Preventing Early Renal Loss in Diabetes (PERL) Study: A Randomized Double-Blinded Trial of Allopurinol-Rationale, Design, and Baseline Data.

OBJECTIVE: Higher serum uric acid (SUA) is associated with diabetic kidney disease (DKD). Preventing Early Renal Loss in Diabetes (PERL) evaluates whether lowering SUA with allopurinol slows glomerular filtration rate (GFR) loss in people with type 1 diabetes (T1D) and mild to moderate DKD. We present the PERL rationale, design, and baseline characteristics. RESEARCH DESIGN AND METHODS: This double-blind, placebo-controlled, multicenter trial randomized 530 participants with T1D, estimated GFR (eGFR) of 40-99.9 mL/min/1.73 m2, SUA ≥4.5 m/dL, and micro- to macroalbuminuric DKD or normoalbuminuria with declining kidney function (NDKF) (defined as historical eGFR decline ≥3 mL/min/1.73 m2/year) to allopurinol or placebo. The primary outcome is baseline-adjusted iohexol GFR (iGFR) after 3 years of treatment plus a 2-month washout period. RESULTS: Participants are 66% male and 84% white. At baseline, median age was 52 years and diabetes duration was 35 years, 93% of participants had hypertension, and 90% were treated with renin-angiotensin system inhibitors (median blood pressure 127/71 mmHg). Median HbA1c was 8%, SUA 5.9 mg/dL, iGFR 68 mL/min/1.73 m2, and historical eGFR slope -3.5 mL/min/1.73 m2/year. Compared with participants with albuminuria (n = 419), those with NDKF (n = 94) were significantly older (56 vs. 52 years), had lower HbA1c (7.7 vs. 8.1%) and SUA (5.4 vs. 6.0 mg/dL), and had higher eGFR (82 vs. 74 mL/min/1.73 m2) and historical eGFR loss (-4.7 vs. -2.5 mL/min/1.73 m2/year). These differences persisted when comparing groups with similar rates of historical eGFR loss. CONCLUSIONS: PERL will determine the effect of allopurinol on mild to moderate DKD in T1D, with or without albuminuria. Participants with normoalbuminuria and rapid GFR loss manifested many DKD risk factors of those with albuminuria, but with less severity.

Glomerular structural-functional relationship models of diabetic nephropathy are robust in type 1 diabetic patients.

Studies of structural-functional relationships have improved understanding of the natural history of diabetic nephropathy (DN). However, in order to consider structural end points for clinical trials, the robustness of the resultant models needs to be verified. This study examined whether structural-functional relationship models derived from a large cohort of type 1 diabetic (T1D) patients with a wide range of renal function are robust. The predictability of models derived from multiple regression analysis and piecewise linear regression analysis was also compared. T1D patients (n = 161) with research renal biopsies were divided into two equal groups matched for albumin excretion rate (AER). Models to explain AER and glomerular filtration rate (GFR) by classical DN lesions in one group (T1D-model, or T1D-M) were applied to the other group (T1D-test, or T1D-T) and regression analyses were performed. T1D-M-derived models explained 70 and 63% of AER variance and 32 and 21% of GFR variance in T1D-M and T1D-T, respectively, supporting the substantial robustness of the models. Piecewise linear regression analyses substantially improved predictability of the models with 83% of AER variance and 66% of GFR variance explained by classical DN glomerular lesions alone. These studies demonstrate that DN structural-functional relationship models are robust, and if appropriate models are used, glomerular lesions alone explain a major proportion of AER and GFR variance in T1D patients.

Microalbuminuria in patients with cystic fibrosis.

OBJECTIVE: We previously found that microalbuminuria (MA) is present in 14% of patients with long-standing cystic fibrosis-related diabetes (CFRD). However, others have reported much higher rates of MA in CF patients with and without diabetes (32-67%), suggesting this test is not sufficiently specific for diabetic nephropathy screening in CF. We investigated transient (TMA) and persistent (PMA) microalbuminuria in CF patients to resolve these contradictory findings. RESEARCH DESIGN AND METHODS: We reviewed 1,449 outpatient urinary albumin measurements from 467 patients aged ≥10 years, which were collected over a decade. TMA was defined as a single episode of MA that subsequently was resolved. PMA was defined as two consecutive or two out of three consecutive measurements in the MA range. RESULTS: The prevalence of TMA that subsequently was resolved in CF patients was similar to the general population. It was found in 7.6% of patients, including 5% of youth (aged 10-17 years) and 9% of adults. PMA was found in 6.1% of the overall CF population, including 2% of youth and 8% of adults. The odds of PMA were increased sevenfold in patients with CFRD (95% CI 2.5-20, P=0.0002) and 48-fold in patients with both CFRD and organ transplant (95% CI 13-177, P<0.0001). The five patients with PMA in the absence of CFRD or transplant included two youths with presumed benign orthostatic MA and three adults with hypertension. CONCLUSIONS: The spot urine albumin-to-creatinine ratio is specific enough to be a valid screening test for diabetic kidney disease in CFRD.

Fatores de risco para a recidiva da tuberculose / Risk factors for recurrence of tuberculosis

OBJETIVO: Identificar fatores de risco para a recidiva da tuberculose. MÉTODOS: Estudou-se uma coorte de 610 pacientes com tuberculose pulmonar bacilífera inscritos para tratamento entre 1989 e 1994 e curados com o esquema contendo rifampicina, isoniazida e pirazinamida (RHZ). Avaliaram-se os seguintes fatores de risco: idade, sexo, cor, duração dos sintomas, cavitação das lesões, extensão da doença, diabetes melito, alcoolismo, infecção pelo HIV, negativação tardia do escarro, adesão ao tratamento e doses dos fármacos. Para detecção das recidivas, os pacientes foram seguidos por 7,7 ± 2,0 anos, após a cura, pelo sistema de informação da Secretaria Estadual da Saúde do Rio Grande do Sul. Nas análises utilizaram-se os testes t de Student, qui-quadrado ou exato de Fisher e a regressão de Cox. RESULTADOS: Ocorreram 26 recidivas (4,3 por cento), correspondendo a 0,55/100 pessoas-ano. A taxa de recidiva foi de 5,95 e 0,48/100 pessoas-ano, respectivamente, nos pacientes HIV-positivos e nos HIV-negativos (p < 0,0001). Na análise multivariada, a infecção pelo HIV [RR = 8,04 (IC95 por cento: 2,35-27,50); p = 0,001] e o uso irregular da medicação [RR = 6,43 (IC95 por cento: 2,02-20,44); p = 0,002] mostraram-se independentemente associados às recidivas. CONCLUSÕES: A recidiva da tuberculose foi mais freqüente nos pacientes HIV-positivos e naqueles que não aderiram ao tratamento auto-administrado (esquema-RHZ). Pacientes com pelo menos um destes fatores de risco poderão se beneficiar com a implantação de um sistema de vigilância pós-tratamento para detecção precoce de recidivas. Para prevenir a não-adesão ao tratamento da tuberculose, a alternativa seria a utilização de tratamento supervisionado.

OBJECTIVE: To identify risk factors for recurrence of tuberculosis. METHODS: We studied a cohort of 610 patients with active pulmonary tuberculosis who were enrolled for treatment between 1989 and 1994 and cured using a three-drug treatment regimen of rifampin, isoniazid and pyrazinamide (RHZ). The risk factors studied were age, gender, race, duration of symptoms, lesion cavitation, extent of disease, diabetes mellitus, alcoholism, HIV infection, delayed negative sputum conversion, treatment compliance, and medication doses. In order to detect recurrence, the patients were monitored through the Rio Grande do Sul State Healt Department Information System for 7.7 ± 2.0 years after cure. Data were analyzed using the Student's t-test, the chi-square test or Fisher's exact test, and Cox regression models. RESULTS: There were 26 cases of recurrence (4.3 percent), which corresponds to 0.55/100 patients-year. The recurrence rate was 5.95 and 0.48/100 patients-year in HIV-positive and HIV-negative patients, respectively (p < 0.0001). In the multivariate analysis, HIV infection [RR = 8.04 (95 percent CI: 2.35-27.50); p = 0.001] and noncompliance [RR = 6.43 (95 percent CI: 2.02-20.44); p = 0.002] proved to be independently associated with recurrence of tuberculosis. CONCLUSIONS: Recurrence of tuberculosis was more common in HIV-positive patients and in patients who did not comply with the self-administered treatment (RHZ regimen). Patients presenting at least one of these risk factors can benefit from the implementation of a post-treatment surveillance system for early detection of recurrence. An alternative to prevent noncompliance with tuberculosis treatment would be the use of supervised treatment.

Diferenças na apresentação clínico-radiológica da tuberculose intratorácica segundo a presença ou não de infecção por HIV / Differences in the clinical and radiological presentation of intrathoracic tuberculosis in the presence or absence of HIV infection

OBJETIVO: Descrever as diferenças na apresentação clínico-radiológica da tuberculose segundo a presença ou não de infecção por HIV. MÉTODOS: Examinou-se uma amostra consecutiva de 231 adultos com tuberculose pulmonar bacilífera internados em hospital de tisiologia. A presença de infecção por HIV, AIDS e fatores associados foi avaliada e as radiografias de tórax foram reinterpretadas. RESULTADOS: Havia 113 pacientes HIV-positivos (49 por cento). Estes pacientes apresentavam maior freqüência de tuberculose pulmonar atípica (lesões pulmonares associadas a linfonodomegalias intratorácicas), tuberculose de disseminação hemática e tuberculose pulmonar associada a linfonodomegalias superficiais e menor freqüência de lesões pulmonares escavadas do que os pacientes HIV-negativos. Isto também ocorreu entre os pacientes HIV-positivos com AIDS e os HIV-positivos sem AIDS. Não se observaram diferenças entre os pacientes HIV-positivos sem AIDS e os HIV-negativos. Os valores medianos de CD4 foram menores nos pacientes HIV-positivos com linfonodomegalias intratorácicas e lesões pulmonares em comparação aos com lesões pulmonares exclusivas (47 vs. 266 células/mm³; p < 0,0001), nos pacientes HIV-positivos com AIDS em comparação aos HIV-positivos sem AIDS (136 vs. 398 células/mm³; p < 0,0001) e nos pacientes com tuberculose pulmonar atípica em comparação aos com outros tipos de tuberculose (31 vs. 258 células/mm³; p < 0,01). CONCLUSÃO: Há um predomínio de formas atípicas e doença disseminada entre pacientes com imunossupressão avançada. Em locais com alta prevalência de tuberculose, a presença de tuberculose pulmonar atípica ou de tuberculose pulmonar associada a linfonodomegalias superficiais é definidora de AIDS.

OBJECTIVE: To describe the differences in the clinical and radiological presentation of tuberculosis in the presence or absence of HIV infection. METHODS: A sample of 231 consecutive adults with active pulmonary tuberculosis admitted to a tuberculosis hospital were studied, assessing HIV infection, AIDS, and associated factors, as well as re-evaluating chest X-rays. RESULTS: There were 113 HIV-positive patients (49 percent) Comparing the 113 HIV-positive patients (49 percent) to the 118 HIV-negative patients (51 percent), the former presented a higher frequency of atypical pulmonary tuberculosis (pulmonary lesions accompanied by intrathoracic lymph node enlargement), hematogenous tuberculosis, and pulmonary tuberculosis accompanied by superficial lymph node enlargement, as well as presenting less pulmonary cavitation. The same was found when HIV-positive patients with AIDS were compared to those without AIDS. There were no differences between the HIV-positive patients without AIDS and the HIV-negative patients. Median CD4 counts were lower in HIV-positive patients with intrathoracic lymph node enlargement and pulmonary lesions than in the HIV-positive patients with pulmonary lesions only (47 vs. 266 cells/mm³; p < 0.0001), in HIV-positive patients with AIDS than in those without AIDS (136 vs. 398 cells/mm³; p < 0.0001) and in patients with atypical pulmonary tuberculosis than in those with other forms of tuberculosis (31 vs. 258 cells/mm³; p < 0.01). CONCLUSION: Atypical forms and disseminated disease predominate among patients with advanced immunosuppression. In regions where TB prevalence is high, the presence of atypical pulmonary tuberculosis or pulmonary tuberculosis accompanied by superficial lymph node enlargement should be considered an AIDS-defining condition.

Value of diagnostic tools for myocardial ischemia used in routine clinical practice to predict cardiac events in patients with type 2 diabetes mellitus: a prospective study

OBJETIVO: Analisar os testes usados na prática clínica de rotina para diagnóstico de isquemia miocárdica na predição do desenvolvimento de eventos cardíacos em pacientes com diabetes mellitus tipo 2 (DM2). MÉTODOS: A ocorrência de eventos cardíacos (novo infarto do miocárdio [IM], procedimentos de re-vascularização miocárdica, insuficiência cardíaca congestiva, edema agudo de pulmão, morte súbita e morte após IM ou edema pulmonar) foi avaliada prospectivamente em uma coorte de 135 pacientes com DM2 após até 7 anos de acompanhamento. Na condição basal, a doença arterial coronariana (DAC) foi avaliada pelo questionário cardiovascular da OMS, eletrocardiograma de repouso e cintilografia do miocárdio sob stress. RESULTADOS: 48 eventos cardíacos foram observados em 41 pacientes (10,5 eventos/100 pacientes-ano). No modelo de risco proporcional de Cox apenas a presença de sintomas de DAC no questionário cardiovascular da OMS isoladamente (RR= 2,13, 95% CI 1,11­4,07, P= 0,022) ou em combinação com anormalidades no ECG de repouso (RR= 2,03, 95% CI 1,05­3,92, P= 0,034) ou cintilografia do miocárdio (RR= 1,89, 95% CI 1,001­3,57, P= 0,050) predisseram eventos cardíacos, ajustados para a glicemia de jejum, pressão arterial média, índice de massa corporal, doença vascular periférica e nefropatia diabética. CONCLUSÃO: O questionário cardiovascular da OMS, um procedimento simples para o diagnóstico da DAC, é um preditor significativo de eventos cardíacos em pacientes com DM2.

Diabetic nephropathy: diagnosis, prevention, and treatment.

Diabetic nephropathy is the leading cause of kidney disease in patients starting renal replacement therapy and affects approximately 40% of type 1 and type 2 diabetic patients. It increases the risk of death, mainly from cardiovascular causes, and is defined by increased urinary albumin excretion (UAE) in the absence of other renal diseases. Diabetic nephropathy is categorized into stages: microalbuminuria (UAE >20 microg/min and < or =199 microg/min) and macroalbuminuria (UAE > or =200 microg/min). Hyperglycemia, increased blood pressure levels, and genetic predisposition are the main risk factors for the development of diabetic nephropathy. Elevated serum lipids, smoking habits, and the amount and origin of dietary protein also seem to play a role as risk factors. Screening for microalbuminuria should be performed yearly, starting 5 years after diagnosis in type 1 diabetes or earlier in the presence of puberty or poor metabolic control. In patients with type 2 diabetes, screening should be performed at diagnosis and yearly thereafter. Patients with micro- and macroalbuminuria should undergo an evaluation regarding the presence of comorbid associations, especially retinopathy and macrovascular disease. Achieving the best metabolic control (A1c <7%), treating hypertension (<130/80 mmHg or <125/75 mmHg if proteinuria >1.0 g/24 h and increased serum creatinine), using drugs with blockade effect on the renin-angiotensin-aldosterone system, and treating dyslipidemia (LDL cholesterol <100 mg/dl) are effective strategies for preventing the development of microalbuminuria, in delaying the progression to more advanced stages of nephropathy and in reducing cardiovascular mortality in patients with type 1 and type 2 diabetes.

Cellular basis of diabetic nephropathy: II. The transforming growth factor-beta system and diabetic nephropathy lesions in type 1 diabetes.

Transforming growth factor-beta (TGF-beta) may be critical in the development of diabetic nephropathy (DN), and genetic predisposition is an important determinant of DN risk. We evaluated mRNA expression levels of TGF-beta system components in cultured skin fibroblasts (SFs) from type 1 diabetic patients with fast versus slow development of DN. A total of 125 long-standing type 1 diabetic patients were ranked by renal mesangial expansion score (MES) based on renal biopsy findings and diabetes duration. Patients in the highest quintile of MES who were also microalbuminuric or proteinuric (n = 16) were classified as "fast-track" for DN, while those in the lowest quintile who were also normoalbuminuric (n = 23) were classsified as "slow-track" for DN. Twenty-five normal subjects served as control subjects. SFs were cultured in medium with 25 mmol/l glucose for 36 h. SF mRNA expression levels for TGF-beta1, TGF-beta type II receptor (TGF-beta RII), thrombospondin-1, and latent TGF-beta binding protein-1 (LTBP-1) were measured by real-time RT-PCR. LTBP-1 mRNA expression was reduced in slow-track (0.99 +/- 0.38) versus fast-track patients (1.65 +/- 0.52, P = 0.001) and control subjects (1.41 +/- 0.7, P = 0.025). mRNA levels for TGF-beta1, TGF-beta RII, and thrombospondin-1 were similar in the three groups. Reduced LTBP-1 mRNA expression in SFs from slow-track patients may reflect genetically determined DN protection and suggests that LTBP-1 may be involved in the pathogenesis of DN through the regulation of TGF-beta activity.

Hipertiroidismo com fibrilaçäo atrial: é necessário anticoagular todos os pacientes? / Hyperthyroidism with atrial fibrillation: is it necessary to make anticoagulation in all the patients?

O emprego da anticoagulaçao oral em pacientes com hipertiroidismo e fibrilaçao atrial ainda é controverso. O objetivo da presente revisao é propor uma conduta contemporânea sobre a necessidade de anticoagulaçao em pacientes com hipertiroidismo e fibrilaçao atrial, com base no conhecimento atual dos fatores de risco associados ao desenvolvimento de fenômenos troboembólicos. A fibrilaçao atrial ocorre em cerca de 13 a 35 por cento dos pacientes com hipertiroidismo, especialmente entre os pacientes com insuficiência cardíaca e após os 60 anos de idade. Provavelmente, há uma associaçao entre as manifestaçoes cardiovasculares do hipertiroidismo e a doença cardíaca intrínseca. A reversao para o rítmo sinusal ocorre espontaneamente em 60 por cento dos pacientes, usualmente cerca de 3 semanas após ter sindo atingido o eutiroidismo. Alguns estudos observacionais em pacientes com hipertiroidismo sugerem que estes indivíduos sejam mais suscetíveis ao desenvolvimento de fenômenos tromboembólicos. Entretanto, os pacientes com hipertiroidismo nao apresentam qualquer peculiaridade que justifique esta suposta suscetibilidade. Assim, estas observaçoes devem ser analizadas à luz de recentes ensaios prospectivos e randomizados que identificaram os seguintes fatores de risco para o desenvolvimento de acidente vascular cerebral isquêmico em pacientes com fibrilaçao atrial: idade maior que 60 anos; fenômeno tromboembólico prévio; diabete mélito; história de hipertensao arterial sistêmica; presença de insuficiência cardíaca; e, na ecocardiografia, átrio esquerdo aumentado (> 2,5 cm/m2 de superfície corporal) e disfunçao sistólica do ventrículo esquerdo. Embora nao existam estudos prospectivos e randomizados de pacientes com hipertiroidismo e fibrilaçao atrial, sugerimos que a anticoagulaçao oral seja empregada apenas em pacientes que apresentem pelo menos um dos fatores de risco mencionados. Pacientes sem fatores de risco podem ser tratados com ácido acetil salicílico.

Ruído: fator de risco no gênese da hipertensäo arterial? / Noise: a risk fator withe origins of arterial hypertension ?

O ruído ambiental tem sido implicado como um possível agente etiológico na hipertensäo arterial sistêmica. Face a importância deste aspecto ecológico, revisamos a literatura quanto aos efeitos agudos e crônicos da exposiçäo ao estresse sonoro sobre o aparelho cardiovascular, bem como os prováveis mecanismos fisisológicos capazes de participar na gênese destas alteraçöes. Discute-se a associaçäo entre a exposiçäo ao ruído e os aspectos epidemiológicos referentes a este problema, assim como a necessidade de adoçäo de medidas sanitárias capazes de permitir um melhor equacionamento do problema

Simulaçöes clínicas en medicina interna / Clinical simulations in internal medicine

Simulaçöes säo um instrumento didático valioso para o treinamento da tomada de decisöes clínicas, aspecto fundamental na formaçäo médica. O uso do computador pode tornar esse método mais ágil e eficiente. É nosso objetivo implementá-lo nas disciplinas do departamento de Medicina Interna da Faculdade de Medicina da Universidade Federal do Rio Grande do Sul. Com o auxílio de um microcomputador, dezessete simulaçöes clínicas estäo sendo experimentalmente aplicadas em uma turma do sexto semestre cursando a disciplina de Medicina Interna. A experiência inicial näo permite uma avaliaçäo da efetividade do método