The Protective Role of Protocol Biopsy for Allograft Kidney Maintenance in Kidney Transplantation

The Protective Role of Protocol Biopsy for Allograft Kidney Maintenance in Kidney Transplantation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Protective Role of Protocol Biopsy for Allograft Kidney Maintenance in Kidney Transplantation Okjoo Lee, Kyo Won Lee, Jae Berm Park, Jung Eun Lee, Na Young Hwang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-822374/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Many studies have reported that protocol biopsy (PB) may help preserve kidney function in kidney transplant recipients. Early detection and treatment of subclinical rejection may reduce the incidence of chronic allograft nephropathy and graft failure. However, no consensus has been reached regarding PB effectiveness, timing, and policy. This study aimed to evaluate the protective role of routine PB performed 2 weeks and 1 year after kidney transplantation. We reviewed 854 kidney transplant recipients at the Samsung Medical Center between July 2007 and August 2017, with PBs planned at 2 weeks and 1 year after transplantation. We compared the trends in graft function, chronic kidney disease progression, new-onset chronic kidney disease, infection, and patient and graft survival between the 504 patients who underwent PB and 350 who did not undergo PB. The PB group was again divided into two groups: the single PB group (n = 207) and the double PB group (n = 297). In the PB group, the donors and recipients were significantly older and there was a greater presence of recipient diabetes mellitus and donor hypertension, donor-specific antigen, and a higher proportion of ABO-incompatible kidney transplantations. The PB group was significantly different from the no-PB group in terms of the trends in graft function (estimated glomerular filtration rate). The Kaplan-Meier curve showed that PB did not significantly improve graft survival or overall patient survival. However, in the multivariate Cox analysis, the double PB group had advantages in graft survival, chronic kidney disease progression, and new-onset chronic kidney disease. PB can play a protective role in the maintenance of kidney grafts in kidney transplant recipients. Surgery Hospital Medicine Kidney transplantation biopsy chronic renal insufficiency progression Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Kidney transplantation (KT) has been shown to result in longer patient survival compared to dialysis and is now the treatment of choice for chronic kidney disease (CKD) 1 . In addition, cost and quality of life are better with KT compared with dialysis, though graft management is essential for long-term maintenance 2 , 3 . Therefore, proper management strategies to maintain long-term graft survival are necessary. One strategy that many institutions have adopted is protocol biopsy (PB) with follow-up of transplant recipients 4 , 5 . As histological diagnosis is the most effective modality for graft evaluation, the primary goal of PB is the early detection and treatment of subclinical rejection (SCR), which is characterized by tubule-interstitial infiltration of the renal allograft without clinical deterioration 6 , 7 . SCR diagnosed by PB is associated with chronic allograft nephropathy, which is the most common cause of allograft failure in KT 8 – 11 . Furthermore, chronic allograft nephropathy and graft survival are strongly correlated with acute rejection episodes during the first year after renal transplantation 12 – 15 ; therefore, the early detection and treatment of SCR might reduce the progression of chronic allograft nephropathy and improve graft survival 8 , 16 , 17 . PBs can also be used to evaluate the baseline status of donor renal grafts and to detect BK polyomaviral (BKV) nephropathy, calcineurin inhibitor nephrotoxicity, interstitial fibrosis, and tubular atrophy early 18 , 19 . In our institution, routine PBs are performed 2 weeks and 1 year after KT. Routine PBs are implemented to detect SCR early and administer high-dose corticosteroid pulse therapy to appropriately manage the risk of chronic tubule-interstitial damage. In addition, routine PBs are performed to detect primary disease recurrence (e.g., immunoglobulin A nephropathy, focal segmental glomerulosclerosis, diabetic nephropathy), to proceed with appropriate treatment. Therefore, this study aimed to evaluate the protective effects of PB by comparing renal allograft function (estimated glomerular filtration rate [eGFR]), CKD progression, new-onset CKD, and graft and patient survival before and after the application of routine PB. Methods Study Population. From July 2007 to August 2017, 1,361 KTs were performed at the Samsung Medical Center (Fig. 1). Patients with dual kidney or multi-organ transplants (including simultaneous liver grafts), re-transplantation and pediatric transplants were excluded from the study (n = 337). Additionally, patients who transplanted during the PB strategy period but did not undergo PB, and those diagnosed with SCR but who were not treated, were also excluded (n = 170). The remaining 854 eligible patients were included in the study. After enrollment, the patients were divided into two groups: the no-protocol biopsy (nPB) strategy period group (July 2007 to July 2012; n = 350) and the PB strategy period group (August 2012 to August 2017; n = 504). The PB group was then divided into two additional groups: the single protocol biopsy (sPB) group, for which PB was performed once at 2 weeks or 1 year after transplantation (n = 207), and the double protocol biopsy (dPB) group, for which PB was performed both at 2 weeks and 1 year after transplantation (n = 297). After group classification, we compared the trends in graft function, CKD progression, new-onset CKD, infection, and patient and graft survival among the groups (nPB vs. PB and nPB vs. sPB vs. dPB). Protocol biopsy and t reatment of rejection. PBs were performed percutaneously under real-time ultrasonographic guidance at 2 weeks and 1 year after transplantation. Pathologic evaluation of the biopsies according to the Banff criteria of that period was performed by our transplant pathologists 20 . For our treatment strategy, a borderline pathologic change is considered acute rejection and requires treatment. Clinical rejection was defined as the diagnosis with indicational biopsy, which is performed when the patient shows suspicious finding of acute rejection such as elevation of serum creatinine level or new onset proteinuria. SCR was defined as the findings of a protocol biopsy performed without any suspicion of acute rejection. Both Clinical rejection and SCR were included in the rejection episode analysis. When patients were diagnosed with acute cellular rejection (ACR), steroid therapy was initiated. Intravenous methylprednisolone 500 mg/day for 3 days, tapered by half every day to 60 mg/day was the initial steroid regimen. Oral methylprednisolone was then initiated at 32 mg/day and then tapered to 4–8 mg/day within 1–2 weeks and to 4 mg/day for maintenance. For PB-confirmed antibody-mediated rejection (AMR), intravenous immunoglobulins were administered, or plasmapheresis was performed. Immunosuppression protocol. Depending on the routine induction medication, rabbit antithymocyte globulin (rATG) or basiliximab were administered. In living donor KT, rATG was administered at 1.5 mg/kg/day from the time of surgery to postoperative day 2, in positive human leukocyte antigen (HLA) crossmatch, donor-specific antigen (DSA) with a mean fluorescence intensity ≥ 2,500, and ABO-incompatible KT. In deceased donor KT, rATG was administered in extended criteria donor KT. Otherwise, basiliximab was administered at a dose of 20 mg/day at the time of surgery and on postoperative day 4. All patients received triple immunosuppressive therapy regimens consisting of tacrolimus, mycophenolate mofetil, and methylprednisolone. Any patient who did not receive this regimen was excluded from the study. Tacrolimus (FK506, Prograf; Astellas Fujisawa, Osaka, Japan, and generic tacrolimus) was started on postoperative day 1 at 0.1–0.15 mg/kg/day and adjusted to maintain whole-blood trough levels at 8–10 ng/mL for 1–2 months postoperatively and at 6–8 ng/mL thereafter. Mycophenolate mofetil (Myfortic; Novartis Pharma AG, Basel, Switzerland) was started at a dose of 540 mg/day on postoperative day 1 and adjusted according to the white blood cell count. Methylprednisolone was started on the day of surgery at an intravenous dose of 500 mg/day and administered for 2 days and then tapered by half every day to 60 mg/day. Thereafter, oral methylprednisolone was administered at 32 mg/day for 7 days, 16 mg/day for the next 2 weeks, 8 mg/day for the next month, and 4 mg/day for maintenance. Prophylaxis of infectious diseases. Our protocol for the prophylaxis and diagnosis of infectious diseases was uniform throughout the study period. All patients underwent routine screening for cytomegalovirus (CMV) antigenemia, and recipients with rATG induction received intravenous ganciclovir prophylaxis at 5 mg/kg/day for 2 weeks. Screening for polyomavirus infection was based on routine urinary cytology testing followed by plasma polymerase chain reaction for BKV DNA and graft biopsy. All patients also received 1 tab/day of trimethoprim/sulfamethoxazole (TMP/SMX, 80 mg TMP/400 mg SMX) for Pneumocystis jirovecii prophylaxis. As preemptive prophylaxis for fungal and viral infections, TMP/SMX was administered for up to 6 months after KT in all patients, and itraconazole was additionally administered for up to 2 weeks for patients who underwent rATG induction. After steroid pulse therapy, TMP/SMX was administered for 6 weeks. Definition of the variables. The primary outcome assessed in this study was the inter-stage progression of CKD, with a > 25% decrease in the eGFR. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation, and patients were assigned to a CKD stage based on the Kidney Disease: Improving Global Outcomes guidelines (KDIGO guidelines) 21 .CKD inter-stage progression was calculated using all measured outpatient creatinine values and consecutive 6-month intervals. Stage progression was defined as a significant enough decrease in the mean eGFR in a given 3-month block to result in the inter-stage progression of CKD. If no values were obtained during the block, no progression was considered to have occurred. Pretransplant renal function was determined and initially assessed for its potential effect on disease progression on 1-year post-operation. Since disease progression was based on renal function at 1-year post-transplantation, we did not analyze the pretransplant renal function. New-onset CKD was defined in patients with an eGFR of 60 mL/min/1.73 m 2 or higher who were not diagnosed with CKD. Utilizing the KDIGO guidelines for eGFR, new-onset CKD was defined as an eGFR < 60 mL/min/1.73 m 2 (GFR categories G3a–G5) lasting more than 3 months. Post-KT glomerulonephritis was defined as newly diagnosed or recurrent immunoglobulin A nephropathy, focal segmental glomerulosclerosis, or diabetic nephropathy, and viral infection was defined as influenza or zoster virus infection (not including CMV and BKV). Statistical analysis. All variables are expressed as the mean ± standard deviation or number and percentage. Between-group differences for continuous variables were compared using the Mann-Whitney test, and between-group differences for numbers and percentages were compared using the χ 2 test or Fisher’s exact test. Kaplan-Meier survival curves were used to estimate CKD progression, new-onset CKD, and graft and overall survival. A linear mixed model was used to analyze the difference in the trend of graft function among the three groups. Cox regression analysis was performed with adjustments for significant risk factors in the univariate analysis, as well as other factors previously known to be associated with CKD progression, new-onset CKD, and graft survival. Statistical significance was set at p < 0.05. All statistical analyses were performed using IBM SPSS Statistics for Windows (version 25.0; SPSS, Inc., Chicago, IL, USA). Results Baseline characteristics. The PB group had a significantly higher donor and recipient age, the proportion of males, presence of recipient diabetes mellitus (DM), and donor hypertension than the nPB group (Table 1). However, there was no significant difference between the sPB and dPB groups. Additionally, there was no difference in donor type between the PB and nPB groups. However, when the three groups were compared, there were more deceased donors in the sPB group, which remained true when comparing the sPB and dPB groups. High HLA II mismatch KT, the presence of DSA, ABO-incompatible KT, cold ischemic time, and warm ischemic time were higher in the PB group, but there were no significant differences between the sPB and dPB groups. In the PB group, rATG was used more frequently as an induction regimen. Among all patients, the number of rejection episodes was higher in the PB group, but the proportion of clinical rejection was higher in the nPB group. Moreover, post-KT glomerulonephritis, CKD progression, new-onset CKD, and graft failure were higher in the nPB group (Table 2). Comparing the two groups, clinical rejection and rejection episodes were higher in the dPB group, but CKD progression and new-onset CKD were lower in the dPB group, and graft failure and mortality rates were significantly lower in the sPB group. Trends in graft function and CKD progression. Graft function was analyzed using eGFR trends. Comparing the two groups (PB vs. nPB) and the three groups (nPB vs. sPB vs. dPB), there was a significant difference in the eGFR trends (Fig. 2). Graft function, in general, was lower in the early period after the transplant and improved around 1 year after KT, but was better maintained in the PB group, especially in the dPB group. There was a significant difference in CKD progression between the PB and nPB groups and between the nPB and dPB groups according to the Kaplan-Meier curve (Fig. 3). In the Cox regression analysis of CKD progression, donor DM, and post-KT glomerulonephritis as risk factors, rejection episodes were significantly associated with CKD progression, but dPB and sPB played a significant protective role in CKD progression (Table 3). There was no significant difference in new-onset CKD between the PB and nPB groups according to the Kaplan-Meier curve; however, in the three-group analysis, there was a significant difference between the dPB and the other groups (Fig. 4). In the Cox regression analysis of new-onset CKD, high HLA I mismatch, and post-KT glomerulonephritis as risk factors, rejection episodes were significantly associated with new-onset CKD, and dPB played a significant protective role in new-onset CKD (Table 4). Graft survival and infection outcomes. In the graft survival analysis using the Kaplan-Meier curve, no significant difference was observed between the two groups (Fig. 5). In the multivariate Cox regression analysis of graft survival, recipient DM, and post-KT glomerulonephritis as risk factors, rejection episodes were significantly associated with poor prognosis, but dPB played a significant protective role in graft survival (Table 5). In terms of the number of infections up to 2 years after KT, the PB group had more fungal, viral, and CMV infections than the nPB group, but there was no difference between the sPB and dPB groups (Table 2). In the PB group, almost all patients recovered; however, there were 8 infection-related deaths (bacterial, 3; fungal, 4; and viral, 1). The most common cause of death was multi-organ failure associated with sepsis resulting from urinary tract infection and pneumonia. In the multivariate Cox regression analysis, there was no significant difference between CMV and BKV infections for predicting CKD progression, new-onset CKD, or graft survival (Tables 3-5). Discussion Due to donor organ shortage, the transplant graft must be properly managed to maintain its function over time; therefore, periodic laboratory examinations are conducted to monitor graft function. However, laboratory data alone is not sufficient to determine the condition of the graft. Therefore, PB is a useful diagnostic tool for identifying lesions, predicting the risk of graft failure, and guiding future directions for both organ recipients and donors 22 . However, a survey of US kidney transplant centers found that only 17% perform PBs routinely on all transplant recipients, and studies show that noninvasive methods such as fibroscans or the evaluation of biological markers are effective at detecting SCR 23 , 24 . Moreover, PBs are inconvenient for patients, carry a risk for complications, are invasive and costly, and require technical expertise 25 – 27 . Therefore, there is no current consensus on the timing and method of PBs, or their effectiveness 28 . In addition, consensus regarding appropriate guidelines for PB has not yet been established, and while some studies on PBs have been performed, only a small number of enrolled patients have been included 8 , 19 , 28 . As previously mentioned, the current policy at our institution is to conduct PB twice, once at 2 weeks and again 1 year after transplantation, because rejection that occurs soon after transplantation is considered a major risk factor for chronic rejection and graft failure. In addition, interstitial fibrosis and tubular atrophy are present in approximately half of all grafts with stable function by 1 year after transplantation 15 . This study demonstrated the protective role of PB in KT. The trend of graft function preservation was more apparent in the PB group than in the nPB group, and PB was associated with significant protective effects on CKD progression and new-onset CKD. This is likely because SCR was detected and treated relatively early in this group, which is thought to lead to better results. In addition, dPB had more significant results than sPB in terms of new-onset CKD. Therefore, PB may have advantages over nPB, and dPB may be superior to sPB. PB is invasive and carries a small but real risk of complications, with the best estimates for major complications between 0.4% and 1.0% 27,29 . In this study, there were no complications requiring intervention after PB. However, from 2012 to 2019, the rate of major complications from PB at the Samsung Medical Center was 0.45% (4/882) at 2 weeks and 0.17% (1/556) at 1-year post-transplantation in 1,438 KT recipients (yet unpublished data). This is consistent with previous studies and should not limit the application of PB. PB is an evaluative strategy that can be used to accurately diagnose and monitor for rejection, but steroid pulse therapy after PB can be a risk factor for viral infection. Theoretically, this could lead to worse results in those undergoing PB. In terms of infection outcomes in this study, the PB group had more fungal, viral, and CMV infections than the nPB group, which was likely the result of steroid pulse therapy. The mortality rate from infections for all patients in the PB group was 0.60% bacterial (3/504), 0.79% fungal (4/504), and 0.20% viral (1/504). However, when comparing the patients diagnosed with infections, the mortality rate was significantly higher with fungal infections (4/14; 28.57%) compared to bacterial (3/88; 3.41%) or viral (1/10; 10.00%) infections. A study at our institution has identified that treatments for rejection could be a risk factor for invasive pulmonary aspergillosis-associated mortality 30 . However, in the current study, no relationship was found between patient mortality and rejection treatment. This is likely because no infection occurred during the treatment of SCR diagnosed by PB. Indeed, at least one year had elapsed between the treatment of SCR and death, and the cause of death was the rapid progression of infection, likely due to immunosuppression. Therefore, the treatment of SCR diagnosed by PB was not considered a risk factor for infection-related mortality in patients diagnosed with infections. Additionally, the CMV infection rate was also high; however, unlike previous studies, graft survival was not affected. This may be because at our center, ganciclovir is administered as preemptive prophylaxis with periodic CMV monitoring. However, to reach a consensus concerning the prevention of life-threatening infections in KT recipients, more extensive study is needed. In our study, there was no significant difference in the survival rate based on the Kaplan-Meier curve for graft survival. This is thought to be the result of specific characteristics of the donors and recipients. The PB group included donors and recipients who were significantly older and there was a higher presence of recipient DM and donor hypertension. Therefore, the eGFRs within 1 year after KT were lower in PB group as shown in Fig. 2 . Moreover, a number of mismatched HLA II, a presence of DSA, and longer cold and warm ischemic times, which are known risk factors for graft failure, were higher in the PB group 17 , 31 . Owing to these differences in baseline characteristics, no significant differences in graft survival trends were observed. However, in the multivariate analysis for graft failure, the Cox regression model showed statistically significant results for the dPB group. Therefore, we concluded that performing PB twice at these time points can play a protective role in the management of kidney grafts. There were some limitations to this study. First, it was a retrospective, single-center analysis of a cohort in South Korea. Therefore, the results might not be generalizable to other countries and continents. Second, the nPB group included patients who had undergone KT in the relatively recent past; although most conditions were adjusted for, poor results may have resulted from adverse conditions in the medical environment. Third, the prevalence of SCR is higher in the early period after transplantation and falls to low levels by 1 year after KT; therefore, the sPB and dPB groups may not have been homogenous. Next, the patients in the sPB group may have been in a relatively poorer condition. We could not strictly analyze the reasons patients received PB only once, but bleeding tendency and use of anticoagulation medication for cardiovascular disease were some common reasons. Finally, ACR and AMR were not measured separately because most rejections were ACR. For reference, at our center, the rate of ACR is 14.8% and the AMR is 1.7% at 2 weeks post-transplantation, and the ACR is 30.8% and the AMR is 1.8% at 1-year post-transplantation. In conclusion, PBs can play a protective role in graft kidney maintenance in KT recipients. Rather than a single PB, managing SCR through more active biopsy implementation within 1 year of KT is recommended since the dPB group showed significant protective effects for CKD progression, new-onset CKD, and patient survival in this study. The results of this study indicated that PB with SCR treatment can be a more feasible and safe option for kidney graft evaluation since the risk of complications and life-threatening infections was low. A large-scale, prospective, randomized study is needed to further investigate the long-term outcomes of PB. With the careful and definitive evaluation of PB, we expect increased graft survival and excellent patient prognosis. Abbreviations Protocol biopsy PB Kidney transplantation KT Chronic kidney disease CKD Subclinical rejection SCR BK polyomavirus BKV Glomerular filtration rate GFR Estimated glomerular filtration rate eGFR Acute cellular rejection ACR Antibody-mediated rejection AMR Human leukocyte antigen HLA Donor-specific antigen DSA Rabbit antithymocyte globulin rATG Cytomegalovirus CMV Trimethoprim/sulfamethoxazole TMP/SMX Kidney disease: improving global outcomes KDIGO Diabetes mellitus DM Declarations Ethical approval and informed consent. This retrospective study was approved by the Institutional Review Board of Samsung Medical Center (No. 2020-11-013), and the need for informed consent was waived. All methods were carried out in accordance with Declaration of Helsinki. Author contributions O.L., K.W.L., and J.B.P. participated in the study design, data analysis, data interpretation, and article writing. J.E.L. and K.K. participated in the study design, data analysis, and data interpretation. N.Y.H. participated in the data analysis and data interpretation. Funding No funding was received for this study. Competing interests The authors of this manuscript have no conflicts of interest, as described by the Nephrology Dialysis Transplantation, to disclose. Data availability statement The data that support the findings of this study are available from corresponding author upon reasonable request. References 1. Wolfe, R. A. et al. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N. Engl. J. Med. 341 , 1725-1730, http://doi.org/10.1056/NEJM199912023412303 (1999). 2. Howard, K. et al. The cost-effectiveness of increasing kidney transplantation and home-based dialysis. Nephrology (Carlton) 14 , 123-132, http://doi.org/10.1111/j.1440-1797.2008.01073.x (2009). 3. Tonelli, M. et al. Systematic review: kidney transplantation compared with dialysis in clinically relevant outcomes. Am. J. 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Thaunat, O., Legendre, C., Morelon, E., Kreis, H. & Mamzer-Bruneel, M. F. To biopsy or not to biopsy? Should we screen the histology of stable renal grafts? Transplantation 84 , 671-676, http://doi.org/10.1097/01.tp.0000282870.71282.ed (2007). 29. Morgan, T. A., Chandran, S., Burger, I. M., Zhang, C. A. & Goldstein, R. B. Complications of Ultrasound-Guided Renal Transplant Biopsies. Am. J. Transplant. 16 , 1298-1305, http://doi.org/10.1111/ajt.13622 (2016). 30. Seok, H. et al. Risk factors for development and mortality of invasive pulmonary Aspergillosis in kidney transplantation recipients. Eur. J. Clin. Microbiol. Infect. Dis. 39 , 1543-1550, http://doi.org/10.1007/s10096-020-03871-2 (2020). 31. Gigliotti, P. et al. Early subclinical rejection treated with low dose i.v. steroids is not associated to graft survival impairment: 13-years' experience at a single center. J. Nephrol. 29 , 443-449, http://doi.org/10.1007/s40620-015-0206-0 (2016). Tables Due to technical limitations, table 1-5 is only available as a download in the Supplemental Files section. Additional Declarations No competing interests reported. Supplementary Files Theprotectiveroleofprotocolbiopsytablescientificreports.pdf Table 1-5 Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-822374","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":47035669,"identity":"db7621c2-00ee-41da-ab5d-6bb27d5db891","order_by":0,"name":"Okjoo Lee","email":"","orcid":"","institution":"Sungkyunkwan University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Okjoo","middleName":"","lastName":"Lee","suffix":""},{"id":47035670,"identity":"dab845cf-1f43-4081-9d47-fb1c132fdf00","order_by":1,"name":"Kyo Won Lee","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6klEQVRIiWNgGAWjYBACCQbGxgcfDBhkGBiYD4D4MkRoYW42nFHBwMPAwJYA4vMQoYW9TZrnDEgLjwFIgLAWyRmJbZIz2xh4+Nl7Pr+6UWPBw8B++OgGfFqkJRKbLT4CtUj2nN1mnXMM6DCetLQb+LTISSc23gTZYnAjd5txDhtQiwSPGSEtDdK8QC329988M875R4QWaenEJrD3DSR4mB/nthGhRXL+Q1AgS/BInEkzY87tk+BhI+QXiTPHHwKj0kaOv/3w48853+rk+NkPH8OrBaYTRLBBSCKUwwHzB1JUj4JRMApGwcgBAEgrQ6VEcW1gAAAAAElFTkSuQmCC","orcid":"","institution":"Sungkyunkwan University School of Medicine","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Kyo","middleName":"Won","lastName":"Lee","suffix":""},{"id":47035671,"identity":"f2488e8b-06b1-46e3-98a9-506357603afc","order_by":2,"name":"Jae Berm Park","email":"","orcid":"","institution":"Sungkyunkwan University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jae","middleName":"Berm","lastName":"Park","suffix":""},{"id":47035672,"identity":"55e307ed-29b6-45c0-b38b-ca3b070c3aff","order_by":3,"name":"Jung Eun Lee","email":"","orcid":"","institution":"Sungkyunkwan University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jung","middleName":"Eun","lastName":"Lee","suffix":""},{"id":47035673,"identity":"1df7de7b-252b-41bf-9f26-85dadd507bf7","order_by":4,"name":"Na Young Hwang","email":"","orcid":"","institution":"Sungkyunkwan University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Na","middleName":"Young","lastName":"Hwang","suffix":""},{"id":47035674,"identity":"8023376e-0bcc-45bb-b346-bda5c5a6c397","order_by":5,"name":"Kyunga Kim","email":"","orcid":"","institution":"Sungkyunkwan University School of Medicine","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Kyunga","middleName":"","lastName":"Kim","suffix":""}],"badges":[],"createdAt":"2021-08-18 04:14:02","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-822374/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-822374/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":12698411,"identity":"9fdf1b5d-30bc-4b5f-b07f-05512f791cdd","added_by":"auto","created_at":"2021-08-23 23:02:40","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":189458,"visible":true,"origin":"","legend":"Flow diagram of patient selection.","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-822374/v1/899f68fe1ae59eda62793ee6.png"},{"id":12698476,"identity":"8ad59900-9d80-4835-a946-740f00889bda","added_by":"auto","created_at":"2021-08-23 23:05:40","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":259642,"visible":true,"origin":"","legend":"Linear mixed model showing the differences in the graft function trends between the two groups (PB vs. nPB) and the three groups (nPB vs. sPB vs. dPB). Graft function was lower in the early period after transplantation and improved around 1 year after KT, and was better maintained in the PB group, especially in the dPB group.","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-822374/v1/9a28a32cbf1777a6f08b7927.png"},{"id":12698478,"identity":"d159586b-29f1-4c6a-a2e2-f6d1e1a0a689","added_by":"auto","created_at":"2021-08-23 23:05:40","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":173807,"visible":true,"origin":"","legend":"According to the Kaplan-Meier curve, a significant difference in CKD progression was found between the PB and nPB groups in the two-group analysis and between the nPB and dPB groups in the three-group analysis.","description":"","filename":"Figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-822374/v1/5b3a17411add3a6e24978dec.png"},{"id":12698416,"identity":"d5e07a72-7e48-4f0b-961e-93af6eccd0d4","added_by":"auto","created_at":"2021-08-23 23:02:40","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":166560,"visible":true,"origin":"","legend":"According to the Kaplan-Meier curve, no significant difference in new-onset CKD was found between the PB and nPB groups in the two-group analysis, but a significant difference was found between the dPB and the other groups in the three-group analysis.","description":"","filename":"Figure4.png","url":"https://assets-eu.researchsquare.com/files/rs-822374/v1/2b75cebdeccb3be5004be026.png"},{"id":12698413,"identity":"7be51200-9d81-4dda-9e2d-7567bdaea9d5","added_by":"auto","created_at":"2021-08-23 23:02:40","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":131415,"visible":true,"origin":"","legend":"According to the Kaplan-Meier curve, no significant difference was found between the PB and nPB groups in terms of graft survival (A) and overall survival (B).","description":"","filename":"Figure5.png","url":"https://assets-eu.researchsquare.com/files/rs-822374/v1/e46d6404ae02ce19c6a1f911.png"},{"id":27002682,"identity":"0cbbccb5-1ec0-40c0-a42a-bb672ca59acb","added_by":"auto","created_at":"2022-09-27 04:14:20","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1020854,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-822374/v1/bbccb6c9-016a-4e08-a744-ea4f0a5a49a0.pdf"},{"id":12698474,"identity":"6124ad5f-0681-44a7-af71-75737439195f","added_by":"auto","created_at":"2021-08-23 23:05:40","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":88363,"visible":true,"origin":"","legend":"Table 1-5","description":"","filename":"Theprotectiveroleofprotocolbiopsytablescientificreports.pdf","url":"https://assets-eu.researchsquare.com/files/rs-822374/v1/019bdf44525702bccdb525f0.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eThe Protective Role of Protocol Biopsy for Allograft Kidney Maintenance in Kidney Transplantation\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eKidney transplantation (KT) has been shown to result in longer patient survival compared to dialysis and is now the treatment of choice for chronic kidney disease (CKD)\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. In addition, cost and quality of life are better with KT compared with dialysis, though graft management is essential for long-term maintenance\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTherefore, proper management strategies to maintain long-term graft survival are necessary. One strategy that many institutions have adopted is protocol biopsy (PB) with follow-up of transplant recipients\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. As histological diagnosis is the most effective modality for graft evaluation, the primary goal of PB is the early detection and treatment of subclinical rejection (SCR), which is characterized by tubule-interstitial infiltration of the renal allograft without clinical deterioration\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eSCR diagnosed by PB is associated with chronic allograft nephropathy, which is the most common cause of allograft failure in KT\u003csup\u003e\u003cspan additionalcitationids=\"CR9 CR10\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. Furthermore, chronic allograft nephropathy and graft survival are strongly correlated with acute rejection episodes during the first year after renal transplantation\u003csup\u003e\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e; therefore, the early detection and treatment of SCR might reduce the progression of chronic allograft nephropathy and improve graft survival\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. PBs can also be used to evaluate the baseline status of donor renal grafts and to detect BK polyomaviral (BKV) nephropathy, calcineurin inhibitor nephrotoxicity, interstitial fibrosis, and tubular atrophy early\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn our institution, routine PBs are performed 2 weeks and 1 year after KT. Routine PBs are implemented to detect SCR early and administer high-dose corticosteroid pulse therapy to appropriately manage the risk of chronic tubule-interstitial damage. In addition, routine PBs are performed to detect primary disease recurrence (e.g., immunoglobulin A nephropathy, focal segmental glomerulosclerosis, diabetic nephropathy), to proceed with appropriate treatment.\u003c/p\u003e \u003cp\u003eTherefore, this study aimed to evaluate the protective effects of PB by comparing renal allograft function (estimated glomerular filtration rate [eGFR]), CKD progression, new-onset CKD, and graft and patient survival before and after the application of routine PB.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Population. \u0026nbsp;\u003c/strong\u003eFrom July 2007 to August 2017, 1,361 KTs were performed at the Samsung Medical Center (Fig. 1). Patients with dual kidney or multi-organ transplants (including simultaneous liver grafts), re-transplantation and pediatric transplants were excluded from the study (n = 337). Additionally, patients who transplanted during the PB strategy period but did not undergo PB, and those diagnosed with SCR but who were not treated, were also excluded (n = 170). The remaining 854 eligible patients were included in the study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAfter enrollment, the patients were divided into two groups: the no-protocol biopsy (nPB) strategy period group (July 2007 to July 2012; n = 350) and the PB strategy period group (August 2012 to August 2017; n = 504). The PB group was then divided into two additional groups: the single protocol biopsy (sPB) group, for which PB was performed once at 2 weeks or 1 year after transplantation (n = 207), and the double protocol biopsy (dPB) group, for which PB was performed both at 2 weeks and 1 year after transplantation (n = 297).\u003c/p\u003e\n\u003cp\u003eAfter group classification, we compared the trends in graft function, CKD progression, new-onset CKD, infection, and patient and graft survival among the groups (nPB vs. PB and nPB vs. sPB vs. dPB).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProtocol biopsy and t\u003c/strong\u003e\u003cstrong\u003ereatment of rejection. \u0026nbsp;\u0026nbsp;\u003c/strong\u003ePBs were performed percutaneously under real-time ultrasonographic guidance at 2 weeks and 1 year after transplantation. Pathologic evaluation of the biopsies according to the Banff criteria\u0026nbsp;of that period\u0026nbsp;was performed by our transplant pathologists\u003csup\u003e20\u003c/sup\u003e.\u0026nbsp;For our treatment strategy, a borderline pathologic change is considered acute rejection and requires treatment. Clinical rejection was defined as the diagnosis with indicational biopsy, which is performed when the patient shows suspicious finding of acute rejection such as elevation of serum creatinine level or new onset proteinuria.\u0026nbsp;SCR was defined as the findings of a protocol biopsy performed without any suspicion of acute rejection. Both Clinical rejection and SCR were included in the rejection episode analysis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhen patients were diagnosed with acute cellular rejection (ACR), steroid therapy was initiated. Intravenous methylprednisolone 500 mg/day for 3 days, tapered by half every day to 60 mg/day was the initial steroid regimen. Oral methylprednisolone was then initiated at 32 mg/day and then tapered to 4\u0026ndash;8 mg/day within 1\u0026ndash;2 weeks and to 4 mg/day for maintenance. For PB-confirmed antibody-mediated rejection (AMR), intravenous immunoglobulins were administered, or plasmapheresis was performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImmunosuppression protocol. \u0026nbsp;\u003c/strong\u003eDepending on the routine induction medication, rabbit antithymocyte globulin (rATG)\u0026nbsp;or\u0026nbsp;basiliximab were administered.\u0026nbsp;In living donor KT,\u0026nbsp;rATG was administered at 1.5 mg/kg/day from the time of surgery to postoperative day 2, in positive human leukocyte antigen (HLA) crossmatch, donor-specific antigen (DSA) with a mean fluorescence intensity \u0026ge; 2,500, and ABO-incompatible KT.\u0026nbsp;In deceased donor KT,\u0026nbsp;rATG was administered in extended criteria donor KT.\u0026nbsp;Otherwise,\u0026nbsp;basiliximab was administered at a dose of 20 mg/day at the time of surgery and on postoperative day 4.\u003c/p\u003e\n\u003cp\u003eAll patients received triple immunosuppressive therapy regimens consisting of tacrolimus, mycophenolate mofetil, and methylprednisolone. Any patient who did not receive this regimen was excluded from the study. Tacrolimus (FK506, Prograf; Astellas Fujisawa, Osaka, Japan, and generic tacrolimus) was started on postoperative day 1 at 0.1\u0026ndash;0.15 mg/kg/day and adjusted to maintain whole-blood trough levels at 8\u0026ndash;10 ng/mL for 1\u0026ndash;2 months postoperatively and at 6\u0026ndash;8 ng/mL thereafter. Mycophenolate mofetil (Myfortic; Novartis Pharma AG, Basel, Switzerland) was started at a dose of 540 mg/day on postoperative day 1 and adjusted according to the white blood cell count. Methylprednisolone was started on the day of surgery at an intravenous dose of 500 mg/day and administered for 2 days and then tapered by half every day to 60 mg/day. Thereafter, oral methylprednisolone was administered at 32 mg/day for 7 days, 16 mg/day for the next 2 weeks, 8 mg/day for the next month, and 4 mg/day for maintenance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eProphylaxis of infectious diseases. \u0026nbsp;\u003c/strong\u003eOur protocol for the prophylaxis and diagnosis of infectious diseases was uniform throughout the study period. All patients underwent routine screening for cytomegalovirus (CMV) antigenemia, and recipients with rATG induction received intravenous ganciclovir prophylaxis at 5 mg/kg/day for 2 weeks. Screening for polyomavirus infection was based on routine urinary cytology testing followed by plasma polymerase chain reaction for BKV DNA and graft biopsy.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAll patients also received 1 tab/day of trimethoprim/sulfamethoxazole (TMP/SMX, 80 mg TMP/400 mg SMX) for \u003cem\u003ePneumocystis jirovecii\u003c/em\u003e prophylaxis. As preemptive prophylaxis for fungal and viral infections, TMP/SMX was administered for up to 6 months after KT in all patients, and itraconazole was additionally administered for up to 2 weeks for patients who underwent rATG induction. After steroid pulse therapy, TMP/SMX was administered for 6 weeks.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDefinition of the variables. \u0026nbsp;\u003c/strong\u003eThe\u0026nbsp;primary outcome assessed in this study was the inter-stage progression of CKD, with a \u0026gt; 25% decrease in the eGFR. The eGFR was calculated using the Chronic Kidney Disease Epidemiology Collaboration equation, and patients were assigned to a CKD stage based on the Kidney Disease: Improving Global Outcomes guidelines (KDIGO guidelines)\u003csup\u003e21\u003c/sup\u003e.CKD inter-stage progression was calculated using all measured outpatient creatinine values and consecutive 6-month intervals. Stage progression was defined as a significant enough decrease in the\u0026nbsp;mean eGFR in a given 3-month block to result in the inter-stage progression of CKD. If no values were obtained during the block, no progression was considered to have occurred.\u0026nbsp;Pretransplant renal function was determined and initially assessed for its potential effect on disease progression on 1-year post-operation. Since disease progression was based on renal function at 1-year post-transplantation, we did not analyze the pretransplant renal function. New-onset CKD was defined in patients with an eGFR of 60 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e or higher who were not diagnosed with CKD. Utilizing the KDIGO guidelines for eGFR, new-onset CKD was defined as an eGFR \u0026lt; 60 mL/min/1.73 m\u003csup\u003e2\u003c/sup\u003e (GFR categories G3a\u0026ndash;G5) lasting more than 3 months.\u003c/p\u003e\n\u003cp\u003ePost-KT glomerulonephritis was defined as newly diagnosed or recurrent immunoglobulin A nephropathy, focal segmental glomerulosclerosis, or diabetic nephropathy, and viral infection was defined as influenza or zoster virus infection (not including CMV and BKV).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis. \u0026nbsp;\u003c/strong\u003eAll variables are expressed as the mean \u0026plusmn; standard deviation or number and percentage. Between-group differences for continuous variables were compared using the Mann-Whitney test, and between-group differences for numbers and percentages were compared using the \u0026chi;\u003csup\u003e2\u003c/sup\u003e test or Fisher\u0026rsquo;s exact test. Kaplan-Meier survival curves were used to estimate CKD progression, new-onset CKD, and graft and overall survival. A linear mixed model was used to analyze the difference in the trend of graft function among the three groups. Cox regression analysis was performed with adjustments for significant risk factors in the univariate analysis, as well as other factors previously known to be associated with CKD progression, new-onset CKD, and graft survival. Statistical significance was set at p \u0026lt; 0.05. All statistical analyses were performed using IBM SPSS Statistics for Windows (version 25.0; SPSS, Inc., Chicago, IL, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline characteristics. \u0026nbsp;\u003c/strong\u003eThe PB group had a significantly higher donor and recipient age, the proportion of males, presence of recipient diabetes mellitus (DM), and donor hypertension than the nPB group (Table 1). However, there was no significant difference between the sPB and dPB groups. Additionally, there was no difference in donor type between the PB and nPB groups. However, when the three groups were compared, there were more deceased donors in the sPB group, which remained true when comparing the sPB and dPB groups. High HLA II mismatch KT, the presence of DSA, ABO-incompatible KT, cold ischemic time, and warm ischemic time were higher in the PB group, but there were no significant differences between the sPB and dPB groups. In the PB group, rATG was used more frequently as an induction regimen.\u003c/p\u003e\n\u003cp\u003eAmong all patients, the number of rejection episodes was higher in the PB group, but the proportion of clinical rejection was higher in the nPB group. Moreover, post-KT glomerulonephritis, CKD progression, new-onset CKD, and graft failure were higher in the nPB group (Table 2). Comparing the two groups, clinical rejection and rejection episodes were higher in the dPB group, but CKD progression and new-onset CKD were lower in the dPB group, and graft failure and mortality rates were significantly lower in the sPB group.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrends in graft function and CKD progression. \u0026nbsp;\u003c/strong\u003eGraft function was analyzed using eGFR trends. Comparing the two groups (PB vs. nPB) and the three groups (nPB vs. sPB vs. dPB), there was a significant difference in the eGFR trends (Fig. 2). Graft function, in general, was lower in the early period after the transplant and improved around 1 year after KT, but was better maintained in the PB group, especially in the dPB group.\u003c/p\u003e\n\u003cp\u003eThere was a significant difference in CKD progression between the PB and nPB groups and between the nPB and dPB groups according to the Kaplan-Meier curve (Fig. 3). In the Cox regression analysis of CKD progression, donor DM, and post-KT glomerulonephritis as risk factors, rejection episodes were significantly associated with CKD progression, but dPB and sPB played a significant protective role in CKD progression (Table 3).\u003c/p\u003e\n\u003cp\u003eThere was no significant difference in new-onset CKD between the PB and nPB groups according to the Kaplan-Meier curve; however, in the three-group analysis, there was a significant difference between the dPB and the other groups (Fig. 4). In the Cox regression analysis of new-onset CKD, high HLA I mismatch, and post-KT glomerulonephritis as risk factors, rejection episodes were significantly associated with new-onset CKD, and dPB played a significant protective role in new-onset CKD (Table 4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGraft survival and infection outcomes. \u0026nbsp;\u003c/strong\u003eIn the graft survival analysis using the Kaplan-Meier curve, no significant difference was observed between the two groups (Fig. 5). In the multivariate Cox regression analysis of graft survival, recipient DM, and post-KT glomerulonephritis as risk factors, rejection episodes were significantly associated with poor prognosis, but dPB played a significant protective role in graft survival (Table 5).\u003c/p\u003e\n\u003cp\u003eIn terms of the number of infections up to 2 years after KT, the PB group had more fungal, viral, and CMV infections than the nPB group, but there was no difference between the sPB and dPB groups (Table 2). In the PB group, almost all patients recovered; however, there were 8 infection-related deaths (bacterial, 3; fungal, 4; and viral, 1).\u003c/p\u003e\n\u003cp\u003eThe most common cause of death was multi-organ failure associated with sepsis resulting from urinary tract infection and pneumonia. In the multivariate Cox regression analysis, there was no significant difference between CMV and BKV infections for predicting CKD progression, new-onset CKD, or graft survival (Tables 3-5).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDue to donor organ shortage, the transplant graft must be properly managed to maintain its function over time; therefore, periodic laboratory examinations are conducted to monitor graft function. However, laboratory data alone is not sufficient to determine the condition of the graft. Therefore, PB is a useful diagnostic tool for identifying lesions, predicting the risk of graft failure, and guiding future directions for both organ recipients and donors\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, a survey of US kidney transplant centers found that only 17% perform PBs routinely on all transplant recipients, and studies show that noninvasive methods such as fibroscans or the evaluation of biological markers are effective at detecting SCR\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Moreover, PBs are inconvenient for patients, carry a risk for complications, are invasive and costly, and require technical expertise\u003csup\u003e\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Therefore, there is no current consensus on the timing and method of PBs, or their effectiveness\u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. In addition, consensus regarding appropriate guidelines for PB has not yet been established, and while some studies on PBs have been performed, only a small number of enrolled patients have been included\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAs previously mentioned, the current policy at our institution is to conduct PB twice, once at 2 weeks and again 1 year after transplantation, because rejection that occurs soon after transplantation is considered a major risk factor for chronic rejection and graft failure. In addition, interstitial fibrosis and tubular atrophy are present in approximately half of all grafts with stable function by 1 year after transplantation\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThis study demonstrated the protective role of PB in KT. The trend of graft function preservation was more apparent in the PB group than in the nPB group, and PB was associated with significant protective effects on CKD progression and new-onset CKD. This is likely because SCR was detected and treated relatively early in this group, which is thought to lead to better results. In addition, dPB had more significant results than sPB in terms of new-onset CKD. Therefore, PB may have advantages over nPB, and dPB may be superior to sPB.\u003c/p\u003e \u003cp\u003ePB is invasive and carries a small but real risk of complications, with the best estimates for major complications between 0.4% and 1.0%\u003csup\u003e27,29\u003c/sup\u003e. In this study, there were no complications requiring intervention after PB. However, from 2012 to 2019, the rate of major complications from PB at the Samsung Medical Center was 0.45% (4/882) at 2 weeks and 0.17% (1/556) at 1-year post-transplantation in 1,438 KT recipients (yet unpublished data). This is consistent with previous studies and should not limit the application of PB.\u003c/p\u003e \u003cp\u003ePB is an evaluative strategy that can be used to accurately diagnose and monitor for rejection, but steroid pulse therapy after PB can be a risk factor for viral infection. Theoretically, this could lead to worse results in those undergoing PB. In terms of infection outcomes in this study, the PB group had more fungal, viral, and CMV infections than the nPB group, which was likely the result of steroid pulse therapy. The mortality rate from infections for all patients in the PB group was 0.60% bacterial (3/504), 0.79% fungal (4/504), and 0.20% viral (1/504). However, when comparing the patients diagnosed with infections, the mortality rate was significantly higher with fungal infections (4/14; 28.57%) compared to bacterial (3/88; 3.41%) or viral (1/10; 10.00%) infections. A study at our institution has identified that treatments for rejection could be a risk factor for invasive pulmonary aspergillosis-associated mortality\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eHowever, in the current study, no relationship was found between patient mortality and rejection treatment. This is likely because no infection occurred during the treatment of SCR diagnosed by PB. Indeed, at least one year had elapsed between the treatment of SCR and death, and the cause of death was the rapid progression of infection, likely due to immunosuppression. Therefore, the treatment of SCR diagnosed by PB was not considered a risk factor for infection-related mortality in patients diagnosed with infections. Additionally, the CMV infection rate was also high; however, unlike previous studies, graft survival was not affected. This may be because at our center, ganciclovir is administered as preemptive prophylaxis with periodic CMV monitoring. However, to reach a consensus concerning the prevention of life-threatening infections in KT recipients, more extensive study is needed.\u003c/p\u003e \u003cp\u003eIn our study, there was no significant difference in the survival rate based on the Kaplan-Meier curve for graft survival. This is thought to be the result of specific characteristics of the donors and recipients. The PB group included donors and recipients who were significantly older and there was a higher presence of recipient DM and donor hypertension. Therefore, the eGFRs within 1 year after KT were lower in PB group as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Moreover, a number of mismatched HLA II, a presence of DSA, and longer cold and warm ischemic times, which are known risk factors for graft failure, were higher in the PB group\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. Owing to these differences in baseline characteristics, no significant differences in graft survival trends were observed. However, in the multivariate analysis for graft failure, the Cox regression model showed statistically significant results for the dPB group. Therefore, we concluded that performing PB twice at these time points can play a protective role in the management of kidney grafts.\u003c/p\u003e \u003cp\u003eThere were some limitations to this study. First, it was a retrospective, single-center analysis of a cohort in South Korea. Therefore, the results might not be generalizable to other countries and continents. Second, the nPB group included patients who had undergone KT in the relatively recent past; although most conditions were adjusted for, poor results may have resulted from adverse conditions in the medical environment. Third, the prevalence of SCR is higher in the early period after transplantation and falls to low levels by 1 year after KT; therefore, the sPB and dPB groups may not have been homogenous. Next, the patients in the sPB group may have been in a relatively poorer condition. We could not strictly analyze the reasons patients received PB only once, but bleeding tendency and use of anticoagulation medication for cardiovascular disease were some common reasons. Finally, ACR and AMR were not measured separately because most rejections were ACR. For reference, at our center, the rate of ACR is 14.8% and the AMR is 1.7% at 2 weeks post-transplantation, and the ACR is 30.8% and the AMR is 1.8% at 1-year post-transplantation.\u003c/p\u003e \u003cp\u003eIn conclusion, PBs can play a protective role in graft kidney maintenance in KT recipients. Rather than a single PB, managing SCR through more active biopsy implementation within 1 year of KT is recommended since the dPB group showed significant protective effects for CKD progression, new-onset CKD, and patient survival in this study. The results of this study indicated that PB with SCR treatment can be a more feasible and safe option for kidney graft evaluation since the risk of complications and life-threatening infections was low. A large-scale, prospective, randomized study is needed to further investigate the long-term outcomes of PB. With the careful and definitive evaluation of PB, we expect increased graft survival and excellent patient prognosis.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eProtocol biopsy \u003cstrong\u003ePB\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eKidney transplantation \u003cstrong\u003eKT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eChronic kidney disease\u003cstrong\u003e\u0026nbsp;CKD\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSubclinical rejection \u003cstrong\u003eSCR\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eBK polyomavirus\u003cstrong\u003e\u0026nbsp;BKV\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGlomerular filtration rate\u003cstrong\u003e\u0026nbsp;GFR\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEstimated glomerular filtration rate \u003cstrong\u003eeGFR\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAcute cellular rejection \u003cstrong\u003eACR\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAntibody-mediated rejection \u003cstrong\u003eAMR\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHuman leukocyte antigen \u003cstrong\u003eHLA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDonor-specific antigen \u003cstrong\u003eDSA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRabbit antithymocyte globulin \u003cstrong\u003erATG\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCytomegalovirus \u003cstrong\u003eCMV\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTrimethoprim/sulfamethoxazole \u003cstrong\u003eTMP/SMX\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eKidney disease: improving global outcomes \u003cstrong\u003eKDIGO\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDiabetes mellitus \u003cstrong\u003eDM\u003c/strong\u003e\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and informed consent.\u0026nbsp;\u003c/strong\u003eThis retrospective study was approved by the Institutional Review Board of Samsung Medical Center (No. 2020-11-013), and the need for informed consent was waived. All methods were carried out in accordance with Declaration of Helsinki.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eO.L., K.W.L., and J.B.P. participated in the study design, data analysis, data interpretation, and article writing. J.E.L. and K.K. participated in the study design, data analysis, and data interpretation. N.Y.H. participated in the data analysis and data interpretation.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo funding was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors of this manuscript have no conflicts of interest, as described by the Nephrology\u003c/p\u003e\n\u003cp\u003eDialysis Transplantation, to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from corresponding author upon\u003c/p\u003e\n\u003cp\u003ereasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cbr\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003cp\u003e1. Wolfe, R. 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N.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Protocol biopsy of the stable renal transplant: a multicenter study of methods and complication rates. \u003cem\u003eTransplantation\u003c/em\u003e\u003cstrong\u003e76\u003c/strong\u003e, 969-973, http://doi.org/10.1097/01.TP.0000082542.99416.11 (2003).\u003c/p\u003e\n\u003cp\u003e28. Thaunat, O., Legendre, C., Morelon, E., Kreis, H. \u0026amp; Mamzer-Bruneel, M. F. To biopsy or not to biopsy? Should we screen the histology of stable renal grafts? \u003cem\u003eTransplantation\u003c/em\u003e\u003cstrong\u003e84\u003c/strong\u003e, 671-676, http://doi.org/10.1097/01.tp.0000282870.71282.ed (2007).\u003c/p\u003e\n\u003cp\u003e29. Morgan, T. A., Chandran, S., Burger, I. M., Zhang, C. A. \u0026amp; Goldstein, R. B. Complications of Ultrasound-Guided Renal Transplant Biopsies. \u003cem\u003eAm. J. Transplant.\u003c/em\u003e\u003cstrong\u003e16\u003c/strong\u003e, 1298-1305, http://doi.org/10.1111/ajt.13622 (2016).\u003c/p\u003e\n\u003cp\u003e30. Seok, H.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Risk factors for development and mortality of invasive pulmonary Aspergillosis in kidney transplantation recipients. \u003cem\u003eEur. J. Clin. Microbiol. Infect. Dis.\u003c/em\u003e\u003cstrong\u003e39\u003c/strong\u003e, 1543-1550, http://doi.org/10.1007/s10096-020-03871-2 (2020).\u003c/p\u003e\n\u003cp\u003e31. Gigliotti, P.\u003cem\u003e\u0026nbsp;et al.\u003c/em\u003e Early subclinical rejection treated with low dose i.v. steroids is not associated to graft survival impairment: 13-years' experience at a single center. \u003cem\u003eJ. Nephrol.\u003c/em\u003e\u003cstrong\u003e29\u003c/strong\u003e, 443-449, http://doi.org/10.1007/s40620-015-0206-0 (2016).\u003c/p\u003e"},{"header":"Tables","content":"\u003cp\u003eDue to technical limitations, table 1-5 is only available as a download in the Supplemental Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Kidney transplantation, biopsy, chronic renal insufficiency, progression","lastPublishedDoi":"10.21203/rs.3.rs-822374/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-822374/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMany studies have reported that protocol biopsy (PB) may help preserve kidney function in kidney transplant recipients. Early detection and treatment of subclinical rejection may reduce the incidence of chronic allograft nephropathy and graft failure. However, no consensus has been reached regarding PB effectiveness, timing, and policy. This study aimed to evaluate the protective role of routine PB performed 2 weeks and 1 year after kidney transplantation. We reviewed 854 kidney transplant recipients at the Samsung Medical Center between July 2007 and August 2017, with PBs planned at 2 weeks and 1 year after transplantation. We compared the trends in graft function, chronic kidney disease progression, new-onset chronic kidney disease, infection, and patient and graft survival between the 504 patients who underwent PB and 350 who did not undergo PB. The PB group was again divided into two groups: the single PB group (n = 207) and the double PB group (n = 297). In the PB group, the donors and recipients were significantly older and there was a greater presence of recipient diabetes mellitus and donor hypertension, donor-specific antigen, and a higher proportion of ABO-incompatible kidney transplantations. The PB group was significantly different from the no-PB group in terms of the trends in graft function (estimated glomerular filtration rate). The Kaplan-Meier curve showed that PB did not significantly improve graft survival or overall patient survival. However, in the multivariate Cox analysis, the double PB group had advantages in graft survival, chronic kidney disease progression, and new-onset chronic kidney disease. PB can play a protective role in the maintenance of kidney grafts in kidney transplant recipients.\u003c/p\u003e","manuscriptTitle":"The Protective Role of Protocol Biopsy for Allograft Kidney Maintenance in Kidney Transplantation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-08-23 23:02:38","doi":"10.21203/rs.3.rs-822374/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"24c03dfb-9704-4a3c-94fb-8d5d4282b162","owner":[],"postedDate":"August 23rd, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":6646861,"name":"Surgery"},{"id":6646862,"name":"Hospital Medicine"}],"tags":[],"updatedAt":"2022-09-27T04:14:15+00:00","versionOfRecord":[],"versionCreatedAt":"2021-08-23 23:02:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-822374","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-822374","identity":"rs-822374","version":["v1"]},"buildId":"FbvkV6FR0MCFSLy54lSbu","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}