willing to accept greater long-term donor risks than potential recipients and transplant professionals. Moreover, these potential donors were significantly more likely to agree that living donation was acceptable when long-term donor risks were uncertain. Potential kidney donors readily accept high long-term risks, whereas potential recipients were the most averse to donor risk. Our study shows that transplant professionals facilitate the best decisions by appreciating the willingness of their patients to accept donor health risks along with their own risk tolerance.

Chronic kidney disease and postoperative mortality: a systematic review and meta-analysis.

Whether renal dysfunction is an important factor in postoperative risk assessment has been difficult to prove. In an attempt to provide more compelling evidence, we conducted a systematic review comparing the risk of death and cardiac events in patients with and without chronic kidney disease who underwent elective noncardiac surgery. From electronic databases, web search engines, and bibliographies, 31 cohort studies were selected, evaluating postoperative outcomes in patients with chronic kidney disease. These patients had higher risks of postoperative death and cardiovascular events compared to those with preserved renal function. The pooled incidence of postoperative death was significantly less in those with preserved renal function than in those patients with chronic kidney disease. Meta-regression showed a graded relationship between disease severity and postoperative death. In adjusted analysis, chronic kidney disease had a similar strength of association with postoperative death as diabetes, stroke, and coronary disease. Our review identifies chronic kidney disease as an independent risk factor for postoperative death and cardiovascular events after elective, noncardiac surgery.

Arthritis risk after acute bacterial gastroenteritis.

OBJECTIVES: Reactive arthritis (ReA) may occur from bacterial gastroenteritis. We studied the risk of arthritis after an outbreak of Escherichia coli O157:H7 and Campylobacter species within a regional drinking water supply to examine the relationship between the severity of acute diarrhoea and subsequent symptoms of arthritis. METHODS: Participants with no known history of arthritis before the outbreak participated in a long-term follow-up study. Of the 2299 participants, 788 were asymptomatic during the outbreak, 1034 had moderate symptoms of acute gastroenteritis and 477 had severe symptoms that necessitated medical attention. The outcomes of interest were new arthritis by self-report and a new prescription of medication for arthritis during the follow-up period. RESULTS: After a mean follow-up of 4.5 yrs after the outbreak, arthritis was reported in 15.7% of participants who had been asymptomatic during the outbreak, and in 17.6 and 21.6% of those who had moderate and severe symptoms of acute gastroenteritis, respectively (P-value for trend = 0.009). Compared with the asymptomatic participants, those with moderate and severe symptoms of gastroenteritis had an adjusted relative risk of arthritis of 1.19 [95% confidence interval (CI) 0.99-1.43] and 1.33 (95% CI 1.07-1.66), respectively. No association was observed between gastroenteritis and the subsequent risk of prescription medication for arthritis (P = 0.49). CONCLUSIONS: Acute bacterial gastroenteritis necessitating medical attention was associated with a higher risk of arthritic symptoms, but not arthritic medications, up to 4 yrs afterwards. The nature and chronicity of these arthritic symptoms requires further study.

Imputing variance estimates do not alter the conclusions of a meta-analysis with continuous outcomes: a case study of changes in renal function after living kidney donation.

OBJECTIVE: To assess how different imputation methods used to account for missing variance data in primary studies influence tests of heterogeneity and pooled results from a meta-analysis with continuous outcomes. STUDY DESIGN AND SETTING: Point and variance estimates for changes in serum creatinine, glomerular filtration rate, systolic blood pressure, and diastolic blood pressure were variably reported among 48 primary longitudinal studies of living kidney donors (71%-78% of point estimates were reported, 8%-13% of variance data were reported). We compared the results of meta-analysis, which either were restricted to available data or used four methods to impute missing variance data. These methods used reported P-values, reported nonparametric summaries, results from other similar studies using multiple imputation, or results from estimated correlation coefficients. RESULTS: Significant heterogeneity was present in all four outcomes regardless of the imputation methods applied. The random effects point estimates and 95% confidence intervals varied little across imputation methods, and the differences were not clinically significant. CONCLUSIONS: Different methods to impute the variance data in the primary studies did not alter the conclusions from this meta-analysis of continuous outcomes. Such reproducibility increases confidence in the results. However, as with most meta-analyses, there was no gold standard of truth, and results must be interpreted judiciously. The generalization of these findings to other meta-analyses, which differ in outcomes, missing data, or between-study heterogeneity, requires further consideration.

Associations between Deceased-Donor Urine MCP-1 and Kidney Transplant Outcomes.

INTRODUCTION: Existing methods to predict recipient allograft function during deceased-donor kidney procurement are imprecise. Understanding the potential renal reparative role for monocyte chemoattractant protein-1 (MCP-1), a cytokine involved in macrophage recruitment after injury, might help predict allograft outcomes. METHODS: We conducted a sub-study of the multicenter prospective Deceased Donor Study cohort, which evaluated deceased kidney donors from five organ procurement organizations from May 2010 to December 2013. We measured urine MCP-1 (uMCP-1) concentrations from donor samples collected at nephrectomy to determine associations with donor acute kidney injury (AKI), recipient delayed graft function (DGF), 6-month estimated GFR (eGFR), and graft failure. We also assessed perfusate MCP-1 concentrations from pumped kidneys for associations with DGF and 6-month eGFR. RESULTS: AKI occurred in 111 (9%) donors. Median (interquartile range) uMCP-1 concentration was higher in donors with AKI compared to donors without AKI (1.35 [0.41-3.93] ng/ml vs. 0.32 [0.11-0.80] ng/ml, p<0.001). DGF occurred in 756 (31%) recipients, but uMCP-1 was not independently associated with DGF. Higher donor uMCP-1 concentrations were independently associated with higher 6-month eGFR in those without DGF [0.77 (0.10, 1.45) ml/min/1.73m2 per doubling of uMCP1]. However, there were no independent associations between uMCP-1 and graft failure over a median follow-up of about 2 years. Lastly, perfusate MCP-1 concentrations significantly increased during pump perfusion but were not associated with DGF or 6-month eGFR. CONCLUSION: Donor uMCP-1 concentrations were modestly associated with higher recipient 6-month eGFR in those without DGF. However, the results suggest that donor uMCP-1 has minimal clinical utility given no associations with graft failure.

Insurability of living organ donors: a systematic review.

Being an organ donor may affect one's ability to obtain life, disability and health insurance. We conducted a systematic review to determine if insurability is affected by living organ donation, and if concern about insurability affects donor decision making. We searched MEDLINE, EMBASE, SCI, EconLit and Cochrane databases for articles in any language, and reviewed reference lists from 1966 until June 2006. All studies discussing the insurability of living organ donors or its impact on donor decision making were included. Data were independently abstracted by two authors, and the methodological quality appraised. Twenty-three studies, from 1972 to 2006, provided data on 2067 living organ donors, 385 potential donors and 239 responses from insurance companies. Almost all companies would provide life and health insurance to living organ donors, usually with no higher premiums. However, concern about insurability was still expressed by 2%-14% of living organ donors in follow-up studies, and 3%-11% of donors actually encountered difficulties with their insurance. In one study, donors whose insurance premiums increased were less likely to reaffirm their decision to donate. Based on available evidence, some living organ donors had difficulties with insurance despite companies reporting otherwise. If better understood, this potential barrier to donation could be corrected through fair health and underwriting policies.

Transplant professionals vary in the long-term medical risks they communicate to potential living kidney donors: an international survey.

BACKGROUND: Discussing long-term medical risks with potential living donors is a vital aspect of informed consent. We considered whether there are global practice variations in the information communicated to potential living kidney donors. METHODS: Transplant professionals participated in a survey to determine which long-term risks are communicated to potential living kidney donors. Self-administered questionnaires were distributed in person and by electronic mail. RESULTS: We surveyed 203 practitioners from 119 cities in 35 different countries. Sixty-three percent of participants were nephrologists, and 27% were surgeons. Risks of hypertension, proteinuria or kidney failure requiring dialysis were frequently discussed (usually over 80% of practitioners discussed each medical condition). However, many practitioners do not believe these risks are increased after donation, with surgeons being less convinced of long-term sequelae compared with nephrologists (P < 0.01). About 30% of practitioners discuss long-term risks of premature cardiovascular disease or death with potential donors. CONCLUSIONS: Transplant professionals vary in the long-term risks they communicate to potential donors. Improving consensus will enhance decision-making, and emphasize best practices which maintain good, long-term donor health.

Absence of renal sequelae after childhood Escherichia coli O157:H7 gastroenteritis.

Although a quarter of children who survive diarrhea-associated hemolytic uremic syndrome develop long-term renal sequelae, the prognosis of acute, self-limited Escherichia coli O157:H7 gastroenteritis has never been previously studied. Four years after a drinking water outbreak of E. coli O157:H7, we examined the risk of high blood pressure (>95th percentile expected for age, sex, and height), reduced kidney function, and microalbuminuria among previously healthy children and adolescents. Of the 951 participants, 313 were asymptomatic during the outbreak, 305 had moderate symptoms of acute gastroenteritis, and 333 had severe symptoms that necessitated medical attention. An additional 23 children who developed hemolytic uremic syndrome during the outbreak were excluded from this analysis. There were no differences in mean systolic blood pressure between those who had no, moderate, or severe symptoms of acute gastroenteritis during the outbreak (109, 110, and 107 mm Hg). Similarly, there were no group differences in diastolic blood pressure, estimated glomerular filtration rate, or random urine albumin to creatinine ratio (P ranged from 0.14 to 0.52), or in the adjusted relative risk of high blood pressure, a glomerular filtration rate <80 ml/min per 1.73 m(2), or microalbuminuria (P ranged from 0.23 to 0.89). Patients who presented to medical attention with gastroenteritis during this E. coli O157:H7 outbreak had an absence of renal sequelae 4 years later. With no existing data to support screening after self-limited E. coli O157:H7 gastroenteritis, we recommend that only those children who develop recognized features of hemolytic uremic syndrome be followed for long-term renal health.

Psychosocial health of living kidney donors: a systematic review.

Knowledge of the psychosocial benefits and harms faced by living kidney donors is necessary for informed consent and follow-up. We reviewed any English language study where psychosocial function was assessed using questionnaires in 10 or more donors after nephrectomy. We searched MEDLINE, EMBASE, Web of Science, Psych INFO, Sociological Abstracts and CINAHL databases and reviewed reference lists from 1969 through July 2006. Independently, two reviewers abstracted data on study, donor and control group characteristics, psychosocial measurements and their outcomes. Fifty-one studies examined 5139 donors who were assessed an average of 4 years after nephrectomy. The majority experienced no depression (77-95%) or anxiety (86-94%), with questionnaire scores similar to controls. The majority reported no change or an improved relationship with their recipient (86-100%), spouse (82-98%), family members (83-100%) and nonrecipient children (95-100%). Some experienced an increase in self-esteem. A majority (83-93%) expressed no change in their attractiveness. Although many scored high on quality of life measures, some prospective studies described a decrease after donation. A small proportion of donors had adverse psychosocial outcomes. Most kidney donors experience no change or an improvement in their psychosocial health after donation. Harms may be minimized through careful selection and follow-up.

Proteinuria and reduced kidney function in living kidney donors: A systematic review, meta-analysis, and meta-regression.

We reviewed any study where 10 or more healthy adults donated a kidney, and proteinuria, or glomerular filtration rate (GFR) was assessed at least 1 year later. Bibliographic databases were searched until November 2005. 31 primary authors provided additional information. Forty-eight studies from 27 countries followed a total of 5048 donors. An average of 7 years after donation (range 1-25 years), the average 24 h urine protein was 154 mg/day and the average GFR was 86 ml/min. In eight studies which reported GFR in categories, 12% of donors developed a GFR between 30 and 59 ml/min (range 0-28%), and 0.2% a GFR less than 30 ml/min (range 0-2.2%). In controlled studies urinary protein was higher in donors and became more pronounced with time (three studies totaling 59 controls and 129 donors; controls 83 mg/day, donors 147 mg/day, weighted mean difference 66 mg/day, 95% confidence interval (CI) 24-108). An initial decrement in GFR after donation was not accompanied by accelerated losses over that anticipated with normal aging (six studies totaling 189 controls and 239 donors; controls 96 ml/min, donors 84 ml/min, weighted mean difference 10 ml/min, 95% CI 6-15; difference not associated with time after donation (P=0.2)). Kidney donation results in small increases in urinary protein. An initial decrement in GFR is not followed by accelerated losses over a subsequent 15 years. Future studies will provide better estimates, and identify those donors at least risk of long-term morbidity.

Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery.

Acute kidney injury (AKI) is a frequent complication of cardiopulmonary bypass (CPB). The lack of early biomarkers for AKI has impaired our ability to intervene in a timely manner. Urinary neutrophil gelatinase-associated lipocalin (NGAL) is recently demonstrated as an early biomarker of AKI after CPB, increasing 25-fold within 2 h and declining 6 h after surgery. In the present study, we tested whether interleukin-18 (IL-18) is a predictive biomarker for AKI in the same group of patients following CPB. Exclusion criteria included pre-existing renal insufficiency and nephrotoxin use. Serial urine samples were analyzed by enzyme-linked immunosorbent assay for IL-18 in 20 patients who developed AKI (defined as a 50% or greater increase in serum creatinine after CPB) and 35 controls (age, race, and gender-matched patients who did not develop AKI after CPB). Using serum creatinine, AKI was detected only 48-72 h after CPB. In contrast, urine IL-18 increased at 4-6 h after CPB, peaked at over 25-fold at 12 h, and remained markedly elevated up to 48 h after CPB. The performance of IL-18 as demonstrated by area under the receiver operating characteristics curve for diagnosis of AKI at 4, 12, and 24 h after CPB was 61, 75, and 73% respectively. Also, on multivariate analysis, both IL-18 and NGAL were independently associated with number of days in AKI among cases. Our results indicate that IL-18 is an early, predictive biomarker of AKI after CPB, and that NGAL and IL-18 are increased in tandem after CPB. The combination of these two biomarkers may allow for the reliable early diagnosis and prognosis of AKI at all times after CPB, much before the rise in serum creatinine.

Dose-reducing H2 receptor antagonists in the presence of low glomerular filtration rate: a systematic review of the evidence.

BACKGROUND: While it is recommended that H2 receptor antagonists (H2RAs) be dose reduced in the presence of low glomerular filtration rate (GFR), in practice such adjustments often do not occur. We reviewed the evidence for this recommendation. METHODS: We searched multiple medical reference databases for relevant cohort studies and randomized clinical trials. Studies that enrolled five or more participants with low GFR who also received at least one unadjusted dose of an H2RA, and who were compared with controls were included. Data were abstracted on study and participant characteristics and drug-related adverse effects. Pharmacokinetic measures were pooled using meta-analysis. RESULTS: A total of 22 articles were included, comprising 19 unique cohort studies. With declining GFR, there was a significant increase in the area under the curve (AUC) and elimination half-life (t(1/2)) of the serum drug concentration of H2RAs (P < 0.001). Compared with a GFR >80 ml/min/1.73 m2, drug AUC increased by 200% when the GFR was 30 ml/min/1.73 m2, and by 300% when the GFR was 20 ml/min/1.73 m2. In hospitalized patients with low GFR, reducing the interval dose of intravenous H2RA was associated with fewer adverse reactions. The gastro-protective effects of H2RAs were similar with reduced and unadjusted doses. CONCLUSIONS: Reducing the dose of H2RAs in persons with low GFR will decrease drug expenditure and may prevent adverse events, without a change in efficacy. Quality assurance programmes, which improve deficiencies in H2RAs prescribing, appear justified.