A doença renal como fator de risco cardiovascular
Faculdade de Medicina de Botucatu – UNESP - Botucatu, SP
Estima-se que aproximadamente 10% da população estadunidense tenha algum grau de doença renal, ainda que assintomática. Com relação ao Brasil, não há dados a respeito da prevalência da doença renal crônica. Vários estudos evidenciam relação direta e estreita entre grau de disfunção renal e risco cardiovascular. Esse acréscimo de risco cardiovascular, apesar de máximo na insuficiência renal terminal, começa a ser observado a partir de reduções discretas de função renal. Além disso, a presença de lesão renal, mesmo com função renal normal, evidenciada pela presença de proteinúria ou microalbuminúria, também representa potente fator de risco cardiovascular. Atualmente, as principais causas de doenças renais são a nefropatia diabética e a nefrosclerose hipertensiva, aceleradas pelo tabagismo e pela dislipidemia. Assim, seria possível que o aumento do risco cardiovascular entre os renais crônicos fosse secundário ao acúmulo desses fatores de risco clássicos. Entretanto, esses pacientes apresentam freqüência de eventos cardiovasculares superior ao predito pelas equações que levam em conta tais fatores clássicos. Portanto, deve haver mecanismos intrínsecos à lesão renal capazes de acelerar a aterosclerose sistêmica. Dessa maneira, a própria toxicidade urêmica, o aumento do estresse oxidativo, a alteração na cascata de coagulação, alterações lipídicas e hipervolemia têm origem na gênese da aterosclerose precoce, ocorrida nos pacientes com doença renal crônica. Cabe aos clínicos, nefrologistas, especialistas em hipertensão e cardiologistas identificarem esses pacientes através da dosagem de creatinina sérica, urinálise e determinação da microalbuminúria para, mediante terapêutica intensiva, reverter, ao menos em parte, o elevado risco cardiovascular dessa parcela doente da população.
Em 1945, Langendorf e Pirani foram pioneiros em descrever as alterações cardíacas em necropsias de portadores de insuficiência renal crônica. Pela macroscopia, eles observaram acentuada hipertrofia ventricular e, pela microscopia, fibrose e edema intersticial intensos. Nesse estudo, a causa de morte havia sido a própria uremia, tendo em vista que a diálise clínica rotineira não estava disponível1.
Em 1975, Lindner e cols. descreveram elevada prevalência de doença cardiovascular com aterosclerose precoce na primeira coorte longitudinal de pacientes em hemodiálise2. Em 1960, em Seatle, dos 39 pacientes que tinham em média 37 anos de idade, ao iniciarem tratamento por hemodiálise, 23 pacientes (59%) foram a óbito, após 6,5 anos do início do programa. Desses 23,14 (61%) faleceram por doenças cardiovasculares. O risco cardiovascular dessa primeira coorte foi estimado como trinta vezes superior ao obtido na população geral do local de origem. Assim, em razão da terapia renal substitutiva, os portadores de insuficiência renal crônica terminal tiveram prolongamento de sua expectativa de vida, em razão da eliminação da causa imediata de morte por uremia, e passaram a apresentar as doenças cardiovasculares como principal causa de óbito: em idade precoce e em freqüência muito superior à esperada para a população geral.
Calcula-se que existam 19,1 milhões de estadunidenses (11% da população daquele país) com algum grau de doença renal, definida como presença de albuminúria ou filtração glomerular inferior a 60 mL/min, ou seja, creatinina sérica superior a 1,3 mg/dL para mulheres, ou superior a 1,5 mg/dL para homens3. Já os dados do Registro Americano de Diálise e Transplante contabilizam 300 mil renais crônicos em tratamento substitutivo da função renal4. Desse modo, mesmo levando-se em conta o subdiagnóstico e o crescimento esperado da população em diálise daquele país, estima-se que a maior parte dos pacientes com disfunção renal deva falecer antes da necessidade de tratamento renal substitutivo. A morte desses pacientes é devida, principalmente, a causas cardiovasculares, e o risco cardiovascular dos portadores de disfunção renal, ainda que assintomática, é sensivelmente superior ao predito pelas equações de Framingham5. Assim, é importante frisar que é muito mais provável que um portador de disfunção renal venha a morrer de doença cardiovascular do que de insuficiência renal propriamente dita.
Entre os hipertensos, de maneira geral, os dados do
Os resultados do estudo
Ainda mencionando o estudo HOT, a diferença de mortalidade entre os grupos tratados com ou sem aspirina foi mais pronunciada entre os portadores de disfunção renal. Apenas entre os portadores de creatinina basal superior a 1,3 mg/dL houve redução significativa de eventos cardiovasculares com o uso de aspirina. Esse resultado associou-se principalmente ao elevado risco cardiovascular apresentado por esses pacientes com maior benefício potencial14. Já quanto ao nível de pressão considerada ideal, no subgrupo de pacientes com disfunção renal, o controle intensivo da pressão arterial apresentou tendência, não estatisticamente significante, a reduzir o risco cardiovascular de maneira mais pronunciada que entre os pacientes com função renal normal10. Ainda, analisando-se a interação entre tratamento anti-hipertensivo e função renal, no estudo
O significado prognóstico da elevação da creatinina não é uniforme em todos os estratos populacionais. A redução da filtração glomerular mostrou-se fator de risco moderado entre indivíduos de baixo risco cardiovascular17, cresce em valor preditivo entre subgrupos populacionais de maior risco: idosos18, hipertensos6, e tem importância ainda mais intensa entre pacientes com altíssimo risco, ou seja, portadores de doença vascular periférica ou diabetes11, pós-operatórios de revascularização miocárdica cirúrgica19 ou por angioplastia percutânea20, síndromes coronarianas agudas21 e insuficiência cardíaca22. Ou seja, a redução da filtração glomerular apresenta significado nefasto nessas situações clínicas específicas.
Os mecanismos pelos quais a disfunção renal pode levar a doença cardiovascular são múltiplos. Tanto fatores de risco tradicionais como não-tradicionais têm papel na patogênese da doença cardiovascular, nos renais crônicos. Os fatores de risco tradicionais principais são hipertensão arterial, diabetes, hiperuricemia e dislipidemia (principalmente elevação de triglicérides e diminuição de HDL-colesterol, secundários a resistência periférica à ação da insulina, causada pela própria toxicidade urêmica)5. Dentre os fatores de risco não-tradicionais destacam-se variáveis avaliadas rotineiramente entre os renais crônicos, tais como: hiperparatireoidismo e alterações do metabolismo dos íons divalentes23, anemia24 e sobrecarga hidrossalina25,26, bem como variáveis não acessadas de rotina na prática clínica: hiper-homocistinemia27, aumento do estresse oxidativo, disfunção endotelial, alterações lipídicas pouco avaliadas, como a elevação da apolipoproteína(a)28, acúmulo de dimetil arginina assimétrica29, atividade inflamatória prócoagulante30 e comportamento anormal da pressão arterial durante o sono31.
A presença de hipertrofia ventricular esquerda é fator de risco cardiovascular independente que, na hipertensão arterial, imprime ominoso prognóstico. Dentre os portadores de insuficiência renal crônica, mesmo em estágios precoces, há aumento da prevalência da hipertrofia ventricular esquerda, acima do esperado, para o grau de hipertensão25. A prevalência de hipertrofia ventricular acentua-se ainda mais à medida que a disfunção renal progride32. Vários mecanismos concorrem para a patogênese desse crescimento ventricular desproporcional, além do esperado para o grau de hipertensão arterial, tais como a anemia33 e o hiperparatireoidismo34. Nosso grupo evidenciou a importância da retenção de sódio, independentemente do seu efeito hipertensor, no desenvolvimento dessa anormalidade cardíaca dos renais crônicos26.
Há que ressaltar, contudo, que houve, nos últimos anos, crescimento intenso das doenças crônicodegenerativas (hipertensão e diabete melito) como causa de insuficiência renal crônica, e essas, via de regra, são as mesmas que produzem lesão cardiovascular4,35. Portanto, quando a lesão renal do diabetes ou da hipertensão se estabelece, via de regra, já existe a lesão cardíaca correspondente. Dessa maneira, impõe-se a pergunta: a disfunção renal leve é apenas um marcador de dano vascular mais extenso ou a própria insuficiência renal pode ter um papel fisiopatogênico no desenvolvimento das lesões cardiovasculares?
Algumas evidências podem ser pontuadas a favor do papel direto da uremia no desenvolvimento da doença cardiovascular. Estudo que avaliou o tratamento por hemodiálise, durante cerca de quatorze anos, em dezesseis jovens, variando de sete a trinta anos de idade, mostrou que quatorze apresentavam evidência tomográfica de calcificação coronariana, comparando-se a três de sessenta controles normais36. Ademais, obteve-se algum grau de aterosclerose coronariana, em 80% dos casos de uma série de necropsias de crianças falecidas durante tratamento por hemodiálise37. Essa prevalência é evidentemente superior à prevalência de aterosclerose coronariana, na população geral de mesma idade.
Uma segunda evidência epidemiológica forte, a favor da participação da uremia
A detecção de disfunção renal reveste-se de importância fundamental na prática clínica, uma vez que estudos epidemiológicos dos Estados Unidos, como já mencionado, indicam a presença de aproximadamente vinte milhões de norte-americanos com algum dano renal4,35. Ainda, entre os portadores de miocardiopatia, 50% apresentam algum grau de disfunção renal, situação essa em que há evidente subdiagnóstico38. Como já se afirmou antes, a disfunção renal entre miocardiopatas, coronarianos, bem como entre os hipertensos, de modo geral, implica um pior prognóstico. Ainda, entre portadores de insuficiência coronariana, a presença concomitante de doença arterial aterosclerótica renal associa-se a prognóstico sombrio39. Postula-se que esse comportamento pode ser devido à ativação do sistema renina-angiotensina-aldosterona que, invariavelmente, acompanha essa situação clínica.
Há que recordar que não só a disfunção renal, mas a mera lesão renal, avaliada pela presença de microalbuminúria, também se associa a maior risco cardiovascular, de maneira independente da presença de diabetes40,41 ou grau de hipertensão arterial42,43. Em diabéticos, o padrão não "dipper", ou seja, a ausência do descenso fisiológico31 da pressão arterial noturna, mesmo entre diabéticos tipo I normotensos, associa-se à presença de microalbuminúria e, muitas vezes, precede o seu desenvolvimento. A ocorrência de microalbuminúria associa-se tanto à presença de lesões em órgãos-alvo em estudos transversais44,45 como representa um indicador prognóstico adverso em estudos longitudinais, relacionados à mortalidade geral e também cardiovascular40-42. No estudo
Os portadores de microalbuminúria apresentam acúmulo de fatores de risco associados, o que poderia explicar o excesso de mortalidade44; entretanto, assim como ocorre com a disfunção renal assintomática, o risco cardiovascular desses pacientes é superior ao calculado pelas equações preditoras46. Esse excesso de mortalidade cardiovascular, além de refletir maior severidade de lesões de órgãos-alvo, associa-se à presença de disfunção endotelial47 e a alterações inflamatórias48 e dos sistemas fibrinolítico e da coagulação49.
No estudo Life, observou-se que não só a presença de microalbuminúria, no momento inicial, mas também a regressão da microalbuminúria associaram-se à redução do risco cardiovascular41. A regressão da microalbuminúria foi obtida mais freqüente e intensamente nos pacientes que receberam losartan, comparados aos pacientes que receberam atenolol, sugerindo, portanto, a necessidade de moldar o tratamento anti-hipertensivo de acordo com a presença e regressão da microalbuminúria. Nesse sentido, o estudo
O objetivo primário avaliou o papel do irbesartan na evolução da nefropatia diabética no estágio incipiente, definido como a presença de microalbuminúria, para a etapa seguinte, que seria de proteinúria estabelecida. Enquanto 15% do grupo-controle que usava terapêutica anti-hipertensiva convencional, exceto inibidor da ECA ou antagonista da AII, evoluíram para proteinúria, apenas 5% do grupo tratado com a maior dose do irbesartan tiveram a doença piorada. Como desfechos secundários, houve normalização da microalbuminúria, passando, portanto, para normoalbuminúria, também em uma parcela significativa de pacientes tratados com irbesartan. Como a microalbuminúria é fator de risco cardiovascular e marcador de lesão endotelial, a menor ocorrência de eventos cardíacos no grupo tratado com antagonistas da AII, em razão da redução da taxa anormal de excreção de albumina pela urina, reforça o papel de proteção de órgão-alvo dessa classe de anti-hipertensivos. Desse modo, a regressão da microalbuminúria poderia ser considerada um objetivo a ser cumprido, no tratamento do hipertenso.
Assim, o
Apesar dessas recomendações, dados epidemiológicos recentes mostram que portadores de disfunção renal recebem, com menor freqüência, medicações e intervenções cardiovasculares, do que pacientes com filtração glomerular preservada, apesar de que esses mesmos estudos mostram que a utilização dessas medicações e procedimentos associou-se aos mesmos benefícios que entre os pacientes com filtração glomerular normal55.
No tratamento de portadores de insuficiência renal crônica, para obtenção de níveis de pressão arterial adequados é necessário o uso de múltiplas medicações, sendo mandatório o uso de inibidores da enzima conversora e/ou bloqueadores do receptor da angiotensina, por sua ação renoprotetora adicional à ação anti-hipertensiva, e, invariavelmente necessários, os diuréticos, por sua eficácia anti-hipertensiva, nesse subgrupo de pacientes49-52.
Além da redução mais intensa da pressão arterial, outros fatores de risco devem ser controlados, de maneira mais intensa, entre os renais crônicos. Dessa maneira, a hemoglobina A1c deve estar abaixo dos 7%56 e o colesterol de baixa densidade deve ser inferior aos 100 mg/dL57. Os fatores de risco não tradicionais também devem ser abordados com manutenção da hemoglobina entre 11 e 12 mg/dL58, à custa de suplementação criteriosa de ferro e uso de eritropoetina. Os íons divalentes devem ser estritamente controlados com quelantes à base de cálcio ou isentos desse íon, conforme o caso, para evitar calcificações vasculares. O hormônio da paratireóide deve ser controlado com uso parcimonioso de vitamina D59. O uso de aspirina em baixa dose mostrou-se seguro e eficaz nesse subgrupo de pacientes, mormente entre os diabéticos e dislipidêmicos14. Diferentemente do uso de antiinflamatórios não-hormonais, que deve ser fortemente desencorajado, em todos os graus de insuficiência renal60. Por fim, esses pacientes não devem ser preteridos na realização de procedimentos cardiológicos, que devem ser indicados, nos renais crônicos, da mesma maneira que na população geral55.
Rezumindo: a lesão renal, mesmo que assintomática, é situação freqüente e subdiagnosticada; imprime risco cardiovascular elevado ao seu portador e deve ser aces-sada, rotineiramente, em todos os hipertensos, diabéticos, portadores de insuficiência cardíaca conges tiva ou insuficiência coronariana. Quando identificada a anormalidade renal, devem-se empregar intensivamente medidas que visem não só à preservação da função renal, como também a menor progressão da doença cardiovascular60.
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Correspondência: Roberto Jorge da Silva Franco Rua Carlos Guadanini, 1805 18610-120 Botucatu, SP E-mail:
Renal disease as a cardiovascular risk factor
Faculdade de Medicina de Botucatu – UNESP - Botucatu, SP - Brazil
An estimated 10% of the American population has some degree of renal disease, although asymptomatic. In Brazil, no data are available on the prevalence of chronic renal disease. A number of studies show a direct and close relationship between the degree of renal dysfunction and cardiovascular risk. This increased cardiovascular risk, despite being maximal in end-stage renal failure, begins to be noticed with slight declines in renal function. In addition, the presence of renal injury, even with normal renal function, evidenced by proteinuria or microalbuminuria, is also a potent cardiovascular risk factor. At present, the primary causes of renal disease are diabetic nephropathy and hypertensive nephrosclerosis, accelerated by cigarette smoking and dyslipidemia. Hence, increased cardiovascular risk in patients with chronic renal disease may be secondary to the accumulation of these classical risk factors; however, frequency of cardiovascular events in these patients is higher than that predicted by equations that take into account such classical factors. Therefore, there may be mechanisms intrinsic to renal lesion capable of accelerating systemic atherosclerosis. Accordingly, uremic toxicity itself, increased oxidative stress, change in the coagulation cascade, changes in lipid levels and hypervolemia are involved in the genesis of early atherosclerosis in patients with chronic renal disease. It is incumbent on clinicians, nephrologists, hypertension specialists, and cardiologists to identify these patients through urinalysis, serum creatinine measurement, and microalbuminuria screening in order to reduce, through intensive treatment, to revert at least in part, the high cardiovascular risk of that diseased portion of the population.
In 1945, Langendorf and Pirani first described cardiac changes in postmortem examinations performed on patients with chronic renal failure. By gross analysis, these authors identified marked ventricular hypertrophy and, by microscopy, severe fibrosis and interstitial edema. In their study, uremia itself had been the cause of death, since routine dialysis was not available at that time.1
In 1975, Lindner et al. described a high prevalence of cardiovascular disease with early atherosclerosis in the first longitudinal cohort study of patients in hemodialysis.2 In 1960, in Seattle, of the 39 patients who were, on average 37 years old by the time they started hemodialysis therapy, 23 (59%) died 6.5 years after joining the program. Of these 23, 14 (61%) died from cardiovascular diseases. Cardiovascular risk for this first cohort was estimated to be 30 times greater than that of the local general population. Thus, because of renal replacement therapy, life expectancy of patients with end-stage chronic renal failure increased, once the immediate cause of death from uremia was eliminated, and cardiovascular diseases became the main cause of death: at an early age and at a much higher frequency than expected for the general population
About 19.1 million Americans (11% of the US population) have some degree of renal disease, defined by the presence of albuminuria or glomerular filtration rate below 60 mL/min, that is to say, serum creatinine above 1.3 mg/dL for women or above 1.5 mg/dL for men.3 On the other hand, according to data from the American Registry of Dialysis and Transplantation, 300,000 chronic renal disease patients are under renal replacement therapy.4 Therefore, even taking into account both underdiagnosis and the predicted growth of the dialysis population in that country, most patients with renal dysfunction are expected do die before they require renal replacement therapy. In these patients, death is mainly due to cardiovascular causes, and cardiovascular risk for patients with renal dysfunction, although asymptomatic, is significantly higher than that predicted by the Framingham equations5. It should be emphasized that a patient with renal dysfunction is much more likely to die from cardiovascular disease than from actual renal failure.
Data from the Hypertension Detection and Follow-up Program (HDFP) were the first to show a correlation between serum creatinine and cardiovascular mortality among hypertensive patients. This association was independent of other cofactors evaluated: gender, race, blood pressure, diabetes or degree of obesity.6,7 Creatininemia thus emerged as a major predictor of cardiovascular disease.
The Hypertension Optimal Treatment (HOT) trial results have corroborated the relationship between creatininemia and cardiovascular risk among hypertensive patients under drug therapy. In that study, serum creatinine was the most powerful risk predictor of the assessed factors.7 Data from many other cohorts consistently point to renal dysfunction as an important cardiovascular risk factor.8-13
With further regard to the HOT trial, the difference in mortality between groups treated with and without aspirin was more significant in patients with renal dysfunction. Only among patients with baseline serum creatinine above 1.3 mg/dl was there a significant reduction of cardiovascular events in which aspirin was used. This result was associated especially to the high cardiovascular risk showed by these patients with more potential benefit.14 On the other hand, as far as optimal blood pressure is concerned, intensive blood pressure control was found to be more likely to reduce cardiovascular risk in the subgroup of patients with renal dysfunction than in the subgroup of patients with normal renal function, although this trend was not statistically significant.10 Additionally, the analysis of interaction between anti-hypertensive therapy and renal function in the Systolic Hypertension Elderly Program (SHEP) trial revealed that treatment of isolated systolic blood pressure was more effective in preventing cardiac events in older patients with renal dysfunction than in those with normal renal function.15 Both in the Hypertension Detection and Follow-up Program (HDFP)6 and in the Modification of Diet in Renal Disease (MDRD)16 trial, renal protection was found to be enhanced in patients with more effective blood pressure control. Thus, it seems that patients with renal dysfunction should be managed with tight blood pressure control and aspirin, not only to provide renal protection, but also to optimize cardioprotection.
Prognostic significance of increased serum creatinine levels is not consistent in all population strata. Decline in glomerular filtration rate has been proven to be a moderate risk factor in patients with low risk for cardiovascular disease,17 with greater predictive value in subgroups at higher risk, such as elderly and hypertensive subjects,6 and even greater in patients at extremely high risk, that is, patients with peripheral vascular disease or diabetes,11 acute coronary syndromes,21 heart failure,21 CABG19 or percutaneous angioplasty post-operatives.20 In other words, decline in glomerular filtration rate has deleterious consequences in these specific situations.
The mechanisms by which renal dysfunction may lead to cardiovascular disease are multiple. Traditional and non-traditional risk factors alike play a role in the pathogenesis of cardiovascular disease in patients with chronic renal disease. Primary traditional risk factors include arterial hypertension, diabetes, hyperuricemia, dyslipidemia (particularly increased triglyceride levels and decreased HDL-cholesterol levels, secondary to peripheral resistance to insulin action, caused by uremic toxicity itself). Non-traditional risk factors include variables routinely assessed in patients with chronic renal disease, such as: hyperparathyroidism and altered divalent ion metabolism,23 anemia,24 and hydrosaline overload,25,26 together with variables not routinely assessed in clinical practice: hyperhomocystinemia,27 increased oxidative stress, endothelial dysfunction, changes in lipid levels not frequently assessed, such as apolipoprotein(a),28 build-up of asymmetric dimethyl arginine,28 inflammatory procoagulant activity,30 and abnormal behavior of blood pressure during sleep.31
Left ventricular hypertrophy is an independent cardiovascular risk factor that, in the arterial hypertension setting, portends an ominous prognosis. A higher prevalence of left ventricular hypertrophy is found among patients with chronic renal failure, even in early stages, greater than would be expected for the degree of hypertension.25 This prevalence becomes even higher as renal dysfunction progresses.32 A number of mechanisms contribute to the pathogenesis of this disproportionate ventricular enlargement, beyond that expected for the degree of arterial hypertension, such as anemia33 and hyperparathyroidism.34
Our group showed the important role played by sodium retention, regardless of its hypertensive effect, in the development of this cardiac abnormality in patients with chronic renal disease.26
Conversely, it should be noted that recent years have witnessed a sharp increase in chronic degenerative diseases (hypertension and diabetes mellitus) as cause of chronic renal failure, the same conditions that usually produce cardiovascular lesion.4,35 Therefore, by the time diabetes or hypertension renal lesion develops, a corresponding heart lesion usually already exists. Thus, a question rises as to whether mild renal dysfunction is only a marker of more extensive vascular damage or the very renal failure may be involved in the pathophysiology of cardiovascular lesions.
Some evidence points to a direct role of uremia in the development of cardiovascular disease. A study evaluating hemodialysis therapy during about 14 years in 16 young people, ages ranging from 7 to 30, demonstrated that 14 patients showed tomographic evidence of coronary artery calcification, compared to 3 out of 60 normal controls.36 Moreover, some degree of coronary atherosclerosis was found in 80% of the cases of a series of autopsies performed on children who died during hemodialysis treatment.37 This prevalence is clearly higher than that of coronary atherosclerosis in the general population of the same age.
A second strong piece of epidemiological evidence supporting that uremia "per se" is implied in the acceleration of atherosclerotic process comes from a series of patients who underwent coronary angiography. Among them, patients with increased creatinine levels were twice as likely to experience a coronary event. This heightened risk was independent of other comorbidities, including the angiographic pattern of coronary disease.13
Detection of renal dysfunction is of utmost importance in clinical practice, for epidemiological studies in the United States, as already stated, suggest that approximately 20 million Americans have some degree of renal injury.4,35 Additionally, 50% of cardiomyopathic patients show some degree of renal dysfunction, which often goes underdiagnosed.38 As previously mentioned, renal dysfunction in patients with cardiomyopathy, coronary artery disease, and hypertension usually carries a worse prognosis. Patients with concomitant coronary insufficiency and renal artery atherosclerotic disease also have poor prognosis.39 It has been postulated that this behavior may be due to the activation of the reninangiotensin-aldosterone system which invariably follows this clinical condition.
It should be kept in mind that not only renal dysfunction, but also mere renal injury, identified by microalbuminuria, is associated with increased cardiovascular risk, regardless of the presence of diabetes40,41 or the degree of arterial hypertension.42,43
In diabetics, the "non-dipper" pattern, that is, the lack of the physiological drop in nocturnal blood pressure,31 even among normotensive type I diabetics, is associated with microalbuminuria and often precedes its development. In cross-sectional studies44,45 microalbuminuria is associated with target-organ damages, and in longitudinal studies represents an indicator of adverse prognosis regarding both general and cardiovascular mortality.40-42 In the Heart Outcomes Prevention Evaluation (HOPE) trial, microalbuminuria was associated with a 61% increase in cardiovascular risk and with a doubling of all-cause mortality.40
Patients with microalbuminuria have an accumulation of associated risk factors, which may explain this excess mortality44; nonetheless, as with asymptomatic renal dysfunction, these patients' cardiovascular risk is higher than that calculated by the predictive equations.46 In addition to reflecting increased severity of target-organ damage, this excess cardiovascular mortality is associated with endothelial dysfunction47 and inflammatory changes,48 as well as changes in the coagulation and fibrinolytic systems.49
In the Life trial, not only the presence of baseline microalbuminuria, but also regression of microalbuminuria was associated with a decline in cardiovascular risk.41 Losartan was more effective than atenolol in promoting microalbuminuria regression, thus suggesting that anti-hypertensive treatment be tailored based on the presence of microalbuminuria regression. In this sense, the Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria (IRMA II) was the first trial to study50 the class of AII antagonists in secondary prevention of nephropathy. The primary endpoint was to evaluate the role of irbesartan in the progression from incipient diabetic nephropathy, defined as the presence of microalbuminuria, to the next stage, namely, overt proteinuria. While 15% of the patients in the control group receiving conventional anti-hypertensive therapy, except ACE inhibitors and AII antagonists, progressed to proteinuria, only 5% of the patients receiving the highest dose of irbesartan had their condition worsened. As the secondary endpoint, microalbuminuria was normalized, reverting, therefore, to normoalbuminuria, in a significant number of patients treated with irbesartan. As microalbuminuria is both cardiovascular risk and marker of endothelial damage, the lower rate of cardiac events in the group treated with AII antagonists, due to decreased rates of abnormal urinary albumin excretion, stress the role of this anti-hypertensive class on target-organ protection. Regression of microalbuminuria may, therefore, be considered a goal to be achieved in the treatment of hypertensive patients.
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) highlights renal dysfunction as a major cardiovascular risk and emphasizes the importance of identification and tighter control of blood pressure in this subgroup of patients, and thus recommend a BP goal of 130/80 mm Hg.51 The European Society of Hypertension/ European Society of Cardiology guidelines recognizes mild renal dysfunction as target-organ lesion and classify these patients as being at high risk for cardiovascular disease.52 In 1988, the National Kidney Foundation (NKF) Task Force on Cardiovascular Disease in Chronic Renal Disease recommended that patients with chronic renal disease be considered in the highest-risk group for their treatment design.53 Based on results from the MDRD, the IV Brazilian Guidelines recommend BP levels of 120/75 mm Hg in patients with diabetic nephropathy and proteinuria above 1.0 g/24h and in patients with general nephropathy and proteinuria above 3.0 g /24h54.
In spite of these recommendations, recent epidemiological data show that patients with renal dysfunction receive cardiovascular medications and interventions less frequently than patients with preserved glomerular filtration rate, although these very studies demonstrate that the use of these medications and procedures are associated with the same benefits obtained by patients with normal glomerular filtration.
Patients with chronic renal failure require multiple drug therapy if adequate blood pressure levels are to be achieved, and the use of angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin-receptor blockers (ARBs) are mandatory owing to their renoprotective action, in addition to their anti-hypertensive effect. Diuretics are also invariably necessary, because of their anti-hypertensive effectiveness in this subgroup of patients.49-52
Besides greater reduction in blood pressure, other risk factors should be tightly controlled in these patients. Accordingly, hemoglobin A1c levels should be below 7%56 and low-density lipoprotein cholesterol levels, below 100 mg/dL57. Non-traditional risk factors should be addressed as well, by maintaining hemoglobin between 11 and 12 mg/dL58 through meticulous iron supplementation and erythropoietin. Divalent ions should be strictly controlled with calcium chelators or calcium-free chelators, according to the case, to prevent vascular calcifications. Parathyroid hormone levels should be regulated with vitamin D used parsimoniously.59 Low-dose aspirin proved to be safe and effective in this subgroup of patients, particularly diabetics and dyslipidemics.14 The use of non-hormonal anti-inflammatory drugs, though, should be strongly discouraged in all degrees of renal failure.60 Finally, these patients should be considered for cardiac procedures, which should be indicated for patients with chronic renal disease and the general population alike.55
In sum, renal injury, even if asymptomatic, is a common condition that tends to be underdiagnosed; it carries high cardiovascular risk and should be routinely assessed in all patients with hypertension, diabetes, congestive heart failure, or coronary insufficiency. If a renal abnormality is found, appropriate measures should be taken vigorously aiming not only to preserve renal function, but also prevent cardiovascular disease progression.
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33. Zehnder C, Zuber M, Sulzer M et al. Influence of long-term amelioration of anemia and blood pressure control on left ventricular hypertrophy in hemodialyzed patients. Nephron 1992; 61: 21-5.