Decreased Kidney Graft Survival in Low Immunological Risk Patients Showing Inflammation in Normal Protocol Biopsies

Ortiz, Fernanda; Gelpi, Rosana; Helanterä, Ilkka; Melilli, Edoardo; Honkanen, Eero; Bestard, Oriol; Grinyó, Josep M.; Cruzado, Josep M.

doi:10.1371/journal.pone.0159717

Cited by 22 publications

(23 citation statements)

References 35 publications

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“…Secondly, biomarkers may be superior to serum creatinine measurement in detecting the presence or absence of subclinical rejection, which normally would stay below the radar of detection when using merely serum creatinine as indicator. Subclinical rejection has an incidence of 5% within the first 6 months after transplantation (47) and significantly impacts long-term graft survival (48).…”

Section: Challenges and Future Directionsmentioning

confidence: 99%

Non-invasive Biomarkers of Acute Rejection in Kidney Transplantation: Novel Targets and Strategies

et al. 2019

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Kidney transplantation is considered the favored treatment for patients suffering from end-stage renal disease, since successful transplantation is associated with longer survival and improved quality of life compared to dialysis. Alloreactive immune responses against the donor kidney may lead to acute rejection of the transplant. The current diagnosis of renal allograft rejection mainly relies on clinical monitoring, including serum creatinine, proteinuria, and confirmation by histopathologic assessment in the kidney transplant biopsy. These parameters have their limitations. Identification and validation of biomarkers, which correlate with or predict the presence of acute rejection, and which could improve therapeutic decision making, are priorities for the transplantation community. There is a need for alternative, less invasive but sensitive markers to diagnose acute graft rejection. Here, we provide an overview of the current status on research of biomarkers of acute kidney transplant rejection in blood and urine. We specifically discuss relatively novel research strategies in biomarker research, including transcriptomics and proteomics, and elaborate on donor-derived cell-free DNA as a potential biomarker.

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Section: Challenges and Future Directionsmentioning

confidence: 99%

Non-invasive Biomarkers of Acute Rejection in Kidney Transplantation: Novel Targets and Strategies

et al. 2019

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“…The incidence of both clinical and subclinical acute rejection was low, in line with the results achieved with current immunosuppression in the low immunological risk population. 33 There were no differences between PAR and CAL regarding rejection and de novo donor-specific antibody development. These findings suggested that PAR, in comparison with nutritional vitamin D replenishment, was not associated with a higher prevention of immunologically mediated allograft damage.…”

Section: Discussionmentioning

confidence: 91%

Paricalcitol Versus Calcifediol for Treating Hyperparathyroidism in Kidney Transplant Recipients

Cruzado

Lauzurica

Pascual

et al. 2018

Kidney International Reports

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IntroductionSecondary hyperparathyroidism (SHPT) and vitamin D deficiency are common at kidney transplantation and are associated with some early and late complications. This study was designed to evaluate whether paricalcitol was more effective than nutritional vitamin D for controlling SHPT in de novo kidney allograft recipients.MethodsThis was a 6-month, investigator-initiated, multicenter, open-label, randomized clinical trial. Patients with pretransplantation iPTH between 250 and 600 pg/ml and calcium <10 mg/dl were randomized to paricalcitol (PAR) or calcifediol (CAL). The intention-to-treat population (PAR: n = 46; CAL: n = 47) was used for the analysis. The primary endpoint was the percentage of patients with serum iPTH >110 pg/ml at 6 months. Secondary endpoints were bone mineral metabolism, renal function, and allograft protocol biopsies.ResultsThe primary outcome occurred in 19.6% of patients in the PAR group and 36.2% of patients in the CAL group (P = 0.07). However, there was a higher percentage of patients with iPTH <70 pg/ml in the PAR group than in the CAL group (63.4% vs. 37.2%; P = 0.03). No differences were observed in bone turnover biomarkers and bone mineral density. The estimated glomerular filtration rate was significantly higher in the CAL group than in the PAR group without differences in albuminuria. In protocol biopsies, interstitial fibrosis and tubular atrophy tended to be higher in the PAR group than in the CAL group (48% vs. 23.8%; P = 0.09). Both medications were well tolerated.ConclusionBoth PAR and CAL reduced iPTH, but PAR was associated with a higher proportion of patients with iPTH <70 pg/ml. These results do not support the use of PAR to treat posttransplantation hyperparathyroidism.

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“…We arbitrarily employed an i-score ≥ 1 as the threshold to distinguish between inflammation and no inflammation. This decision was based on previous observations showing that an i-score ≥ 1 is associated with decreased graft survival, while isolated tubulitis has a minor and controversial influence on outcome [ 35 , 36 , 37 ]. Despite the low degree of inflammation, TAC levels were significantly higher in early biopsies without inflammation, and the time below the therapeutic range was longer in late biopsies, suggesting that even in low immunological risk patients receiving a high TAC schedule, interstitial inflammation in healthy interstitial areas is modulated by TAC exposure.…”

Section: Discussionmentioning

confidence: 99%

Progression of Interstitial Fibrosis and Tubular Atrophy in Low Immunological Risk Renal Transplants Monitored by Sequential Surveillance Biopsies: The Influence of TAC Exposure and Metabolism

Chamoun

Gabaldon

Sellarès

et al. 2021

JCM

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The combination of tacrolimus (TAC) and mycophenolate is the most widely employed maintenance immunosuppression in renal transplants. Different surrogates of tacrolimus exposure or metabolism such as tacrolimus trough levels (TAC-C0), coefficient of variation of tacrolimus (CV-TAC-C0), time in therapeutic range (TTR), and tacrolimus concentration dose ratio (C/D) have been associated with graft outcomes. We explore in a cohort of low immunological risk renal transplants (n = 85) treated with TAC, mycophenolate mofetil (MMF), and steroids and then monitored by paired surveillance biopsies the association between histological lesions and TAC-C0 at the time of biopsy as well as CV-TAC-C0, TTR, and C/D during follow up. Interstitial inflammation (i-Banff score ≥ 1) in the first surveillance biopsy was associated with TAC-C0 (odds ratio (OR): 0.69, 95% confidence interval (CI): 0.50–0.96; p = 0.027). In the second surveillance biopsy, inflammation was associated with time below the therapeutic range (OR: 1.05 and 95% CI: 1.01–1.10; p = 0.023). Interstitial inflammation in scarred areas (i-IFTA score ≥ 1) was not associated with surrogates of TAC exposure/metabolism. Progression of interstitial fibrosis/tubular atrophy (IF/TA) was observed in 35 cases (41.2%). Multivariate regression logistic analysis showed that mean C/D (OR: 0.48; 95% CI: 0.25–0.92; p = 0.026) and IF/TA in the first biopsy (OR: 0.43, 95% CI: 0.24–0.77, p = 0.005) were associated with IF/TA progression between biopsies. A low C/D ratio is associated with IF/TA progression, suggesting that TAC nephrotoxicity may contribute to fibrosis progression in well immunosuppressed patients. Our data support that TAC exposure is associated with inflammation in healthy kidney areas but not in scarred tissue.

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Decreased Kidney Graft Survival in Low Immunological Risk Patients Showing Inflammation in Normal Protocol Biopsies

Cited by 22 publications

References 35 publications

Non-invasive Biomarkers of Acute Rejection in Kidney Transplantation: Novel Targets and Strategies

Non-invasive Biomarkers of Acute Rejection in Kidney Transplantation: Novel Targets and Strategies

Paricalcitol Versus Calcifediol for Treating Hyperparathyroidism in Kidney Transplant Recipients

Progression of Interstitial Fibrosis and Tubular Atrophy in Low Immunological Risk Renal Transplants Monitored by Sequential Surveillance Biopsies: The Influence of TAC Exposure and Metabolism

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