Improved ability to achieve target trough levels with liquid versus capsule tacrolimus in kidney transplant patients with HIV on protease inhibitor- or cobicistat-based regimens.

HIV + patients are commonly accepted for kidney transplantation. However, patients on protease inhibitor (PI)- or cobicistat (cobi)-based regimens have trouble achieving optimal tacrolimus (Tac) levels. Our study compared the ability to achieve target levels using liquid versus immediate-release capsule Tac in kidney transplant patients with HIV on PI- or cobi-based regimens. The study included four kidney transplant patients who were converted to liquid Tac due to inability to achieve acceptable drug levels on the capsule formulation. Tac trough levels were analyzed retrospectively to compare target levels before and after conversion. The individual patient time in the therapeutic range (TTR) was calculated using Rosendaal's linear interpolation method, and the difference between before and after conversion TTR was determined. In combined data, 44.63% of all Tac trough levels were within the target range after conversion to liquid Tac compared to 22.07% prior to conversion (P < .001). Furthermore, 3.31% and 7.44% of Tac trough levels were lower than 3 ng/mL or higher than 12 ng/mL, respectively, after conversion compared to 11.72% (P = .0564) and 24.14% (P < .0001) prior to conversion. The overall mean TTR was 45.1% after conversion to liquid Tac compared to 16.2% prior to conversion (P = .097). Finally, the coefficient of variation for Tac trough levels was 42.6 after conversion compared to 56.4 prior to conversion. A significantly improved ability to achieve target trough Tac levels was achieved with liquid Tac extemporaneous versus capsule formulation in kidney transplant patients with HIV taking a PI- or cobi-based regimen.

A pilot study of immunosuppression resumption following BK viremia resolution.

BACKGROUND: Immunosuppression reduction for BK viremia is associated with de novo humoral responses, which are a risk factor for rejection and graft loss. In this pilot project, we tested a protocol of immunosuppression resumption to standard dose after viral clearance for optimal protection against humoral immunity in patients undergoing treatment for BK viremia. METHODS: Thirty-six consecutive kidney transplant recipients who developed BK viremia from 7/1/2014 to 11/18/2016 underwent immunosuppression reduction. After 4 weeks of absent viremia, mycophenolate mofetil (MMF) was increased by 500mg/day every 2 weeks up to standard dosage, followed by increase of tacrolimus trough levels to 5-7 ng/mL. If viremia recurred during the increase, immunosuppression was reduced in this same stepwise fashion, with stepwise increase again after 2 months of negative viremia. RESULTS: Mean tacrolimus trough level (ng/mL) was 8.3 ± 2.7 at viremia onset, 5.3 ± 3.6 at resolution, and 5.6 ± 2.0 at study end date. Mean daily dose (mg) of MMF was 1574 ± 355 at onset, 910 ± 230 at resolution, and 1377 ± 451 at study end date. Only one patient developed low level viremia recurrence (peak 2875 copies/mL) during the period of immunosuppression resumption that ultimately resolved. CONCLUSIONS: The results of our pilot project indicate that following BK viremia resolution, resumption of standard immunosuppression can be achieved safely without BK viremia recurrence. Larger trials with long-term follow up are required to determine whether such an approach improves long-term graft survival.

Outcomes of induction antibody therapies in the nonbroadly sensitized adult deceased donor kidney transplant recipients: a retrospective cohort registry analysis.

The outcomes of lymphocyte-depleting antibody induction therapy (LDAIT), [thymoglobulin (ATG) or alemtuzumab (ALM)] versus interleukin-2 receptor antagonist (IL-2RA) in the nonbroadly-sensitized [pretransplant calculated panel reactive antibody (cPRA), <80%] adult deceased donor kidney transplant recipients (adult-DDKTRs) are understudied. In this registry, study of 55 593 adult-DD-KTRs, outcomes of LDAIT [(ATG, N = 32 985) and (ALM, N = 9429)], and IL-2RA (N = 13 179) in <10% and 10-79% cPRA groups was analyzed. Adjusted odds ratio (aOR) of one-year biopsy-proven acute rejection (BPAR) was lower; while, aOR of 1-year composite of re-hospitalization, graft loss, or death was higher with LDAIT than IL2-RA in both cPRA groups. Adjusted odds ratio (aOR) of delayed graft function was higher with LDAIT than IL-2RA in the <10% cPRA group. Adjusted hazard ratio (aHR) of 5-year death-censored graft loss (DCGL) in both <80% cPRA groups seemed higher with ALM than other inductions [(<10% cPRA: ALM versus IL2RA, aHR = 1.11, 95% CI = 1.00-1.23 and ATG versus ALM: aHR = 0.84, 95% CI = 0.77-0.91; 10-79% cPRA: ALM versus IL2RA, aHR = 1.29, 95% CI = 1.02-1.64; and ATG versus ALM, aHR = 0.83, 95% CI = 0.70-0.98)]. Five-year aHR of death did not differ among induction therapies in both cPRA groups. In nonbroadly sensitized adult-DDKTRs, LDAIT is more protective against 1-year BPAR (not 5-year mortality) than IL-2RA; the trend of a higher 5-year DCGL risk with ALM than ATG or IL-2RA needs further investigation.

Effects of Serum Uric Acid on Estimated GFR in Cardiac Surgery Patients: A Pilot Study.

BACKGROUND: The aim of the study was to investigate the effects of serum uric acid (SUA) on acute kidney injury (AKI) in patients undergoing cardiac surgery. METHODS: Prospectively collected data from a previous study were analyzed to investigate the relationship between SUA and AKI as assessed by neutrophil gelatinase-associated lipocalin (NGAL), serum creatinine (SCr) and kinetic estimated glomerular filtration rate (KeGFR). RESULTS: Patients undergoing cardiovascular surgery (n = 37) were included. SUA was measured at postoperative 1 h. Statistically significant correlations were present between SUA and NGAL measured at postoperative 1 h (r = 0.39, p = 0.008), 6 h (r = 0.31, p = 0.029) and 24 h (r = 0.31, p < 0.001), respectively. Significant correlations were also noted between SUA and SCr measured on postoperative day 1 (r = 0.41, p = 0.006), day 2 (r = 0.29, p = 0.042) and day 3 (r = 0.42, p = 0.009). Negative correlations were demonstrated between SUA and day 1 (r = -0.44, p = 0.007), day 2 (r = -0.43, p = 0.007), day 3 (r = -0.44, p = 0.006 and day 4 KeGFR (r = -0.35, p = 0.035). The inverse relationship of SUA and KeGFR was also demonstrated with a different method (Jelliffe) of measurement. CONCLUSIONS: A reduction in glomerular filtration rate (GFR) can lead to a rise in SUA. However, in this study, we are able to show that SUA at 1 h (maximal dilution time) effectively predicts subsequent changes in urinary NGAL, SCr, KeGFR, and the development of AKI. Thus, these findings suggest that uric acid precedes and predicts acute changes in renal function and cannot be ascribed to a simple relationship in which a reduced GFR raises SUA.

Age-modified risk factors for mortality of non-elderly adult kidney transplant recipients: a retrospective database analysis.

PURPOSE: We aimed to investigate the role of the recipient's age strata in modifying the associations between risk factors and mortality in non-elderly adult kidney transplant (KT) recipients (KTR). METHODS: We stratified 108,695 adult KTRs between 2000 and 2016 with conditional 1-year survival after KT into cohorts based on age at transplant: 18-49 years and 50-64 years. We excluded KTRs aged < 18 years or > / = 65 years. KTRs were observed for 5 years during the 2nd through 6th years post-KT for the outcome, all-cause mortality. RESULTS: Increasing recipient age strata (18-49-year-old and 50-64-year-old) correlated with decreasing 6-year post-KT survival rates conditional on 1-year survival (79% and 57%, respectively, p < 0.0001). Middle adult age stratum was associated with a higher risk of all-cause mortality than young adult age stratum in KTRs of Hispanic/Latino and other races [HR = 1.23, 95% CI = 1.04-1.45 and HR = 1.51, 95% CI = 1.16-1.97, respectively] and with a primary native renal diagnosis of hypertension or glomerulonephritis [HR = 1.32, 95% CI = 1.12-1.55 and HR = 1.29, 95% CI = 1.10-151, respectively]. When compared with the young adult age stratum, the middle adult age stratum had a mitigating effect on the higher risk of mortality associated with sirolimus-mycophenolate or sirolimus-tacrolimus than the standard calcineurin inhibitor-mycophenolate regimen [HR = 0.75, 95% CI = 0.57-0.99 and HR = 0.71, 95% CI = 0.57-0.89, respectively]. CONCLUSION: Among adult non-elderly KTRs, the age strata, 18-49 years, and 50-64 years, have varying modifying effects on the strength and direction of associations between some specific risk factors and all-cause mortality.

Common predictors of adverse outcomes in adult deceased donor kidney transplant recipients with varying sensitization.

OBJECTIVE: Our objective was to identify consistent predictors of multiple adverse outcomes of adult deceased donor (DD) kidney transplant recipients (KTRs) of varying sensitization status. METHODS: We used the national transplant database in studying 62037 adult DD-KTRs between Dec. 2007 and Jun. 2015 stratified into sensitization cohorts based on calculated panel reactive antibody (CPRA) of <10%, 10%-79%, and ≥80%. We used multivariable logistic regressions for the analysis of risks for delayed graft function (DGF), and of acute rejection (AR) and hospitalization in the first year of transplant, and Cox hazard regression for 5-year overall graft loss (OAGL) and death. RESULTS: The kidney donor risk index (KDRI) highest two quartiles ≥1.45 and 1.15-1.44 were the most consistent predictors for 100% of adverse outcomes (OAGL, death, DGF, AR, and hospitalization) with high significance (P<0.0001) across all sensitization cohorts. The two risk factors that were consistently associated with 80% of adverse outcomes across sensitization cohorts were: (1) pre-transplant dialysis duration >2 years was significantly associated with increased risks of overall graft loss, death, DGF, and hospitalization; and (2) Black KTR race was significantly associated with increased risks of DGF, AR, and hospitalization, and decreased risk of death. Diabetes and KTR age >65 (years) were significant risk factors for overall loss and death across sensitization cohorts. CONCLUSIONS: The two highest KDRI quartiles, pre-transplant dialysis duration >2 years, and African American recipient race are consistent predictors of multiple adverse outcomes in adult DDKTRs across sensitization strata and should be among the factors considered in clinical decision-making and research models in kidney transplantation.

Role of standard HLA mismatch in modifying associations between non-pharmacologic risk factors and solid organ malignancy after kidney transplantation.

BACKGROUND: Human leukocyte antigen mismatch(es) (HLA-mm) between donors and recipients has not been extensively studied either as a risk factor for solid organ malignancy (SOM) or as a modifier of associations between nonpharmacologic risk factors and SOM in kidney transplant recipients (KTRs). METHODS: In a secondary analysis from a previous study, 166,256 adult KTRs in 2000-2018 who survived the first 12 months post-transplant free of graft loss or malignancy were classified into 0, 1-3, and 4-6 standard HLA-mm cohorts. Multivariable cause-specific Cox regressions analyzed the risks of SOM and all-cause mortality (ac-mortality) in 5 years following the first KT year. Comparisons of associations between SOM and risk factors in HLA mismatch cohorts were made by estimating the ratios of adjusted hazard ratios. RESULTS: Compared with 0 HLA-mm, 1-3 HLA-mm was not associated, and 4-6 HLA-mm was equivocally associated with increased risk of SOM [hazard ratio, (HR) = 1.05, 95%, confidence interval (CI) = 0.94-1.17 and HR = 1.11, 95% CI = 1.00-1.34, respectively]. Both 1-3 HLA-mm and 4-6 HLA-mm were associated with increased risk of ac-mortality compared with 0 HLA mm [hazard ratio (HR) = 1.12, 95%, Confidence Interval (CI) = 1.08-1.18) and (HR = 1.16, 95% CI = 1.09-1.22), respectively]. KTR's history of pre-transplant cancer, age 50-64, and >/=65 years were associated with increased risks of SOM and ac-mortality in all HLA mismatch cohorts. Pre-transplant dialysis >2 years, diabetes as the primary renal disease, and expanded or standard criteria deceased donor transplantation were risk factors for SOM in the 0 and 1-3 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. KTRs male sex or history of previous kidney transplant was a risk factor for SOM in the 1-3 and 4-6 HLA-mm cohorts and of ac-mortality in all HLA-mm cohorts. CONCLUSION: Direct association between SOM and the degree of HLA mismatching is equivocal and limited to the 4-6 HLA-mm stratum; however, the degree of HLA mismatching has significant modifying effects on the associations between specific nonpharmacologic risk factors and SOM in KTRs.

Massive Lymphocele Associated with Allograft Hydronephrosis: An Ultrasound Case Study.

Lymphocele is a lymphocyte-rich fluid collection that results from disruption of lymphatics in the recipient during renal transplantation. While small collections resolve spontaneously, larger, symptomatic ones may cause obstructive nephropathy requiring percutaneous or laparoscopic drainage. Prompt diagnosis using bedside sonography may obviate the need for renal replacement therapy. Herein, we present a case of a 72-year-old kidney transplant recipient who developed allograft hydronephrosis secondary to compression by a lymphocele.

Reduction of immunosuppression for post-transplant lymphoproliferative disorder (PTLD): a single-center experience of allograft survival outcomes.

Post-transplant lymphoproliferative disorder (PTLD) is a well-known complication of hematopoietic stem cell transplant and solid organ transplant. While reduction in immunosuppression (RIS) is the first-line treatment for PTLD, outcomes of allograft function as a result of RIS remain understudied. In this retrospective study, we examine rates of allograft rejection and graft failure after RIS in 141 patients diagnosed with PTLD at the University of Florida. Compared to prior literature demonstrating around 32-40% rate of allograft rejection as result of RIS, our institutional analysis revealed a much lower treatment-related allograft rejection rate of 18.4%. Out of the patients who experienced acute allograft rejection, 23.1% ultimately progressed to allograft failure. Interestingly, acute allograft rejection episodes during PTLD treatment were not statistically found to impact overall survival. RIS remains an overall beneficial treatment modality of PTLD due to its low allograft rejection rate relative to treatment rate.

Natriuretic peptides in acute kidney injury - A sojourn on parallel tracks?

OBJECTIVE: The focus of this review was to elicit the mechanistic logic of the experimental and clinical study designs of natriuretic peptides (NP) in acute kidney injury (AKI) and to understand their respective outcomes. METHODS: Online search of PubMed and manual review of articles. Randomized trials, observational and physiologic studies of NPs and AKI were extracted. Rationale, design and study outcomes were analyzed. RESULTS: In experimental models of AKI, infusion of NP prevented post-ischemic fall in renal blood flow (RBF) or improvement in RBF, GFR, diuresis and natriuresis and demonstrated anti-inflammatory properties. NPs were most effective in the early stages of AKI, also in established phase of AKI but their effectiveness were limited to the time of infusion. Hypotension was a major side-effect. Based on these observations, preliminary clinical studies were performed which demonstrated improved urine output, RBF and GFR and reduced need for dialysis. However, randomized, controlled trials failed to demonstrate improvement in dialysis-free survival in different cohorts and study designs. Although NPs reduced the incidence of AKI in the postoperative period in cardiac surgery, it was not associated with improved long-term survival. In contrast to randomized trials, meta-analysis reported favorable results. CONCLUSIONS: Reasons for the divergence of experimental and clinical outcomes of NPs in AKI are discussed in this review article.

Outcomes of sirolimus regimens in 65-year-old and older kidney transplant recipients: a registry-based observational study.

PURPOSE: In large observational studies of adult kidney transplant recipients (KTRs) where older adults (65 years old and older) were not well represented, the mammalian target of rapamycin inhibitors (mTOR inhibitors) has poorer outcomes than the standard tacrolimus-mycophenolate-steroids (TAC-MPA-S) regimen. We conducted this study to compare the outcomes of regimens containing the common mTOR inhibitor, sirolimus (SRL) against TAC-MPA-S in older adult KTRs. METHODS: Using the 2000-2016 Scientific Registry of Transplant Recipients, Cox multivariable regression models were conducted to analyze the patient and graft outcomes associated with regimens containing SRL, steroids (S) and cyclosporine (CSA), tacrolimus (TAC), or mycophenolate (MPA) vs. the standard (TAC-MPA-S) regimen in older adult KTRs. RESULTS: Included in the analysis were 15,008 (95.19%) older adult KTRs on standard (TAC-MPA-S) regimen, 242 (1.53%) on SRL-MPA-S, 300 (1.90%) on SRL-TAC-S, and 217 (1.38%) on SRL-CSA-S. Compared with the standard regimen, the adjusted risks of all-cause death and overall graft loss over a maximum 5-year follow-up were highest with SRL-MPA-S, intermediate with SRL-TAC-S and not significantly different with SRL-CSA-S. The adjusted risks of all-cause death and overall graft loss were modified by a pre-transplant history of malignancy in older adult KTRs on SRL-TAC-S, not in those on SRL-MPA-S or SRL-CSA-S. CONCLUSIONS: In older adult kidney transplant recipients, SRL-TAC-S or SRL-MPA-S, but not SRL-CSA-S is associated with higher risks of death and allograft loss than standard TAC-MPA-S regimen and a pre-transplant malignancy history worsens these risks in patients on SRL-TAC-S. Confirmation of our findings by a prospective randomized trial is needed before translation into clinical practice can be recommended.

Static pressures, intra-access blood flow and dynamic Kt/V profiles in the prediction of dialysis access function.

BACKGROUND: Hemodialysis machine-generated circuit pressures and clearance profiles are potential predictors of quality assurances. In our practice, we previously we observed that elevated static access pressures were associated with abnormal Kt/V values, high access recirculation and deviation of the Kt/V profile (Abnormal Kt/V profile) from normally expected values (Normal Kt/V profile). AIM: To hypothesize that static or derived access pressures would correlate with direct intra-access blood flow rates and that clearance (Kt/V) profiles would correlate with measured Kt/V values. METHODS: Static access pressures, real-time adequacy of dialysis and intra-access blood flow were investigated in end stage renal disease patients undergoing hemodialysis. Wilcoxon-Mann-Whitney test, chi-square test or Fisher's exact test was used to investigate differences between the groups; Spearman's rank correlation test to investigate relationships between static pressures, direct intra-access pressures and Kt/V profiles; and multinomial logistic regression models to identify the independent effect of selected variables on Kt/V profiles. Odds ratio were calculated to measure the association between the variables and Kt/V profiles. RESULTS: One hundred and seven patients were included for analysis. There were no significant differences between genders, and types of vascular access between the normal vs. abnormal clearance (Kt/V) profile groups. No significant correlation could be demonstrated between static access pressures and Kt/V profiles, static access pressures and intra-access blood flow, intra-access blood flow and Kt/V profiles, measured Kt/V and Kt/V profiles or recirculation and Kt/V profiles. CONCLUSION: In this study utilizing measured versus estimated data, we could not validate that dialysis machine generated elevated static pressures predict intra-access blood flow disturbances or that abnormal Kt/V profiles predict access recirculation or inadequate dialysis. These parameters, though useful estimates, cannot be accepted as quality assurance for dialysis adequacy or access function without further evidences.

The Role of Uric Acid in Acute Kidney Injury.

Studies have demonstrated the presence of a strong association between serum uric acid (SUA) and acute kidney injury (AKI) consistently across several disease models. Exposure to SUA at different time periods and concentrations has reliably resulted in AKI whether assessed by conventional or novel biomarkers or by kinetic estimated glomerular filtration rate (KeGFR) engineered for non-steady dynamic states. In experimental models, moderate hyperuricemia was associated with an absence of intrarenal crystals, manifestation of tubular injury, macrophage infiltration, and increased expression of inflammatory mediators that were attenuated with uric acid lowering therapy with rasburicase, a recombinant urate oxidase. In a pilot clinical trial, treatment with rasburicase was associated with a decreased incidence of AKI and evidence for less renal structural injury. Lowering SUA also improved KeGFR and estimated glomerular filtration rate in 2 separate studies. SUA has also been linked to diabetic nephropathy, hypertension, cardiovascular disease, chronic kidney disease, metabolic syndrome, and their mechanisms of action share many common traits. In this article, we explore the evidence for the causal role of SUA in AKI using Bradford Hill criteria as a guideline with data integration from related fields.

Parapelvic cysts mimicking hydronephrosis.

Point-of-care renal ultrasonography performed by physicians at bedside assists in rapid evaluation of hydronephrosis, nephrolithiasis and other structural abnormalities, and guides management. As such, it is important to differentiate between various renal pathologies that can mimic one another and herein, we present a case where parapelvic cysts mimicked hydronephrosis.

Not all inflammation in a renal allograft is rejection.

High index of suspicion for adenovirus infection is required in renal graft dysfunction, especially in the setting of hematuria. Histology can mimic acute rejection, which creates a diagnostic dilemma. Tissue adenovirus immunostains, though usually reliable, may not be always positive like in our case.

Two transplant renal arteries: One important lesson.

High index of suspicion is required for ischemic nephropathy in renal transplant recipients presenting with unexplained acute kidney injury, as it is potentially reversible. Carbon dioxide (CO2) angiogram is a good alternative to evaluate vasculature in patients with renal dysfunction where iodinated contrast is relatively contraindicated.

MPO-C-ANCA-associated necrotising and crescentic glomerulonephritis.

The patterns of ANCA staining usually relate closely to antibodies against myeloperoxidase and proteinase-3. C-ANCA is mainly antibodies to proteinase-3 and P-ANCA is antibodies to myeloperoxidase. C-ANCA with antibodies to MPO with clinical sequelae is unusual.

Office orthostatic blood pressure measurements and ambulatory blood pressure monitoring in the prediction of autonomic dysfunction.

BACKGROUND: In this retrospective analysis we investigated the predictive performance of orthostatic hypotension (OH) and ambulatory blood pressure monitoring (ABP) to predict autonomic dysfunction. METHODS: Statistical associations among the candidate variables were investigated and comparisons of predictive performances were performed using Receiver Operating Characteristics (ROC) curves. RESULTS: Ninety-four patients were included for analysis. No significant correlations could be demonstrated between OH and components of ABP (reversal of circadian pattern, postprandial hypotension and heart rate variability), nor between OH and autonomic reflex screen. Reversal of circadian pattern did not demonstrate significant correlation (r = 0.12, p = 0.237) with autonomic reflex screen, but postprandial hypotension (r = 0.39, p = 0.003) and heart rate variability (r = 0.27, p = 0.009) demonstrated significant correlations. Postprandial hypotension was associated with a five-fold (OR 4.83, CI95% 1.6-14.4, p = 0.005) increased risk and heart rate variability with a four-fold (OR 3.75, CI95% 1.3-10.6, p = 0.013) increased risk for autonomic dysfunction. Per ROC curves, heart rate variability (0.671, CI95% 0.53-0.81, p = 0.025) and postprandial hypotension (0.668, CI95% 0.52-0.72, p = 0.027) were among the best predictors of autonomic dysfunction in routine clinical practice. CONCLUSION: Postprandial hypotension and heart rate variability on ambulatory blood pressure monitoring are among the best predictors of autonomic dysfunction in routine clinical practice.