Everything we always wanted to know about furosemide but were afraid to ask.

Furosemide is a widely used, potent natriuretic drug, which inhibits the Na(+)-K(+)-2Cl(-) cotransporter (NKCC)-2 in the ascending limb of the loop of Henle applied to reduce extracellular fluid volume expansion in heart and kidney disease. Undesirable consequences of furosemide, such as worsening of kidney function and unpredictable effects on sodium balance, led to this critical evaluation of how inhibition of NKCC affects renal and cardiovascular physiology. This evaluation reveals important knowledge gaps, involving furosemide as a drug, the function of NKCC2 (and NKCC1), and renal and systemic indirect effects of NKCC inhibition. Regarding renal effects, renal blood flow and glomerular filtration rate could become compromised by activation of tubuloglomerular feedback or by renin release, particularly if renal function is already compromised. Modulation of the intrarenal renin angiotensin system, however, is ill-defined. Regarding systemic effects, vasodilation followed by nonspecific NKCC inhibition and changes in venous compliance are not well understood. Repetitive administration of furosemide induces short-term (braking phenomenon, acute diuretic resistance) and long-term (chronic diuretic resistance) adaptations, of which the mechanisms are not well known. Modulation of NKCC2 expression and activity in kidney and heart failure is ill-defined. Lastly, furosemide's effects on cutaneous sodium stores and on uric acid levels could be beneficial or detrimental. Concluding, a considerable knowledge gap is identified regarding a potent drug with a relatively specific renal target, NKCC2, and renal and systemic actions. Resolving these questions would increase the understanding of NKCCs and their actions and improve rational use of furosemide in pathophysiology of fluid volume expansion.

Diastolic heart failure: a confusing concept.

Descriptions of the pathophysiology of heart failure have gone through a substantial evolution in the last 50 years. It is now recognised that heart failure can occur in the presence and also in the absence of a reduction in left ventricular function. In the former situation, this classically has been described to lead to hypotension and secondary salt and volume retention by the kidneys, further aggravating cardiac function. In the latter, this has been described to lead to pulmonary congestion because of impaired cardiac diastolic filling. These concepts have further evolved in the discrimination of 'acute vascular' versus 'acute congestive' heart failure. The current paper builds the argument from numerous smaller observational studies that irrespective of the clinical presentation of heart failure, fluid congestion is the key. If left ventricular function is preserved, fluid retention is probably due to the inability of damaged kidneys to excrete the large amounts of salt ingested with modern diet. In the extreme of end-stage renal disease requiring haemodialysis, heart failure is frequent, but can be prevented almost entirely by strict volume control. Unfortunately, the absence of systematic studies describing fluid volumes and renal haemodynamic and reabsorptive function in patients with acute heart failure precludes the final proof of our concept. This paper therefore is a strong call for mechanistic research in this area.