These results strongly suggest that the strategy of 'volume control', also when applied with conventional dialysis times, normalizes BP and increases survival of dialysis patients. Cardiomegaly, as evidenced on the chest X-ray despite normal BP, had a strong negative influence on survival. The large majority of the patients had low-normal BP after long periods of treatment and showed the lowest mortality, favouring the view that target BP should be lower than advised by most authors.

The results of this uncontrolled retrospective study suggest that good long-term BP control and a decrease of LVM can be achieved by continuous efforts to control hypervolaemia. The decrease in volume may be even more important than pressure reduction to achieve this goal.

Estimations of proximal tubule sodium reabsorption with the FELi method come closer to direct measurements than any other indirect method. There is little doubt that most lithium reabsorption takes place in the proximal tubules, very likely in proportion to the reabsorption of sodium and water. It is also likely that changes in proximal tubule sodium reabsorption due to changes in volume status are paralleled by changes in proximal tubule lithium reabsorption, at least in the superficial nephrons. Nonetheless, changes in FELi probably do not purely reflect changes in proximal reabsorption, since lithium is also handled beyond the proximal tubules. Acknowledged problems are lithium reabsorption in Henle's loop and in the late distal and collecting tubules. The latter occurs in the rat and the dog, but not or much less in men. Sodium restriction enhances this lithium transport considerably. It is as yet uncertain whether other conditions, such as increased vasopressin activity or lowering of renal perfusion pressure, also influence this transport. Amiloride appears to prevent this reabsorption of lithium. Therefore, this drug can be used in lithium clearance studies whenever unwanted "distal" lithium reabsorption is expected. Lithium reabsorption in Henle's loop forms a greater problem as it cannot be prevented by any drug without influencing proximal tubule reabsorption. It is estimated that about 7% of the filtered lithium (one-tenth of total lithium reabsorption) is normally taken up here, preferentially in deep nephrons. In view of studies with furosemide, this reabsorption probably varies with sodium intake, but the proportion of this variation to that of proximal tubule lithium reabsorption is obscure. This remains an uncertain factor in any circumstance where the lithium clearance method is used. In some conditions the change in FELi may be so large relative to the expected changes in proximal reabsorption, that use of FELi as marker of end-proximal solute delivery seems unjustified. Disproportionately large suppression is likely during mineralo-corticoid-induced volume expansion, and stimulation during prostaglandin synthesis inhibition and vasopressin. Based on observations in these conditions the potential range of lithium reabsorption in the loop of Henle would be 0 to 15% of filtered load. In this review attention was paid mainly to the validity of lithium clearance as a pure "proximal marker". Many of our interpretations suffer from incomplete certainty with respect to the renal effects of tested maneuvers, a problem which is acknowledged.(ABSTRACT TRUNCATED AT 400 WORDS)

The disagreement in the literature concerning the role of aldosterone in the maintenance of potassium homeostasis in chronic renal disease might be partially explained by differences in plasma renin activity (PRA) among individual patients. Therefore, a study was done in 28 selected patients with varying degrees of renal insufficiency whose serum potassium and PRA concentrations were within the normal range. The results indicate that at comparable serum potassium and PRA concentrations, plasma aldosterone is in most instances elevated when creatinine clearance is lower than 50% of normal.

SUMMARY Twenty-three patients with different degrees of renal insufficiency were studied after equilibration on two levels of salt intake. Blood pressure was found to increase after increased salt intake. This blood pressure increase, when related to sodium excretion increase (salt sensttirity index), tended to be larger in patients with a greater loss of kidney function. In fact, the salt sensitivity of blood pressure rose exponentially with tbe decline of the kidney function, which resulted In a linear negative relationship between tbe log of salt sensitivity index and creatinine clearance (r -0.89, p < 0.0001). After increased salt intake, plasma renin activity (PRA) decreased, whereas body-fluid volumes Increased. Concotnitantly, the products of log PRA and extracellular-fluid volume or blood volume decreased (p < 0.005). Weak interrelations were found between increases of body fluid volumes and blood pressure (r -0.49, p < 0.05). When the patients were divided into two groups according to creatinine clearance, Group 2 (creatinlne clearance < 22 ml/mln, n • 13) showed a significantly greater increase of blood pressure for any given expansion of extracellular fluid volume than Group 1 (creatinine clearance > 32 ml/mln, n -9). Moreover, for any given increase in sodium excretion blood volume increased more in Group 2 than in Group 1 (p < 0.03), whereas the increase of extracellular fluid volume was similar in the two groups. Consequently, after increase of salt intake the plasma volume/interstitial fluid volume ratio (PV/IF) tended to decrease in Group 1 and to increase in Group 2. This difference In PV/IF ratio behavior was significant (p < 0.01). A significant interrelation was also found between the salt sensitivity index and change of PV/IF ratio (r =• 0.60, p < 0.01). It is concluded that, with decrease in functioning renal mass, the salt sensitivity of tbe blood pressure increases. This increase in salt sensitivity is accompanied by an increased intra/extravascular-fluld volume ratio after salt loading, which suggests a change of tissue-capillary filtration forces in patients with renal insufficiency.

We studied the effect of standardized ultrafiltration (UF, 2 liters in 60 min) on plasma volume (PV, 131I-albumin space) and its recovery, with special reference to the tissue hydration before UF. Twenty-one UF sessions were performed in 15 patients with endstage renal failure. The PV reduction, which varied considerably, was maximal at the end of UF (range, -0.7 to -21.9%); after that PV recovered reaching a plateau in the second hour after UF. A highly significant negative correlation was found between the interstitial fluid volume (IVF, calculated from 82Br space-PV) and the PV reduction at this stage (r = -0.89, P less than 0.0001). Despite avoidance of major changes in total extracellular fluid in the next 24 hr, a further restoration of PV took place which was partial in subjects with normal tissue hydration, but complete or even excessive in grossly overfilled subjects. This PV repletion was accompanied by an increase in the intravascular mass of albumin (P less than 0.02). The negative correlation between initial IFV and PV change persisted after 24 hr (r = -0.83, P less than 0.0005). In most occasions the blood pressure fell, but only in eight occasions frank hypotension followed. Heart rate remained remarkably unaltered, even during hypotensive episodes. Changes in plasma renin activity followed no uniform pattern. Our findings indicate that the tissue hydration state has a strong influence on changes in PV during fluid removal and the subsequent repletion of PV.

Huang X, Dorhout Mees E, Vos P, Hamza S, Braam B. Everything we always wanted to know about furosemide but were afraid to ask. Am J Physiol Renal Physiol 310: F958 -F971, 2016. First published February 24, 2016 doi:10.1152/ajprenal.00476.2015.-Furosemide is a widely used, potent natriuretic drug, which inhibits the Na ϩ -K ϩ -2Cl Ϫ 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. extracellular fluid volume; natriuresis; renal function; chronic kidney disease; heart failure DIURETICS BLOCKING THE Na ϩ -K ϩ -2Cl Ϫ cotransporter (NKCC) have an important place in the treatment of fluid overload, specifically in the context of kidney disease and heart failure (64). Of the drugs that inhibit the NKCC2 in the loop of Henle (furosemide, bumetanide, torsemide, ethacrynic acid), furosemide is most commonly applied (66) and Ͼ40 million prescriptions are dispensed every year in the USA (66a). However, many uncertainties remain about intrarenal and systemic actions of furosemide, including its two main targets NKCC1 and NKCC2.Clinically, there are a number of undesirable consequences of the use of furosemide, of which the pathophysiological mechanisms have not been sufficiently investigated. Furosemide has been associated with worsening of kidney function in patients treated for volume overload admitted for acute heart failure (104) and even glomerular filtration rate (GFR) ...

We studied the adaptation to early (72 hr) and late (20 days) K loading (400 mmol/day, 4 equal meals every 6 hour) in six healthy humans. Throughout the study, each single K meal was followed by an acute transient rise in plasma K, aldosterone and kaliuresis. "K balance" (urinary K excretion approximately 80% of intake) was achieved in the second 24 hour period of K loading. This was associated with elevated plasma K and aldosterone, slightly negative sodium (Na) balance and stimulated plasma renin activity. At 20 days of K loading Na loss had been compensated. Plasma renin activity and aldosterone had returned to baseline, although the latter kept increasing after each single K meal. Compared to the first K meal, the K meals at 72 hours and 20 days of K loading were followed by more kaliuresis, while the natriuretic effect had disappeared. Abrupt discontinuation of K loading was followed by negative K balance, lasting only 24 hour, and by Na retention, lasting 72 hours. In conclusion, switching to a high K diet in humans is immediately followed by increased renal K excretion, and by Na loss. K excretion increases over a few days, while Na loss is halted. This can be explained by the rise in plasma aldosterone, secondary to elevated plasma K and renin activity. After weeks, renal adaptation forms an additional factor promoting K excretion and preventing natriuresis. The latter appears specifically from the Na retention which occurs after discontinuation of K loading in the absence of persistent aldosterone stimulation.