Surinder Cheema-Dhadli

Requirements for a high rate of potassium excretion in rats consuming a low electrolyte diet.

Control mechanisms for potassium (K+) excretion in humans developed in Palaeolithic times when diets were sodium poor and episodically K+ rich. Nevertheless, our understanding of the regulation of K+ excretion comes from experiments in rats with large sodium and K+ intakes. Our objective was to identify how K+ excretion was regulated when rats consumed a low NaCl diet to reflect Palaeolithic conditions. Rats that were given mineralocorticoids plus either NaCl, mannitol, or NaHCO3 had a small kaliuresis. In contrast, KCl load induced a large kaliuresis and a near‐maximal luminal [K+] in the terminal cortical collecting duct ([K+]CCD). The time course of events was important. The rise in the [K+]CCD was prompt, but the initial kaliuresis was only modest. Over the next 4 h, kaliuresis increased markedly due solely to a higher calculated distal flow rate, which appeared to be due to diminished reabsorption of NaCl in the loop of Henle; of note, the measured papillary [K+] rose. In summary, the increase in the [K+]CCD in rats given KCl is likely to be due to an increase in the number of luminal K+ channels rather than to mechanisms that are known to induce a lumen‐negative voltage in cortical distal nephron segments. The higher distal flow rate might be due to a higher interstitial [K+], which inhibited NaCl reabsorption in the loop of Henle. Thus, to understand which of the potential control mechanisms are operating, one must look very closely at the conditions imposed by the experimental setting.

Hyperglycemia During Normothermic Cardiopulmonary Bypass: The Role of the Kidney

BACKGROUNDnHyperglycemia commonly occurs during cardiopulmonary bypass. We studied the quantitative impact of glucose input and its renal excretion on hyperglycemia during cardiopulmonary bypass.nnnMETHODSnThe quantity of glucose infused and metabolite and hormone concentrations in plasma, as well as oxygen consumption, carbon dioxide production, and renal glucose excretion, were determined before, during, and after cardiopulmonary bypass in 8 patients.nnnRESULTSnHyperglycemia (14 to 29 mmol/L) was accompanied by an increase in plasma insulin levels. The degree of hyperglycemia was directly related to the amount of glucose infused. The rate of oxygen consumption did not decrease and the rate of urea appearance (gluconeogenesis) did not rise. Despite a very high filtered load of glucose, there was very little glucosuria, indicating a markedly enhanced renal absorption of glucose.nnnCONCLUSIONSnHormonal and metabolic factors permit the development of hyperglycemia during cardiopulmonary bypass but its severity depends on the quantity of glucose infused and, what appears to be a new finding, a markedly enhanced renal reabsorption of filtered glucose. Thus the kidney plays an important role in the development of severe hyperglycemia during cardiopulmonary bypass.

Kaliuretic response to aldosterone : influence of the content of potassium in the diet

The excretion of potassium (K+) decreased by 50% (30 v 63 mEq/d, P < .01) when subjects consumed a diet that was low in K+ for 3 days. Although part of this conservation of K+ was achieved in part by suppressing the release of aldosterone, nevertheless providing exogenous mineralocorticoids did not lead to a large kaliuresis when there was a modest degree of K+ depletion. Accordingly, the purpose of this study was to evaluate possible mechanisms for this antikaliuretic response to mineralocorticoids. The renal handling of K+ was examined by independent analysis of the two factors that influence its excretion, the driving force to secrete K+ and the urine volume. This driving force is reflected in a noninvasive fashion by the transtubular [K+] gradient (TTKG). Stimuli to increase the rate of excretion of K+ in subjects on a normal and a low-K+ diet included the administration of 200 micrograms fludrocortisone (9 alpha F), the induction of a high urine flow rate (9 alpha F+furosemide), the induction of bicarbonaturia (9 alpha F+acetazolamide), and the excretion of Cl(-)-poor urine (< 15 mEq/L). On the low-K+ diet, the peak value for the TTKG 3 to 4 hours after 9 alpha F was less than half that while on the normal diet (6.4 v 14, P < 0.01). In contrast, the TTKG was not significantly different on either diet when there was bicarbonaturia or the excretion of a Cl(-)-poor urine (18 v 17 and 17 v 16, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Dogmas and controversies in the handling of nitrogenous wastes: Excretion of nitrogenous wastes in human subjects

SUMMARY Two major nitrogenous waste products, urea and ammonium (NH4+), are produced in humans when proteins are oxidized, and in this manuscript their excretions are examined from two perspectives. First, the specific physiology of each nitrogenous waste is reviewed and the current dogmas summarized. Second, their excretions are considered in the context of integrative physiology, i.e. the need to ensure that the urine composition is appropriate to minimize the risk of kidney stone formation. After the latter analysis, weak links in our understanding of the overall physiology become apparent and a conundrum is defined. The conundrum for the excretion of urea focuses on the fact that urea is not an effective osmole in the medullary-collecting duct when vasopressin acts. As a result, it appears that urinary urea cannot prevent a large decline in the urine flow rate and thereby minimize the risk of forming kidney stones in electrolyte-poor urine. The conundrum for the excretion of NH4+ is: high rates of NH4+ excretion require a low urine pH, yet a pH ∼6.0 must be maintained in order to reduce the risk of precipitating uric acid in the urine. Possible ways of resolving these conundrums require novel physiological interpretations.

An Acute Infusion of Lactic Acid Lowers the Concentration of Potassium in Arterial Plasma by Inducing a Shift of Potassium into Cells of the Liver in Fed Rats

Background: Potassium (K⁺) input occurs after meals or during ischemic exercise and is accompanied by a high concentration of L-lactate in plasma (P_L-lactate). Methods: We examined whether infusing 100 µmol L-lactic acid/min for 15 min would lead to a fall in the arterial plasma K⁺ concentration (P_K). We also aimed to evaluate the mechanisms involved in normal rats compared with rats with acute hyperkalemia caused by a shift of K⁺ from cells or a positive K⁺ balance. Results: There was a significant fall in P_K in normal rats (0.25 mM) and a larger fall in P_K in both models of acute hyperkalemia (0.6 mM) when the P_L-lactate rose. The arterial P_K increased by 0.8 mM (p < 0.05) 7 min after stopping this infusion despite a 2-fold rise in the concentration of insulin in arterial plasma (P_Insulin). There was a significant uptake of K⁺ by the liver, but not by skeletal muscle. In rats pretreated with somatostatin, P_Insulin was low and infusing L-lactic acid failed to lower the P_K. Conclusions: A rise in the P_L-lactate in portal venous blood led to a fall in the P_K and insulin was permissive. Absorption of glucose by the Na⁺-linked glucose transporter permits enterocytes to produce enough ADP to augment aerobic glycolysis, raising the P_L-lactate in the portal vein to prevent postprandial hyperkalemia.

Influence of hypernatraemia and urea excretion on the ability to excrete a maximally hypertonic urine in the rat

Rats normally excrete 20‐25 mmol of sodium (Na+) + potassium (K+) per kilogram per day. To minimize the need for a large water intake, they must excrete urine with a very high electrolyte concentration (tonicity). Our objective was to evaluate two potential factors that could influence the maximum urine tonicity, hypernatraemia and the rate of urea excretion. Balance studies were carried out in vasopressin‐treated rats fed a low‐electrolyte diet. In the first series, the drinking solution contained an equivalent sodium chloride (NaCl) load at 150 or 600 mmol l−1. In the second series, the maximum urine tonicity was evaluated in rats consuming 600 mmol l−1 NaCl with an 8‐fold range of urea excretion. Hypernatraemia (148 ± 1 mmol l−1) developed in all rats that drank 600 mmol l−1 saline. Although the rate of Na++ K+ excretion was similar in both saline groups, the maximum urine total cation concentration was significantly higher in the hypernatraemic group (731 ± 31 vs. 412 ± 37 mmol l−1). Only when the rate of excretion of urea was very low, was there a further increase in the maximum urine total cation concentration (1099 ± 118 mmol l−1). Thus hypernatraemia was the most important factor associated with a higher urine tonicity.

Non-natriuretic doses of furosemide: potential use for decreasing the workload of the renal outer medulla with minimal magnesium wasting in the rat.

Background/Aims: Since furosemide (FS) inhibits active Na+ reabsorption by medullary thick ascending limb (mTAL) in the renal outer medulla, it may decrease its work during periods of low O2 supply to deep in the renal outer medulla. This study was designed to demonstrate that there may be a dose of FS would reduce its metabolic work while preventing the excessive loss of magnesium (Mg2+). Mg2+ is important because the ATP needed to perform work must have bound Mg2+ to it. Methods: Rats were injected intraperitoneally with a range of doses of FS. The measured outcomes were urine flow rate and parameters of functions of the mTAL (i.e. urine and renal papillary osmolality and urinary excretion of Na+, Cl-, K+ and Mg2+, and concentrations of Mg2+ in serum). Results: The urine flow rate increased significantly starting at 2.4 mg FS/kg. The renal papillary osmolality decreased at ≥0.4 mg FS/kg, and the large detectable natriuresis started at 1.6 mg FS/kg. At this latter dose, the urinary excretion of Mg2+ rose significantly. Conclusion: In rats, the non-natriuretic dose of FS may reduce the work of the mTAL. The earliest indicator of reduced work in the mTAL appears to be a decrease in urine osmolality rather than a rise in urine flow rate. Higher doses of FS should be avoided, as they induce high rates of Mg2+ excretion, which can deplete the body of this essential electrolyte.

Importance of Residual Water Permeability on the Excretion of Water during Water Diuresis in Rats

When the concentration of sodium (Na+) in arterial plasma (PNa) declines sufficiently to inhibit the release of vasopressin, water will be excreted promptly when the vast majority of aquaporin 2 water channels (AQP2) have been removed from luminal membranes of late distal nephron segments. In this setting, the volume of filtrate delivered distally sets the upper limit on the magnitude of the water diuresis. Since there is an unknown volume of water reabsorbed in the late distal nephron, our objective was to provide a quantitative assessment of this parameter. Accordingly, rats were given a large oral water load, while minimizing non-osmotic stimuli for the release of vasopressin. The composition of plasma and urine were measured. The renal papilla was excised during the water diuresis to assess the osmotic driving force for water reabsorption in the inner medullary collecting duct. During water diuresis, the concentration of creatinine in the urine was 13-fold higher than in plasma, which implies that ~8% of filtered water was excreted. The papillary interstitial osmolality was 600 mOsm/L > the urine osmolality. Since 17% of filtered water is delivered to the earliest distal convoluted tubule micropuncture site, we conclude that half of the water delivered to the late distal nephron is reabsorbed downstream during water diuresis. The enormous osmotic driving force for the reabsorption of water in the inner medullary collecting duct may play a role in this reabsorption of water. Possible clinical implications are illustrated in the discussion of a case example.

Effect of Fasting for Two Days on the Excretion of Ammonium in Dogs with Chronic Metabolic Acidosis

Background: The source of glutamine for renal ammonium production is ultimately dietary protein in the fed state and body proteins in fasting. Objective: Our objective was to determine if less NH⁺₄ would be excreted by fasted dogs with chronic metabolic acidosis resulting in conservation of lean body mass. Methods: Acid-loaded fed and fasted dogs were given 10 mmol NH₄Cl/kg for 5 days; the fasted group had food withheld on days 4 and 5. Results: The renal production of NH⁺₄ was not significantly different in both acid-loaded groups, yet the rate of NH⁺₄ excretion was significantly lower in the fasted dogs (8 vs. 21 mmol NH⁺₄/mmol creatinine). The urine pH was significantly higher (6.0 versus 5.5) while titratable acid and the urine flow rate were significantly lower in these fasted dogs. Despite nearly equal urine flow rates and Na⁺ excretion rates after an infusion of saline, the fasted dogs failed to increase the rate of excretion of NH⁺₄ to rates seen in the fed group. Conclusions: The lower rate of excretion of NH⁺₄ in fasted, acidotic dogs appeared to be due to a lower distal H⁺ secretion. This may help preserve lean body mass during fasting.

Is there escape from renal actions of vasopressin in rats with a hyponatremia for greater than 48 hours

Escape from the renal actions of vasopressin is said to occur in rats with chronic hyponatremia. Our objective was to provide specific evidence to test this hypothesis. Hence the osmolality in the excised renal papilla and in simultaneously voided urine (UOsm) was measured in rats with and without hyponatremia. To induce hyponatremia, rats were fed low-electrolyte chow for 6 days. In the first 3 days, water was provided ad lib. On days 4 to 6, a long acting vasopressin preparation (dDAVP) was given every 8 hours to induce water retention. The hyponatremic rats drank 21 mL 5% sucrose on day 4 and 6 mL on day 5. On the morning of day 6, these rats were given 10 mL of 5% glucose in water (D5W) by the intraperitoneal route at 09:00 hour and at 11:00 hour. Analyses were performed in blood, urine, and the excised renal papilla at 13:00 hour on day 6. The concentration of Na+ in plasma (PNa) in rats without intraperitoneal D5W was 140±1 mEq/L (n=7) whereas it was 112±3 mEq/L in the hyponatremic group (n=12). The hyponatremic rats had a higher osmolality in the excised papillary (1,915±117 mOsm/kg H2O) than the UOsm (1,528±176 mOsm/kg H2O, P<0.05). One explanation for this difference is that the rats escaped from the renal action of vasopressin. Nevertheless, based on a quantitative analysis, other possibilities will be considered.