The Preliminary Results of Bortezomib Used as A Primary Treatment for An Early Acute Antibody-Mediated Rejection after Kidney Transplantation—A Single-Center Case Series

Proteasome inhibitor bortezomib has been used in the treatment of refractory cases of acute and chronic antibody-mediated rejection (AMR) in kidney transplant recipients. However, its efficacy and safety as a primary treatment for early AMR has been scarcely investigated. We herein present our preliminary experience with bortezomib- and plasmapheresis-based primary treatment for early AMR. Thirteen patients transplanted between October 2015 and September 2019 were treated (starting at median 19th post-transplant day) with bortezomib/plasmapheresis protocol for early biopsy-proven AMR. Twelve out of thirteen patients received 4 doses and one patient recieved 3 doses of bortezomib (1.3 mg/m2 per dose). In 11/13 patients, 4–7 concomitant plasmapheresis sessions were performed, with or without intravenous immunoglobulin (IVIG). Of note, rituximab was not used in all study patients. The kidney graft and patient survival were 100%. The mean 3-month estimated glomerular filtration rate (eGFR) was 55.3 (95%CI: 44.9–65.8) mL/min/1.73m2, 8/13 patients completed 12-month follow-up with mean eGFR 60.4 (45.4–75.4) mL/min/1.73m2, and 6/13 patients completed a 24-month follow-up period with mean eGFR 73.9 (56.7–91.1) mL/min/1.73m2. Neutropenia < 1 G/L was observed in one patient, third or fourth grade thrombocytopenia in two patients, and eleven patients needed a blood transfusion (median: 2 units/patient). The mid-term results of a primary bortezomib-based treatment for kidney AMR showed its non-inferiority as compared to preceding regimens and acceptable safety. However, our data should be validated in a multicenter randomized trial.

Download Full-text

Serological response and disease-specific neutralizing antibodies in kidney transplant recipients with SARS-CoV-2 infection – a case series

10.21203/rs.3.rs-110295/v1 ◽

2020 ◽

Author(s):

Claudius Speer ◽

Paul Schnitzler ◽

Thomas Giese ◽

Anna Plaszczyca ◽

Ralf Bartenschlager ◽

...

Keyword(s):

Kidney Transplant ◽

Neutralizing Antibodies ◽

Case Series ◽

Immunological Response ◽

Kidney Graft ◽

Serological Response ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Disease Specific

Abstract Background Since SARS-CoV-2 is a highly contagious virus without an available disease-specific medication, the hope is focused on a sustained immunity after SARS-CoV-2 infection and a near-term successful vaccination therapy. A sufficient anti-SARS-CoV-2 antibody production with neutralizing antibodies is crucial to prevent further viral spreading and for protection against prospective reinfection. Kidney transplant recipients may have a potentially aggravated risk for COVID-19 complications as well as a reduced vaccine response due to the allograft protecting immunosuppressive therapy. However, little is known about the strength and duration of their immunological response upon SARS-CoV-2 infection.Case presentation Here we report on 4 kidney transplant recipients proven to have SARS-CoV-2 infection by positive PCR testing, focusing on their immunological response with the production of disease-specific neutralizing antibodies. All kidney transplant recipients developed a sufficient antibody response including specific neutralizing antibodies against SARS-CoV-2 within 2 to 3 weeks after the first onset of symptoms that sustained during the follow-up of 15 weeks. After 6 weeks, the virus was eliminated in all patients. Most important, the serological response and viral shedding were achieved and sustained in the presence of immunosuppression. Acute kidney graft deterioration was common but reconstituted in all transplant recipients during follow-up. Conclusions Immunocompromised kidney transplant recipients showed a functional serological response with disease-specific neutralizing antibodies upon SARS-CoV-2 infection, a basic prerequisite for a prospective successful vaccination response.

Download Full-text

P1762THE EFFECT OF IMMUNOSUPPRESSIVE THERAPY ON THE CLINICAL FOLLOW-UP OF BK VIRUS IN KIDNEY TRANSPLANT RECIPIENTS

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfaa142.p1762 ◽

2020 ◽

Vol 35 (Supplement_3) ◽

Author(s):

Gulay Yilmaz ◽

Volkan Polatkan ◽

Ebru Ozdemir ◽

Turker Erturk ◽

Emel Tatli ◽

...

Keyword(s):

Immunosuppressive Therapy ◽

Kidney Transplant ◽

Antiviral Treatment ◽

Immunosuppressive Treatment ◽

Bk Virus ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Group I ◽

The Mean

Abstract Background and Aims BK virus nephropathy occurs in up to 10% of kidney transplant recipients and can result in graft loss. The reactivation of BK virus is largely asymptomatic, and routine surveillance especially in the first 12-24 months after transplant is necessary for early recognition and intervention. Reduced immunosuppression and antiviral treatment in the early stages may be effective in stopping BK virus replication. This study is designed to investigate the effect of management in immunosuppressive therapy on BK virus titers and graft functions in our kidney transplant group. Method A total of 370 kidney transplant recipients between the ages of 18-69 years and receiving a triple immunosuppressive therapy (Tacrolimus+Mycophenoloic Acid+Prednisolone) were included in the study. Demographic characteristics, BK virus titers, serum creatinine and immunosuppressive drug (Tacrolimus, Everolimus) levels were measured at regular intervals in the first 24 months. Among these patients 43 of them were found to have BK virus positivity. At the time of the detection of BK virus positivity, patients were divided into three groups regarding the change in the immunosuppressive protocols: Group I: Tacrolimus + Everolimus + Prednisolone, Group II: Everolimus + Prednisolone, Group III: Tacrolimus + Prednisolone. BK virus titers and graft functions of all three groups were compared with each other. SPSS 15 for Windows was used for statistical analysis. Results The mean age of the patients was 45.3 years, and the mean duration of transplantation was 16.3 months at the time of the BK virus positivity. During the follow-up, mean Tacrolimus levels were found to be in their highest value (14.1 ng/mL) in the posttransplant three months while BK virus titer reached the highest value (1.1x106 copies/ml) in the posttransplant seven to nine months. Increased creatinine values two months after BK virus positivity were strongly correlated (p = 0.02, p = 0.008, p = 0.05, p = 0.002 at 6th, 9th, 12th and 24th months, respectively). A significant decrease in BK virus titers was observed in all three groups due to reductions in immunosuppressive treatment protocol (p = 0.005, p = 0.003, p = 0.028, in groups I, II, III respectively). Conclusion Our study favors the benefits of the prospective screening for BK virus to identify early viral replication, permit intervention, and prevent progression to nephropathy or allograft loss. The best studied treatment for BK viremia and nephropathy is careful reduction of immunosuppression

Download Full-text

Temporal virus serological profiling of kidney graft recipients using VirScan

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1821166116 ◽

2019 ◽

Vol 116 (22) ◽

pp. 10899-10904 ◽

Cited By ~ 6

Author(s):

Pierre Isnard ◽

Tomasz Kula ◽

Véronique Avettand Fenoel ◽

Dany Anglicheau ◽

Fabiola Terzi ◽

...

Keyword(s):

Immunosuppressive Treatment ◽

Cost Effective ◽

Antibody Responses ◽

Screening Tests ◽

Kidney Graft ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Emerging Viruses ◽

Unbiased Manner

At this time, pretransplant viral screening of donors and recipients is based on serological status and limited to certain viruses. After transplantation, patient follow-up is based on a monitoring strategy using ELISA or PCR. Such approaches exclude other emerging viruses that can affect the transplant outcome. Recently, a multiplex unbiased array, VirScan, was developed. This tool allows the detection of antibodies against viruses, using a synthetic human virome, with minimal serum and cost. We decided to test the value of VirScan in the follow-up of a cohort of transplant recipients. We enrolled 45 kidney transplant recipients and performed virus serological profiling at day 0 and day +365, using VirScan. We compared the results obtained with ELISA/PCR assays. We detected antibody responses to 39 of the 206 species of virus present in the VirScan library, with an average of 12 species of virus per sample. VirScan gave similar results to PCR/ELISA screening tests. Using VirScan, we found that anti-viral antibody responses were largely conserved in patients during the first year after transplantation, regardless of immunosuppressive treatment. Our study suggests VirScan offers an unprecedented opportunity to screen and monitor posttransplant virus infection in a cost-effective, easy, and unbiased manner.

Download Full-text

MO995DO THE TIMELINE AND SPECTRUM OF INFECTIONS CHANGE AFTER ANTI-REJECTION THERAPY IN KIDNEY TRANSPLANT RECIPIENTS?

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab111.0019 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Arvind Krishnakumar ◽

Selvin Sundar Raj Mani ◽

Rizwan Alam ◽

Manish Lalwani ◽

Athul Thomas ◽

...

Keyword(s):

Acute Rejection ◽

Kidney Transplant ◽

Median Time ◽

Graft Loss ◽

Renal Transplant Recipients ◽

Care Hospital ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Antibody Mediated Rejection

Abstract Background and Aims The infections in kidney transplant recipients has been well defined. The timeline of infections and type of infection among patients who received anti-rejection therapy for acute rejection when compared to the patients who did not develop an acute rejection. Method Renal transplant recipients with post-transplant median follow up of four years from July 2009-June 2018 were included in a retrospective cohort study at a tertiary care hospital. Demographic characteristics, biopsy proven rejections, infections and graft and patient outcome were collected from transplant records and the hospital clinical workstation. Early and late acute rejections were defined as less than and more than 3 months respectively. The rates of various infections, type and time to develop an infection in the acute rejection group were compared with the patients who did not develop any rejection. Results A total of 794 patients underwent kidney transplant during the study with mean age of 35.5±12 years and 78% being male. Two hundred and eight four patients (35.8 %) had one or more biopsy proven rejections during the median follow up of 48 months (IQR 28,77). 213 patients (75%) developed early acute rejection (less than 3 months) while the remainder developed late acute rejection. The median time to develop the first acute rejection was 12 days (IQR 6,93.3). Majority of the patients (176, 62%) developed biopsy proven acute cellular rejection, 77 patients (27.1%) acute antibody mediated rejection and rest (10.9%) either mixed or borderline rejection who were treated. The proportion of BKV infection and infective diarrhea were more in rejection group when compared to no rejection group which was statistically significant (refer Table 1). At follow up, the patients who developed rejection had more graft loss (p value 0.010) but no increase in mortality. The predictors of infection among the patients who received anti-rejection therapy were identified. The median time to develop any infection in both groups were also compared. The spectrum of infections and outcome following early and late rejections were compared. Subgroup analysis was done to look at the eGFR, proteinuria trend, graft outcomes in patients with no rejection, rejection without any infection at follow up and rejection with any infection at follow up. The effect of type of anti-rejection therapy on spectrum of infections was also studied. Conclusion This is one of the few studies which looked at the effect of anti-rejection therapy in kidney transplant recipients. Anti-rejection treatment received post kidney transplant resulted in increased rates of BKV infection and infective diarrhea. Patients with acute rejection had more graft loss during follow up with no significant effect on mortality.

Download Full-text

Kidney graft function before pregnancy as a predictor of graft, maternal and fetal outcomes in pregnant renal transplant recipients

Journal of Perinatal Medicine ◽

10.1515/jpm-2021-0102 ◽

2021 ◽

Vol 0 (0) ◽

Author(s):

Filipe S. Mira ◽

Joana Oliveira ◽

Filipa Sousa ◽

Dora Antunes ◽

Ana Carolina Figueiredo ◽

...

Keyword(s):

Kidney Transplant ◽

Graft Function ◽

Adverse Outcomes ◽

Hypertensive Disorder ◽

Renal Transplant Recipients ◽

Kidney Graft ◽

Transplant Recipients ◽

Graft Dysfunction ◽

Kidney Transplant Recipients

Abstract Objectives Maternal and fetal complications can occur in pregnant kidney transplant recipients. Since these are high-risk pregnancies, they require a multidisciplinary follow-up to prematurely detect adverse events. Identifying factors that would affect fetal, maternal and graft outcomes is essential to further stratify the risk of pregnant kidney transplant recipients. Methods All pregnancies in kidney transplant recipients followed in a single center for 30 years were included. Data included previous transplant information and blood and urine tests performed before pregnancy. Impact of graft function on fetal, maternal and graft outcomes was evaluated. Results There were 41 pregnancies among 34 patients. Mean gestational age of 35 ± 3 weeks. Caesarean section was performed in 69.4% of patients. Five pregnancies were unsuccessful (12.2%). Four patients suffered an acute graft dysfunction (9.8%) and 12 (29.3%) had a serious maternal hypertensive disorder (preeclampsia, eclampsia or HELLP syndrome). Graft function before pregnancy showed significant correlation with adverse outcomes. Conclusions A proteinuria >669 mg/g, serum creatinine >1.75 mg/dL and glomerular filtration rate <36.2 mL/min/1.73 m2 before pregnancy were correlated to graft dysfunction during pregnancy. Similar values of proteinuria were also associated with a risk of maternal hypertensive disorders and pregnancy failure. Therefore, in patients with proteinuria and graft dysfunction, follow-up should be stricter to quickly detect complications.

Download Full-text

Immunoadsorption Combined with Membrane Filtration to Counteract Early Treatment-Refractory Antibody-Mediated Rejection

Blood Purification ◽

10.1159/000506504 ◽

2020 ◽

Vol 49 (5) ◽

pp. 576-585 ◽

Cited By ~ 1

Author(s):

Konstantin Doberer ◽

Gregor Bond ◽

Johannes Kläger ◽

Heinz Regele ◽

Robert Strassl ◽

...

Keyword(s):

Membrane Filtration ◽

Therapeutic Option ◽

High Grade ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Antibody Mediated Rejection ◽

Peritubular Capillaries ◽

Allograft Function ◽

Treatment Refractory

Introduction: Immunoadsorption (IA) represents a therapeutic option for acute antibody-mediated rejection (ABMR) after kidney transplantation. The addition of membrane filtration (MF) to enhance elimination of macromolecular components that potentially contribute to rejection, such as key complement component C1q and alloreactive IgM, may be an effective strategy to further improve its therapeutic efficiency. Results: Here we present 4 consecutive patients with episodes of HLA donor-specific antibody-positive ABMR nonresponsive to cycles of 6–16 sessions of IA treatment. Rejection episodes were characterized by severe microvascular injury (high-grade microcirculation inflammation and/or signs of thrombotic microangiopathy) and evidence of intense complement activation in peritubular capillaries (diffuse C4d-positivity). IA combined with MF led to substantial morphologic improvement (follow-up biopsies: g + ptc and C4d scores ≤1) and stabilization of allograft function. Conclusions: Our findings provide evidence for an effect of combination of IA + MF in refractory early acute/active ABMR in kidney transplant recipients.

Download Full-text

Renal transplant patients with preformed anti-HLA antibodies: early biopsy findings and clinical outcomes

Brazilian Journal of Nephrology ◽

10.1590/2175-8239-jbn-2018-0244 ◽

2020 ◽

Vol 42 (2) ◽

pp. 201-210

Author(s):

Marcos Vinicius de Sousa ◽

Ricardo de Lima Zollner ◽

Marilda Mazzali

Keyword(s):

Renal Function ◽

Ischemia Reperfusion Injury ◽

Interstitial Fibrosis ◽

Ischemia Reperfusion ◽

Graft Function ◽

Kidney Graft ◽

Kidney Transplant Recipients ◽

Hla Antibodies ◽

Antibody Mediated Rejection

Abstract Introduction: Renal fibrosis is the end point of a process that begins at transplant, with ischemia reperfusion and early inflammation, and progresses over time with immunological and non-immunological phenomena. Early identification of morphological markers and intervention could improve graft function and survival. Objective: to evaluate the correlation between intensity and specificity of pre-transplant anti-HLA antibodies and kidney allograft pathology in order to identify early risk factors or markers of allograft dysfunction. Methods: A retrospective cohort of kidney transplant recipients with pre-transplant anti-HLA antibodies who underwent graft biopsy within the first two years post-transplant was divided into two groups according to the specificity of anti-HLA antibodies: nonspecific (non-DSA, n = 29) and specific (DSA+, n = 16). Kidney graft pathology, renal function, and proteinuria were analyzed. Results: general characteristics were similar in both groups, except for the higher dose of thymoglobulin in DSA+ group (p < 0.05). The non-DSA group had higher scores for glomerulosclerosis, interstitial inflammation (i) and interstitial fibrosis (ci) (p < 0.05) and higher incidence of cell-mediated acute rejection. No statistical difference in incidence of antibody-mediated rejection, renal function, and proteinuria was observed during follow up. Discussion and conclusions: the difference in inflammation scores and interstitial fibrosis may be associated to the higher incidence of acute cell-mediated rejection and polyomavirus nephropathy in the Non-DSA group. We also should take into account the protective effect of higher doses of thymoglobulin, reducing ischemia reperfusion injury in the DSA+ group. The short follow-up might have been insufficient to detect long-term changes in allograft tissue, renal function, and proteinuria.

Download Full-text

MO202RITUXIMAB TREATMENT IN NEPHROLOGY

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfab092.0080 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

Mouna Malki abidi ◽

Samia Barbouch ◽

Hajji Mariem ◽

Tasnim Mesbahi ◽

Amel Harzallah ◽

...

Keyword(s):

B Cells ◽

Kidney Transplant ◽

Large Cell ◽

Kidney Transplant Patient ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

Antibody Mediated Rejection ◽

Maintenance Immunosuppression ◽

Interesting Alternative

Abstract Background and Aims The B cells have a central role in the pathogenesis of several renal pathologies. Rituximab, a monoclonal antibody directed against the CD20 receptor expressed on the surface of B cells is an interesting alternative to conventional treatments of kidney pathologies. Method We conducted a descriptive retrospective study of the use of rituximab in nephrology patients. Results We collected 25 patients including 12 women and 13 men. The mean age was 33,5 [16-55] years. The rituximab was indicated for an extramembranous glomerulopathy in 6 patients, a focal segmental glomerulosclerosis in 4 patients, a minimal change disease in 4 patients, a lupus nephritis in 5 patients, and a granulomatosis with polyangiitis in 2 patients. Four kidney transplant patient received rituximab for the treatment of antibody mediated rejection in 3 cases and large cell lymphoma in 1 case. The average time between the diagnosis of the renal disease and starting treatment with rituximab was of 76 +/- 46,5 months. And it was of 16 [ 0,7 ; 59,8] months after transplantation in kidney transplant recipients. Side effects have been observed in 11 cases (44%). A favorable response has been obtained in 10 cases (40 %), within an average of 2,27 months, with at least one relapse in 4 cases. The follow-up time was 36,33 +/- 31,67 months. Conclusion Rituximab has been shown to be helpful in several cases of kidney disease. It may reduce the need for maintenance immunosuppression and help in some cases that are refractory to other therapies.

Download Full-text

Soluble Complement Component 1q Receptor 1 (sCD93) Is Associated with Graft Function in Kidney Transplant Recipients

Biomolecules ◽

10.3390/biom11111623 ◽

2021 ◽

Vol 11 (11) ◽

pp. 1623

Author(s):

Małgorzata Kielar ◽

Paulina Dumnicka ◽

Ewa Ignacak ◽

Alina Będkowska-Prokop ◽

Agnieszka Gala-Błądzińska ◽

...

Keyword(s):

Kidney Transplant ◽

Graft Function ◽

Complement Component ◽

Clinical State ◽

Kidney Graft ◽

Inverse Association ◽

Transplant Recipients ◽

Kidney Transplant Recipients ◽

One Year

Cluster of differentiation 93 (CD93), also known as complement component 1q receptor 1 is a transmembrane glycoprotein expressed in endothelial and hematopoietic cells and associated with phagocytosis, cell adhesion, angiogenesis and inflammation. The extracellular part, soluble CD93 (sCD93), is released to body fluids in inflammation. Data on sCD93 in kidney diseases are limited. Our aim was to evaluate serum sCD93 in long-term kidney transplant recipients as a marker of inflammation and endothelial dysfunction that may be potentially useful in early recognition of graft dysfunction. Seventy-eight adult patients with functioning kidney graft and stable clinical state were examined at least one year after kidney transplantation. Serum sCD93 was measured by enzyme immunosorbent assay. Estimated glomerular filtration rate (eGFR) and albuminuria or proteinuria were assessed at baseline and over one-year follow-up. Increased sCD93 was associated with lower baseline eGFR independently of the confounders. Moreover, sCD93 was negatively associated with eGFR during one-year follow-up in simple analysis; however, this was not confirmed after adjustment for confounders. Baseline sCD93 was positively associated with baseline albuminuria and with increased proteinuria during the follow-up. Serum sCD93 was not correlated with other studied inflammatory markers (interleukin 6, C-reactive protein, procalcitonin and C3 and C4 complement components). To the best of our knowledge, this is the first report regarding the concentrations of sCD93 in kidney transplant recipients and one of the first reports showing the inverse association between sCD93 and renal function. Serum sCD93 should be further evaluated as a diagnostic and prognostic marker in renal transplantation.

Download Full-text