Reabsorptive Function Research Articles

Early recovery of the actin cytoskeleton during renal ischemic injury in vivo

The actin cytoskeleton of proximal tubule cells is important for both the maintenance of membrane domains and attachment to neighboring cells and underlying substrata. Adenosine triphosphate (ATP) depletion during ischemic injury causes early alterations in the actin cytoskeleton, resulting in loss of membrane domains and cellular attachment. We examined the actin cytoskeleton during recovery from ischemic injury. As shown previously in cell culture studies, ATP depletion to 14% of control values from in vivo ischemia resulted in decreases in G-actin consistent with net polymerization of the cytoskeleton. After 20 minutes of recovery restored ATP levels to 24% of control values, percent G-actin increased back to control values, yet cytoplasmic actin polymerized with little evidence of apical recovery. After 120 minutes of recovery, ATP levels had increased to 48% of control values with little qualitative or quantitative change in actin polymerization from 20 minutes of recovery. When ATP levels recovered to 65% of control values at 360 minutes after ischemia, movement of F-actin back toward the apical surface was observed. These data, along with prior data using maleic acid, suggest that thresholds of cellular ATP may cause differing effects on distinct cellular actin pools. We conclude that actin cytoskeletal recovery occurs very early and may be necessary for reestablishment of polarity essential for normal reabsorptive functions.

Effect of cisplatin on renal function in rabbits: mechanism of reduced glucose reabsorption.

This study was performed to determine the effect of cisplatin (cis-diamminedichloroplatinum II) on renal function in rabbits. Injection of a single i.p. dose of 4 mg/kg cisplatin caused an increase in fractional excretion of Na+ and K+ and a decrease in urine osmolality (Uosm), free-water reabsorption, (TcH2O), and urine to plasma creatinine ratio (U/Pcr). Urine flow was decreased following cisplatin treatment, which was accompanied by marked reduction in GFR. Cisplatin induced glucosuria, phosphaturia, and aminoaciduria. These results suggest that cisplatin results in impaired proximal tubular reabsorptive function and the renal concentrating defect. Cisplatin treatment impaired the accumulation of PAH and TEA and ouabain-sensitive oxygen consumption in renal cortical slices. Na(+)-K(+)-ATPase activity in renal cortical microsomes and basolateral membrane vesicles was significantly depressed in cisplatin-treated animals. Cisplatin treatment did not affect the Na(+)-dependent uptake of glucose and L-glutamate by brush-border membrane vesicles (BBMV), but caused a significant decrease in Na(+)-dependent succinate and H(+)-dependent TEA uptake. Morphological observations showed that cisplatin caused a focal loss of the microvillus brush border. These results suggest that (1) cisplatin induces oliguric acute renal failure in rabbits and (2) glucosuria induced by cisplatin was not due to a direct impairment of glucose transporter in brush-border membranes but due to an inhibition of Na(+)-pump activity and a decrease in area for active glucose reabsorption in the proximal tubule.

Ultrastructure of the metanephridial system in Aeolosoma bengalense (Annelida)

The excretory system of Aeolosoma bengalense has been examined by light and electron microscopy. The system consists of seven serially arranged paris of metanephridia and six pairs of podocytes (referring to the first zoid of an animal chain). The podocytes surround blood spaces of the alimentary canal forming dorsoventrally running loops that emerge on both sides of it. The two elements of the system have a correlative position, each podocyte extending in close proximity to the funnel of a metanephridium. Only in the region of the first metanephridia are podocytes lacking. The nephrostome of the metanephridia consists of two cells, an inner one, the terminal duct cell, and an outer one enwrapping it, called the mantle cell. Nephrostomal cilia that extend into the coelomic space arise exclusively from the rim of the mantle cell whereas those of the terminal duct cell arranged on its luminal surface protrude into the canal forming a flame. The nephridial canal is ciliated throughout and is either intra- or extracellular. Its initial loops aggregate to form a compact organ, the nephridial body. The middle part of the duct constitutes a loop that ascends at each side of the alimentary canal where it is in intimate contact with its blood spaces. Ultrastructural features of the duct cells suggest a reabsorptive function in two regions, the nephridial body and the uppermost part of the loop. The terminal part of the duct passes through the nephridial body and opens ventrolaterally. Generally, the transverse vascular loops at the gut consist of one podocyte each. In the oesophageal region, where only one pair of podocytes is present, the loops connect the dorsal with the ventral longitudinal vessel. Three pairs of podocytes are present in the dilated region of the intestine emerging from its lateral wall and joining the median ventral vessel or blood spaces near by. In the hind gut, where two pairs of podocytes occur, the loops arise from the dorsolateral part and enter directly the ventral vessel. Cytological features of podocytes resemble those of other animals. The results are discussed on the basis of current theories on the function and the phylogenetic significance of excretory systems in the Annelida.

Luminal and intracellular cGMP inhibit the mTAL reabsorptive capacity through different pathways

Since, in the presence of ANF, urinary cGMP was shown to be of glomerular origin, a possible paracrine effect of luminal cGMP on the medullary thick ascending limb (mTAL) function was investigated. Net chloride reabsorption (JCl) was determined on isolated microperfused tubules from mouse kidney. Addition of 10(-6) M cGMP to the lumen significantly decreased JCl by 46.5 +/- 4.6%. A concentration-dependent decrease of the transepithelial voltage was observed, with a 10(-8) M threshold. Added to the bath, ANF (10(-7) M) as well as urodilatin (6 x 10(-8) M) decreased JCl by 29.8 +/- 3.9% and 36.9 +/- 5.1%, respectively, an effect reproduced by 8-bromo cGMP and associated with a significant increase in tubular cGMP content. The inhibitory effect of ANF was similar whether or not cGMP was present in the lumen. Furthermore, increasing intracellular cGMP content by 8-bromo cGMP did not prevent a further effect of luminal cGMP. Finally, H-8, which blocked the effect of ANF, urodilatin, and 8-bromo cGMP, failed to abolish the luminal cGMP-induced decrease of JCl, suggesting that this effect did not require a cGMP-dependent protein kinase activation. It is concluded that luminal cGMP inhibits the reabsorptive function of the mTAL through a pathway different from the intracellular cGMP production.

Coordinate development of oxidative enzymes and Na-K-ATPase in thick ascending limb: role of corticosteroids.

The postnatal development of mitochondrial ATP-producing pathways and Na-K-adenosinetriphosphatase (ATPase) in the rat medullary thick ascending limb of Henle (MTAL) was studied by measuring the activities of 3-ketoacid-CoA transferase, fumarase, citrate synthase, and Na-K-ATPase in microdissected MTAL of 16, 21, and 30-day-old pups and in adults. The role of adrenal steroids in the development of these four markers was also investigated by studying 21-day-old rats adrenalectomized on day 16 and given dexamethasone or aldosterone or NaCl injections from day 16 to day 21. There were large and correlated increases in the activities of the oxidative enzymes in the MTAL of control rat kidneys between 16 and 30 days after birth; Na-K-ATPase activity in the MTAL also greatly increased during the same period. Adrenalectomy completely prevented the developmental increases in MTAL oxidative enzymes and Na-K-ATPase; dexamethasone restored the development of all four enzymes, whereas aldosterone had no effect. We conclude that the postnatal maturation of Na+ reabsorption functions in MTAL cells involves coordinated increases in the capacity to produce ATP by oxidative metabolism and in Na-K-ATPase activity. This maturation process is probably triggered by the rise in circulating glucocorticoids that occurs during the weaning period.

Transport of the cationic fluorochrome rhodamine 123 in an insect's Malpighian tubule: indications of a reabsorptive function of the secondary cell type.

The pathway of rhodamine 123 was examined after injection into Sarcophaga flies and after in vitro labeling of the Malpighian tubules. After in vitro labeling the primary cells only retained this potential-sensitive dye for a short period while all secondary cells accumulated the dye from the tubule lumen. In vivo the secondary cells also accumulated rhodamine 123 from the lumen, but the primary cells in the distal parts of all four tubules retained the dye for prolonged periods. This was most pronounced in the distal part of the anterior Malpighian tubules, where rhodamine 123 was eventually precipitated on the luminal concretions. Rhodamine 123 initially accumulated in the secondary cell mitochondria and eventually in intensely fluorescing vesicles, probably lysosomes. No evidence for endocytotic processes from the lumen was found using Lucifer Yellow CH, fluorescent dextrans and fluorescent albumin. Prior incubation with the ionophores valinomycin, nigericin, CCCP (all 1 micrograms/ml), dinitrophenol (1 mM) and NaN3 (10(-2) M) inhibited the selective accumulation of rhodamine 123 to a large extent while monensin (1-5 micrograms/ml) showed little inhibitory effect. Furthermore, only cationic and no anionic or neutral dyes were accumulated by the secondary cells. In the fleshfly Calliphora and the fruitfly Drosophila, the dye rhodamine 123 also selectively accumulated in the secondary cells, as well in vitro as in vivo.

Platelet activating factor inhibits Cl and K transport in the medullary thick ascending limb.

Since the kidney medulla was reported to generate platelet activating factor (PAF), we investigated a possible effect of this agent on the reabsorptive function of in vitro microperfused medullary thick ascending limbs from mouse kidney (mTAL). PAF, 10(-7) M in the bath, significantly decreased the net chloride flux (JCl) from 48.8 +/- 7.1 to 27.4 +/- 5.7 pmol/min. This effect was reversible, blocked by the antagonist BN 50730, and not reproduced by the inactive metabolite lyso-PAF. PAF inhibited the transepithelial potential difference with a threshold at 10(-9) M. In the presence of isoproterenol, the PAF-induced decrease of JCl was not significantly different from that observed in basal conditions; moreover, PAF did not modify the adenylate cyclase activity in isolated mTALs, either in basal condition or under stimulation by isoproterenol. The effect of PAF on JCl was not prevented by mepacrine, NDGA associated with proadifen, or adenosine desaminase. When the apical Na-K-2Cl cotransport was blocked by furosemide or bumetanide, a net K secretion occurred (-1.1 +/- 0.2 pmol/min), which was significantly decreased by PAF (-0.06 +/- 0.3 pmol/min). Moreover, it was verified on isolated mTALs that PAF did not modify the Na,K-ATPase activity. It is concluded that PAF inhibits the reabsorptive function of the mTAL, as indicated by the decrease of Cl reabsorption and K secretion. This effect could not be accounted for by adenosine or arachidonic acid metabolite action, and was not mediated by an inhibition of the adenylate cyclase activity.

Molecular biology of renal injury

The developments in molecular biology of the past decade have created a powerful technology with important, if not revolutionary, clinical applications. This review discusses the molecular biology of renal injury focusing on the renin-angiotensin system as a model, first considering the molecular physiology of the renin angiotensin system within the kidney and then considering its abnormalities in renal injury. All of the components of the renin-angiotensin system are present within the kidney and are involved in modulation of glomerular microcirculation, in proximal tubular reabsorptive function, in control of glomerular/tubular balance, in modulation of medullary blood flow, and in growth and repair of the renal tubule. A new understanding of these multiple roles of the renin-angiotensin system within the kidney is made feasible by combining physiological studies with techniques such as mRNA analysis (e.g., Northern and slot blots, in situ hybridization, and RNA protection assays), transgenic animal studies, transfection studies, and restriction fragment length polymorphism analysis. The ways in which such approaches have been used to examine the role of the renin-angiotensin system in acute renal failure, proteinuric states, renal hypertension, and diabetes mellitus are discussed.

Synergistic Intrarenal Actions of Angiotensin on Tubular Reabsorption and Renal Hemodynamics

There is a growing awareness that the direct intrarenal actions of angiotensin II (ANG II) on both tubular and vascular structures contribute to sodium conservation. Even very low concentrations of ANG II (10(-1)) mol/L) stimulate proximal reabsorption rate. Recent studies indicate that this stimulatory action is due to an enhanced activity of the sodium/hydrogen exchanger of the luminal membrane. Elevated ANG II levels in the renal interstitium, effected either through increased delivery of ANG II via the circulation or as a consequence of conversion of angiotensin I (ANG I) generated locally, can also enhance proximal reabsorption rate. One consequence of enhanced proximal reabsorption rate is reduced distal volume delivery, which would be expected to elicit arteriolar vasodilation mediated by the tubuloglomerular feedback (TGF) mechanism. It has been observed, however, that peritubular capillary infusions of either ANG I or ANG II, at doses sufficiently low to be without obvious direct effects on glomerular dynamics, can increase the sensitivity of the TGF mechanism. This enhanced TGF sensitivity serves to minimize or prevent TGF mediated increases in glomerular filtration rate in the face of reduced distal delivery. With greater increases in interstitial ANG II concentration, reductions in glomerular pressure have been observed, demonstrating a powerful action on preglomerular arterioles that predominates over the well known effects on efferent arterioles. At these higher doses, the direct hemodynamic actions of ANG II, plus the effects on the glomerular filtration coefficient, will directly reduce filtered sodium load. Through these synergistic effects on both tubular reabsorptive and hemodynamic function, ANG II can elicit sustained decreases in distal nephron sodium delivery which contribute greatly to its efficacy as a regulator of sodium excretion.

Influence of Intrarenally Generated Angiotensin II on Renal Hemodynamics and Tubular Reabsorption

There is growing recognition that angiotensin II (ANG II) formed intrarenally exerts direct effects on renal hemodynamics and tubular reabsorption. In vivo micropuncture experiments performed in anesthetized rats have shown that peritubular capillary infusion of either ANG II or angiotensin I (ANG I), at rates that do not markedly influence baseline vascular resistance, can increase proximal tubular reabsorption rate and enhance the responsiveness of the tubuloglomerular feedback mechanism. With higher ANG II or ANG I infusion rates, pronounced preglomerular vasoconstriction occurs, resulting in reduced glomerular capillary pressure and single nephron glomerular filtration rate. The effects of peritubular capillary infusion of ANG I on glomerular function have been shown to be inhibited by the ANG II receptor antagonist, saralasin, indicating that the observed effects of ANG I on proximal tubular reabsorption and glomerular function are not due to direct effects of the decapeptide but are mediated by increases in the interstitial ANG II concentrations resulting from intrarenally generated ANG II. Interestingly, neither peritubular capillary infusion nor systemic administration of large doses of the angiotensin-converting enzyme (ACE) inhibitor, enalaprilat, elicited significant blockade of the single nephron hemodynamic responses to peritubular infusion of ANG I. These findings indicate that intrarenal conversion of ANG I to ANG II occurs, at least in part, at a site which is inaccessible to acutely administered ACE inhibitors, or that there is an alternative pathway for the intrarenal conversion of ANG I to ANG II that is not blocked by ACE inhibitors.

A Case with Renal Tubular Damage: Differentiation of Na Reabsorption Function by Lithium Clearance.

The recovery of the renal proximal and distal tubular sodium (Na) reabsorption was evaluated by analysis of the physiological metabolism of lithium reabsorbed by the renal tubules in a patient with toxic interstitial nephropathy. Administration of glucocorticoid facilitated the rapid recovery of the proximal tubular Na reabsorption (-0.63 to 3 mmol/min for 2 wk) followed by recovery of phosphate reabsorption (51 to 82% for 2 months). Distal Na reabsorption was not altered for 2 months. Although Li clearance has been previously performed in healthy volunteers, we could differentiate the recovery of the proximal and distal renal tubular function even in a diseased patient.

Model of gentamicin-induced nephrotoxicity and its amelioration by calcium and thyroxine

The exact mechanism of gentamicin-induced acute renal failure is presently unknown; various mechanisms have been proposed but there is no proposed commonality between them. In animals, dietary calcium loading and L-thyroxine administration have been shown to ameliorate toxicity, with again no common process. A mechanism of competitive displacement of calcium and other cations from anionic phospholipids at the plasma and organelle membrane level, resulting in a decrease in Na +K + ATPase, adenylate cyclase, mitochondrial function and ATP production, protein synthesis, solute reabsorption and overall cellular function is proposed. A further proposal is dietary calcium loading and thyroxine (which increases intracellular calcium) reverse gentamicin-induced acute renal failure by increasing the calcium and solute flux, thereby competitively inhibiting the primary lesion: anionic phospholipid binding.

Evaluation of the renal tubulo-toxic effect of gossypol by urinary protein analysis with SDS-polyacrylamide gel electrophoresis

The present study assessed the urinary protein with SDS-PAGE technique and by using gentamicin as a positive control for a comparative study to evaluate the renal toxic effect of gossypol. Results indicated that gentamicin could induce proteinuria by alteration of glomerular permeability to cause over-filtration of high molecular weight proteins, damage the brush border (BB) membrane of proximal renal tubules and impair tubular reabsorption function. Gossypol could also induce proteinuria in certain cases of guinea pigs but not at all in gossypol-treated rats. However, an increase in low molecular weight protein bands (M.W. range 20–30kd) in urinary electrophoregram of gossypol-treated rats were detectable.

Relationship between energy requirements for Na+reabsorption and other renal functions

In the mammalian kidney, the use of the ratio, delta net T-Na+/delta Q-O2, provides an overestimate of the energy requirements for unidirectional active Na+ transport. In the proximal tubule, the overestimate of the energy cost for T-Na+ is due to these phenomena: (1) The "leaky" characteristics of the proximal tubule does not permit an accurate estimate to be made of the active fraction of the unidirectional flux of Na+. Thus, the net Na+ or net HCO3- reabsorption rate alone cannot be used to determine the stoichiometry for unidirectional extrusion of Na+ (with HCO3-) by the Na,K-ATPase, since backflux of HCO3- into the lumen occurs. (2) There is a moiety of active Na+ with Cl- along the pars recta. Whether this reabsorptive rate is altered and O2 uptake also changed when GFR or NaHCO3 reabsorption is varied is not yet known. (3) The occurrence of energy-requiring synthetic functions (substrate-interconversions) in the proximal tubule, coupled, in part, to the rate of Na+ entry into the proximal tubule cells, results in changes in renal O2 uptake proportional to some (undetermined) fraction of the change in Na+ reabsorption. The utilization of a portion of these reabsorbed substrates in endergonic syntheses must account for a portion of the Na+-stimulated suprabasal O2 uptake rate. Hence, the presence of synthetic functions in the proximal tubule also contributes to the overestimation of the energy value of net Na+ reabsorption when the ratio, delta net TNa-+/delta Q-O2, is used.(ABSTRACT TRUNCATED AT 250 WORDS)

Reabsorption of horseradish peroxidase by proximal tubules in rats with Heymann nephritis.

The distribution of the histochemical protein tracer, horseradish peroxidase, was studied in proximal tubules of rats with Heymann nephritis. Peroxidase reabsorption was substantially reduced in stage 2 of Heymann nephritis, a period during which the brush border of proximal tubules is severely damaged by specific antibodies. Impairment of the reabsorption function could not be attributed either to proteinuria or disturbances of proximal tubule metabolism and appeared to result from loss of microvilli. Recovery of brush border membrane morphology in stage 4 of Heymann nephritis was not accompanied by recovery of the normal capacity to reabsorb peroxidase. Functional deficits resulting from immunologic injury to proximal tubules in Heymann nephritis may persist despite waning of the anti-brush border antibody response and regeneration of the brush border of proximal tubule cells.

Evidence for beta adrenoceptors in proximal tubules. Isoproterenol-sensitive adenylate cyclase in pars recta of canine nephron.

Observations in vivo suggest that catecholamines modulate reabsorptive functions of proximal tubules by acting on beta-adrenoceptors. However, beta-catecholamine binding sites or beta-adrenoceptor-sensitive adenylate cyclase (AdC) has not been found in segments of proximal tubules of rat, rabbit, or mouse kidney. In the present study, we investigated the responsiveness of AdC to catecholamines, [8-Arg]vasopressin (AVP), and to parathyroid hormone (PTH) in proximal convoluted tubules (PCT), proximal straight tubules (PST), and in late distal convoluted tubules (LDCT) microdissected from canine kidney. Isoproterenol (ISO) caused a marked and dose-dependent stimulation of AdC in PST (maximum: delta + 850%; half maximum stimulation at 10(-7) M ISO), but ISO had no effect on AdC in PCT. The AdC in both PCT and PST was markedly stimulated by PTH; AVP stimulated the AdC in LDCT but not in PST or in PCT. The stimulatory effect of 10(-5) M ISO in PST (delta + 725%) was significantly greater than in LDCT (delta + 307%); norepinephrine and epinephrine had stimulatory effects in PST similar to ISO. The stimulation of AdC in PST by ISO was blocked by propranolol and by beta 2-blocker ICI-118551. On the other hand, alpha-blocker phentolamine and beta 1-blocker metoprolol did not abolish the stimulation of AdC in PST by ISO. The accumulation of cAMP in intact PCT and PST incubated in vitro was stimulated by PTH both in PST and in PCT, but ISO elevated cAMP (delta + 683%) only in PST. Our results show that proximal tubules of canine nephron, PST but not PCT, contain beta-adrenoceptors of beta 2 subtype coupled to AdC. These observations provide direct evidence that the effects of catecholamines, either released from renal nerve endings or arriving from blood supply, can act directly on beta 2-adrenoceptors located in proximal tubules, and also suggest that at least some of the catecholamine effects in proximal tubules are mediated via cAMP generation.

Comparative Physiology of the Renal Proximal Tubule

The comparative physiology of the renal proximal tubule (PT) is reviewed in the context of vertebrate evolution and vertebrate strategies of salt and water balance. Though extrarenal mechanisms of salt and water balance contribute importantly to extracellular fluid (ECF) homeostasis in the lower vertebrates, the kidney acquires these functions with evolutionary progress and becomes the dominant organ of ECF homeostasis in mammals. In acquiring the major responsibility over the ECF compartment the kidney favored filtration-reabsorption as the preferred mechanism for the rapid turnover of ECF with the advantage of providing quick renal regulatory responses. In spite of this specialization the structure and function of the PT do not appear to have undergone major evolutionary changes. In present-day vertebrates the PT remains as an immensely diverse transport epithelium with impressive capacities for both reabsorptive and secretory work, as exemplified by the mammalian PT with mostly reabsorptive functions and the PT of aglomerular kidneys with mostly secretory functions. The recent evidence for NaCl and fluid secretion in the PT of, unexpectedly, glomerular kidneys is consistent with the functional diversity and the conservative nature of evolution in the case of the PT.

Light and electron microscopic observations of choroid plexus in N-methyl-nitrosourea-induced dysgenetic hydromicrocephalic rat offsprings.

The choroid plexus in the N-methylnitrosourea (MNU)-induced dysgenetic hydromicrocephalic rat offsprings was examined morphologically at the ages of 1, 3, 12, and 27 weeks. Hydromicrocephalus became more severe with advanced age, and apparent desquamation of choroidal cells and interstitial edema were first detected at the age of 12 weeks. At the age of 27 weeks, a decrease in number and size of choroidal cells and remarkable edematous widening of the interstitium were noticed. Ultrastructually, at the age of 3 weeks, the choroidal cells with decreased or irregularly distributed nuclear chromatin and narrower cisternae of rough endoplasmic reticulum were prominent. At the luminal surface of these cells, microvilli were anomalous in number and size, and intercellular spaces were slightly dilated. In the interstitium there were distention of perivascular spaces and increase in number of pinocytotic vesicles in the capillary endothelium. At the age of 12 weeks degenerated choroidal cells showed irregular distribution of nuclear chromatin and had a large number of rough endoplasmic reticulum showing short tubular structures. Microvilli were severely destructed into membraneous and fused forms. Membraneous or floccurent materials were present in markedly dilated Golgi saccules and intercellular spaces. In the interstitium, prominent dilatation of perivascular spaces and flattened capillary endothelial cells were observed. These findings suggest that excessive leakage of blood plasma through the choroidal epithelium into the lumen and reduction of reabsorptive function of choroidal cells are important for the cause of the hydrocephalus.

Maleic acid-induced reabsorptive dysfunction in the proximal and distal nephron.

Micropuncture and clearance studies were performed to assess reabsorptive function in the proximal and distal nephron of rats with experimental Fanconi's syndrome induced by maleic acid. Anesthetized rats were studied by free-flow micropuncture of the late proximal tubule 90-120 min after continuous intravenous administration of maleic acid, 100 mg X kg-1 X h-1. Compared with control rats, the reabsorption of sodium and phosphate was significantly reduced (P less than 0.001 and less than 0.02, respectively). Tubular fluid-to-ultrafiltrate (TF/UF) chloride concentration ratio was 1.00 +/- 0.02 compared with 1.16 +/- 0.03 (P less than 0.01) in controls, suggesting a nearly total inhibition of proximal bicarbonate reabsorption. Whole kidney fractional excretions of sodium and chloride were increased significantly (P less than 0.02) but could not be explained by enhanced delivery of these solutes out of the late proximal tubule. To assess whether distal nephron reabsorption of sodium and chloride were inhibited by maleic acid, clearance studies were performed during water diuresis in awake rats. During maleic acid administration, 200 mg X kg-1 X h-1, urine flow rate (P less than 0.02) and the fractional excretions of sodium and chloride (P less than 0.001) increased significantly, but fractional free water clearance decreased from 7.16 +/- 0.42 to 4.03 +/- 0.68% (P less than 0.001). In acetazolamide-treated control rats but not in maleic acid-treated rats with similar bicarbonaturia, the magnitude of fractional free water clearance closely approximated the simultaneously measured fractional distal delivery of chloride. These studies suggest that maleic acid inhibits reabsorption at a distal nephron site or sites as well as in the proximal tubule.

Pathophysiology of the acutely failing kidney.

The term “acute renal failure” (ARF) describes a curtailment of glomerular function and tubular reabsorptive and secretory processes. The kidneys loose their ability to concentrate the urine and to lower the urinary sodium concentration to values below approximately 40 mmol per 1. Glomerular filtration rate (GFR) is always considerably reduced, which leads to an accumulation of creatinine and urea in the blood. The impairment of cellular metabolism, either through oxygen deprivation or nephrotoxins, is the causal event in the generation of ARF. Each etiological factor leading to the phenomenon of ARF will initially affect different individual cellular functions; for example, ATP formation during anoxia, the formation of membrane characteristics by metal ions, or DNA synthesis by toxic peptides. Although their initial effects differ, the final changes in overall cellular function induced by anoxia or nephrotoxic substances are similar and reflect the inherent function of the tubular cells. In the kidney it is the diminished reabsorptive and secretory functions of the tubular cells which determine the excretory function of the kidney during ARF. Because of the different etiological factors different intrarenal pathophysiological reactions follow and dominate, such as intratubular cast formation, increased tubular permeability, reduced filtration area or filtration permeability of the glomerular capillaries, stimulation of the tubuloglomerular feedback system, and renal vasoconstriction. A specific combination of the various abnormalities becomes typical during ARF and the significance of the various pathogenetic factors may differ during its course over time.