Decrease In Tubular Reabsorption Research Articles

Current Understanding of Pressure Natriuresis.

Pressure natriuresis refers to the concept that increased renal perfusion pressure leads to a decrease in tubular reabsorption of sodium and an increased sodium excretion. The set point of blood pressure is the point at which pressure natriuresis and extracellular fluid volume are in equilibrium. The term "abnormal pressure natriuresis" usually refers to the expected abnormal effect of a certain level of blood pressure on sodium excretion. Factors that cause abnormal pressure natriuresis are known. Sympathetic nerve system, genetic factors, and dietary factors may affect an increase in renal perfusion pressure. An increase in renal perfusion pressure increases renal interstitial hydrostatic pressure (RIHP). Increased RIHP affects tubular reabsorption through alterations in tight junctional permeability to sodium in proximal tubules, redistribution of apical sodium transporters, and/or release of renal autacoids. Renal autocoids such as nitric oxide, prostaglandin E2, kinins, and angiotensin II may also regulate pressure natriuresis by acting directly on renal tubule sodium transport. In addition, inflammation and reactive oxygen species may mediate pressure natriuresis. Recently, the use of new drugs associated with pressure natriuretic mechanisms, such as angiotensin receptor neprilysin inhibitor and sodium glucose co-transporter 2 inhibitors, has been consistently demonstrated to reduce mortality and hypertension-related complications. Therefore, the understanding of pressure natriuresis is gaining attention as an antihypertensive strategy. In this review, we provide a basic overview of pressure natriuresis to the target audience of nephrologists.

Cisplatin Decreases ENaC Activity Contributing to Renal Salt Wasting Syndrome.

Cisplatin (CDDP) is an important anticancer drug. A common side effect of CDDP is renal salt and water-wasting syndrome (RSWS). The origin of RSWS is obscure. Emerging evidence, though, suggests that broad inhibition of sodium transport proteins by CDDP may result in decreases in tubular reabsorption, causing increases in sodium and water excretion. In this sense, CDDP would be acting like a diuretic. The effect of CDDP on the epithelial Na+ channel (ENaC), which is the final arbiter fine-tuning renal Na+ excretion, is unknown. We test here whether CDDP affects ENaC to promote renal salt and water excretion. The effects of CDDP and benzamil (BZM), a blocker of ENaC, on excretion of a sodium load were quantified. Similar to BZM, CDDP facilitated renal Na+ excretion. To directly quantify the effects on ENaC, principal cells in split-open tubules were patch clamped. CDDP, at doses comparable to those used for chemotherapy (1.5 µM), significantly decreased ENaC activity in native tubules. To further elaborate on this mechanism, the dose-dependent effects of CDDP on mouse ENaC (mENaC) heterologously expressed in Chinese Hamster Ovary (CHO) cells were tested using patch clamping. As in native tubules, CDDP significantly decreased the activity of mENaC expressed in CHO cells. Dose–response curves and competition with amiloride identified CDDP as a weak inhibitor of ENaC (apparent IC50 = 1 µM) that competes with amiloride for inhibition of the channel, weakening the inhibitory actions of the latter. Such observations are consistent with CDDP being a partial modulator of ENaC, which possibly has a binding site that overlaps with that of amiloride. These findings are consistent with inhibition of ENaC by CDDP contributing to the RSWS caused by this important chemotherapy drug.

Cisplatin Decreases ENaC Activity Contributing to Renal Sodium Wasting

Cisplatin (CDDP) is a platinum‐containing compound that has antineoplastic effects due to its ability to bind DNA and inhibit replication. While an important chemotherapy drug, CDDP results in a renal salt and water‐wasting syndrome and is nephrotoxic. The origin of the renal salt and water‐wasting caused by CDDP is obscure; though, some evidence suggests that broad inhibition of the Na+/K+‐ATPase by CDDP results in generalized decreases in tubular reabsorption causing increases in sodium and water excretion. The effects of CDDP on the epithelial Na+ channel (ENaC), which is the final arbiter of renal Na+ excretion, are unknown. We test here if CDDP affects the activity of ENaC to influence renal salt and water excretion. These studies focus on understanding the cellular mechanism by which CDDP may affect ENaC. For these studies, C57Bl/6 male mice were randomly divided into 3 groups, as follow: 1) Saline, 2) CDDP and 3) Benzamil (BZM) treated. For metabolic cages experiments, C57Bl/6 male mice received a Na+ load (100 μL of a 0.9% NaCl solution) and were treated with CDDP (25 mg/kg, i.p.) or BZM (1.4 mg/kg, i.p.). Then, water consumption, Na+ intake, urine volume, urinary Na+ and creatine excretion were evaluated every 2 h over a 10 h period. To directly quantify ENaC activity in these animals, principal cells were patch‐clamped in split‐open tubules using the cell‐attached configuration. After recording baseline ENaC activity for 5 min in these tubules, they were treated with CDDP (0.5 to 1.5 μM) with ENaC activity quantified in the presence of this drug over the next 5 min. Preliminary results show that CDDP increases excretion of a Na+ load, increases fractional excretion of sodium (FeNa) and decreases ENaC activity in isolated tubules. Importantly, our studies show that, unlike ouabain, CDDP does not affect channel conductance in cell‐attached patches. Such observations are most consistent with CDDP not affecting the electrochemical forces driving Na+ transport across principal cells, which would change in response to changes in pump activity, but rather decreasing ENaC activity through direct effects on the channel or a channel regulator. In conclusion, these observations are consistent with CDDP actions on ENaC, independent of effects on the pump, contributing to the renal salt and water wasting caused by this chemotherapy drug.Support or Funding InformationThis research was supported by NIH/NIDDK grants R01DK113816 and R01DK117909.

Prevalence and clinical impact of magnesium disorders in end-stage renal disease: a protocol for a systematic review.

BackgroundMagnesium plays a key role in maintaining internal homeostasis through actions in the musculoskeletal, nervous, endocrine and cellular messenger systems. Renal excretion is the major route of magnesium elimination from the body. A positive magnesium balance would be expected in renal failure. However, a compensatory decrease in tubular reabsorption is expected to operate to maintain adequate urinary magnesium excretion even when glomerular filtration rate is very low.Patients with end-stage renal disease and those on dialysis have impaired regulatory mechanisms, predisposing them to disturbances in magnesium levels. The effects of high or low magnesium can have deleterious health outcomes, which impact on the co-morbidities and outcomes of chronic renal disease. This systematic review aims to determine the prevalence and clinical outcomes of magnesium disorders in end-stage renal disease.Methods/DesignWe will undertake a comprehensive search of various databases, MEDLINE, PubMED, EMBASE, Cochrane Library, Cochrane Collaboration, CIHNAL (Ebsco), Web of Science and Google Scholar, for observational studies and clinical trials on magnesium disorders in end-stage renal disease using key terms to identify papers for inclusion. Paper selection and data extraction (where appropriate) will be performed in duplicate on socio-demographic characteristics of participants, diagnosis of end-stage renal disease, magnesium levels, prevalence and clinical outcomes. An assessment of quality will be performed using a modified Newcastle-Ottawa Scale (NOS), including identification of any bias, which may influence findings. Data will be pooled together according to whether the studies were on pre-dialysis, hemodialysis or peritoneal dialysis participants. References from individual papers will also be screened as appropriate. Paper organisation and data extraction and analysis will take place using Microsoft Excel® and Stata version 13®.DiscussionThis systematic review will represent a significant effort at pooling together information on prevalence and outcomes of magnesium disturbances amongst end-stage renal disease patients, which may guide further research and management of the disorders.Systematic review registrationPROSPERO: CRD42014014354Electronic supplementary materialThe online version of this article (doi:10.1186/s13643-015-0063-x) contains supplementary material, which is available to authorized users.

Urinary excretion of alpha1-microglobulin and albumin in acute myocardial infarction

Microalbuminuria associated with myocardial infarction (MI) is normally ascribed to glomerular factors, but could just as well involve pathophysiological processes located in other parts of the nephron, e.g. proximal tubules where plasma albumin normally filtered through the glomerulus is almost completely reabsorbed. The aims of this study were to establish whether impaired tubular reabsorption of filtered albumin contributes to microalbuminuria during MI, and whether the urinary excretion of protein relates to plasma levels of C-reactive protein (CRP) and troponin I. We monitored plasma CRP and troponin I as well as the urinary excretion of albumin and alpha1-microglobulin, a low-molecular-weight plasma protein and marker of tubular proteinuria, in 18 patients with MI. The urinary excretion of alpha1-microglobulin and albumin was significantly elevated in nine patients, and the urinary excretion of the two proteins correlated significantly. A decrease in tubular reabsorption of albumin may thus be at least one of the causative factors underlying microalbuminuria during MI. The plasma levels of CRP and troponin I were also significantly higher in this group of nine patients, and correlated with urinary protein excretion, suggesting an interrelationship between inflammatory response and tubular dysfunction. Extrarenal inflammatory processes seem to affect renal tubular function, thereby contributing to microalbuminuria during MI.

Mechanisms of pressure natriuresis.

A central component of the feedback system for long-term control of arterial pressure is the pressure-natriuresis mechanism, whereby increases in renal perfusion pressure lead to decreases in sodium reabsorption and increases in sodium excretion. The specific intrarenal mechanism for the decrease in tubular reabsorption in response to increases in renal perfusion pressure appears to be related to increases in hemodynamic factors such as medullary blood flow and renal interstitial hydrostatic pressure (RIHP), and renal autocoids such as nitric oxide, prostaglandins, kinins, and angiotensin II. Increases in renal perfusion pressure are associated with significant increases in RIHP, nitric oxide, prostaglandin E2, and kinins, and decreases in angiotensin II. The mechanism whereby RIHP increases in the absence of discernible changes in whole kidney renal blood flow and peritubular capillary hydrostatic and/or oncotic pressures may be related to increases in renal medullary flow as a result of nitric oxide-induced reductions in renal medullary vascular resistance. Several lines of investigation support an important quantitative role for RIHP in mediating pressure natriuresis. Preventing RIHP from increasing in response to increases in renal perfusion pressure markedly attenuates pressure natriuresis. Furthermore, direct increases in RIHP, comparable to increases measured in response to increases in renal perfusion pressure, have been shown to significantly decrease tubular reabsorption of sodium in the proximal tubule and increase sodium excretion. The exact mechanism whereby RIHP influences tubular reabsorption is unknown, but may be related to alterations in tight junctional permeability to sodium in proximal tubules, redistribution of apical sodium transporters, and/or release of renal autacoids such as prostaglandin E2.

Attenuation of urinary sodium excretion during cold-air exposure in trained athletes.

To clarify whether an increase in urinary sodium (Na) excretion during cold-air exposure is attenuated in trained athletes, we analyzed the urinary and hormonal responses to cold-air exposure at 15 degrees C in trained (TR, n = 9) and untrained men (UT, n = 9). During 15 degrees C exposure in the UT group, the urinary Na excretion (UNaV), fractional excretion of Na and urinary Na to K ratio (UNa/K) increased significantly (p<0.01-0.05), but there were no variations in creatinine clearance or the filtered Na load. In the TR group, however, no significant changes were demonstrated in these parameters. The amount of increase in plasma noradrenaline and of decrease in plasma volume were greater, and the ADH and adrenaline responses were smaller in the TR group than those found in the UT group during 15 degrees C air exposure. A significant positive correlation was demonstrated between the increase of UNaV and both the relative changes of UNa/K and mean blood pressure. These results indicated that natriuresis during cold-air exposure was induced by the decrease in tubular reabsorption of Na, and that natriuresis was attenuated in trained athletes.

Renal effects of nitric oxide synthesis inhibition in cirrhotic rats.

In the present study, we have characterized the renal response to inhibition of endogenous nitric oxide (NO) synthesis [intravenous NG-nitro-L-arginine methyl ester (L-NAME) for 3 h] in anesthetized cirrhotic rats, with (ASC) and without (CIR) ascites, at doses that do not change blood pressure (BP). Administration of L-NAME induced opposite effects on water (UV) and sodium (UNaV) excretion in cirrhotic and control animals. Infusion of 1 microgram.kg-1.min-1 of L-NAME in CIR (n = 5) decreased renal plasma flow (RPF) at the end of the 3-h period, whereas UV, UNaV, and glomerular filtration rate (GFR) were unaltered. In contrast, infusion of L-NAME at 10 micrograms.kg-1.min-1 in six more CIR increased UV and UNaV significantly by the 1st h, without changes in BP or GFR, and these parameters remained elevated throughout the experiment. Infusion of 1 microgram.kg-1.min-1 in ASC (n = 6) did not change BP or GFR but significantly enhanced UV and UNaV after the 1st h. These effects were prevented by pretreatment with L-arginine (0.1 mg.kg-1.min-1) in another group of ASC infused with 1 microgram.kg-1.min-1 of L-NAME. These results indicate that, in ASC and CIR cirrhotic rats, inhibition of NO synthesis at nonpressor does improves renal excretion of sodium and water via a decrease in tubular reabsorption. NO is an important mediator of the renal excretory and hemodynamic alterations of experimental liver cirrhosis.

Chronic health effects of orally administered cadmium in dogs

Abstract The effects of orally administered cadmium on the health of beagle dogs, at dose levels of 1,3,10,50 and 100 mg/day over a period of eight years are reported. There were no remarkable clinical and biochemical changes in blood and urine examinations of the dogs that received less than 10 mg Cd/day, although cadmium levels in their blood and urine increased with time according to the dose. The male dog given 100 mg Cd/day showed a slight decrease in hemoglobin and hematocrit (HCT), and larger decreases in tubular reabsorption of phosphate (%TRP) and 24‐hour creatinine clearance (Ccr‐24h) after about 50 weeks, an increase in daily urine volume, a decrease in the specific gravity of urine after 70–80 weeks, an increase in the daily excretion of total protein in urine after about 100 weeks, an increase in s2‐microglobulin (s‐MG) in urine after 120–130 weeks, and glycosuria after 150 weeks. The male dog given 50 mg Cd/day also showed symptoms of renal dysfunction, but not to the extent observed in the ...

Pressure natriuresis. Role of renal interstitial hydrostatic pressure.

The kidneys play a major role in the long-term regulation of extracellular fluid volume and arterial pressure. A central component of the feedback system for long-term control of arterial pressure is the pressure-natriuresis mechanism, whereby increases in renal perfusion pressure lead to decreases in sodium reabsorption and increases in sodium excretion. The specific intrarenal mechanism for the decrease in tubular reabsorption in response to increases in renal perfusion pressure appears to be related to increases in renal interstitial hydrostatic pressure (RIHP). Increases in renal perfusion pressure are associated with significant increases in RIHP. The mechanism whereby RIHP increases in the absence of discernible changes in whole kidney renal blood flow and peritubular capillary hydrostatic and/or oncotic pressures may be related to alterations in renal medullary hemodynamics. Several lines of investigation support an important quantitative role for RIHP in mediating pressure natriuresis. Preventing RIHP from increasing in response to increases in renal perfusion pressure markedly attenuates pressure natriuresis. Furthermore, direct increases in RIHP, comparable to increases measured in response to increases in renal perfusion pressure, have been shown to significantly decrease tubular reabsorption of sodium in the proximal tubule and increase sodium excretion. The exact mechanism whereby RIHP influences tubular reabsorption is unknown but may be related to alterations in tight junctional permeability to sodium in proximal tubules and/or release of renal autacoids such as prostaglandins.

EFFECT OF MAGNESIUM INFUSION ON CALCIUM HANDLING IN THE RAT KIDNEY

Anaesthesized rats were infused with 100 microliters min-1 of 0.9% saline or saline containing 2 or 4 mmol l-1 of magnesium chloride and renal function was studied. Magnesium had no effect on urine flow rate, excretion of sodium or potassium, or glomerular filtration rate (GFR). Infusion of either dose of magnesium increased calcium excretion and calcium concentration in the urine. The increased urinary calcium excretion is due to a decrease in tubular reabsorption of calcium.

The renal action of atrial natriuretic peptide during control of glomerular filtration

Studies were performed in anesthetized dogs (N = 7) to determine the effects of synthetic atrial natriuretic peptide (ANP) on sodium excretion in the presence and absence of control of glomerular filtration rate produced by suprarenal aortic clamping. Intrarenal infusion of synthetic atrial natriuretic peptide (0.3 micrograms/kg/min) significantly increased glomerular filtration rate from 29.3 +/- 3.0 to 43.2 +/- 4.4 ml/min, urinary sodium excretion from 20.1 +/- 10.3 to 223.3 +/- 52.3 microEq/min, fractional sodium excretion from 0.47 +/- 0.19 to 3.75 +/- 0.59%. In contrast, aortic clamping blocked the increase in glomerular filtration rate in association with an attenuated natriuresis. Urinary sodium excretion increased from 6.3 +/- 2.3 to 68.3 +/- 23.4 microEq/min and fractional sodium excretion increased from 0.15 +/- 0.04 to 0.90 +/- 0.30%. Despite this differential response in glomerular filtration rate and sodium excretion, whole kidney fractional delivery of sodium from the proximal tubule as estimated by the fractional excretion of lithium increased during both unclamped (17.7 +/- 1.8 to 30.4 +/- 0.8%) and clamped (12.9 +/- 2.1 to 23.9 +/- 2.7%) periods. These studies demonstrate that atrial natriuretic peptide-induced natriuresis is importantly mediated by an increase in glomerular filtration rate and decrease in tubular reabsorption.

Selective glutathione depletion on function and structure of the isolated perfused rat kidney

The role of glutathione (GSH) in the preservation of renal function and the pathogenesis of renal injury has been investigated using the isolated perfused rat kidney as a model. In kidneys perfused for 80 min with 5 mM glucose as the only exogenous substrate, tissue GSH becomes depleted, renal function deteriorates, and a degenerative change appears, restricted to the medullary thick ascending limb. These abnormalities can be ameliorated by providing amino acid supplements or by adding GSH itself to the perfusion. To distinguish between the effects of amino acid supplementation and GSH depletion per se, selective depletion of GSH was accomplished in several different ways. Synthesis of GSH was inhibited by the addition of dl-buthionine-SR-sulfoximine, a specific inhibitor of gamma-glutamyl cysteine synthetase. GSH depletion was also produced by 2-cyclohexene-1-one and diethylmaleate, both known to diminish the concentration of GSH selectively without affecting protein thiols. Perfused kidneys selectively depleted of GSH showed significant impairment of concentrating ability, and less marked decreases in tubular reabsorption of sodium. The degenerative changes in the medullary thick ascending limb, on the other hand, were unaltered.(ABSTRACT TRUNCATED AT 250 WORDS)

Tubular handling of Pi in young growing and adult rats.

The tubular transport of inorganic phosphate (Pi) is controlled by a parathyroid hormone-independent mechanism that responds to variations in the Pi intake. This adaptation mechanism could also respond to growth-mediated variation in the utilization of Pi by the organism. In the present work we have determined the maximal net Pi reabsorption per volume of glomerular filtrate (max TRPi/ml GF) in the young growing (2-mo) and adult 8- to 9-mo) rats. Max TRP[i/ml GF was significantly lower in intact adult (1.44 +/- 0.06 mumol/ml) compared with intact young growing animals (2.22 +/- 0.12 mumol/ml GF). This difference was maintained after removal of the thyroparathyroid glands; adult, 2.89 +/- 0.25, young, 4.56 +/- 0.25 mumol/ml. It was not associated with a difference in the urinary excretion of cAMP, GFR, renal handling of sodium, plasma calcium, or acid-base status. Administration of growth hormone preparations to adult rats did not raise max TRPi/ml GF to the level observed in young intact animals. With regard to the tubular Pi adaptation to Pi restriction, lowering the phosphorus content in the diet from 0.8 to 0.2 g/100 g resulted in an attenuated and delayed enhancement in max TRPi/ml in adult as compared with the response observed in young growing rats. These results show that the decrease in tubular reabsorption of Pi that occurs when rats become adult in a parathyroid hormone-independent phenomenon. It is suggested that this change is an adaptation of the tubular Pi transport to a reduction in the utilization of Pi in relation to the diminished growth rate of the animals.

The effect of saline-induced extracellular volume expansion on the kidney function.

The functional parameters of renal function of non-hydrated and hydrated dogs (saline-infused to an extent of 1-2% of the body weight) have been compared. The directly measured renal blood flow and the total renal vascular resistance were the same in the two groups. No difference has been found in glomerular filtration rate, the Cinulin was the same in the two groups. There was no important difference in the PAH clearance and PAH extraction. In the hypervolaemic group, the sodium and water excretion was about threefold that of the non-hydrated animals. The plasma protein concentration was significantly lower in the hydrated group. In our experiments we did not find glomerular factors responsible for the increase of sodium and water excretion. The decrease of tubular reabsorption is attributed partly to the decreased plasma protein concentration, partly to unknown (perhaps natriuretic) humoral factors.

Severe Hypophosphatemia Due to Hypokalemia

Severe hypokalemia, induced by the chronic ingestion of licorice and hydrochlorothiazide, appears to have caused a marked increase in phosphate clearance, a decrease in tubular reabsorption of phosphate, and hypophosphatemia. A decrease in phosphate clearance and a return of the plasma phosphate concentration to normal levels occurred after correction of the potassium deficit.

Tubular reabsorption of calcium in normal and hypercalciuric subjects.

Tubular reabsorption and excretion of calcium were studied at different levels of filtered calcium by means of calcium infusion in normal and hypercalciuric subjects and in patients with idiopathic nephrolithiasis. Calcium reabsorption and excretion rose linearly with filtered load and in no case was a maximum tubular reabsorptive capacity for calcium reached. No decrease in tubular reabsorption of calcium was found in hypercalciuric as compared with normocalciuric subjects, and no difference in tubular reabsorption was found between patients with idiopathic nephrolithiasis and normal subjects. Calcium excretion and reabsorption calculated from the endogenous creatinine clearance during calcium infusion were virtually identical with the corresponding values calculated from the inulin clearance.

Excretion of water and sodium loading by isolated perfused dog kidney

Isolated dog kidney submitted to artificial perfusion by heparinized blood is able to reject a water and sodium load. The influence of extrarenal hormonal factors is ruled out. Although the interference of lowering of haematocrit and plasma protein level and increase of plasma flow cannot be discarded, other factors related to blood dilution must play a role. Sodium and water rejection depend on a decrease of tubular reabsorption rather than on an increase in glomerular filtration.

RENAL CLEARANCE OF SODIUM AND POTASSIUM IN HYPOTHERMIA

The handling of sodium and potassium by the renal tubules at various levels of hypothermia was studied. Fourteen dogs were anesthetized with 30 mg/kg sodium pentobarbital. After suitable control clearance measurements, the rectal temperature was lowered progressively by ice-packing to about 25 °C while renal clearances were continuously measured. Artificial respiration was not used. No change in plasma sodium was detected but plasma potassium fell significantly from a control value of 4.1 ± 0.09 meq/1. at 38 °C to 3.4 ± 0.12 meq/1. at 25 °C. Urine sodium concentration fell during exposure to cold while potassium concentration increased slightly. In spite of the marked fall in glomerular nitration rate (69.0 ± 3.1 ml/minute control to 17.0 ± 3.6 ml/minute at 25 °C) the final urine flow at 25 °C was slightly greater than that of control. The clearance ratios (in percentage) increased significantly, reflecting the marked decrease in tubular reabsorption: water, 0.49 ± 0.05 at 38 °C to 2.02 ± 0.25 at 25 °C; sodium, 0.47 ± 0.12 to 1.13 ± 0.27; potassium, 18.0 ± 2.6 to 54.0 ± 12.0. The difference in clearance ratio alterations is a reflection of the dissimilar effect of hypothermia on particular renal regulations.

RENAL CLEARANCE OF SODIUM AND POTASSIUM IN HYPOTHERMIA

The handling of sodium and potassium by the renal tubules at various levels of hypothermia was studied. Fourteen dogs were anesthetized with 30 mg/kg sodium pentobarbital. After suitable control clearance measurements, the rectal temperature was lowered progressively by ice-packing to about 25 °C while renal clearances were continuously measured. Artificial respiration was not used. No change in plasma sodium was detected but plasma potassium fell significantly from a control value of 4.1 ± 0.09 meq/1. at 38 °C to 3.4 ± 0.12 meq/1. at 25 °C. Urine sodium concentration fell during exposure to cold while potassium concentration increased slightly. In spite of the marked fall in glomerular nitration rate (69.0 ± 3.1 ml/minute control to 17.0 ± 3.6 ml/minute at 25 °C) the final urine flow at 25 °C was slightly greater than that of control. The clearance ratios (in percentage) increased significantly, reflecting the marked decrease in tubular reabsorption: water, 0.49 ± 0.05 at 38 °C to 2.02 ± 0.25 at 25 °C; sodium, 0.47 ± 0.12 to 1.13 ± 0.27; potassium, 18.0 ± 2.6 to 54.0 ± 12.0. The difference in clearance ratio alterations is a reflection of the dissimilar effect of hypothermia on particular renal regulations.