Treatment of renal congestion by tolvaptan

Abstract

Reduced renal function is associated with increased cardiovascular events and mortality, and chronic kidney disease is a risk factor for heart failure. Conversely, heart failure is a known risk factor for renal dysfunction. Thus, a vicious cycle is formed, mediated by cardio-renal functional correlations, and this cycle is commonly observed in patients with heart failure and exacerbates the prognosis of the disease [1]. Several mechanisms have been reported to be involved in the cardio-renal connection. Notably, vasoconstrictive neurohormones including the renin–angiotensin system, vasopressin and catecholamines are known to play a major role. In heart failure, arterial underfilling stimulates these neurohormones, which induce renal ischemia, hypoxia, and Na retention and enhance volume overload. In this regard, a recent report by Chiba et al. [2] examined the mechanism of the cardio-renal connection using Dahl salt-sensitive rats and a model of hypertensive cardiorenal failure. They conducted a study in which renal hemodynamic changes were measured during the induction of heart failure. Local renal blood flow (RBF) was measured by renal ultrasound, and renal medullary pressure was measured using a fiber-optic pressure sensor. The resistance index and venous impedance index were significantly increased in response to hypertensive cardio-renal failure by a high salt diet, suggesting that renal medullary blood flow was reduced. Due to its vascular and tubular anatomy, the kidney is hypoxic, especially in the renal medulla. The medulla is actively rendered hypoxic by a countercurrent mechanism, in which oxygen diffuses from arteries to veins that run parallel to each other. The oxygen pressure at the deep renal medulla can be as low as 10–20 mmHg [3]. The collecting duct and the thin limb of Henle, which are major tubules in the inner medulla, do not actively transport sodium and thus do not require much oxygen. In contrast, the proximal tubules and the thick ascending limb in the outer medulla actively transport sodium and require large amounts of oxygen, causing the outer medulla to become the most vulnerable region to hypoxia. Na–K–2Cl cotransporters exist in the luminal side of the thick ascending limb, whose activity is dependent on the concentration of sodium, which is pumped out of the tubules by basolateral Na–K ATPases. The Na–K ATPase activity is determined by oxygen-consuming mitochondrial ATP production. In addition, medullary blood flow is only 10% or less of the total RBF, and even small changes in renal medullary blood flow can induce hypoxia in the medulla [4]. Therefore, an imbalance between renal medullary blood flow and oxygen consumption could cause severe hypoxia in the outer medulla. It has been reported that the outer medulla is where a tubulointerstitial injury is initially observed in animal models of ischemic renal diseases, such as hypertension, diabetes and ischemic acute kidney injury [5]. Renal medullary circulation is important in the pathogenesis of cardio-renal failure. Using laser Doppler flowmetry in rats, it has been shown that medullary blood flow, as well as total or cortical blood flow, is not autoregulated during changes in renal arterial perfusion pressure [4]. Thus, reduction of the renal perfusion pressure due to arterial underfilling during heart failure results in the reduction of medullary blood flow and enhances outer medullary ischemia and hypoxia. Renal medullary circulation is also involved in the regulation of Na and fluid volume [4, 5]. A mere 10–30% reduction in medullary blood flow results in increased Na retention in the renal tubules. A reduction of medullary blood flow in heart failure induces further increases in Na retention and volume overload [5]. Moreover, renal venous congestion could also contribute to the pathogenesis of cardio-renal failure [5]. It has been * Takefumi Mori [email protected]