Postobstructive diuresis. Studies in a dialyzed patient with a solitary kidney

Urinary excretion was studied in a volume-expanded, dialyzed patient who experienced a profound diuresis after passage of a uric acid calculus which had obstructed the ureter of his solitary horseshoe kidney. Natriuresis (23 per cent of the filtered load of sodium at peak flow) was accompanied by massive urinary losses of water, potassium, magnesium, calcium, bicarbonate, phosphate and uric acid. The data suggest that inhibition of proximal tubular reabsorptive processes was the major factor producing diuresis. Persistent free water clearance and initial potassium secretion indicate that the function of the distal tubule was largely intact. This diuretic pattern in association with retained ability to modulate sodium excretion after completion of diuresis suggests that volume expansion was the primary cause of blockade to proximal tubular reabsorption. Recommendations are made for the clinical management of the patient with diuresis after relief of obstruction.     

Reduced drug elimination in congestive heart failure: Studies using aminopyrine as a model drug

Aminopyrine disposition was studied in 11 patients with congestive heart failure (CHF) and 15 control patients. The aminopyrine metabolic clearance rate was 29.7 ± 7.1 ml/min (mean ± SEM) in the patients with CHF and 125.1 ± 5.7 ml/min (mean ± SEM) in the control patients (p < 0.01). The aminopyrine breath test was 2.6 ± 0.4 per cent (mean ± SEM) in the patients with CHF and 5.6 ± 0.3 per cent (mean ± SEM) in the control subjects (p < 0.01). Probably due to fluid retention in CHF, the apparent volume of distribution of aminopyrine increased to 63.3 ± 4.9 liters (mean ± SEM) in patients with CHF from 43.1 ± 1.9 liters (mean ± SEM) in control patients, thereby further impairing aminopyrine elimination in patients with CHF (p < 0.01). The aminopyrine breath test was measured in a group of eight patients before treatment for an acute episode of CHF and seven to 10 days after initiation of therapy: in each patient clinical improvement was associated with an increased aminopyrine breath test, mean values of aminopyrine breath test increasing from 2.8 per cent before treatment to 5.2 per cent after initiation of treatment (p < 0.01). These results suggest that in patients with CHF hepatic drug-metabolizing activity is impaired, and the volume of distribution of drugs is increased, with consequent retardation in rates of drug elimination.     

Body fluid homeostasis in congestive heart failure and cirrhosis with ascites

The urinary excretion of salt and water in man is regulated by a variety of renal and extrarenal mechanisms that respond to changes in dietary sodium intake as well as to alterations in the holding capacity of the vascular and interstitial compartments. Changes in extracellular fluid volume are detected by volume sensors located in the intrathoracic vascular bed, the kidney and other organs. These sensing mechanisms gauge the adequacy of intravascular volume relative to capacitance at various sites within the circulation. Congestive heart failure and cirrhosis with ascites are two disease states of man in which a hemodynamic disturbance within a given circulatory subcompartment is perceived by these sensing mechanisms and results in renal sodium retention. While the primary disturbance in both of these conditions originates outside the kidney, a variety of renal effector mechanisms respond to the perceived circulatory disturbance and result in enhanced tubule reabsorption of salt and water. These effector mechanisms involve physical adjustments in renal microvascular hemodynamics, tubule fluid composition and flow rate and transtubular ion gradients. These in turn are partially regulated by a variety of neural and humoral pathways including the renin-angiotensin-aldosterone axis, prostaglandins and kinins.     

Volume of the extracellular liquid and renal function during short-term administration of angiotensin converting enzyme inhibitors in essential hypertension

Short term angiotensin converting enzyme inhibition may induce a transient salt and water retention in patients with hypertension or heart failure. To verify the glomerular and tubular effects of short term converting enzyme inhibition, thirteen patients with mild to moderate essential hypertension (WHO I-II) were treated orally either with perindopril (4 mg o.d.) or captopril (25 mg b.i.d.) for one week. Both drugs reduced supine mean blood pressure significantly (p less than 0.01) (perindopril from 126 +/- 11 to 108 +/- 7 mmHg, mean +/- SD, and captopril from 132 +/- 12 to 121 +/- 16). Plasma volume (radio-iodinated albumin space) was unchanged while mean extracellular fluid volume (inulin space) increased although not significantly (from 5.05 +/- 1.32 l/sqm to 5.71 +/- 2.21 with perindopril and from 4.96 +/- 2.6 to 5.6 +/- 1.7 with captopril). Sodium clearance decreased (from 1.4 +/- 0.6 to 1.1 +/- 0.5 ml/min 1.73 sqm with perindopril, p less than 0.05, and from 0.97 +/- 0.44 to 0.88 +/- 0.51 with captopril, n.s.). In 9 patients (6 on captopril and 3 on perindopril) extra-cellular fluid volume increased simultaneously with reduction in glomerular filtration rate and in proximal tubule sodium re-absorption as well as an increase in distal tubule sodium reabsorption. In these patients the changes in proximal and distal tubule sodium reabsorption were significantly (p = 0.05) different from those of the patients with no extra-cellular fluid expansion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Disorders of proximal nephron function

The proximal nephron is responsible for reabsorbing 80 to 99 percent of several filtered solutes, including amino acids, glucose and bicarbonate. Separate, high-affinity sodium co-transport mechanisms are used. Increasing luminal concentration of each of these solutes stimulates its active transcellular reabsorption until there is saturation. Slightly less than half of the filtered chloride is reabsorbed, partly by passive mechanisms that are linked to the reabsorption of organic solutes and bicarbonate, as well as by less well defined independent cellular and/or paracellular mechanisms that appear to be sensitive to transepithelial osmotic pressure gradients. Proximal tubule reabsorption is isosmotic and isonatric, and about 50 to 60 percent of the filtered sodium and water is reabsorbed.Disorders of proximal nephron function include conditions in which luminal, cellular and/or peritubular factors affecting reabsorption are altered. Clinical disorders caused by modification of theluminal reabsorptive determinants include conditions in which tubular flow rate is increased or luminal composition is altered, as when non-reabsorbable solutes (mannitol) are filtered or when reabsorbable solutes (glucose) are filtered in concentrations exceeding their tubular transport capacity. Other disorders occur due to loss of affinity or capacity of thecellular active transport systems for specific solutes, such as amino acids (renal aminoacidurias), glucose (renal glycosurias) and bicarbonate (proximal renal tubular acidosis), or for all solutes (Fanconi syndrome). Finally, disorders due to changes in theperitubular factors affecting reabsorption include states of altered peritubular Starling forces or pH, which modify sodium chloride or sodium bicarbonate reabsorption, respectively.     

The kidney in congestive heart failure: ‘are natriuresis,sodium, and diuretics really the good,the bad and the ugly?’

This review discusses renal sodium handling in heart failure. Increased sodium avidity and tendency to extracellular volume overload, i.e. congestion, are hallmark features of the heart failure syndrome. Particularly in the case of concomitant renal dysfunction, the kidneys often fail to elicit potent natriuresis. Yet, assessment of renal function is generally performed by measuring serum creatinine, which has inherent limitations as a biomarker for the glomerular filtration rate (GFR). Moreover, glomerular filtration only represents part of the nephron's function. Alterations in the fractional reabsorptive rate of sodium are at least equally important in emerging therapy‐refractory congestion. Indeed, renal blood flow decreases before the GFR is affected in congestive heart failure. The resulting increased filtration fraction changes Starling forces in peritubular capillaries, which drive sodium reabsorption in the proximal tubules. Congestion further stimulates this process by augmenting renal lymph flow. Consequently, fractional sodium reabsorption in the proximal tubules is significantly increased, limiting sodium delivery to the distal nephron. Orthosympathetic activation probably plays a pivotal role in those deranged intrarenal haemodynamics, which ultimately enhance diuretic resistance, stimulate neurohumoral activation with aldosterone breakthrough, and compromise the counter‐regulatory function of natriuretic peptides. Recent evidence even suggests that intrinsic renal derangements might impair natriuresis early on, before clinical congestion or neurohumoral activation are evident. This represents a paradigm shift in heart failure pathophysiology, as it suggests that renal dysfunction—although not by conventional GFR measurements—is driving disease progression. In this respect, a better understanding of renal sodium handling in congestive heart failure is crucial to achieve more tailored decongestive therapy, while preserving renal function.     

Nephron sites of the natriuretic effect of intrarenal infusion of atrial natriuretic peptide in the rat

Since renal mechanisms by which ANP induces a natriuresis remain unclear, the effects of the infusion of 0.03 micrograms/min/kg body weight of rANP 1-28 into the right renal artery (via a very thin catheter inserted into the suprarenal artery) were studied in anesthetized rats using lithium clearance to monitor proximal tubular function. Intrarenal ANP did not cause changes in arterial pressure and hematocrit, nor in contralateral kidney handling of sodium. Its natriuretic effect on the right kidney resulted from an increase in the filtered load of sodium and from a decrease in reabsorption in the distal segments of the nephron. Proximal tubule sodium reabsorption increased in proportion to the filtered load.     

The mechanism of hypocalciuria with NaCl cotransporter inhibition

Thiazide diuretics are used to prevent the recurrence of calcium-containing kidney stones. The ability of these drugs to reduce urinary calcium excretion has a key role in this process. Although studies have shown a reduction in the recurrence rate of calcium-containing stones in patients treated with thiazides, whether hypocalciuria results from increased calcium reabsorption in the proximal or distal nephron is still unclear. When extracellular fluid volume is considerably reduced, the proximal tubule is likely to have a major role in thiazide-induced hypocalciuria. This process frequently occurs when high doses of thiazides and sodium restriction are prescribed for the treatment of kidney stone disease. The distal tubule is predominantly involved in NaCl cotransporter inhibition-induced hypocalciuria when the extracellular fluid volume is not reduced, a clinical scenario observed in patients with Gitelman syndrome. In this Perspectives article, we discuss the evidence supporting the hypocalciuric effects of NaCl cotransporter inhibition in the proximal and distal nephron.     

Effects of vasodilators on pulmonary hemodynamics and gas exchange in left ventricular failure

Nitroprusside (NP) has been shown to improve left ventricular function in patients with congestive heart failure, but despite an increased cardiac output and decreased pulmonary capillary pressure, arterial oxygen tension (P_aO₂) may fall. In order to determine the mechanism of this hypoxemia, and to determine if similar effects occur with non-parenteral vasodilators, hemodynamic, respiratory, and blood gas responses to NP, hydralazine (H), and hydralazine combined with isiosorbide dinitrate (H+N) were studied in 10 patients with left ventricular failure. At the dosages used, all three drug regimens increased cardiac output equivalently, but pulmonary vascular responses differed. NP and H+N decreased mean pulmonary artery pressure, pulmonary wedge pressure, and pulmonary arteriolar resistance, while H did not. NP decreased P_aO₂ by 10.4 mm. Hg (p < .01) and H+N decreased it by 5.3 mm. Hg (p < .06) while H did not alter P_aO₂. Arteriolar-alveolar oxygen gradient increased with NP (150 ± 39 per cent, p < .01) and with H+N (73 ± 23 per cent, p < .01) but not H alone (51 ± 16 per cent). Similarly, per cent change in venous admixture increased on NP (28.7 ± 3.3 to 38.5 ± 3.1 per cent, p < .01) and H+N (28.1 ± 3.3 to 36.8 ± 3.5 per cent, p < .01) but not H alone (28.1 ± 3.3 to 31.5 ± 4.1 per cent). There was no increase in arterial carbon dioxide tension or change in pulmonary function studies with any of the drugs. Due to the increase in cardiac output, oxygen delivery index (cardiac output times arterial oxygen content) increased with each regimen despite the changes in P_aO₂. Changes in arteriolar-alveolar oxygen gradient correlate with the changes in pulmonary arteriolar resistance. Thus vasodilators which have prominent pulmonary vascular effects can decrease P_aO₂ in patients with congestive heart failure, and this effect is most likely due to increasing ventilation-perfusion inequities.     

The role of angiotensin II-stimulated renal tubular transport in hypertension

The kidney contains a renin-angiotensin system that appears to regulate systemic blood pressure. Angiotensin II (Ang II) has stimulatory effects on sodium transport in multiple nephron segments via binding to plasma membrane AT1 receptors. In the proximal tubule, Ang II production is substantial. The stimulatory effect of Ang II on proximal sodium transport is enhanced by renal nerves, and is associated with internalization of apical and basolateral receptors. In the cortical collecting duct, AT1 receptors stimulate transport through apical sodium channels, and in the inner medulla, urea transport is enhanced by Ang II, contributing to increased sodium and water reabsorption. AT1 receptors may also be linked to increased expression of certain tubular sodium transporters. In contrast to the stimulatory effects of AT1 receptors on sodium transport, AT2 receptors expressed in the adult kidney are linked to increased urinary sodium excretion and decreased blood pressure. This suggests that renal tubular AT1 receptor activation serves as a protective mechanism to increase sodium reabsorption and blood pressure when extracellular fluid volume is threatened, whereas AT2 receptors dampen this response. The interplay between these two receptor pathways in the kidney could have significant effects on long-term blood pressure control.     

Role of physical and neuroendocrine factors in proximal electrolyte reabsorption

Isotonic reabsorption by the proximal tubule is mediated by an active transport process that is subject to physiologic control mechanisms. One school of thought proposes that the primary, and perhaps overriding, variables regulating proximal transport are physical factors (oncotic and hydrostatic pressures) in the peritubule environment. However, recent data indicate that membrane permeability is an important variable that must be considered when evaluating the regulatory role of physical factors. Such changes in membrane permeability could be the mechanism by which certain hormones regulate reabsorption by the proximal tubule. Hormones effecting sodium transport per se, such as aldosterone, do not have any effect on proximal reabsorption. However, hormones, such as parathyroid hormone, which have a primary effect on an anion reabsorption, specifically bicarbonate and phosphate, are effective in regulating proximal reabsorption. It is suggested that the physiologic regulation of isotonic reabsorption by the proximal tubule is mediated by hormonal regulation of these anions.     

Suppression of the renin-angiotensin system by intravenous digoxin in chronic congestive heart failure

Recent studies have demonstrated that therapy with digitalis preparations may be of inconsistent benefit in the treatment of chronic congestive heart failure. One explanation may be a varying effect on vasoconstrictor hormones, as digoxin has been shown to suppress plasma renin activity in normal and hypertensive persons. Therefore, the effect of short-term digoxin administration on plasma renin activity and plasma aldosterone in six patients with compensated, severe, chronic congestive heart failure was evaluated. Intravenous administration of digoxin (0.50 mg) resulted in a reduction of plasma renin activity from 4.3 ± 0.9 to 2.0 ± 0.9 ng/ml per hour and plasma aldosterone from 34 ± 16 to 14 ± 6 ng/dl (both p < 0.05). Maximal response occurred at three hours after administration, with return to baseline by seven hours. Therefore, evaluation of the role of digitalis in chronic heart failure requires consideration of its direct or indirect effect on angiotensin-mediated vasoconstriction and aldosterone-mediated sodium retention, as well as other neurohormonal mechanisms of vasoconstriction.     

Use of diuretics in the treatment of ascites in patients with cirrhosis

The cirrhotic patient with ascites has an increased tubular reabsorption of sodium. Diuretic therapy allows an urinary loss of sodium. The strongest diuretics which inhibit sodium reabsorption in the ascending limb of the loop of Henle (like furosemide) are not the most effective in cirrhotic patients; indeed the increased load of sodium arriving in the distal part of the tubule is reabsorbed because of hyperaldosteronism. Potassium-sparing diuretics, like spironolactone, which act beyond the sites of reabsorption of most of the filtered sodium, are mostly effective when combined with other diuretics which impair sodium reabsorption more proximally. We propose to treat ascites by: 1. Sodium restriction (maximum: 60 mmol per day); 2. Spironolactone 100 to 500 mg per day, combined with furosemide 40 to 200 mg per day if spironolactone does not induce a natriuretic effect.     

Hyperosmolal crisis following infusion of hypertonic sodium chloride for purposes of therapeutic abortion

Transabdominal injection of 250 ml of 23.4 per cent sodium chloride for purposes of inducing abortion during the 18th week of gestation in a 15 year old girl was followed by acute cerebral, cardiac, respiratory and renal failure. Widespread organic damage was attributable to intravascular injection or rapid intravascular absorption of the hypertonic sodium chloride, with consequent expansion of intravascular volume and cellular dehydration. A marked reduction in colloid osmotic pressure was associated with persistent pulmonary edema after reversal of congestive heart failure. A favorable course followed volume repletion, digitalization, administration of corticosteroids, mechanical ventilation and peritoneal dialysis. Except for a minor cerebral deficit that persisted for approximately three months, there was no residual organic impairment.     

Effects of the peroxisome proliferator-activated receptor (PPAR)-γ agonist pioglitazone on renal and hormonal responses to salt in diabetic and hypertensive individuals

Aims/hypothesis  

Glitazones are powerful insulin sensitisers prescribed for the treatment of type 2 diabetes. Their use is, however, associated with fluid retention and an increased risk of congestive heart failure. We previously demonstrated that pioglitazone increases proximal sodium reabsorption in healthy volunteers. This study examines the effects of pioglitazone on renal sodium handling in individuals prone to insulin resistance, i.e. those with diabetes and/or hypertension.     

Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition

Healthy kidneys filter ～160 g/day of glucose (～30% of daily energy intake) under euglycaemic conditions. To prevent valuable energy from being lost in the urine, the proximal tubule avidly reabsorbs filtered glucose up to a limit of ～450 g/day. When blood glucose levels increase to the point that the filtered load exceeds this limit, the surplus is excreted in the urine. Thus, the kidney provides a safety valve that can prevent extreme hyperglycaemia as long as glomerular filtration is maintained. Most of the capacity for renal glucose reabsorption is provided by sodium glucose cotransporter (SGLT) 2 in the early proximal tubule. In the absence or with inhibition of SGLT2, the renal reabsorptive capacity for glucose declines to ～80 g/day (the residual capacity of SGLT1), i.e. the safety valve opens at a lower threshold, which makes it relevant to glucose homeostasis from day-to-day. Several SGLT2 inhibitors are now approved glucose lowering agents for individuals with type 2 diabetes and preserved kidney function. By inducing glucosuria, these drugs improve glycaemic control in all stages of type 2 diabetes, while their risk of causing hypoglycaemia is low because they naturally stop working when the filtered glucose load falls below ～80 g/day and they do not otherwise interfere with metabolic counterregulation. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. Because SGLT2 reabsorbs sodium along with glucose, SGLT2 blockers are natriuretic and antihypertensive. Also, because they work in the proximal tubule, SGLT2 inhibitors increase delivery of fluid and electrolytes to the macula densa, thereby activating tubuloglomerular feedback and increasing tubular back pressure. This mitigates glomerular hyperfiltration, reduces the kidney’s demand for oxygen and lessens albuminuria. For reasons that are less well understood, SGLT2 inhibitors are also uricosuric. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.     

Assessment of proximal tubular sodium reabsorption during water diuresis in patients with heart disease

In order to examine the relation between cardiac state and the capacity to excrete a water load, 10 normal subjects and 61 patients with heart disease were studied during water diuresis. Under these conditions, urine flow approximates to the rate of delivery of filtrate, and therefore of sodium, from the proximal tubule of the kidney to the loop of Henle, while free water clearance is a function of distal sodium reabsorption. In 12 patients with complete heart block, ventricular pacing was associated with increased urine flow and free water clearance. Oral propranolol in 3 normal subjects and in 9 patients with intact atrial septa caused a reduction, and oral practolol in 4 normal subjects and 8 patients caused no change. In 6 patients with atrial septal defect, propranolol was without effect. Maximum urine flow correlated with left ventricular end-diastolic pressure but not mean left atrial pressure in 16 patients with chronic rheumatic heart disease. In 7 patients with ischaemic heart disease, maximum urine flow was higher than in those with chronic rheumatic heart disease and similar increase in left ventricular end-diastolic pressure. These results reflect a close relation between proximal tubular sodium reabsorption and cardiac state, and suggest that inappropriate sodium reabsorption at this site may contribute to fluid retention in heart disease.     

Assessment of proximal tubular sodium reabsorption during water diuresis in patients with heart disease

In order to examine the relation between cardiac state and the capacity to excrete a water load, 10 normal subjects and 61 patients with heart disease were studied during water diuresis. Under these conditions, urine flow approximates to the rate of delivery of filtrate, and therefore of sodium, from the proximal tubule of the kidney to the loop of Henle, while free water clearance is a function of distal sodium reabsorption. In 12 patients with complete heart block, ventricular pacing was associated with increased urine flow and free water clearance. Oral propranolol in 3 normal subjects and in 9 patients with intact atrial septa caused a reduction, and oral practolol in 4 normal subjects and 8 patients caused no change. In 6 patients with atrial septal defect, propranolol was without effect. Maximum urine flow correlated with left ventricular end-diastolic pressure but not mean left atrial pressure in 16 patients with chronic rheumatic heart disease. In 7 patients with ischaemic heart disease, maximum urine flow was higher than in those with chronic rheumatic heart disease and similar increase in left ventricular end-diastolic pressure. These results reflect a close relation between proximal tubular sodium reabsorption and cardiac state, and suggest that inappropriate sodium reabsorption at this site may contribute to fluid retention in heart disease.     

Micropuncture study of tubule sodium reabsorption in dilutional hyponatremia

Clearance and micropuncture techniques were utilized to evaluate tubule sodium reabsorption and sodium excretion in an animal model of the syndrome of inappropriate secretion of antidiuretic hormone. When compared to controls, dogs with dilutional hyponatremia, induced by vasopressin and water, had a greater rate of sodium excretion both before and after saline infusion. Fractional sodium reabsorption in the proximal tubule was also less in the experimental group before and after the saline infusion. The decrease in proximal sodium reabsorption provides a potential explanation for the greater sodium excretion observed in the dogs with dilutional hyponatremia.     

Renal distal tubular handling of sodium in central fluid volume homoeostasis in preascitic cirrhosis.

BACKGROUND/AIMS: Patients with preascitic liver cirrhosis have an increased central plasma volume, and, for any given plasma aldosterone concentration, they excrete less sodium than healthy controls. A detailed study of the distribution of sodium reabsorption along the segments of the renal tubule, especially the distal one, is still lacking in preascitic cirrhosis. METHODS: Twelve patients with Child-Pugh class A cirrhosis and nine control subjects (both groups on a normosodic diet) were submitted to the following investigations: (a) plasma levels of active renin and aldosterone; (b) four hour renal clearance of lithium (an index of fluid delivery to the loop of Henle), creatinine, sodium, and potassium; (c) dopaminergic activity, as measured by incremental aldosterone response to intravenous metoclopramide. RESULTS: Metoclopramide induced higher incremental aldosterone responses, indicating increased dopaminergic activity in patients than controls, which is evidence of an increased central plasma volume (+30 min: 160.2 (68.8) v 83.6 (35.2) pg/ml, p<0.01; +60 min: 140.5 (80.3) v 36. 8 (36.1) pg/ml, p<0.01). Patients had increased distal fractional sodium reabsorption compared with controls (26.9 (6.7)% v 12.5 (3. 4)% of the filtered sodium load, p<0.05). In the patient group there was an inverse correlation between: (a) absolute distal sodium reabsorption and active renin (r -0.59, p<0.05); (b) fractional distal sodium reabsorption and sodium excretion (r -0.66, p<0.03). CONCLUSIONS: These data suggest that in preascitic cirrhosis the distal fractional tubular reabsorption of sodium is increased and critical in regulating both central fluid volume and sodium excretion.