Kidney tubule health scores and their associations with incident CKD in women living with HIV.

OBJECTIVES: Individual kidney tubule biomarkers are associated with chronic kidney disease (CKD) risk in people living with HIV (PLWH). Whether a combination of kidney biomarkers can be integrated into informative summary scores for PLWH is unknown. METHODS: We measured eight urine biomarkers of kidney tubule health at two visits over a 3-year period in 647 women living with HIV in the Women's Interagency Health Study. We integrated biomarkers into factor scores using exploratory factor analysis. We evaluated associations between CKD risk factors and factor scores, and used generalized estimating equations to determine associations between factor scores and risk of incident CKD. RESULTS: Factor analysis identified two unique factor scores: a tubule reabsorption score comprising alpha-1-microglobulin, beta-2-microglobulin and trefoil factor-3; and a tubule injury score comprising interleukin-18 and kidney injury molecule-1. We modelled the two factor scores in combination with urine epidermal growth factor (EGF) and urine albumin. Predominantly HIV-related CKD risk factors were independently associated with worsening tubule reabsorption scores and tubule injury scores. During a median follow-up of 7 years, 9.7% (63/647) developed CKD. In multivariable time-updated models that adjusted for other factor scores and biomarkers simultaneously, higher tubule reabsorption scores [risk ratio (RR) = 1.27, 95% confidence interval (CI): 1.01-1.59 per 1 SD higher time-updated score], higher tubule injury scores (RR = 1.36, 95% CI: 1.05-1.76), lower urine EGF (RR = 0.75, 95% CI: 0.64-0.87), and higher urine albumin (RR = 1.20, 95% CI: 1.02-1.40) were jointly associated with risk of incident CKD. CONCLUSIONS: We identified two novel and distinct dimensions of kidney tubule health that appear to quantify informative metrics of CKD risk in PLWH.

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.

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.

Glutathione S-transferase iso-enzymes in perfusate from pumped kidneys are associated with delayed graft function.

Accurate and reliable assessment tools are needed in transplantation. The objective of this prospective, multi-center study was to determine the associations of the alpha and pi iso-enzymes of glutathione S-transferase (GST), measured from perfusate solution at the start and end (base and post) of kidney allograft machine perfusion, with subsequent delayed graft function (DGF). We also compared GST iso-enzyme perfusate levels from discarded versus transplanted kidneys. A total of 428 kidneys were linked to outcomes as recorded by the United Network of Organ Sharing. DGF, defined as any dialysis in the first week of transplant, occurred in 141 recipients (32%). Alpha- and pi-GST levels significantly increased during machine perfusion. The adjusted relative risks (95% confidence interval) of DGF with each log-unit increase in base and post pi-GST were 1.14 (1.0-1.3) and 1.36 (1.1-1.8), respectively. Alpha-GST was not independently associated with DGF. There were no significant differences in GST values between discarded and transplanted kidneys, though renal resistance was significantly higher in discarded kidneys. We found pi-GST at the end of machine perfusion to be independently associated with DGF. Further studies should elucidate the utility of GST for identifying injured kidneys with regard to organ allocation, discard and recipient management decisions.

Reimbursing live organ donors for incurred non-medical expenses: a global perspective on policies and programs.

Methods to reimburse living organ donors for the non-medical expenses they incur have been implemented in some jurisdictions and are being considered in others. A global understanding of existing legislation and programs would help decision makers implement and optimize policies and programs. We searched for and collected data from countries that practice living organ donation. We examined legislation and programs that facilitate reimbursement, focusing on policy mechanisms, eligibility criteria, program duration and types of expenses reimbursed. Of 40 countries, reimbursement is expressly legal in 16, unclear in 18, unspecified in 6 and expressly prohibited in 1. Donor reimbursement programs exist in 21 countries; 6 have been enacted in the last 5 years. Lost income is reimbursed in 17 countries, while travel, accommodation, meal and childcare costs are reimbursed in 12 to 19 countries. Ten countries have comprehensive programs, where all major cost categories are reimbursed to some extent. Out-of-country donors are reimbursed in 10 jurisdictions. Reimbursement is conditional on donor income in 7 countries, and recipient income in 2 countries. Many nations have programs that help living donors with their financial costs. These programs differ in operation and scope. Donors in other regions of the world are without support.

Chronic kidney disease after hematopoietic cell transplantation: a systematic review.

Advances in hematopoietic cell transplantation (HCT) have broadened its indications for use and resulted in more long-term HCT survivors. Some survivors develop chronic kidney disease (CKD); however, the incidence and risk factors are unclear. We performed a systematic review of studies identified from databases (MEDLINE, EMBASE, Science Citation Index), conference abstracts and reference lists from selected manuscripts. From 927 manuscripts, 28 patient cohorts were identified in which 9317 adults and children underwent HCT and 7317 (79%) survived to at least 100 days, permitting inclusion of 5337 (73% of survivors) in quantitative analyses. Although definitions and measurements varied widely, approximately 16.6% of HCT patients developed CKD and estimated glomerular filtration rate (eGFR in mL/min/1.73 m(2)) decreased by 24.5 after 24 months. This decrease was greater amongst patients undergoing allogeneic HCT (DeltaeGFR = -40.0 versus -18.6 for autologous transplants). Several commonly reported risk factors for CKD were investigated, including acute renal failure, total body irradiation, graft versus host disease and long-term cyclosporine use. In conclusion, CKD following HCT is likely to be common; however, prospective studies with uniform definitions of CKD and risk factors are needed to confirm these findings and better define the underlying mechanisms to promote therapies that prevent this complication.

Age, gender, race, and associations with kidney failure following living kidney donation.

INTRODUCTION: Our previous reports suggested that African Americans (AA) are more likely to develop end-stage renal disease (ESRD) following kidney donation when compared with white counterparts. We sought information on age, gender, and race of kidney donors to determine which groups were over-represented on the kidney transplant waiting list. METHODS: We queried the United Network for Organ Sharing United Network for Organ Sharing (UNOS) Organ Procurement Transplantation Network (OPTN) database for former donors who were subsequently placed on the kidney transplant waiting list. Information was retrieved on race, gender, age at donation, years between donation and listing, and diagnosis leading to ESRD. Comparisons were made to all kidney donors between 1988 and 2006 using chi-square testing. RESULTS: In this study, 126 individual kidney donors entered the kidney transplant waiting list. Fifty of the 126 (40%) were AA (P < .0001 compared with all donors, 13% AA). For both AA and whites, male donors and those who donated before age 35 made up a larger proportion of donors on the waiting list than would be expected by their proportion of overall donors. CONCLUSION: AA, males, and young donors may be at higher risk for kidney failure in the years following kidney donation. Mechanisms of increased risk are unclear but deserve further scrutiny. Our data are limited by the small number of patients developing kidney failure, the lack of complete follow-up on all living kidney donors, and the possibility that older donors with kidney failure were not listed because of death or other medical conditions. We believe that discussion of long-term risks may be different for various subgroups, especially for young AA kidney donors.

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.

Acute kidney injury: Better biomarkers and beyond.

We review fundamental epidemiologic concepts for testing the new early acute kidney injury biomarkers in clinical care.

Peeking into the black box: new biomarkers for acute kidney injury.

The development of effective therapies for acute kidney injury (AKI) has been hindered by delayed diagnosis in the clinical setting, varying definitions of AKI, and limited prognostic information. In a study by Portilla et al., elevations in liver fatty acid-binding protein (L-FABP) were found to predict AKI in children undergoing cardiac surgery. New biomarkers offer the promise of earlier and more accurate diagnosis of AKI. Before they can be deemed clinically useful, however, they must undergo rigorous validation in multiple cohorts.

Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review.

The diagnosis of acute kidney injury (AKI) is usually based on changes in serum creatinine, but such measurements are a poor marker of acute deterioration in kidney function. We performed a systematic review of publications that evaluated the accuracy and reliability of serum and urinary biomarkers in human subjects when used for the diagnosis of established AKI or early AKI, or to risk stratify patients with AKI. Two reviewers independently searched the MEDLINE and EMBASE databases (January 2000-March 2007) for studies pertaining to biomarkers for AKI. Studies were assessed for methodologic quality. In total, 31 studies evaluated 21 unique serum and urine biomarkers. Twenty-five of the 31 studies were scored as having 'good' quality. The results of the studies indicated that serum cystatin C, urine interleukin-18 (IL-18), and urine kidney injury molecule-1 (KIM-1) performed best for the differential diagnosis of established AKI. Serum cystatin C and urine neutrophil gelatinase-associated lipocalin, IL-18, glutathione-S-transferase-pi, and gamma-glutathione-S-transferase performed best for early diagnosis of AKI. Urine N-acetyl-beta-D-glucosaminidase, KIM-1, and IL-18 performed the best for mortality risk prediction after AKI. In conclusion, published data from studies of serum and urinary biomarkers suggest that biomarkers may have great potential to advance the fields of nephrology and critical care. These biomarkers need validation in larger studies, and the generalizability of biomarkers to different types of AKI as well as the incremental prognostic value over traditional clinical variables needs to be determined.

Biomarkers of acute kidney injury: can we replace serum creatinine?

Acute kidney injury (AKI) is frequent in hospitalized critically ill patients and mortality associated with AKI is largely unchanged over many decades. The new nomenclature, AKI, reflects the entire spectrum of acute renal failure, recognizing that an acute decline in kidney function can be secondary to an injury that causes functional or structural changes in the kidneys [Mehta et al. 2007]. An abrupt change in serum creatinine level has been the primary method for diagnosing AKI for nearly 60 years despite its well recognized limitations [Addis et al. 1947, Barrett and Addis 1947, Fisher and Wilhelmi 1937, Star 1998]. These limitations are mainly related to the delayed diagnosis of AKI associated with delayed rise in serum creatinine and the lack of specificity and sensitivity associated with small changes in serum creatinine. It is believed that these limitations associated with diagnosis of AKI have prevented progress by interfering with the design of clinical trials for newer therapies. It is now widely believed that the availability of accurate and objective early biomarkers of AKI will stimulate progress in the development of early interventions in AKI. Recognition of this concept has led to a surge in preclinical, translational and clinical research for discovery and validation of biomarkers in AKI. In this review we will discuss the role of biomarkers in AKI and the promising biomarkers on the horizon.

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.

Improving on-line information for potential living kidney donors.

Individuals who consider becoming living kidney donors often search the internet for reliable information before contacting the transplant center. The quality of such information requires due consideration. Using the search engines Google and Yahoo and the WebMD information portal, two reviewers independently abstracted data on the classification, readability, and general quality of websites. The coverage and accuracy of each site's discussion of the risks, benefits, and process of living donation was also assessed against a checklist of recommended information. Eighty-six unique websites on living kidney donation were found. Most were created by transplant programs and transplant organizations. Although the content of most sites was accurate, almost all (98%) were written above the recommended patient reading level (i.e., fifth grade). On average, each site covered 38% of the recommended information on living donation (range 8-76%). Educational topics of potential long-term medical risks, psychological risks, and expected benefits to the donor were often missing. The most visited websites were often not ranked among the best sites to provide information. By better understanding the nature of on-line information, transplant professionals can direct their patients to the best available websites. Local educational efforts, including the effective use of internet resources, will ensure living donation and complete understanding of the risks by potential donors and recipients.

Urine NGAL and IL-18 are predictive biomarkers for delayed graft function following kidney transplantation.

Delayed graft function (DGF) due to tubule cell injury frequently complicates deceased donor kidney transplants. We tested whether urinary neutrophil gelatinase-associated lipocalin (NGAL) and interleukin-18 (IL-18) represent early biomarkers for DGF (defined as dialysis requirement within the first week after transplantation). Urine samples collected on day 0 from recipients of living donor kidneys (n = 23), deceased donor kidneys with prompt graft function (n = 20) and deceased donor kidneys with DGF (n = 10) were analyzed in a double blind fashion by ELISA for NGAL and IL-18. In patients with DGF, peak postoperative serum creatinine requiring dialysis typically occurred 2-4 days after transplant. Urine NGAL and IL-18 values were significantly different in the three groups on day 0, with maximally elevated levels noted in the DGF group (p < 0.0001). The receiver-operating characteristic curve for prediction of DGF based on urine NGAL or IL-18 at day 0 showed an area under the curve of 0.9 for both biomarkers. By multivariate analysis, both urine NGAL and IL-18 on day 0 predicted the trend in serum creatinine in the posttransplant period after adjusting for effects of age, gender, race, urine output and cold ischemia time (p < 0.01). Our results indicate that urine NGAL and IL-18 represent early, predictive biomarkers of DGF.

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.

Acute renal failure in hematopoietic cell transplantation.

Hematopoietic cell transplantation is a common procedure for the treatment of malignancies and some non-malignant hematologic disorders. In addition to other transplant-related organ toxicities, acute renal failure is a common complication following transplantation. This review discusses the incidence, timing, etiologies, risk factors, and prognosis of renal failure associated with three commonly used transplantation procedures - myeloablative autologous, myeloablative allogeneic, and non-myeloablative allogeneic transplantation. It is important to note that the epidemiology and prognosis of renal failure are distinct with these three transplantation procedures. However, the common theme is that mortality increases with worsening renal failure with all three procedures. Moreover, mortality is >80% for patients with renal failure requiring dialysis. It also appears that surviving patients have an increased risk of chronic kidney disease after renal failure. The reduction of acute renal failure will have several advantages, including reducing mortality and the burden of chronic kidney disease following transplantation.

Chronic kidney disease following non-myeloablative hematopoietic cell transplantation.

Chronic kidney disease (CKD) following myeloablative allogeneic hematopoietic cell transplantation (HCT) occurs in 20% of survivors at 1 year and is believed to be due to radiation nephritis. Non-myeloablative allogeneic HCT is a recent procedure that employs significantly lower doses of chemoradiotherapy, however, incidence and risk factors for CKD following non-myleoablative HCT have not been defined. We performed a retrospective cohort study of 122 patients from three institutions who were available for analysis at 6 months following non-myeloablative HCT. Patients received two Gy of radiation; 62% received fludarabine as preconditioning. CKD was defined as at least a 25% reduction in glomerular filtration rate (GFR) from baseline using the abbreviated modified diet in renal disease (MDRD) equation. Eighty-one of 122 patients (66%) showed evidence of CKD at follow-up. Multivariate analysis revealed that acute renal failure (ARF) during the first 100 days post-transplant was associated with development of CKD (Adjusted OR 32.8 with 95% CI 4.3-250) after controlling for other variables. Previous autologous HCT, long-term calcineurin inhibitor use and extensive chronic GVHD were independently associated with CKD. CKD following non-myeloablative HCT appears to be a distinct clinical entity and likely not related to radiation nephritis. Future research should focus on possible mechanisms for alleviating chronic injury and decreasing use of calcineurin inhibitors.

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.