Recurrence of membranous nephropathy after kidney transplantation: A multicenter retrospective cohort study.

Membranous nephropathy (MN) is a leading cause of kidney failure worldwide and frequently recurs after transplant. Available data originated from small retrospective cohort studies or registry analyses; therefore, uncertainties remain on risk factors for MN recurrence and response to therapy. Within the Post-Transplant Glomerular Disease Consortium, we conducted a retrospective multicenter cohort study examining the MN recurrence rate, risk factors, and response to treatment. This study screened 22,921 patients across 3 continents and included 194 patients who underwent a kidney transplant due to biopsy-proven MN. The cumulative incidence of MN recurrence was 31% at 10 years posttransplant. Patients with a faster progression toward end-stage kidney disease were at higher risk of developing recurrent MN (hazard ratio [HR], 0.55 per decade; 95% confidence interval [CI], 0.35-0.88). Moreover, elevated pretransplant levels of anti-phospholipase A2 receptor (PLA2R) antibodies were strongly associated with recurrence (HR, 18.58; 95% CI, 5.37-64.27). Patients receiving rituximab for MN recurrence had a higher likelihood of achieving remission than patients receiving renin-angiotensin-aldosterone system inhibition alone. In sum, MN recurs in one-third of patients posttransplant, and measurement of serum anti-PLA2R antibody levels shortly before transplant could aid in risk-stratifying patients for MN recurrence. Moreover, patients receiving rituximab had a higher rate of treatment response.

IgA nephropathy and kidney transplantation according to the Oxford classification / Nefropatia por IgA e transplante renal segundo a classificação de Oxford

Abstract Introduction: IgA nephropathy (IgAN) is the most common glomerular disease globally, and its susceptibility and the risk for the development of end-stage kidney disease are related to genetic and environmental factors. IgAN recurrence after kidney transplantation is relatively common, impacting graft function and survival. This study evaluated the risk factors and the clinical, laboratory, and histological characteristics of post-transplant IgAN recurrence based on the Oxford classification. Material and methods: Retrospective single-center cohort study including kidney transplant recipients with biopsy-proven pre-transplantation IgAN, with analysis of risk factors and clinical, laboratory, and histological characteristics of the IgAN recurrence cases. Results: 53 patients fulfilled the inclusion criteria and were included in the study. The majority was male, white, eutrophic, with a mean age of 27 ± 9 years at IgAN diagnosis. Systemic arterial hypertension and proteinuria were frequent in the pretransplant period. Four recipients (7.5%) presented IgAN recurrence in a period of 6 to 122 months post-transplant. According to the Oxford classification, they had high scores of mesangial hypercellularity and segmental glomerulosclerosis in the native kidney biopsies and there was mesangial hypercellularity in all analyzed graft biopsies. None of these patients had received induction immunosuppression and all of them presented graft failure in the follow-up. Conclusions: In this series, there was a high prevalence of mesangial hypercellularity and segmental glomerulosclerosis on native kidney biopsies, and mesangial hypercellularity occurred in all IgAN recurrence graft biopsies. Despite the lower incidence of recurrence of IgAN post-transplant compared to previous reports, progression to graft loss was of 100%.

Resumo Introdução: Nefropatia por IgA (NIgA) é a doença glomerular mais comum mundialmente. Sua suscetibilidade e risco para desenvolvimento de doença renal em fase terminal estão relacionados a fatores genéticos e ambientais. A recidiva de NIgA pós-transplante é relativamente comum, impactando na função e sobrevida do enxerto. Este estudo avaliou fatores de risco e características clínicas, laboratoriais e histológicas da recidiva de NIgA pós-transplante, com base na classificação de Oxford. Material e métodos: Estudo de coorte retrospectivo de centro único, incluindo receptores de transplante renal com NIgA pré-transplante comprovada por biópsia, com análise dos fatores de risco e características clínicas, laboratoriais e histológicas dos casos de recidiva de NIgA. Resultados: 53 pacientes preencheram critérios de inclusão e foram incluídos no estudo. A maioria era homem, branco, eutrófico, com idade média de 27 ± 9 anos no diagnóstico de NIgA. Hipertensão arterial sistêmica e proteinúria foram frequentes no período pré-transplante. Quatro receptores (7,5%) apresentaram recidiva de NIgA entre 6-122 meses pós-transplante. Segundo a classificação de Oxford, eles apresentaram altos escores de hipercelularidade mesangial e glomeruloesclerose segmentar nas biópsias de rins nativos. Houve hipercelularidade mesangial em todas as biópsias de enxerto analisadas. Nenhum destes pacientes recebeu imunossupressão de indução. Todos apresentaram falência do enxerto no acompanhamento. Conclusões: Nesta série, houve alta prevalência de hipercelularidade mesangial e glomeruloesclerose segmentar em biópsias de rins nativos, e hipercelularidade mesangial ocorreu em todas as biópsias do enxerto de recidiva da NIgA. Apesar da menor incidência de recidiva de NIgA pós-transplante comparada a relatos anteriores, a progressão para perda do enxerto foi de 100%.

IgA nephropathy and kidney transplantation according to the Oxford classification.

INTRODUCTION: IgA nephropathy (IgAN) is the most common glomerular disease globally, and its susceptibility and the risk for the development of end-stage kidney disease are related to genetic and environmental factors. IgAN recurrence after kidney transplantation is relatively common, impacting graft function and survival. This study evaluated the risk factors and the clinical, laboratory, and histological characteristics of post-transplant IgAN recurrence based on the Oxford classification. MATERIAL AND METHODS: Retrospective single-center cohort study including kidney transplant recipients with biopsy-proven pre-transplantation IgAN, with analysis of risk factors and clinical, laboratory, and histological characteristics of the IgAN recurrence cases. RESULTS: 53 patients fulfilled the inclusion criteria and were included in the study. The majority was male, white, eutrophic, with a mean age of 27 ± 9 years at IgAN diagnosis. Systemic arterial hypertension and proteinuria were frequent in the pretransplant period. Four recipients (7.5%) presented IgAN recurrence in a period of 6 to 122 months post-transplant. According to the Oxford classification, they had high scores of mesangial hypercellularity and segmental glomerulosclerosis in the native kidney biopsies and there was mesangial hypercellularity in all analyzed graft biopsies. None of these patients had received induction immunosuppression and all of them presented graft failure in the follow-up. CONCLUSIONS: In this series, there was a high prevalence of mesangial hypercellularity and segmental glomerulosclerosis on native kidney biopsies, and mesangial hypercellularity occurred in all IgAN recurrence graft biopsies. Despite the lower incidence of recurrence of IgAN post-transplant compared to previous reports, progression to graft loss was of 100%.

Sexual and Reproductive Health Assessment in a Group of Female Renal Transplant Recipients.

BACKGROUND: Fertility and sexual health are impaired in individuals with chronic kidney disease and can be restored after a successful renal transplant. This is a single-center prospective study about the sexual and reproductive health (including contraceptive methods and gynecologic cancer screening) in renal transplant recipients. METHODS: Female renal transplant recipients, aged 18 to 49 years at transplant, were interviewed about their gynecologic history, sexual health, and use of contraceptive methods. RESULTS: Ninety-one patients fulfilled the inclusion criteria. The majority of women maintained menstrual cycles during dialysis therapy, being almost 60% of the women in an irregular rhythm. Pregnancies were reported for 51 women, 20% after transplant, and associated with low-weight newborns. The incidence of spontaneous abortion was 12.5%. Thirty-one patients were denied contraceptive methods due to the vasectomy of the partner (n = 16) or the belief that they would not become pregnant (n = 15). The most common contraceptive method was a condom, and the use of an intrauterine device was rare. Gynecologic assessment and cancer screening were out-of-date in almost one-third of patients. CONCLUSIONS: In this study, the majority of women were from low-income areas and had low levels of education. Despite access to public universal health care, adherence to yearly screening tests and use of contraceptive methods were lower than expected.

De Novo Membranous Nephropathy Associated With Antibody-Mediated Rejection in Kidney Transplant Recipients.

BACKGROUND: Membranous nephropathy (MN) is a rare autoimmune disease that can develop a persistent nephrotic syndrome and end-stage kidney disease, with a recurrence rate of 30% to 40% after kidney transplant. METHODS: Retrospective case series of membranous nephropathy observed in a cohort of kidney transplant recipients with donor-specific anti-human leukocyte antigen antibodies and biopsy-proven antibody-mediated rejection (AMR). RESULTS: We report 4 cases of membranous nephropathy associated with AMR. MN was diagnosed 10 to 92 months posttransplant, associated with de novo donor-specific antibodies, specific to class I in 2 cases, and class II in another 2. All cases presented typical morphology of membranous nephropathy, with subepithelial deposits with spikes at electron microscopy. Immunostaining for immunoglobulin G4 was negative in all cases, and podocyte-expressed M-type phospholipase A2 receptor was detected in glomerular basement membrane of 3 cases. Biopsy specimens from patients with longer follow-up showed more intense microvascular inflammation and chronic injury markers, possibly because of subclinical immunologic injury. AMR therapy included immunoglobulin 2g/kg in 3 patients, isolated or associated with plasmapheresis. One patient was not treated because of an active disseminated infection. Two patients remain with functioning grafts and under antiproteinuric therapy. Two grafts were lost, 1 because of chronic failure and the other because of death secondary to infection. Despite treatment, donor-specific antibodies remain detectable in a 6-month follow-up. CONCLUSIONS: De novo MN is a rare manifestation associated with AMR in kidney transplant recipients. The occurrence of podocyte-expressed M-type phospholipase A2 receptor in de novo MN suggests antibody-mediated activation, despite the use of maintenance immunosuppression.

Recurrence of IgA Nephropathy after Kidney Transplantation in Adults.

BACKGROUND AND OBJECTIVES: In patients with kidney failure due to IgA nephropathy, IgA deposits can recur in a subsequent kidney transplant. The incidence, effect, and risk factors of IgA nephropathy recurrence is unclear, because most studies have been single center and sample sizes are relatively small. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a multicenter, international, retrospective study to determine the incidence, risk factors, and treatment response of recurrent IgA nephropathy after kidney transplantation. Data were collected from all consecutive patients with biopsy-proven IgA nephropathy transplanted between 2005 and 2015, across 16 "The Post-Transplant Glomerular Disease" study centers in Europe, North America, and South America. RESULTS: Out of 504 transplant recipients with IgA nephropathy, recurrent IgA deposits were identified by kidney biopsy in 82 patients; cumulative incidence of recurrence was 23% at 15 years (95% confidence interval, 14 to 34). Multivariable Cox regression revealed a higher risk for recurrence of IgA deposits in patients with a pre-emptive kidney transplant (hazard ratio, 3.45; 95% confidence interval, 1.31 to 9.17) and in patients with preformed donor-specific antibodies (hazard ratio, 2.59; 95% confidence interval, 1.09 to 6.19). After kidney transplantation, development of de novo donor-specific antibodies was associated with subsequent higher risk of recurrence of IgA nephropathy (hazard ratio, 6.65; 95% confidence interval, 3.33 to 13.27). Immunosuppressive regimen was not associated with recurrent IgA nephropathy in multivariable analysis, including steroid use. Graft loss was higher in patients with recurrence of IgA nephropathy compared with patients without (hazard ratio, 3.69; 95% confidence interval, 2.04 to 6.66), resulting in 32% (95% confidence interval, 50 to 82) graft loss at 8 years after diagnosis of recurrence. CONCLUSIONS: In our international cohort, cumulative risk of IgA nephropathy recurrence increased after transplant and was associated with a 3.7-fold greater risk of graft loss.

Treatment of Antibody-Mediated Rejection After Kidney Transplantation: Immunological Effects, Clinical Response, and Histological Findings.

BACKGROUND Antibody-mediated rejection (AMR) presents with diverse clinical manifestations and can have a potential negative impact on graft function and survival. If not treated successfully, AMR can lead to 20-30% graft loss after 1 year. Little is known about the efficacy of AMR treatment, and the most appropriate therapeutic strategy has not yet been determined. This study evaluated the effects of AMR treatment with plasmapheresis (PP) and intravenous immunoglobulin (IVIG) on renal function, intensity of anti-HLA antibodies, and graft biopsy morphology. MATERIAL AND METHODS This single-center retrospective cohort study included renal transplant recipients with biopsy-proven AMR who were treated with PP and/or IVIG. Clinical findings, mean fluorescence intensity of donor-specific anti-HLA antibodies (DSA), and graft histology findings, classified according to Banff score at the time of AMR and 6 and 12 months later, were evaluated. RESULTS Of the 42 patients who met the inclusion criteria, 38 (90.5%) received IVIG and 26 (61.9%) underwent PP. At AMR diagnosis, 36 (85.7%) patients had proteinuria, with their estimated glomerular filtration rate remaining stable during follow-up. During the first year, 8 (19.0%) patients experienced graft failure, but none died with a functioning graft. Reductions in the class I panel of reactive antibodies were observed 6 and 12 months after AMR treatment, with significant reductions in DSA-A and -B fluorescence intensity, but no changes in DSA-DQ. Graft biopsy showed reductions in inflammation and C4d scores, without improvements in microvascular inflammation. CONCLUSIONS AMR treatment reduced biopsy-associated and serological markers of AMR, but did not affect DSA-DQ.

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

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.

Optimizing the clinical utility of sirolimus-based immunosuppression for kidney transplantation.

While calcineurin inhibitors (CNIs) are effective for preventing acute rejection in kidney transplant recipients, long-term use may cause chronic kidney injury and is associated with increased risks of cardiovascular events, cancer, and infection-associated death. Immunosuppression strategies are needed to balance risks of acute and subclinical rejection with long-term benefits of improved kidney function. Sirolimus, an inhibitor of mammalian target of rapamycin, is used for immunosuppression in kidney transplantation. Its clinical utility has evolved, over more than 15 years, including de novo sirolimus with and without concomitant CNIs and conversion from CNI-based regimens to sirolimus. Sirolimus-containing regimens are associated with preservation of good renal function, with promising characteristics for improving long-term graft and patient survival, including antiviral and anticancer effects. Based on clinical evidence, use of low-dose sirolimus in a de novo approach with tacrolimus/steroids in the immediate posttransplantation period is appropriate. A feasible alternative is a long term, CNI-free combination with mycophenolate mofetil (following CNI-to-sirolimus conversion at 3-6 months). These strategies are appropriate for a broad range of patients with various levels of immunologic risk, including those receiving expanded criteria donor kidneys or at increased risk of delayed graft function, particular challenges in Latin America and other global regions.

Avaliação da tolerabilidade do micofenolato sódico com revestimento entérico versus micofenolato mofetil em receptores de transplante renal / Evaluation of tolerability of enteric-coated mycophenolate sodium versus mycophenolate mofetil in de novo renal transplantation

ResumoIntrodução:O micofenolato mofetil (MMF), pró-droga do ácido micofenólico (MPA), é um tratamento imunossupressor eficaz na profilaxia da rejeição aguda, mas associado a eventos adversos gastrointestinais. O micofenolato sódico (MPS) com revestimento entérico foi desenvolvido com a intenção de reduzir tais eventos associados ao MPA.Objetivo:Avaliar a tolerabilidade de EC-MPS e MMF em receptores de transplante renal.Métodos:Estudo retrospectivo, multicêntrico, com pacientes submetidos a transplante renal entre 07/01/2004 e 31/07/2007 em 18 centros brasileiros.Resultados:1380 pacientes incluídos, 702 receberam EC-MPS e 678 receberam MMF. A idade média de 42,3 anos, 60% masculino e 62,5% de etnia caucasiana. A incidência de eventos avaliados no desfecho composto de eficácia não foi diferente entre os grupos ao final de 24 meses de acompanhamento (22,9% para EC-MPS versus 19,9% para MMF, p = 0,203). Os pacientes tratados com EC-MPS apresentaram maior incidência de eventos adversos gastrointestinais comparados com os tratados com MMF (57,7% vs. 52,5%). Infecções virais foram mais frequentes no grupo EC-MPS (38,2%) comparado com MMF (32,6%). Não houve diferença nos valores médios tolerados no final do primeiro (1187 ± 344 mg vs. 1209 ± 426 mg, p = 0,294) e segundo ano (1172,3 ± 347mg vs. 1197,4 ± 430,6 mg, p = 0,241) pós-transplante.Conclusão:Não houve diferença estatística na incidência de rejeição aguda, função tardia e eventos gastrointestinais entre os tratamentos. A dose média tolerada de MPA foi semelhante entre os grupos, mas pacientes tratados com MMF foram submetidos a mais reduções de doses e descontinuações do tratamento.

AbstractIntroduction:Mycophenolate mofetil (MMF), pro-drug mycophenolic acid (MPA) is an immunosuppressive effective in the prophylaxis of acute rejection, but associated with gastrointestinal adverse events. Mycophenolate sodium (MPS) with enteric coating was developed with intention of reducing such gastrointestinal adverse events associated with MPA.Objective:To evaluate the tolerability of EC-MPS and MMF in renal transplant recipients.Methods:Retrospective, multicenter study, included 1380 patients who underwent a transplant between 07/01/2004 and 31/07/2007 in 18 Brazilian centers.Results1380 patients enrolled, 702 received EC-MPS and 678 received MMF. The average age of patients was 42.3 years, 60% were male and 62.5% of Caucasian ethnicity. The incidence of events evaluated in the composite endpoint of efficacy was not different between groups at the end of 24 months follow-up (22.9% for EC-MPS to MMF versus19.9%, p = 0.203). Patients treated with EC-MPS had a higher incidence of gastrointestinal adverse events compared to those treated with MMF (57.7%vs. 52.5%), but there was no statistical difference between groups. Viral infections were more frequent in the EC-MPS group (38.2%) compared with MMF (32.6%). There was no difference in mean tolerated dose after the first (1187 ± 344vs. 1209 ± 426 mg, p = 0.294) and second year (1172.3 ± 347 mgvs. 1197.4 ± 430.6 mg, p = 0.241) after transplantation.Conclusion:There was no statistical difference in the incidence of acute rejection, delayed graft function and gastrointestinal events among treatments. The average tolerated dose of MPA was similar between groups; however, patients treated with MMF underwent more dose reductions and discontinuations of treatment.

Bladder function evaluation before renal transplantation in nonurologic disease: is it necessary?

OBJECTIVE: To determine whether preoperative cystometry and a pressure flow study (PFS) are necessary in patients with end-stage renal disease from nonurologic causes who will undergo renal transplantation. METHODS: From April 2009 to June 2010, 30 patients scheduled to undergo renal transplantation were prospectively evaluated with cystometry and PFS. The evaluation was performed immediately before and 6 months after renal transplantation. The inclusion criteria were age >18 years and end-stage renal disease secondary to nonurologic disease. RESULTS: Improvement in the cystometry and PFS parameters was observed after the return of diuresis at 6 months after transplantation. The parameter changes from baseline to the 6-month evaluation were as follows: first sensation of bladder filling, 88.8-168.7 mL (P = .0005); first desire to void, 137.2-251.1 mL (P <.0001); maximal cystometric capacity, 221.2-428.7 mL (P <.0001); bladder compliance, 73.9-138.6 mL/cm H2O (P = .03); and maximal flow rate, 8.1-15.8 mL/s (P <.0001). The Abrams-Griffiths number in the men decreased from 31.8 to 15.2 (P = .002). No significant changes were observed in the detrusor pressure at the maximal flow rate or the postvoid residual urine volume. Patients with a 24-hour urine output <200 mL tended to have had significantly worse parameters before transplantation. CONCLUSION: Significant improvement in the cystometry and PFS parameters was observed in patients with end-stage renal disease, without urologic disease, 6 months after transplantation, and was associated with recovery of the glomerular filtration rate and urine output by the renal graft.

Anemia in chronic renal disease: evaluation of inflammatory activity on erythropoiesis and iron metabolism in patients not submitted to dialysis treatment.

BACKGROUND: Inflammatory activity is one of the factors involved in the physiopathology of anemia in patients with chronic kidney disease (CKD). The majority of studies on anemia, inflammation, and disturbances of iron metabolism have focused on patients in end-stage renal failure and dialysis therapy. However, anemia and inflammation are present in patients in previous stages of renal failure. The objective of this study was to evaluate the possible influence of inflammatory activity on erythropoiesis and iron metabolism in CKD patients without dialytic treatment. METHODS: 114 CKD adult patients were studied. Patients with anemia (n = 72) were compared with those without anemia (n = 46). Anemic patients were classified as renal anemia (n = 46) or iron deficiency anemia (n = 26). In addition the total group was analyzed according to the degree of renal dysfunction. Iron status, erythropoiesis activity (soluble transferrin receptor and erythropoietin determinations), and inflammatory activity (C-reactive protein, interleukin-6, interleukin-lp, and neopterin determinations) were measured using commercial kits. Reticulocyte hemoglobin content (Ret-Y) was also determined. RESULTS: Interleukin-6, interleukin-li, and neopterin concentrations were higher in the anemic group when compared with those without anemia and controls. There was no difference in C-reactive protein values between CKD with and without anemia, although both of them had showed elevated levels when compared with controls. Ret-Y values were lower in iron deficiency anemia when compared with renal anemia and controls. An inverse correlation between interleukin-6 and hemoglobin (r = -0.4287, p= 0.0002) was observed only in the renal anemia group. It was observed that anemia has a tendency to worsen as renal function deteriorates. Reticulocyte count was lower and neopterin concentrations were higher in more advanced renal failure stages. CONCLUSIONS: Inflammatory factors contribute to anemia in renal patients in all stages of renal failure. High levels of neopterin in CKD patients suggest that neopterin contributes to impaired erythropoietin production and anemia in CKD patients.

Use of uric acid-lowering agents limits experimental cyclosporine nephropathy.

BACKGROUND: Hyperuricemia frequently complicates cyclosporine (CsA) therapy. Previous studies have shown that hyperuricemia exacerbates interstitial and vascular lesions in the cyclosporine model. We tested the hypothesis that normalization of uric acid could prevent the development of cyclosporine toxicity. METHODS: CsA nephropathy was induced by administering CsA (15 mg/kg/day) for 7 weeks to rats on a low salt diet (CsA group). The effect of preventing hyperuricemia was determined by concomitant treatment with a xanthine oxidase inhibitor, allopurinol (CsAALP), or with a uricosuric, benzbromarone (CsABENZ), in drinking water. Control groups included vehicle-treated rats. RESULTS: CsA-treated rats developed mild hyperuricemia with arteriolar hyalinosis, tubular atrophy, striped interstitial fibrosis, increased cell proliferation and decreased VEGF expression. Treatment with allopurinol or benzbromarone limited renal disease, with reduced interstitial fibrosis, cell proliferation, macrophage infiltration, osteopontin expression and arteriolar hyalinosis, in association with restoration of VEGF expression. Both drugs provided comparable protection. CONCLUSIONS: An increase in uric acid exacerbates CsA nephropathy in the rat. Concomitant treatment with allopurinol or benzbromarone reduced the severity of renal disease. The similar protection observed with both drugs suggests that the effect is associated more with lowering uric acid levels than the antioxidant effect of allopurinol.

Diretrizes para manutenção de múltiplos órgãos no potencial doador adulto falecido: Parte III. Recomendações órgãos específicas / Guidelines for potential multiple organ donors (adult). Part III: organ-specific recommendations

A morte encefálica induz várias alterações fisiopatológicas que podem causar lesões em rins, pulmões, coração e fígado. Portanto, a atuação do intensivista durante a manutenção do potencial doador falecido exige cuidados específicos com estes órgãos visando sua maior viabilidade para transplantes. O manejo hemodinâmico cuidadoso, os cuidados ventilatórios e de higiene brônquica minimizam a perda de rins e pulmões para o transplante. A avaliação da condição morfológica e funcional do coração auxilia na avaliação do potencial transplantável deste órgão. Por fim, a avaliação da função hepática, assim como o controle metabólico e a realização de sorologias virais são fundamentais para a orientação das equipes transplantadoras na seleção do órgão a ser doado e no cuidado com o receptor.

Brain death (BD) alters the pathophysiology of patients and may damage the kidneys, the lungs, the heart and the liver. To obtain better quality transplant organs, intensive care physicians in charge of the maintenance of deceased donors should attentively monitor these organs. Careful hemodynamic, ventilatory and bronchial clearance management minimizes the loss of kidneys and lungs. The evaluation of cardiac function and morphology supports the transplant viability assessment of the heart. The monitoring of liver function, the management of the patient's metabolic status and the evaluation of viral serology are fundamental for organ selection by the transplant teams and for the care of the transplant recipient.

Uric acid and hypertension: cause or effect?

Uric acid was first associated with primary hypertension in 1874, yet its role in this condition remains unclear. Historically, uric acid was thought to be a secondary response to hypertension or its associated conditions. However, more recent experimental and clinical studies suggest that uric acid could have a contributory role in the pathogenesis of elevated blood pressure. More studies are needed to help dissect the potential mechanisms by which uric acid could initiate this response. It remains possible that uric acid is a marker for xanthine oxidase-associated oxidants and that the latter could be driving the hypertensive response. However, the weight of the evidence suggests that uric acid is a true modifying and possibly causal factor for human primary hypertension. Hence, early management of hyperuricemia might delay the development of essential hypertension.

Administration of neural precursor cells ameliorates renal ischemia-reperfusion injury.

In this study we evaluated whether administration of stem cells of neural origin (neural precursor cells, NPCs) could be protective against renal ischemia-reperfusion injury (IRI). We hypothesized that stem cell outcomes are not tissue-specific and that NPCs can improve tissue damage through paracrine mechanisms, especially due to immunomodulation. To this end, Wistar rats (200-250 g) were submitted to 1-hour ischemia and treated with NPCs (4 x 10(6) cells/animal) at 4 h of reperfusion. To serve as controls, ischemic animals were treated with cerebellum homogenate harvested from adult rat brain. All groups were sacrificed at 24 h of reperfusion. NPCs were isolated from rat fetus telencephalon and cultured until neurosphere formation (7 days). Before administration, NPCs were labeled with carboxyfluorescein diacetate succinimydylester (CFSE). Kidneys were harvested for analysis of cytokine profile and macrophage infiltration. At 24 h, NPC treatment resulted in a significant reduction in serum creatinine (IRI + NPC 1.21 + 0.18 vs. IRI 3.33 + 0.14 and IRI + cerebellum 2.95 + 0.78 mg/dl, p < 0.05) and acute tubular necrosis (IRI + NPC 46.0 + 2.4% vs. IRI 79.7 + 14.2%, p < 0.05). NPC-CFSE and glial fibrillary acidic protein (GFAP)-positive cells (astrocyte marker) were found exclusively in renal parenchyma, which also presented GFAP and SOX-2 (an embryonic neural stem cell marker) mRNA expression. NPC treatment resulted in lower renal proinflammatory IL1-beta and TNF-alpha expression and higher anti-inflammatory IL-4 and IL-10 transcription. NPC-treated animals also had less macrophage infiltration and decreased serum proinflammatory cytokines (IL-1beta, TNF-alpha and INF-gamma). Our data suggested that NPC therapy improved renal function by influencing immunological responses.

Inhibition of COX 1 and 2 prior to renal ischemia/reperfusion injury decreases the development of fibrosis.

Ischemia and reperfusion injury (IRI) contributes to the development of chronic interstitial fibrosis/tubular atrophy in renal allograft patients. Cyclooxygenase (COX) 1 and 2 actively participate in acute ischemic injury by activating endothelial cells and inducing oxidative stress. Furthermore, blockade of COX 1 and 2 has been associated with organ improvement after ischemic damage. The aim of this study was to evaluate the role of COX 1 and 2 in the development of fibrosis by performing a COX 1 and 2 blockade immediately before IRI. We subjected C57Bl/6 male mice to 60 min of unilateral renal pedicle occlusion. Prior to surgery mice were either treated with indomethacin (IMT) at days -1 and 0 or were untreated. Blood and kidney samples were collected 6 wks after IRI. Kidney samples were analyzed by real-time reverse transcription-polymerase chain reaction for expression of transforming growth factor beta (TGF-beta), monocyte chemoattractant protein 1 (MCP-1), osteopontin (OPN), tumor necrosis factor alpha (TNF-alpha), interleukin (IL)-1 beta, IL-10, heme oxygenase 1 (HO-1), vimentin, connective-tissue growth factor (CTGF), collagen I, and bone morphogenic protein 7 (BMP-7). To assess tissue fibrosis we performed morphometric analyses and Sirius red staining. We also performed immunohistochemical analysis of anti-actin smooth muscle. Renal function did not significantly differ between groups. Animals pretreated with IMT showed significantly less interstitial fibrosis than nontreated animals. Gene transcript analyses showed decreased expression of TGF-beta, MCP-1, TNF-alpha, IL-1-beta, vimentin, collagen I, CTGF, and IL-10 mRNA (all P < 0.05). Moreover, HO-1 mRNA was increased in animals pretreated with IMT (P < 0.05). Conversely, IMT treatment decreased osteopontin expression and enhanced BMP-7 expression, although these levels did not reach statistical significance when compared with control expression levels. The blockade of COX 1 and 2 resulted in less tissue fibrosis, which was associated with a decrease in proinflammatory cytokines and enhancement of the protective cellular response.