Renal amyloidosis: a new time for a complete diagnosis

Amyloidoses are a group of disorders in which soluble proteins aggregate and deposit extracellularly in tissues as insoluble fibrils, causing organ dysfunction. Clinical management depends on the subtype of the protein deposited and the affected organs. Systemic amyloidosis may stem from anomalous proteins, such as immunoglobulin light chains or serum amyloid proteins in chronic inflammation or may arise from hereditary disorders. Hereditary amyloidosis consists of a group of rare conditions that do not respond to chemotherapy, hence the identification of the amyloid subtype is essential for diagnosis, prognosis, and treatment. The kidney is the organ most frequently involved in systemic amyloidosis. Renal amyloidosis is characterized by acellular pathologic Congo red-positive deposition of amyloid fibrils in glomeruli, vessels, and/or interstitium. This disease manifests with heavy proteinuria, nephrotic syndrome, and progression to end-stage kidney failure. In some situations, it is not possible to identify the amyloid subtype using immunodetection methods, so the diagnosis remains indeterminate. In cases where hereditary amyloidosis is suspected or cannot be excluded, genetic testing should be considered. Of note, laser microdissection/mass spectrometry is currently the gold standard for accurate diagnosis of amyloidosis, especially in inconclusive cases. This article reviews the clinical manifestations and the current diagnostic landscape of renal amyloidosis.

Contribution of CD4+ T cells to the early mechanisms of ischemia- reperfusion injury in a mouse model of acute renal failure

Renal ischemia-reperfusion (IR) injury is the major cause of acute renal failure in native and transplanted kidneys. Mononuclear leukocytes have been reported in renal tissue as part of the innate and adaptive responses triggered by IR. We investigated the participation of CD4+ T lymphocytes in the pathogenesis of renal IR injury. Male mice (C57BL/6, 8 to 12 weeks old) were submitted to 45 min of ischemia by renal pedicle clamping followed by reperfusion. We evaluated the role of CD4+ T cells using a monoclonal depleting antibody against CD4 (GK1.5, 50 æ, ip), and class II-major histocompatibility complex molecule knockout mice. Both CD4-depleted groups showed a marked improvement in renal function compared to the ischemic group, despite the fact that GK1.5 mAb treatment promoted a profound CD4 depletion (to less than 5 percent compared to normal controls) only within the first 24 h after IR. CD4-depleted groups presented a significant improvement in 5-day survival (84 vs 80 vs 39 percent; antibody treated, knockout mice and non-depleted groups, respectively) and also a significant reduction in the tubular necrosis area with an early tubular regeneration pattern. The peak of CD4-positive cell infiltration occurred on day 2, coinciding with the high expression of ßC mRNA and increased urea levels. CD4 depletion did not alter the CD11b infiltrate or the IFN-g and granzyme-B mRNA expression in renal tissue. These data indicate that a CD4+ subset of T lymphocytes may be implicated as key mediators of very early inflammatory responses after renal IR injury and that targeting CD4+ T lymphocytes may yield novel therapies.

Diabetes mellitus: new therapeutic approaches to treat an old disease

Diabetes mellitus is a widespread disease whose frequency increases constantly and is expected to reach alarming levels by the year 2025. Introduction of insulin therapy represented a major breakthrough; however, a very strict regimen is required to maintain blood glucose levels within the normal range and to prevent or postpone chronic complications associated with this disease. Frequent hyper- and hypoglycemia seriously affect the quality of life of these patients. Reversion of this situation can only be achieved through whole organ (pancreas) transplant or pancreatic islet transplant, the former being a high-risk surgical procedure, while the latter is a much simpler and may be accomplished in only 20-40 min. The advantages and perspectives of islet cell transplantation will be discussed, in the light of tissue engineering and gene therapy. Ongoing research carried out in our laboratory, aimed at developing clinical cell and molecular therapy protocols for diabetes will also be focused

Lamivudine therapy for hepatitis B in renal transplantation

Antiviral therapies are associated with an increased risk of acute rejection in transplant patients. The aim of the present study was to evaluate the efficacy and safety of lamivudine therapy for hepatitis B virus (HBV) infection in renal transplant patients. Six patients were included in this study. They received 150 mg/day of lamivudine during a follow-up period of 24 months. The laboratory tests monitored were HBV DNA, HBsAg, HBeAg, ALT, gamma-GT, serum creatinine and blood cyclosporine levels. The HBV DNA became undetectable in four patients as early as in the third month of treatment. After six months, the viral load was also negative in the other two patients, and remained so until 18 months of follow-up. The medication was well tolerated with no major side effects. Lamivudine was safe and effective in blocking HBV replication in renal transplant patients without any apparent increase in the risk of graft failure for the 24-month period of study

Microencapsulation and tissue engineering as an alternative treatment of diabetes

In the 70's, pancreatic islet transplantation arose as an attractive alternative to restore normoglycemia; however, the scarcity of donors and difficulties with allotransplants, even under immunosuppressive treatment, greatly hampered the use of this alternative. Several materials and devices have been developed to circumvent the problem of islet rejection by the recipient, but, so far, none has proved to be totally effective. A major barrier to transpose is the highly organized islet architecture and its physical and chemical setting in the pancreatic parenchyma. In order to tackle this problem, we assembled a multidisciplinary team that has been working towards setting up the Human Pancreatic Islets Unit at the Chemistry Institute of the University of São Paulo, to collect and process pancreas from human donors, upon consent, in order to produce purified, viable and functional islets to be used in transplants. Collaboration with the private enterprise has allowed access to the latest developed biomaterials for islet encapsulation and immunoisolation. Reasoning that the natural islet microenvironment should be mimicked for optimum viability and function, we set out to isolate extracellular matrix components from human pancreas, not only for analytical purposes, but also to be used as supplementary components of encapsulating materials. A protocol was designed to routinely culture different pancreatic tissues (islets, parenchyma and ducts) in the presence of several pancreatic extracellular matrix components and peptide growth factors to enrich the beta cell population in vitro before transplantation into patients. In addition to representing a therapeutic promise, this initiative is an example of productive partnership between the medical and scientific sectors of the university and private enterprises.

Causas e prognóstico da insuficiência renal aguda hospitalar em pacientes idosos / Causes and prognosis of hospital acute renal failure in elderly patients

OBJETIVOS: O objetivo deste estudo foi analisar as causas e o prognóstico de pacientes idosos (>70 anos de idade) com IRA tratados em nosso Serviço. CASUISTICA E MÉTODOS: Dos 361 pacientes adultos e portadores de IRA, atendidos em nosso serviço no período de janeiro/95 a dezembro/96, acompanhamos 130 pacientes (36 por cento) com idade superior a 70 anos (média de 76,0 ± 4,7 anos, variando de 70 a 94 anos). Destes, 84 (65 por cento) eram do sexo masculino e 66 (51 por cento) estavam no pós-operatório de cirurgias diversas. Os dados foram obtidos através de formulários padronizados usados no Serviço. RESULTADOS: As causas mais freqüentes foram: isquêmicas 48 (38 por cento), sepsis 40 (31 por cento), nefrotóxicas 46 (35 por cento) e obstrutivas 10 (7,7 por cento); em outros 14 (11 por cento) foram diagnosticados mais de um agente causal. IRA nao-oligúrica ocorreu em 81 pacientes (62,8 por cento) e em 50 pacientes (39 por cento) houve necessidade de diálise. A mortalidade na populaçao com idade abaixo de 70 anos foi 43 por cento e nos idosos 53,1 por cento, nao havendo diferença estatística entre os grupos (p=0,085). A mortalidade foi maior (p<0,0001) nos pacientes idosos oligúricos (86 por cento) do que nos idosos nao-oligúricos (32 por cento); maior em casos de IRA cirúrgica (66,7 por cento) do que em IRA de origem médica (41,8 por cento), e em pacientes internados em UTI (69 por cento) do que nos internados em enfermaria (17 por cento). O número de óbitos também foi maior (p<0,0001) no grupo que necessitou de diálise (84 por cento) do que nos nao dialisados (33 por cento). CONCLUSAO: Concluímos que o percentual de pacientes idosos com IRA é elevado; apresentaram mortalidade ao redor de 50 por cento, nao superior ao observado na populaçao mais jovem; oligúria, cirurgia, necessidade de tratamento em UTI e necessidade de diálise foram fatores de prognóstico desfavorável nesta casuística