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1.
Transpl Int ; 32(12): 1286-1296, 2019 Dec.
Article in English | MEDLINE | ID: mdl-31322786

ABSTRACT

Because of the current organ shortage, ABO-incompatible (ABOi) transplantations have been increasingly performed in recent years. The results seem comparable to those of compatible transplantations, but there have also been reports of increased side effects possibly because of the desensitization therapy. To address an increase in severe infectious complications, we compared the outcomes of 48 ABOi transplant recipients to outcomes of 96 matched ABO-compatible (ABOc) controls transplanted at Heidelberg University Hospital from August 2005 to April 2018. Over a follow-up period of 8 years, ABOi transplant recipients had comparable graft and patient survival as well as graft function compared with ABOc patients. T-cell-mediated and antibody-mediated rejections were not different between groups. In ABOi transplant recipients, urosepsis (22.9% vs. 8.5%; P = 0.019) and pneumonia with opportunistic pathogens (8.3% vs. 1.0%, P = 0.025) appeared more frequently. As a consequence, a significantly higher number of deaths from infection have been observed after ABOi transplantations (6.3% vs. 0%, P = 0.010). High-titer recipients (isoagglutinin titer of ≥1:256) showed a higher incidence of BK virus replication and postoperative bleeding complications. ABO-incompatible transplantations can be performed with results that are not different from results after ABOc transplantations. However, an increased rate of serious infectious complications must be taken into account.


Subject(s)
ABO Blood-Group System/immunology , Blood Group Incompatibility/immunology , Desensitization, Immunologic , Immunosorbent Techniques , Kidney Transplantation/adverse effects , Adolescent , Adult , Aged , Female , Graft Rejection , Graft Survival , Humans , Immunosorbent Techniques/instrumentation , Immunosuppression Therapy , Male , Middle Aged , Retrospective Studies , Young Adult
2.
Clin Biochem ; 49(4-5): 320-3, 2016 Mar.
Article in English | MEDLINE | ID: mdl-26851348

ABSTRACT

With the currently available immunosuppression, severe T-cell mediated rejection has become a rare event. With the introduction of modern antibody-detection techniques, such as the L-SAB technology, acute or hyperacute antibody-mediated rejection of the kidney are also seen infrequently. In contrast, chronic antibody-mediated rejection is considered to be a major contributor to graft loss in the late posttransplant phase. Problems in the management of chronic antibody-mediated rejection are effective prevention of the development of alloantibodies against donor HLA and the early identification of patients at risk for this entity. Finally, today there is still noeffective strategy to treat this indolent and slowly progressing form of antibody-mediated rejection. Herein, we review the pathomechanisms of the different forms of rejection and the clinical significance of these entities in human kidney transplantation.


Subject(s)
Graft Rejection/immunology , Kidney Transplantation , Acute Disease , Chronic Disease , Graft Rejection/prevention & control , Humans , Immunosuppressive Agents/administration & dosage , Isoantibodies/immunology
3.
Transpl Int ; 28(5): 553-64, 2015 May.
Article in English | MEDLINE | ID: mdl-25630217

ABSTRACT

Histological evaluations of renal allograft biopsies are essential for diagnosis, but still show a low predictive value for long-term allograft function. One limitation relies on the fact that the analysis is usually based on a single biopsy sample, and therefore, no dynamic changes are considered. Using two distinct approaches, we evaluated the evolution of fibrosis and related markers in 36 stable kidney transplant patients under calcineurin inhibitor therapy with two indication biopsies each, prior and at least 6 months after substitution by mTORi (N = 18), or maintenance on CNI (N = 18). In the method comparison, both Banff chronicity score and the digitally assessed fibrosis were correlated with allograft function at biopsy (r = -0.36 and r = -0.72, P = 0.002 and P < 0.0001, respectively). However, only the progression of fibrosis digitally assessed was correlated with allograft function loss, not only within the time between biopsies (r = -0.47, P = 0.004) but also in the 60-month follow-up (r = -0.47, P = 0.006). In the group analysis, despite of a higher incidence of C4d positivity (P = 0.05), progression of fibrosis, TGF-ß1 expression, and allograft function decline were significantly lower after conversion to mTORi compared with maintenance on CNI (P = 0.05, P = 0.02 and P = 0.01, respectively). PDGF, VEGF, b-FGF, and HIF1A expressions remained stable over time regardless of therapy.


Subject(s)
Calcineurin Inhibitors/therapeutic use , Kidney Failure, Chronic/surgery , Kidney Transplantation , Kidney/pathology , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adult , Allografts/pathology , Biopsy , Complement C4b/metabolism , Disease Progression , Female , Fibroblast Growth Factor 2/metabolism , Fibrosis , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Immunohistochemistry , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Peptide Fragments/metabolism , Platelet-Derived Growth Factor/metabolism , Retrospective Studies , Transforming Growth Factor beta1/metabolism , Vascular Endothelial Growth Factor A/metabolism
4.
Atheroscler Suppl ; 14(1): 199-202, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23357165

ABSTRACT

OBJECTIVE: Due to increasing waiting times for deceased donor kidneys, living donor kidney transplantation is increasingly performed in the presence of donor-specific antibodies (DSA). METHODS: Twenty-three patients with Luminex-detected DSA were successfully desensitized by anti-CD20 therapy and immunoadsorption (N = 19) or plasmapheresis (N = 4) and received a kidney transplant from a living donor. Twelve of the 23 patients (52%) had a positive CDC and/or ELISA crossmatch result before desensitization. Six patients were negative in CDC as well as ELISA screening but positive in Luminex for DSA. RESULTS: The 23 patients received a median of 8 apheresis treatments before and 5 treatments after transplantation. Induction therapy was performed with either thymoglobulin (N = 11) or basiliximab (N = 12). The 2-year graft survival rate was 100%. At last follow up, a median of 12 months after transplantation, median serum creatinine was 1.42 mg/dL, median MDRD-GFR 59.5 mL/min/1.73 m(2), and median urinary protein-to-creatinine ratio 0.12. Ten out of fourteen patients (71%) who had completed the first year after transplantation by the time of analysis had no DSA by day 360. Acute T-cell mediated rejection was diagnosed in one patient (4%), and antibody-mediated changes were found in 5 patients (22%). Four out of these 5 patients showed evidence of persistent (N = 2) or reemerging plus/minus de novo DSA (N = 2) on day 360, and the 2 patients with persistent DSA lost their allograft subsequently on days 750 and 810, respectively. Infectious complications were infrequent. CONCLUSIONS: Our previously described treatment algorithm for desensitization of living donor kidney transplant recipients with DSA results in good graft outcomes with a low rate of side effects.


Subject(s)
Antibodies, Monoclonal, Murine-Derived/therapeutic use , Autoantibodies/blood , Blood Component Removal , Desensitization, Immunologic/methods , Graft Rejection/prevention & control , Graft Survival/drug effects , HLA Antigens/immunology , Immunosuppressive Agents/therapeutic use , Kidney Transplantation/immunology , Living Donors , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal, Murine-Derived/adverse effects , Antilymphocyte Serum/therapeutic use , Basiliximab , Biomarkers/blood , Blood Component Removal/adverse effects , Blood Component Removal/methods , Desensitization, Immunologic/adverse effects , Enzyme-Linked Immunosorbent Assay , Graft Rejection/blood , Graft Rejection/immunology , Histocompatibility , Histocompatibility Testing , Humans , Immunosorbent Techniques , Immunosorbents/therapeutic use , Immunosuppressive Agents/adverse effects , Kaplan-Meier Estimate , Kidney Transplantation/adverse effects , Plasmapheresis , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/therapeutic use , Rituximab , Time Factors , Treatment Outcome
5.
Transpl Int ; 26(3): 290-9, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23279010

ABSTRACT

Regulatory T cells (Tregs) were shown to be involved into the pathogenesis of acute rejection after transplantation. The suppressive activity of the total regulatory T cell pool depends on its percentage of highly suppressive HLA-DR(+) -Treg cells. Therefore, both the suppressive activity of the total Treg pool and the extent of HLA-DR expression of HLA-DR(+) -Tregs (MFI HLA-DR) were estimated in non transplanted volunteers, patients with end-stage renal failure (ESRF), healthy renal transplant patients with suspicion on rejection, due to sole histological Bord-R or sole acute renal failure (ARF), and patients with clinically relevant borderline rejection (Bord-R and ARF). Compared to patients with only Bord-R or only ARF, the suppressive activity of the total Treg cell pool was exclusively reduced in patients with clinically relevant Bord-R. In parallel, the HLA-DR MFI of the DR(+) -Treg subset was significantly decreased in these patients, due to a significantly lower proportion of DR(high+) -Tregs, which were shown to have the highest suppressive capacity within the total Treg pool. Our findings clearly demonstrate that the determination of the HLA-DR MFI of the HLA-DR(+) -Treg subset allows a highly sensitive, specific and non-invasive discrimination between patients with clinically relevant Bord-R (Bord and ARF) and patients with subclinical rejection or other causes of transplant failure.


Subject(s)
Graft Rejection/metabolism , HLA-DR Antigens/metabolism , Kidney Failure, Chronic/surgery , Kidney Transplantation/adverse effects , T-Lymphocytes, Regulatory/metabolism , Adult , Aged , Biomarkers/analysis , Biopsy, Needle , Case-Control Studies , Cohort Studies , Female , Flow Cytometry , Forkhead Transcription Factors/metabolism , Graft Rejection/pathology , HLA-DR Antigens/immunology , Humans , Immunohistochemistry , Kidney Failure, Chronic/mortality , Kidney Failure, Chronic/pathology , Kidney Transplantation/methods , Kidney Transplantation/mortality , Linear Models , Male , Middle Aged , Predictive Value of Tests , ROC Curve , Reference Values , Risk Assessment , Sensitivity and Specificity , Survival Rate , T-Lymphocytes, Regulatory/immunology , Treatment Outcome , Young Adult
6.
Transplantation ; 93(8): 827-34, 2012 Apr 27.
Article in English | MEDLINE | ID: mdl-22382504

ABSTRACT

BACKGROUND: ABO-incompatible kidney transplantation performed after desensitization with antigen-specific immunoadsorption (IA) results in good outcomes. However, a unique single-use IA device is required, which creates high costs. METHODS: From August 2005 to August 2010, 19 patients were desensitized for ABO-incompatible living donor kidney transplantation. Six patients treated with a single-use antigen-specific IA device and 12 patients treated with a reusable non-antigen-specific IA device were analyzed. RESULTS: Six patients who received antigen-specific IA had a median of 5 IA treatments and 12 patients with non-antigen-specific IA had a median of 6 IA treatments preoperatively. Median average titer drop in Coombs technique was 1.2 in antigen-specific IA and 1.7 in non-antigen-specific IA. In two patients with antigen-specific IA and four patients with non-antigen-specific IA, additional plasmapheresis treatments were necessary for recipient desensitization. Despite six treatments with antigen-specific IA and 12 plasmapheresis treatments, one patient with a starting isoagglutinin titer of 1:1024 (Coombs) could not be transplanted. The 18-month graft survival rate for the 17 ABO-incompatible living donor kidney transplants was 100%. One male recipient who was desensitized with antigen-specific IA died 44 months after transplantation from sudden cardiac death with a serum creatinine of 1.2 mg/dL. At last follow-up, a median of 13 months after transplantation, median serum creatinine for 16 patients was 1.5 mg/dL, median glomerular filtration rate as estimated by the modification of diet in renal disease formula 54 mL/min/1.73 m, and median urinary protein-to-creatinine ratio 0.1, with no differences between treatments. CONCLUSIONS: A reusable non-antigen-specific IA device allows high number of treatments at reasonable cost, and at the same time might deplete human leukocyte antigen-alloantibodies.


Subject(s)
Blood Group Incompatibility/immunology , Immunosorbent Techniques , Kidney Transplantation/immunology , Adult , Creatinine/blood , Creatinine/urine , Female , Glomerular Filtration Rate , Graft Survival/immunology , Humans , Kidney Transplantation/economics , Male , Middle Aged
7.
Am J Physiol Renal Physiol ; 301(2): F344-54, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21593188

ABSTRACT

In humans, low glomerular numbers are related to hypertension, cardiovascular, and renal disease in adult life. The present study was designed 1) to explore whether above- or below-normal dietary salt intake during pregnancy influences nephron number and blood pressure in the offspring and 2) to identify potential mechanisms in kidney development modified by maternal sodium intake. Sprague-Dawley rats were fed low (0.07%)-, intermediate (0.51%)-, or high (3.0%)-sodium diets during pregnancy and lactation. The offspring were weaned at 4 wk and subsequently kept on a 0.51% sodium diet. The kidney structure was assessed at postnatal weeks 1 and 12 and the expression of proteins of interest at term and at week 1. Blood pressure was measured in male offspring by telemetry from postnatal month 2 to postnatal month 9. The numbers of glomeruli at weeks 1 and 12 were significantly lower and, in males, telemetrically measured mean arterial blood pressure after month 5 was higher in offspring of dams on a high- or low- compared with intermediate-sodium diet. A high-salt diet was paralleled by higher concentrations of marinobufagenin in the amniotic fluid and an increase in the expression of both sprouty-1 and glial cell-derived neutrophic factor in the offspring's kidney. The expression of FGF-10 was lower in offspring of dams on a low-sodium diet, and the expression of Pax-2 and FGF-2 was lower in offspring of dams on a high-sodium diet. Both excessively high and excessively low sodium intakes during pregnancy modify protein expression in offspring kidneys and reduce the final number of glomeruli, predisposing the risk of hypertension later in life.


Subject(s)
Blood Pressure/drug effects , Kidney Glomerulus/embryology , Maternal Exposure/adverse effects , Sodium Chloride, Dietary/administration & dosage , Albuminuria/etiology , Amniotic Fluid/chemistry , Animals , Animals, Newborn , Body Weight/drug effects , Bufanolides/analysis , Female , Humans , Intercellular Signaling Peptides and Proteins/metabolism , Kidney Glomerulus/drug effects , Litter Size/drug effects , Male , Organ Size/drug effects , Pregnancy , Rats , Rats, Sprague-Dawley , Renin-Angiotensin System/drug effects , Sodium Chloride, Dietary/adverse effects , Sodium-Potassium-Exchanging ATPase/metabolism , Transcription Factors/metabolism
8.
São Paulo; s.n; 2007. [130] p. ilus, tab.
Thesis in Portuguese | LILACS | ID: lil-505539

ABSTRACT

O estudo investigou a influência do tratamento de 10 semanas com paricalcitol (0,1µg/kg 5x/semana) e calcitriol (0,03µg/kg 5x/semana) em modelo de aterosclerose espontânea utilizando camundongos ApoE -/- sham e uninefrectomizados (UNX). Resultados: a densidade capilar por comprimento no tecido cardíaco foi significativamente mais baixa nos animais UNX Controle quando comparados aos shams, o que não ocorreu nos animais UNX tratados com paricalcitol e calcitriol. Nas aortas, a relação parede/lúmen foi significativamente menor no grupo Sham Controle quando comparada à dos grupos UNX Controle e UNX Calcitriol, sendo que nesses últimos, foram evidenciadas calcificações vasculares acompanhadas por células positivas para Runx-2 (cbfa-1). Além disso, foi evidenciada uma menor expressão de TGFß nas aortas dos animais do grupo UNX Paricalcitol em relação aos grupos UNX Controle e UNX Calcitriol. Conclusões: Ambos os tratamentos preveniram alterações na capilarização cardíaca induzidas pela UNX. O tratamento com calcitriol na dose empregada induziu significativas calcificações vasculares, o que não ocorreu com o paricalcitol.


The study investigated the influence of a 10-week treatment with Paricalcitol (0.1µg/kg, 5x/week) or Calcitriol (0.03µg/kg, 5x/week) on cardiovascular disease in spontaneously atherosclerotic ApoE -/- mice submitted to uninephrectomy (UNX). Results: capillary length density of the heart was significantly lower in UNX Control, but not in UNX Paricalcitol and UNX Calcitriol animals, when compared to shams. In the aortas, a significantly lower wall/lumen ratio was observed in the Sham Control group when compared to UNX Control and UNX Calcitriol groups. In the latter, vascular calcifications accompanied by a significant presence of Runx-2 (cbfa-1) positive cells was observed. TGFß aorta expression was significantly higher in UNX Control and UNX Calciriol groups when compared to UNX Paricalcitol. Conclusions: Both treatments were able to prevent the reduction in heart capillarization induced by the UNX model. Treatment with Calcitriol at the employed dose and duration, though, induced significant vascular calcifications.


Subject(s)
Animals , Mice , Cardiovascular Diseases , Mice, Knockout , Vitamin D/analogs & derivatives , Atherosclerosis , Calcitriol , Monckeberg Medial Calcific Sclerosis , Nephrectomy , Renal Insufficiency
9.
Einstein (Säo Paulo) ; 4(4): 277-283, 2006.
Article in Portuguese | LILACS | ID: lil-445368

ABSTRACT

O objetivo deste trabalho foi analisar por imunoistoquímica a expressão in situ de perforina, granzima B, FAS-L e FAS em biópsias de enxerto renal,correlacionando esses achados com o grau histológico de rejeição eprognóstico do enxerto. Biópsias renais (n = 96) foram divididas em três grupos: rejeição aguda (n = 56), rejeição crônica (n = 31), função renal estável (sem rejeição; n = 9). A expressão de perforina, granzima B, FAS-L e FAS foi avaliada por imunoistoquímica. A expressão de perforina e granzima B foi significativamente maior na rejeição aguda (4,84 ± 0,65 e 30,05 ±7,93) quando comparada à rejeição crônica (0,71 ± 0,13 céls./mm2e 11,40 ± 3,84; p < 0,001 e p< 0,05 respectivamente), mas não deFAS-L (24,44 ± 5,56 na rejeição aguda vs. 18,87 ± 6,83 na rejeição crônica). As marcações de perforina, granzima B e FAS-L na rejeição aguda foram significativamente maiores na rejeição aguda que nos casos sem rejeição e controle. A expressão de FAS foi semelhante entre os grupos. Houve modesta correlação entre a expressão de perforina e a gravidade da rejeição aguda (r = 0,28, p = 0,05). A perforina foi o marcador mais confiável para o diagnóstico de rejeição aguda, com 80% de sensibilidade e 84,4% de especificidade. A presença in situ de perforina, granzima B e FAS-L embiópsias de aloenxerto renal na rejeição aguda indica a ocorrênciade intensa atividade citotóxica. Estes dados apontam para a possibilidade de utilização destas moléculas como marcadores de rejeição, podendo vir a se tornar um instrumento na monitorização pós-transplante.


Subject(s)
Humans , Male , Female , Graft Rejection , Immunohistochemistry , Kidney/pathology , Kidney Transplantation/immunology
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