The intrarenal resistive index is routinely measured in many renal-transplantation centers for assessment of renal-allograft status, although the value of the resistive index remains unclear.
In a ...single-center, prospective study involving 321 renal-allograft recipients, we measured the resistive index at baseline, at the time of protocol-specified renal-allograft biopsies (3, 12, and 24 months after transplantation), and at the time of biopsies performed because of graft dysfunction. A total of 1124 renal-allograft resistive-index measurements were included in the analysis. All patients were followed for at least 4.5 years after transplantation.
Allograft recipients with a resistive index of at least 0.80 had higher mortality than those with a resistive index of less than 0.80 at 3, 12, and 24 months after transplantation (hazard ratio, 5.20 95% confidence interval {CI}, 2.14 to 12.64; P<0.001; 3.46 95% CI, 1.39 to 8.56; P=0.007; and 4.12 95% CI, 1.26 to 13.45; P=0.02, respectively). The need for dialysis did not differ significantly between patients with a resistive index of at least 0.80 and those with a resistive index of less than 0.80 at 3, 12, and 24 months after transplantation (hazard ratio, 1.95 95% CI, 0.39 to 9.82; P=0.42; 0.44 95% CI, 0.05 to 3.72; P=0.45; and 1.34 95% CI, 0.20 to 8.82; P=0.76, respectively). At protocol-specified biopsy time points, the resistive index was not associated with renal-allograft histologic features. Older recipient age was the strongest determinant of a higher resistive index (P<0.001). At the time of biopsies performed because of graft dysfunction, antibody-mediated rejection or acute tubular necrosis, as compared with normal biopsy results, was associated with a higher resistive index (0.87 ± 0.12 vs. 0.78 ± 0.14 P=0.05, and 0.86 ± 0.09 vs. 0.78 ± 0.14 P=0.007, respectively).
The resistive index, routinely measured at predefined time points after transplantation, reflects characteristics of the recipient but not those of the graft. (ClinicalTrials.gov number, NCT01879124 .).
Abstract
Background
In haemodialysis, maintaining patency of the extracorporeal circuit requires the use of anticoagulants. Although (low molecular weight) heparins are the mainstay, these are not ...well tolerated in all patients. Alternative approaches include saline infusion, citrate-containing dialysate, regional citrate anticoagulation or the use of heparin-coated membranes. Asymmetric cellulose triacetate (ATA) dialysers have a low degree of platelet contact activation and might be an alternative to heparin-coated dialysers. The aim of this study was to test the clotting propensity of ATA when used without systemic anticoagulation.
Methods
We performed a Phase II pilot study in maintenance dialysis patients. The ‘Strategies for Asymmetrical Triacetate dialyzer heparin-Free Effective hemodialysis’ (SAFE) study was a two-arm open-label crossover study. In Arm A, patients were dialysed using 1.9 m2 ATA membranes in combination with a citrate-containing dialysate (1 mM). In Arm B, the ATA membrane was combined with high-volume predilution haemodiafiltration (HDF) without any other anticoagulation. The primary endpoint was the success rate to complete 4 h of haemodialysis without preterm clotting. Secondary endpoints included time to clotting and measures of dialysis adequacy.
Results
We scheduled 240 dialysis sessions (120/arm) in 20 patients. Patients were randomized 1:1 to start with Arm A or B. All patients crossed to the other arm halfway through the study. A total of 232 (96.7%) study treatments were delivered. Overall, 23 clotting events occurred, 7 in Arm A and 16 in Arm B. The success rate in Arm A (ATA + citrate-containing dialysate) was 90.8/94.0% intention to treat (ITT)/as treated. The success rate in Arm B (ATA + predilution HDF) was 83.3/86.2% (ITT/as treated). Time to clotting was borderline significantly better in Arm A (Mantel-Cox log rank P = 0.05).
Conclusion
ATA dialysers have a low clotting propensity and both predilution HDF and a citrate-containing dialysate resulted in high rates of completed dialysis sessions.
Using meta-analysis of eight independent transplant datasets (236 graft biopsy samples) from four organs, we identified a common rejection module (CRM) consisting of 11 genes that were significantly ...overexpressed in acute rejection (AR) across all transplanted organs. The CRM genes could diagnose AR with high specificity and sensitivity in three additional independent cohorts (794 samples). In another two independent cohorts (151 renal transplant biopsies), the CRM genes correlated with the extent of graft injury and predicted future injury to a graft using protocol biopsies. Inferred drug mechanisms from the literature suggested that two FDA-approved drugs (atorvastatin and dasatinib), approved for nontransplant indications, could regulate specific CRM genes and reduce the number of graft-infiltrating cells during AR. We treated mice with HLA-mismatched mouse cardiac transplant with atorvastatin and dasatinib and showed reduction of the CRM genes, significant reduction of graft-infiltrating cells, and extended graft survival. We further validated the beneficial effect of atorvastatin on graft survival by retrospective analysis of electronic medical records of a single-center cohort of 2,515 renal transplant patients followed for up to 22 yr. In conclusion, we identified a CRM in transplantation that provides new opportunities for diagnosis, drug repositioning, and rational drug design.
•We detected BC particles in and near all structural renal components.•BC particles were observed predominantly in and near the blood vessels and tubules.•A higher BC load was associated with higher ...urinary kidney injury molecule-1.
Ultrafine particles, including black carbon (BC), can reach the systemic circulation and therefore may distribute to distant organs upon inhalation. The kidneys may be particularly vulnerable to the adverse effects of BC exposure due to their filtration function.
We hypothesized that BC particles reach the kidneys via the systemic circulation, where the particles may reside in structural components of kidney tissue and impair kidney function.
In kidney biopsies from 25 transplant patients, we visualized BC particles using white light generation under femtosecond-pulsed illumination. The presence of urinary kidney injury molecule-1 (KIM-1) and cystatin c (CysC) were evaluated with ELISA. We assessed the association between internal and external exposure matrices and urinary biomarkers using Pearson correlation and linear regression models.
BC particles could be identified in all biopsy samples with a geometric mean (5th, 95th percentile) of 1.80 × 103 (3.65 × 102, 7.50 × 103) particles/mm3 kidney tissue, predominantly observed in the interstitium (100 %) and tubules (80 %), followed by the blood vessels and capillaries (40 %), and the glomerulus (24 %). Independent from covariates and potential confounders, we found that each 10 % higher tissue BC load resulted in 8.24 % (p = 0.03) higher urinary KIM-1. In addition, residential proximity to a major road was inversely associated with urinary CysC (+10 % distance: −4.68 %; p = 0.01) and KIM-1 (+10 % distance: −3.99 %; p < 0.01). Other urinary biomarkers, e.g., the estimated glomerular filtration rate or creatinine clearance showed no significant associations.
Our findings that BC particles accumulate near different structural components of the kidney represent a potential mechanism explaining the detrimental effects of particle air pollution exposure on kidney function. Furthermore, urinary KIM-1 and CysC show potential as air pollution-induced kidney injury biomarkers for taking a first step in addressing the adverse effects BC might exert on kidney function.
ABSTRACT
Breast arterial calcification (BAC) is increasingly recognized as a specific marker of medial calcification. The present retrospective observational cohort study aimed to define the ...prevalence, progression rate, risk factors and clinical implications of BAC in chronic kidney disease (CKD) patients across stages of disease. The presence and extent of BAC were determined on mammograms in 310 females (58.7 ± 10.8 years, Caucasian) with CKD across various stages of disease CKD G2–5D n = 132; transplant (Tx) recipients n = 178. In a subset of 88 patients, repeat mammography was performed, allowing us to calculate the annualized BAC rate. Overall, BAC was observed in 34.7% of the patients. BAC prevalence (P = 0.02) and BAC score (P = 0.05) increased along the progression of CKD. In the overall cohort, patients with BAC were characterized by older age, more cardiovascular disease, more inflammation, higher pulse pressure and borderline higher prevalence of diabetes and were more often treated with a vitamin K antagonist (VKA). The BAC progression rate was significantly lower in Tx patients as compared with CKD G5D. Progressors were characterized by more inflammation, worse kidney function, higher BAC score and higher serum phosphate level (Tx only) at baseline and were more often treated with a VKA. Major adverse cardiovascular event-free survival was significantly worse in Tx patients with BAC. In conclusion, BAC is common among CKD patients, progresses at a slower pace in Tx patients as compared with CKD 5D and associates with dismal cardiovascular outcomes. BAC score, kidney function, serum phosphate at baseline and VKA usage seem to be important determinants of progression.
Graphical Abstract
Graphical Abstract
The effect of baseline histology and individual histologic lesions at the time of transplantation on long-term graft survival has been evaluated using different scoring systems, but the predictive ...capacity of these systems has not been adequately validated. All kidney recipients transplanted in a single institution between 1991 and 2009 who underwent a baseline kidney allograft biopsy at transplantation were included in this prospective study (N=548). All baseline biopsies were rescored according to the updated Banff classification, and the relationship between the individual histologic lesions and donor demographics was assessed using hierarchical clustering and principal component analysis. Survival analysis was performed using Cox proportional hazards analysis and log-rank testing. Mean follow-up time was 6.7 years after transplantation. Interstitial fibrosis, tubular atrophy, and glomerulosclerosis associated significantly with death-censored graft survival, whereas arteriolar hyalinosis and vascular intimal thickening did not. Notably, donor age correlated significantly with interstitial fibrosis, tubular atrophy, and glomerulosclerosis and associated independently with graft survival. On the basis of these findings, a novel scoring system for prediction of 5-year graft survival was constructed by logistic regression analysis. Although the predictive performance of previously published histologic scoring systems was insufficient to guide kidney allocation in our cohort (receiver operating characteristic area under the curve ≤0.62 for each system), the new system based on histologic data and donor age was satisfactory for prediction of allograft loss (receiver operating characteristic area under the curve = 0.81) and may be valuable in the assessment of kidney quality before transplantation.
Ambient fine particulate matter (PM < 2.5 μm, PM
) is gaining increasing attention as an environmental risk factor for health. The kidneys are considered a particularly vulnerable target to the toxic ...effects that PM
exerts. Alteration of kidney function may lead to a disrupted homeostasis, affecting disparate tissues in the body. This review intends to summarize all relevant knowledge published between January 2000 and December 2021 on the effects of ambient PM
and the adverse effects on kidney function in adults (≥ 18 years).
Studies published in peer-reviewed journals, written in English, regarding the effects of PM
on kidney function and the development and/or exacerbation of kidney disease(s) were included. Of the 587 nonduplicate studies evaluated, 40 were included, comprising of studies on healthy or diagnosed with pre-existing disease (sub)populations. Most of the studies were cohort studies (n = 27), followed by 10 cross-sectional, 1 ecological and 2 time-series studies. One longitudinal study was considered intermediate risk of bias, the other included studies were considered low risk of bias. A large portion of the studies (n = 36) showed that PM
exposure worsened kidney outcome(s) investigated; however, some studies show contradictory results. Measurement of the estimated glomerular filtration rate, for instance, was found to be positively associated (n = 8) as well as negatively associated (n = 4) with PM
.
The main limitations of the included studies include residual confounding (e.g., smoking) and lack of individual exposure levels. The majority of included studies focused on specific subpopulations, which may limit generalizability. Evidence of the detrimental effects that ambient PM
may exert on kidney function is emerging. However, further investigations are required to determine how and to what extent air pollution, specifically PM
, exerts adverse effects on the kidney and alters its function.
The systematic review protocol was submitted and published by the International Prospective Register of Systematic Reviews (PROSPERO; CRD42020175615 ).
Rejection remains the main cause of premature graft loss after kidney transplantation, despite the use of potent immunosuppression. This highlights the need to better understand the composition and ...the cell-to-cell interactions of the alloreactive inflammatory infiltrate. Here, we performed droplet-based single-cell RNA sequencing of 35,152 transcriptomes from 16 kidney transplant biopsies with varying phenotypes and severities of rejection and without rejection, and identified cell-type specific gene expression signatures for deconvolution of bulk tissue. A specific association was identified between recipient-derived FCGR3A+ monocytes, FCGR3A+ NK cells and the severity of intragraft inflammation. Activated FCGR3A+ monocytes overexpressed CD47 and LILR genes and increased paracrine signaling pathways promoting T cell infiltration. FCGR3A+ NK cells overexpressed FCRL3, suggesting that antibody-dependent cytotoxicity is a central mechanism of NK-cell mediated graft injury. Multiplexed immunofluorescence using 38 markers on 18 independent biopsy slides confirmed this role of FcγRIII+ NK and FcγRIII+ nonclassical monocytes in antibody-mediated rejection, with specificity to the glomerular area. These results highlight the central involvement of innate immune cells in the pathogenesis of allograft rejection and identify several potential therapeutic targets that might improve allograft longevity.
The relative impact on renal allograft outcome of specific histological diagnoses versus nonspecific chronic histological damage remains unclear.
All 1,197 renal allograft recipients who were ...transplanted at a single center between 1991 and 2001 were included. All posttransplant renal allograft indication biopsies performed in this cohort during follow-up (mean, 14.5±2.80 years after transplantation) were rescored according to the current histological criteria and associated with death-censored graft outcome.
In this cohort, 1,365 allograft indication biopsies were performed. Specific diagnoses were present in 69.4% of graft biopsies before graft loss, but 30.6% of grafts did not have specific diagnoses in the last biopsy before graft loss. Only 14.6% of the patients did never have any specific disease diagnosed before graft loss. Extensive interstitial fibrosis and tubular atrophy without a clear cause was identified as the single cause of graft loss in only 6.9% of the cases. Acute T-cell-mediated rejection and changes suggestive of acute antibody-mediated rejection, diagnosed after the first year posttransplant, associated independently with graft survival. Transplant glomerulopathy increased over time after transplantation and represented a major risk for graft loss, as well as de novo or recurrent glomerular pathologies and polyomavirus nephropathy. Chronic histological injury associated with graft outcome, independent of specific diagnoses.
Renal allograft loss is multifactorial. Chronic histological damage and specific diseases had additive and independent impact on graft outcome. Chronic damage should be taken into account in prognostication of renal allograft outcome and could be implemented in treatment algorithms for specific diseases of kidney allografts.
Prior studies have demonstrated the diagnostic potential of urinary chemokines C-X-C motif ligand 9 (CXCL9) and CXCL10 for kidney transplant rejection. However, their benefit in addition to clinical ...information has not been demonstrated. We evaluated the diagnostic performance for detecting acute rejection of urinary CXCL9 and CXCL10 when integrated with clinical information.
Single-center prospective cohort study.
We analyzed 1,559 biopsy-paired urinary samples from 622 kidney transplants performed between April 2013 and July 2019 at a single transplant center in Belgium. External validation was performed in 986 biopsy-paired urinary samples.
We quantified urinary CXCL9 (uCXCL9) and CXCL10 (uCXCL10) using an automated immunoassay platform and normalized the values to urinary creatinine. Urinary chemokines were incorporated into a multivariable model with routine clinical markers (estimated glomerular filtration rate, donor-specific antibodies, and polyoma viremia) (integrated model). This model was then compared with the tissue diagnosis according to the Banff classification for acute rejection.
Acute rejection detected on kidney biopsy using the Banff classification.
Chemokines integrated with routine clinical markers had high diagnostic value for detection of acute rejection (n=150) (receiver operating characteristic area under the curve 81.3% 95% CI, 77.6-85.0). The integrated model would help avoid 59 protocol biopsies per 100 patients when the risk for rejection is predicted to be below 10%. The performance of the integrated model was similar in the external validation cohort.
The cross-sectional nature obviates investigating the evolution over time and prediction of future rejection.
The use of an integrated model of urinary chemokines and clinical markers for noninvasive monitoring of rejection could enable a reduction in the number of biopsies. Urinary chemokines may be useful noninvasive biomarkers whose use should be further studied in prospective randomized trials to clarify their role in guiding clinical care and the use of biopsies to detect rejection after kidney transplantation.
Urinary chemokines CXCL9 and CXCL10 have been suggested to be good noninvasive biomarkers of kidney transplant rejection. However, defining a context of use and integration with clinical information is necessary before clinical implementation can begin. In this study, we demonstrated that urinary chemokines CXCL9 and CXCL10, together with clinical information, have substantial diagnostic accuracy for the detection of acute kidney transplant rejection. Application of urinary chemokines together with clinical information may guide biopsy practices following kidney transplantation and potentially reduce the need for kidney transplant biopsies.
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