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To determine the effect of corticosteroids on active transport processes, unidirectional fluxes of 22Na, 36Cl, and 42K were measured under short-circuit conditions across isolated stripped distal colonic mucosa of the rat in control, secondary hyperaldosterone, and dexamethasone-treated animals. In controls net sodium and chloride fluxes (JNanet and JClnet) and short-circuit current (Isc) were 6.6 +/- 2.2, 7.6 +/- 1.6, and 1.3 +/- 0.2 mu eq X h-1 X cm-2, respectively. Although aldosterone increased Isc to 7.3 +/- 0.5 mu eq X h-1 X cm-2, JNanet (6.9 +/- 0.7 mu eq X h-1 X cm-2) was not altered and JClnet was reduced to 0 compared with controls. Dexamethasone also stimulated Isc but did not inhibit JClnet. In Cl-free Ringer both aldosterone and dexamethasone produced significant and equal increases in JNanet and Isc. Theophylline abolished JNanet in control animals but not in the aldosterone group. Aldosterone reversed net potassium absorption (0.58 +/- 0.11 mu eq X h-1 X cm-2) to net potassium secretion (-0.94 +/- 0.08 mu eq X h-1 X cm-2). Dexamethasone reduced net potassium movement to 0 (-0.04 +/- 0.12 mu eq X h-1 X cm-2). These studies demonstrate that 1) corticosteroids stimulate electrogenic sodium absorption and 2) aldosterone, but not dexamethasone, inhibits neutral NaCl absorption and stimulates active potassium secretion. The effects of mineralocorticoids and glucocorticoids on electrolyte transport are not identical and may be mediated by separate and distinct mechanisms.

The effect of pregnancy on the activity of SLE and that of SLE on the product of conception was analyzed from data reported in nine series of 20 or more pregnancies published between 1956 and 1981. Although pregnancy has an adverse effect on SLE activity, an established diagnosis of SLE does not preclude an outlook for a successful pregnancy even in patients with previous signs of severe multisystem involvement and lupus nephropathy. Complete clinical remission for 6 mo or more prior to conception indicates a favorable prognosis for an uncomplicated course during pregnancy and a live birth. Continued signs of disease activity or renal disease reduce, however, the likelihood for an uncomplicated course and decreases the live birth rate by 25% - 30%. Since there is no evidence that glycocorticoids or cytotoxic agents affect fetal development or induce congenital abnormalities treatment during pregnancy should be directed towards suppression of disease activity and controlling hypertension.

This review of adaptive changes in renal structure and function in subjects with reduced renal mass has two primary goals. One is to provide a description of the remarkable compensatory increases in glomerular filtration rate (GFR), and renal blood flow, at the level of individual nephrons, and the alterations in water and electrolyte transport by tubular epithelium. These processes preserve fluid and electrolyte balance in subjects with progressive renal failure, until whole kidney GFR is reduced to about 20 percent of normal, and provide the basis for conservative clinical medical management. The other aim is an attempt to provide an understanding of the mechanisms involved in compensatory adaptation, since this information, in addition to amplifying our understanding of renal transport processes, helps to elucidate the functional limitations placed on subjects with renal insufficiency. An attempt has been made to analyze both clinical observations and relevant experimental models and an effort has been made to correlate renal function with different patterns of renal injury.

A capacity for both net potassium absorption and net potassium secretion has been demonstrated in the inner medullary collecting duct. The quantitative importance, however, of the inner medullary collecting duct in the regulation of urinary potassium in potassium deficiency, however has not been established. To assess the contribution of this segment to potassium conservation, microcatherization studies were performed in male Sprague-Dawley rats maintained either on a control diet or on a potassium free diet for 72 h. In control animals approximately 15% of the filtered load of potassium was excreted. Analysis of tubule fluid along the inner medullary collecting duct failed to demonstrate evidence of net potassium movement. Administration of a potassium free diet resulted in a marked reduction in potassium excretion to 0.3% of the filtered load. In contrast to control the inner medullary collecting duct of experimental animals absorbed nearly 90% of the amount of potassium entering this segment, since fractional delivery to the terminal portion of the nephron was about 2%. These data indicate that the inner medullary collecting duct makes a significant contribution to maximal renal conservation of potassium, since previous studies have shown that only 5 to 10% of filtered potassium is present in the late distal tubule of surface nephrons in animals on a low potassium intake.

Because the metabolic changes in normal pregnancy are diabetogenic, pregnancy imposes a severe stress on the metabolic milieu of diabetic patients. Moreover, some patients with long-standing diabetes have vascular complications, including renal insufficiency and hypertension, that represent separate risk factors for optimal fetal development. During the past two to three decades, maternal mortality has been eliminated and perinatal deaths have been reduced in all classes of diabetic patients, including those with diabetic nephropathy, to a level approaching that of normal pregnant women. Fetal and neonatal morbidity have also been reduced, although rates of congenital abnormalities and respiratory disease syndrome remain high. In patients with significant vascular complications, such as nephropathy and retinopathy, pregnancy evidently does not alter the natural course of these complications. With meticulous metabolic control and fetal surveillance, however, women with diabetic nephropathy without severe renal insufficiency or severe hypertension can anticipate a pregnancy outcome similar to that of other insulin-dependent diabetic patients.

Two weeks after 75 percent nephrectomy in rats fed a normal diet glomerular filtration rate was found to be reduced by 2/3 and there was no hyperkalemia. Normal K balance was maintained by a threefold increase of fractional urinary potassium excretion. When infused with 0.5 M KCl solution, both normal and 75 percent nephrectomized rats increased their fractional excretion, while normal rats kept on a very high K-diet did not further increase their fractional potassium excretion. Adaptation of fractional excretion to infused KCl was blunted in 75 percent nephrectomized rats given a low K diet.Addition of 0.1 M KCl to the drinking water resulted in a three- to fourfold increase of potassium intake in normal rats: within 7 days, the Na-K-ATPase in the outer medulla of the kidney rose by 30 percent but no change occurred in the cortex. Further increases in dietary K load induced an increase of Na-K-ATPase activity, both in outer medulla and cortex, but not in other tissues. After 75 percent nephrectomy, specific Na-K-ATPase activity increased by 20-25 percent in the outer medulla and in the cortex.Dietary K loading, in normal rats, also resulted in a large increase of net potassium secretion into the perfused colon and of specific Na-K-ATPase activity of the colonic mucosa. These effects of potassium loading were not abolished by adrenalectomy and were accompanied by an increase of transmural PD. It was concluded that chronic potassium loading may enhance secretion of potassium into lower nephron tubular fluid and into colonic contents by primarily stimulating the synthesis of Na-K-ATPase and the resulting increase of the number of pumping sites. 75 percent nephrectomy may induce similar changes in the remaining nephrons.

Children with lipoid nephrosis were studies during clinical relapse and after complete remission. As expected, the calculated serum oncotic pressure was reduced severely from the remission value of 28.6 +/- 0.9 mm Hg to 15.4 +/- 1.1 (P less than 0.005) during relapse. Although no apparent change in plasma volume was noted using the volume of distribution of labeled human albumin, calculated plasma volume was reduced 13 +/- 8% during relapse when estimated from changes in hematocrit. After a water load, the ability to excrete water was markedly blunted during relapse. The clearance of solute-free water (CH2O) was 0.9 +/- 0.8 ml/min during relapse, compared with 3.6 +/- 0.6 ml/min during remission (P less than 0.005). In addition, there was a reduced maximal urinary concentrating ability during relapse in four of the six patients examined. Mean urine osmolality for the group during relapse was 778 +/- 82 mOsm/kgH2O and 991 +/- 71 during remission (P less than 0.05). The demonstrated alteration in nephron function during relapse of nephrotic syndrome could result from either (1) a decrease in the amount of sodium delivered to the ascending limb of the loop of Henle because of increased proximal reabsorption or (2) a change in the intrinsic characteristics for sodium reabsorption in that segment. Although this observation does not prove that proximal reabsorption is increased, it suggests a common underlying mechanism for altered nephron function in all of the major edema-forming conditions.

To determine the effect of variations in body stores of potassium on the rate of active potassium transport in the large intestine, unidirectional 42K fluxes were performed under short-circuit conditions across isolated distal colonic mucosa of control, dietary potassium-depleted and dietary potassium-loaded rats. Potassium depletion stimulated net potassium absorption (JK net) (0.87 +/- 0.19 vs. 0.49 +/- 0.04 mu eq X h-1 X cm-2, P less than 0.025) due to a 40% increase in mucosal-to-serosal potassium transport (JK m----s). In sodium-free Ringer solution JK net in the potassium-depleted group was also significantly greater than in controls (1.93 +/- 0.26 vs. 1.01 +/- 0.11 mu eq X h-1 X cm-2, P less than 0.005). In contrast, in chloride-free Ringer solution JK net was identical in the control and potassium-depleted groups (0.39 +/- 0.05 vs. 0.46 +/- 0.07 mu eq X h-1 X cm-2, P = NS). Potassium loading reversed net potassium absorption to net potassium secretion (-0.76 +/- 0.08 mu eq X h-1 X cm-2, P less than 0.001) as the result of a decrease in JK m----s and an increase in serosal-to-mucosal potassium transport (JK s----m). Net potassium secretion was abolished in the absence of either sodium or chloride from the bathing solution but not by mucosal amiloride. In sodium-free Ringer solution JK net was similar in control and potassium-loaded groups, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Previous studies have shown that the intestinal excretion of potassium increases in patients with renal failure and serves to guard against severe potassium retention. It is not known, however, whether the rise in intestinal potassium excretion occurs because of an increase in intestinal potassium secretion or a reduction in potassium absorption. Therefore, studies were performed to evaluate the rate of potassium secretion in the human rectum of controls and subjects with renal insufficiency, using a dialysis bag technique. The results demonstrate that net potassium secretion was increased in subjects with renal failure (-5.2 +/- 0.9 microEq X min-1) compared with the control value of -2.0 +/- 0.4 microEq (P less than .05). This change in intestinal secretion of potassium was shown to be independent of the passive effects of plasma potassium. The rise in potassium secretion, however, correlated directly with an increase in transepithelial potential difference (lumen-negative). Although plasma aldosterone levels were higher in patients than in controls, the scatter of data precludes an assessment of the role of aldosterone in the mechanism of the rise in potassium secretion. These data suggest that augmented intestinal potassium excretion in patients with chronic renal insufficiency is caused by increased net potassium secretion in the large intestine, and highlight the role of the intestine in maintaining potassium balance.

The renal clearance of iothalamate sodium I 125, identical to that of inulin, permits measurement of glomerular filtration rate with a single injection in varying degrees of renal failure.

The purpose of this study was to characterize the alterations in collecting tubule Na+-K+-ATPase activity produced by sustained increments in dietary potassium in the rat and to evaluate the role of aldosterone in their generation. In adrenal-intact animals, feeding a high-potassium diet (10-fold that of control) or administration of a high physiological dose of aldosterone (5 micrograms X 100 g-1 X day-1), which simulates the delivery rate of this hormone during potassium loading (both for 7 days), caused marked increments in Na+-K+-ATPase activity in the cortical collecting tubule (CCT) but had no effect on the enzyme in the inner stripe of the medullary collecting tubule (MCT). A significant increase in enzyme activity was also observed after smaller dietary potassium increments (2.5 and 5 times the control) and after 4 (but not 2) days of dietary potassium load. In adrenalectomized rats provided with physiological replacement doses of corticosterone and aldosterone (0.8 micrograms X 100 g-1 X day-1), Na+-K+-ATPase activity in both CCT and MCT was similar to that of adrenal-intact controls but remained unchanged after 7 days on the potassium-enriched (10-fold) diet. In contrast, adrenalectomized animals receiving the high physiological dose of aldosterone displayed an increase in Na+-K+-ATPase activity of CCT comparable with that of adrenal-intact animals, whereas the enzyme activity in the MCT was unaffected. In conclusion, 1) following chronic potassium loading Na+-K+-ATPase activity increases significantly in the CCT with no change in its activity in the inner stripe of the MCT.(ABSTRACT TRUNCATED AT 250 WORDS)

The mechanism responsible for K transport in the mammalian colon is controversial. Experiments were performed to determine whether K secretion involves active as well as passive driving forces in controls and in animals with a marked increase in K secretion. In these experiments a steady-state solution was established in proximal and distal colon of both control rats and animals fed a K-enriched diet during in vivo luminal perfusion, to compare the observed luminal [K] with predicted equilibrium [K] when net water and electrolyte movement approached zero. Transmural potential difference was measured simultaneously. A difference between the predicted equilibrium and observed luminal [K] under this condition indicates active transport. In controls the observed [K] of 20 mmol/liter in proximal colon markedly exceeded the predicted value of 6.2 +/- 0.3, mean +/- SE, indicating active secretion. In contrast, the observed [K] in distal colon of 5 mmol/liter was less than predicted (10.0 +/- 1.0), suggesting active absorption. In K-loaded animals active K secretion was demonstrable and increase above control in both segments of colon. In proximal colon the observed [K] rose to 40 mmol/liter, compared to a predicted value of 7.2 +/- 0.3, whereas in distal colon the observed [K] was 50 mmol/liter vs. a predicted value of 7.0 +/- 0.8. These studies suggest active K secretion in proximal, but not in distal colon of control animals. Further, these data suggest that the increase in the capacity for K secretion that occurs in response to chronic K loading involves stimulation of an active mechanism in both proximal and distal colon.

Women with SLE are at risk for developing a greater number of complications during pregnancy and have a lesser chance for a successful outcome for the conceptus than do normal healthy gravidas. These complications probably result, at least in part, from the action of estrogens to stimulate the underlying immunologic disorder of SLE. In addition, women with hypertension, renal functional abnormalities, or other complications resulting from SLE are likely to share the same risk factors as women with these afflictions due to non-SLE disorders. Recent studies, however, show that the incidence of clinical flares during pregnancy and diminished fetal survival are not as exaggerated as were described in earlier reports and small case series, probably owing to more adequate suppression of SLE activity with glucocorticoids and immunosuppressive drugs, and to improvements in fetal monitoring and maternal care. Women in complete clinical remission, regardless of previous manifestations of SLE, appeared to have the best outlook for uncomplicated pregnancies and the highest incidence of fetal survival. In our judgment, gravidas with established SLE should be managed in a perinatal program with an expertise available for careful systematic fetal monitoring; ready access to consultants in nephrology, rheumatology, and other relevant disciplines; and inpatient facilities for complicated gestations. In addition, all women with SLE should be screened for anti-Ro (SS-A) antibodies in order to identify fetuses at risk for cardiac conduction defects. Women with a history of recurrent in utero fetal deaths or spontaneous abortions should be screened for LE-anticoagulant, even in the absence of clinical signs of SLE.

To define the interrelationship between changes in total renal blood flow (TRBF) and proximal tubular hydrostatic pressure (PTP), rats were studied 2, 3, 4, 6, 12, 18, and 24 h after bilateral ureteral occlusion (BUO). In control animals, a peak rise in both TRBF (3.52 +/- 0.26 ml . min-1 . 100 g body wt-1 . kidney-1) and PTP (28.6 +/- 1.3 mmHg) occurred 3 h after BUO. At each subsequent time interval, both TRBF and PTP fell, so that by 24 h after BUO, TRBF was 1.53 +/- 0.34 and PTP was 16.5 +/- 0.6, while in sham-operated rats the values were 2.52 +/- 0.22 ml . min-1 . g body wt-1 . kidney-1 and 12.8 +/- 0.2 mmHg, respectively. In animals treated with indomethacin (10 mg/kg) at the time of BUO, the alterations in both TRBF and PTP were completely ameliorated. At 3 h, TRBF was 1.8 +/- 0.32 ml . min-1 . 100 g body wt-1 . kidney-1 and PTP was 15.3 +/- 1.0 mmHg. TRBF and PTP remained essentially unchanged at each subsequent time period. These data indicate that 1) alterations in TRBF and PTP follow a similar and parallel pattern during BUO; 2) the pattern of changes in TRBF and PTP can be eliminated by treatment with indomethacin; and 3) renal hemodynamics appear to be the dominant factor in producing these changes during the first 12 h after BUO, whereas a sustained increase in tubular hydrostatic pressure may play a primary role in decreasing TRBF 12-24 h after ureteral occlusion.

To investigate the sites of action of aldosterone (Aldo) and chronic potassium loading (high K) and to determine whether dietary K can modulate collecting duct structure independent of Aldo, a morphometric study of the structure of the initial collecting tubule (ICT), the cortical collecting tubule (CCT), the medullary collecting duct in the outer stripe (MCDOS) and the inner stripe (MCDIS), and the papillary collecting duct (PCD) was carried out in a rat model in which plasma levels of Aldo were clamped at basal or physiologically elevated levels and high K could be induced without concomitant hyperaldosteronism. Elevated levels of Aldo increased cell area (Ac) and basolateral membrane surface (BLM) from control values in the ICT, CCT, and MCDOS but not in the MCDIS or PCD. High K with normal physiological levels of Aldo increased BLM in the ICT and CCT without a concomitant change in AC. No response was seen in MCDOS, MCDIS, or PCD. It is concluded that Aldo can modulate principal cell structure in the collecting duct system in segments extending from the ICT through the MCDOS in the rat and that high K independent of Aldo can influence collecting duct structure only in the ICT and CCT.

The course of 41 pregnancies was studied in 25 patients with renal disease. Histological classification of the disease in each patient was made by renal biopsy. The analysis suggests that the course of pregnancy in women with coexistent renal disease correlates with the underlying renal lesion and probably with the glomerular filtration rate and blood pressure. In patients with heavy proteinuria there is increased oedema formation, making the nephrotic syndrome a frequent complication.

Previous studies in rat distal colon provide evidence for an active absorptive process for potassium under basal conditions, and for active potassium secretion during chronic dietary potassium loading. The present studies were performed with conventional and potassium-selective microelectrodes to determine the electrical basis for the increase in transcellular (active) potassium secretion observed during potassium loading. Compared to control tissues, potassium loading resulted in a 5-fold increase in transepithelial voltage (VT) and a 52% decrease in total resistance (RT) in the distal colon. The rise in VT was due to a decrease in apical membrane resistance and an increase in basolateral membrane voltage from -45 +/- 2 mV (cell interior negative) in control to -56 +/- 2 mV (p less than 0.001) in potassium loaded tissues. This difference in basolateral membrane voltage reflected in increase in intracellular potassium activity from 86 +/- 4 mM to 153 +/- 12 mM (P less than 0.001). In control tissues, the sequential mucosal addition of the sodium channel blocker amiloride (0.1 mM) and the potassium channel blocker tetraethylammonium chloride (TEA: 30 mM) produced no effect on the electrical measurements. However, in potassium loaded tissues, amiloride and TEA produced transepithelial changes consistent with inhibition of apical membrane conductances for sodium and potassium, respectively, reflected by increases in the resistance ratio, alpha (ratio of apical to basolateral membrane resistances). These data indicate that the decrease in apical membrane resistance during potassium loading was caused by an increase in apical membrane conductance for both potassium and sodium.

The prognostic markers in 87 consecutive patients with lupus nephritis who underwent renal biopsy are reported for five clinically relevant long-term outcomes--renal insufficiency, renal failure, death due to renal systemic lupus erythematosus, death due to non-renal SLE and death due to SLE, both renal and non-renal. We have demonstrated that a number of previously neglected or rarely studied predictors were important prognostic markers. These included the duration of renal disease before biopsy, overall severity of SLE, as well as the presence of vasculitis, hypertension or a comorbid ailment. Furthermore, the study confirms the predictive importance of serum creatinine, 24-h urinary excretion of protein, C3, and of the activity and chronicity indices on biopsy. However, overall a simple measure of tubulointerstitial disease was the best predictor obtained from biopsy. Prognostic models based on clinical data alone were developed for each of the five outcomes. The models amplify our clinical understanding of lupus nephritis. Markers of renal severity were most important in predicting renal outcomes such as renal insufficiency and renal failure. Prognostic factors less directly related to renal disease (comorbidity and vasculitis) were important predictors of fatality. A marker of immunologic disease activity (C3) was a valuable predictor for many of the outcomes. Thus markers of disease severity reflecting organ damage due to SLE and other comorbid conditions could be combined with markers of immunologic activity to predict a variety of outcomes of relevance to a clinician. When biopsy data obtained by light or electron microscopy were evaluated for their ability to add new predictive information to the clinical models, only a limited value for biopsy was noted. It is likely that this reflected the close correlational relationships between clinical and biopsy variables, the strong clinical models generated, and the inclusion in the clinical models of the previously neglected clinical variables, duration of renal disease before biopsy and the presence of vasculitis or comorbid disease.

Removal of renal tissue stimulates functional and anatomical adaptation in the remaining renal parenchyma. Since recent studies have demonstrated no apparent limitation in compensatory growth following progressive surgical ablation, experiments were performed to determine the changes in glomerular filtration rate and renal blood flow. After removal of 50% of the renal mass mean nephron glomerular filtration rate increased 60%, and after ablation of 75% of the renal tissue it increased 150%. These changes paralleled the increases in renal growth under the same conditions. In comparison, mean glomerular blood flow rose 90% and 240% after 50% and 75% nephrectomy, respectively; these changes in relation to the changes in glomerular filtration rate resulted in a progressive fall in the filtration fraction. Intrarenal blood flow distribution was examined with labeled microspheres. The marked increase in renal blood flow after surgical ablation was characterized by a disproportionate rise in blood flow to the inner cortex. The present investigation, therefore, described the remarkable functional changes that occur as overall glomerular filtration rate declines and provides further insight into the mechanism responsible for maintaining water and electrolyte homeostasis after loss of functioning renal mass.

A quantitative study of compensatory adaptation in renal growth, function, and blood flow after progressive renal ablation was performed in the rat. Four weeks after surgery, renal mass increased 31% in control animals (Group A), 81% in nephrectomized rats with 50% ablation of total renal mass (Group B), and 168% in rats subjected to 75% ablation of total renal mass (Group C). Whole animal glomerular filtration rate (GFR) was reduced to 68% of control levels after nephrectomy (Group B), while renal blood flow (RBF) was 81% of control. Similarly, RBF was 68% of control in Group C with ablation of 75% of renal mass, while GFR was reduced to 49% of control. Since the adaptive increases in RBF exceeded those of GRF, the filtration fraction fell from 0.39 in Group A to 0.35 in Group B, and to 0.29 in Group C. Mean nephron GFR (whole animal GFR per total number of glomeruli) was 47 nl per min in Group A and increased 60% to 76 nl per min in Group B and 136% to 112 nl per min in Group C. Compensatory changes in mean nephron blood flow (RBF per total number of glomeruli) exceeded those of nephron filtration rate. Mean nephron blood flow increased from 215 nl per min in Group A to 404 nl per min in Group B (88%) and to 724 nl per min in Group C (237% over contol). These data indicate that the compensatory changes in growth, function, and blood flow after resection of renal mass correlate with the amount of tissue removed. Changes in RBF parallel but exceed those of mass and function, especially after extensive renal ablation. No apparent limitation to the compensatory response was seen under the conditions of this study.

Repeat DC countershock reproducibly results in myocardial necrosis in dogs. In this model, myocardial technetium-99m pyrophosphate (PYP) uptake correlates linearly with tissue creatine kinase depletion (r = -0.83). The effect of pretreatment with methylprednisolone (MP) was studied with PYP in 25 dogs. In myocardium damaged by countershock, 12 MP dogs had higher tissue radioactivity sample:normal (S:N) ratios than control (P less than 0.05), suggesting increased tissue injury. However, by several other measures of tissue damage, the two groups did not differ. MP-elevated PYP S:N ratios were explained by reduced PYP activity in normal myocardium of MP dogs. Further experiments in 21 dogs revealed that renal PYP clearance, which correlated with glomerular filtration rate (GFR) as measured by creatinine clearance, was increased in Mp dogs, resulting in accelerated urinary excretion of PYP (46.9+/-3.6 vs 35.8+/-2.4 percent injected dose in one hour, P less than 0.01), and reduced blood PYP. Thus MP does not modify countershock-induced myocardial injury. However, by increasing GFR, MP increased PYP excretion, resulting in lowered blood and normal zone myocardial PYP, thereby spuriously affecting myocardial PYP tissue uptake data.

To examine the role of intrarenal hemodynamics in in obstructive nephropathy, we determined cortical blood flow distribution (CBFD) in rats with bilateral ureteral occlusion (BUO) and unilateral ureteral occlusion (UUO) during and after release of obstruction. Prior to release of obstruction of 24 hours' duration, we found that outer cortical perfusion decreased by 20+/-5% in both BUO and UUO rats. Furthermore, one hour after release of BUO, there was rapid normalization of CBFD associated with a modest return of glomerular filtration rate (GFR), an almost complete return of renal blood flow (RBF), and a marked postobstructive diuresis. In contrast, after release of UUO, we observed that outer cortical perfusion remained decreased by 21+/-31%, both GFR and RBF remained markedly depressed, and no diuresis occurred. These data demonstrate (1) marked ischemia of the outer cortex in both BUO and UUO during obstruction, (2) a rapid return of CBFD to a normal pattern after release of BUO, but (3) persistent outer cortical ischemia following release of UUO.

The present experiments were designed to differentiate the effects of aldosterone and chronic potassium loading in the mechanism of colonic potassium adaptation, using a recently described animal model that permits systematic manipulation of aldosterone and dietary potassium. Unidirectional 42K fluxes were performed under short-circuit conditions across isolated distal colonic mucosa from rats with intact adrenal glands and in adrenalectomized, hormone-replaced animals. Administration of a potassium-enriched diet reversed net potassium absorption (+0.43 +/- 0.10 muEq/h.cm2) in intact animals to net potassium secretion (-0.76 +/- 0.08 muEq/h.cm2). Infusion of aldosterone in adrenalectomized animals, in an amount equivalent to that produced by potassium loading in intact rats, reduced JnetK to zero (-0.03 +/- 0.06 muEq/h.cm2). Similarly, zero net potassium transport (-0.14 +/- 0.08 muEq/h.cm2) was observed when experimental rats were fed a potassium-enriched diet and maintained with basal aldosterone levels. Therefore, both elevated aldosterone levels and a potassium-enriched diet had an effect on net potassium transport, but neither produced the full effects of chronic potassium loading. An increase in net potassium secretion (-0.57 +/- 0.07 myEq/h.cm2) comparable to that of intact potassium-loaded animals did, however, occur when potassium loading and elevated aldosterone levels were combined in experimental animals. These studies demonstrate that (a) chronic potassium loading alters active potassium transport by an aldosterone-independent mechanism and (b) the mechanism of chronic potassium adaptation represents the additive effects of increased dietary potassium and aldosterone.

Although it is well established that parathyroid hormone and phosphate are important regulators of 1,25-dihydroxyvitamin D [1,25(OH)2D] production, it remains unclear whether calcitonin affects vitamin D metabolism in vivo. Experiments were performed in the rat to determine the effect of chronic calcitonin infusion (0.2 U X h-1) on plasma levels of vitamin D metabolites and on calcium metabolism. Thyroparathyroidectomized animals fed a calcium-replete or calcium-free diet were studied for as long as 2 wk before they were killed. In control rats, a calcium-free diet alone for 12 d resulted in an increase in 1,25(OH)2D levels from 24 +/- 5 to 139 +/- 37 pg . ml-1, P = 0.025. The infusion of calcitonin also stimulated 1,25(OH)2D levels compared with controls on a regular diet (80 +/- 17 vs. 38 +/- 6 pg . ml-1, P less than 0.05) and on a calcium-free diet (460 +/- 50 vs. 139 +/- 37 pg . ml-1, P less than 0.001). In addition, calcitonin increased plasma calcium levels in animals on a regular diet by 50%; this effect was most likely due to increased intestinal absorption of calcium, because removal of calcium from the diet markedly blunted this effect. In contrast, calcitonin administration did not significantly affect 25(OH)D plasma levels. Collectively, these data suggest that calcitonin and calcium are independent regulators of 1,25(OH)2D production and that calcitonin stimulates intestinal absorption of calcium, by increasing circulating levels of 1,25(OH)2D.

Chronic potassium loading results in an increased capacity of the distal nephron to secrete potassium. The cellular mechanism for this adaptation has been correlated to an increase in the activity of sodium-potassium-ATPase. Because adaptation may be dependent on the greater availability of potassium pumps in the basolateral membrane, a stereologic analysis of the membrane surface area was performed to determine whether the apparent increase in pump sites was due to an increase in cell membrane surface. With potssium adaptation, the number of microplicated cells in the outer medulla was reduced from 31 to 18%. There was a marked increase in the basolateral infolding of principal cells, and membrane surface increased by 32%. In papillary collecting duct cells, the basolateral membrane surface was unchanged but the surface density of the luminal membrane increased by 50%. These observations suggest that amplification of the basolateral cell membrane to increase the number of potassium pump sites per cell plays an important role in the mechanism of potassium adaptation in the outer medulla. A different mechanism involving the luminal membrane operates in the papillary collecting duct. Structural alterations in cell membrane surfaces are thus related to the regulation of the epithelial transport of electrolytes.

Unlabelled: The model of sodium and chloride transport proposed for the colon is based on studies performed in the distal segment and tacitly assumes that ion transport is similar throughout the colon. In rat distal colon, neutral sodium-chloride absorption accounts for the major fraction of overall sodium absorption and aldosterone stimulates electrogenic, amiloride-sensitive sodium absorption. Since we have demonstrated qualitative differences in potassium transport in proximal and distal segments of rat colon, unidirectional 22Na and 36Cl fluxes were performed under short-circuit conditions across isolated proximal colon of control and sodium-depleted rats with secondary hyperaldosteronism. In the control group, net sodium absorption (JNanet) (7.4 +/- 0.5 mu eq/h . cm2) was greater than Isc (1.4 +/- 0.1 mu eq/h . cm2), and JClnet was 0 in Ringer solution. Residual flux (JR) was -5.2 +/- 0.5 mu eq/h . cm2 consistent with hydrogen ion secretion suggesting that neutral sodium absorption may represent sodium-hydrogen exchange. 1 mM mucosal amiloride, which inhibits sodium-hydrogen exchange in other epithelia, produced comparable decreases in JNanet and JR (4.1 +/- 0.6 and 3.2 +/- 0.6 mu eq/h . cm2, respectively) without a parallel fall in Isc. Sodium depletion stimulated JNanet, JClnet, and Isc by 7.0 +/- 1.4, 6.3 +/- 1.9, and 0.8 +/- 0.2 mu eq/h . cm2, respectively, and 1 mM amiloride markedly inhibited JNanet and JClnet by 6.0 +/- 1.1 and 4.0 +/- 1.6 mu eq/h . cm2, respectively, with only a minimal reduction in Isc., Conclusions: the predominant neutral sodium-absorptive mechanism in proximal colon is sodium-hydrogen exchange. Sodium depletion stimulates electroneutral chloride-dependent sodium absorption (most likely as a result of increasing sodium-hydrogen and chloride-bicarbonate exchanges), not electrogenic chloride-independent sodium transport. The model of ion transport in the proximal colon is distinct from that of the distal colon.

Studies were performed in the rat to determine the effect of lithium on electrolyte transport in distal portions of the nephron since steep corticomedullary gradient for lithium has been demonstrated and ionic competition and/or substitution of lithium for sodium and potassium may play a role in inhibition of vasopressin-induced water transport. During the intravenous infusion of LiC1, in the absence of volume expansion and at plasma levels of 2-5 mequiv/liter of Li, maximum urine con-entration was inhibitied. Under the same conditions lithium administration impaired potassium secretion and urinary acidification and resulted in a natriuresis. These results indicate that lithium affects electrolyte transport in the same nephron segments in which the action of vasopressin is inhibitied. In addition, evidence is provided that suggests that during the chronic administration of LiC1, the sustained increase in oral intake of water and urinary flow rate results from an increase in thirst as well as reduced renal concentrating ability.

Increased dietary potassium ("potassium loading") induces several adaptive changes in colonic function, including increased potential-dependent potassium secretion, active potassium secretion, and Na-K-ATPase activity, but does not alter net sodium absorption in vivo. To establish whether potassium loading stimulates active sodium transport, unidirectional, net sodium, and chloride fluxes were determined under voltage-clamp conditions across isolated rat distal colonic mucosa. In normal animals net sodium flux (JNanet), net chloride flux (JClnet) and short-circuit current (Isc) were 6.1 +/- 1.1, 8.4 +/- 1.0, and 0.7 +/- 0.1 mu eq X h-1. cm-2, respectively; potassium loading significantly increased JNanet and Isc by 4.9 +/- 1.4 and 3.5 +/- 0.7 mu eq X h-1 X cm-2, respectively, without changing JClnet. Amiloride (0.1 mM) inhibited the increases in JNanet and Isc produced by potassium loading. In Cl-free Ringer solution in normal animals JNanet was reduced to 0.6 +/- 0.3 mu eq X h-1 X cm-2. Potassium loading produced identical increases in JNanet and Isc, which were also completely inhibited by 0.1 mM amiloride. These studies establish that potassium loading induces amiloride-sensitive electrogenic sodium absorption without affecting electroneutral sodium-chloride absorption.

Studies were performed in the rat, under steady-state conditions, to determine the mode of potassium transport in the late distal tubule. In these experiments the potential difference and potassium activity were measured simultaneously in steady-state fluid droplets in control rats, during acute infusion of KCl, and in potassium-deficient rats. The results demonstrate active potassium secretion in the late distal tubule of the control and KCl-infused animals, since the observed potassium activity of 11.14 +/- 1.39 in control animals and 25.26 +/- 2.96 meq/liter in potassium-loaded animals was significantly greater than the predicted values of 7.75 +/- 0.59 and 14.01 +/- 0.94 meq/liter in the same groups, respectively. In potassium-deficient animals, however, the observed potassium activity in luminal fluid of 4.03 +/- 0.55 meq/liter was not different from the predicted value of 4.26 +/- 0.32. In summary, this study demonstrates that potassium secretion in the late distal tubule of the rat occurs by an active process and fails to demonstrate active absorption in the same tubular segment.

Chronic K loading and Na deficiency increase the capacity of colonic cells to secrete K and are characterized by increases in Na-K-ATPase activity and, as recently shown by our laboratory, the area of basolateral membrane. The present experiments were performed in rat colon to evaluate the quantitative and qualitative changes that occur in the enzymes after induction of K adaptation. Changes in specific binding of [3H]ouabain to a plasma membrane-rich fraction of colonic mucosal cells correlated directly with changes in enzyme activity. In Na-deficient animals the number of ouabain-binding sites increased from 63.6 in controls to 111.2 pmol/mg protein, while the KD for ouabain was unchanged. The Km for ATP was not altered in experimental animals, although Vmax rose twofold. Further studies showed no change in the activity of adenylate cyclase, a marker enzyme for basolateral membrane, in the plasma membrane-rich fraction from experimental cells, although Na-K-ATPase activity increased significantly. These data indicate that increased Na-K-ATPase activity in K-adapted colonic cells reflects an absolute increase in number of pump sites, due, at least in part, to an increase in area of basolateral cell membrane. In addition, in sodium-deprived animals the present data suggest an increase in the density of K pumps in basolateral cell membrane.

Studies were performed to 1) systematically compare Ling-Gerard microelectrodes and electrodes with large tips (3 to 5 mu O.D.) in the measurement of the transepithelial potential difference (PD) in the mammalian distal tubule and 2) to examine the sign and magnitude of the transepithelial PD along the length of the distal tubule. Recordings made with the tips of both types of electrodes placed together in the same tubule segment demonstrated no difference in transepithelial PD. Rapid influx of tubular fluid into the macroelectrode, however, was found to depolarize the tubular membrane, as recorded by both types of electrodes simultaneously. Technical critera were therefore established to prevent rapid influx of fluid and efflux of potassium chloride, filling the electrode, in the use of exploring electrodes with large tips. The sign of the transepithelial PD in early distal tubule was found to be negative and averaged -17.7 +/- 9.4 (mean +/- SEM) in Sprague-Dawley rats and approximately -12 mV in Wistar-Munich rats. The site of puncture was identified by dye transit time rate, microdissection, and cell morphology. The transepithelial PD increased along the length of the distal tubule and averaged -41.9 +/- 8.5 in the last portion accessible to examination.

Both mineralo- and glucocorticoids stimulate renal Na-K-ATPase, but their relative role in the regulation of the enzyme remains controversial. In this study we measured Na-K-ATPase activity in the cortical collecting tubule (CCT) of adrenalectomized rats replaced with either the native mineralocorticoid (aldosterone) or glucocorticoid (corticosterone) in doses calculated to yield previously determined physiologic concentrations of these hormones (5 ng X dl-1 and 5 micrograms X dl-1, respectively). This was achieved by continuous delivery of aldosterone (1 microgram X 100 g-1 X d-1) from an osmotic minipump or of corticosterone (2 pellets of 20 mg each), implanted subcutaneously either at adrenalectomy or 7 d later, when Na-K-ATPase activity reached its nadir. Adrenalectomized rats not receiving hormone replacement and adrenal-intact animals served as controls. The CCT was chosen because it contains the highest concentration of binding sites for both hormones. Na-K-ATPase activity declined 52% in the CCT of untreated adrenalectomized rats after 7 d, and remained unchanged thereafter. Physiologic replacement doses of aldosterone prevented this decline and restored the activity of the enzyme after it had been allowed to decrease maximally following adrenal ablation, whereas similar replacement of corticosterone was without effect. These observations suggest that under physiologic conditions Na-K-ATPase in the CCT, a probable target nephron segment of both hormones, is under mineralocorticoid rather than glucocorticoid control.

The acute effects of single pharmacological doses of glucocorticoid hormones on net electrolyte and water transport and electrical potential difference (pd) in the rectum was studied in control subjects and in patients with either active or inactive ulcerative colitis, using a dialysis technique. Compared with 17 control subjects, nine patients with active ulcerative colitis exhibited marked decreases in net sodium absorption and rectal pd, while these transport parameters were normal in six patients with inactive ulcerative colitis. Intravenous administration of hydrocortisone hemisuccinate (100 mg) resulted five hours later in significant and quantitatively similar increases in net sodium and water absorption and pd in nine control subjects, seven patients with active ulcerative colitis, and six patients with inactive ulcerative colitis. Intravenous administration of methylprednisolone phosphate (40 mg) to eight control subjects produced increases in net sodium and water absorption and pd five hours later, which did not differ significantly from those produced by hydrocortisone; methylprednisolone induced similar changes in two patients with active ulcerative colitis. These results indicate that single pharmacological doses of glucocorticoids stimulate acute increases in rectal sodium and water absorption in control subjects and in patients with acute ulcerative colitis. The ability of systemically administered glucocorticoids to reduce diarrhoea in ulcerative colitis may therefore be related to direct effects on distal colonic sodium and water transport, as well as to their better known anti-inflammatory action.

The age-dependent characteristics of compensatory renal growth were studied in neonatal, weanling and young adult rats. Compensatory growth was demonstrated to be greater in young, sexually immature animals than in adults following unilateral nephrectomy. In the four-week interval following surgery in 21-day-old weanling rats, renal mass increased 240% in control animals (group A) and 407% after unilateral nephrectomy (group B). In similarly prepared adult animals, renal weight increased 31 and 81% in the same groups, respectively. The remarkable response in compensatory growth achieved by the young animal was further demonstrated by a greater absolute increase in renal mass in the experimental kidney of young rats compared to adults. Further studies were performed to determine whether the mechanism of compensatory growth in young rats involved formation of new nephrons. The total glomerular count in the remaining kidney of rats after removal of one kidney at 5 (neonatal) and 21 (weanling) days of life did not differ from the value obtained in control neonatal, weanling or adult kidneys. These data indicate that compensatory renal hypertrophy is age-dependent and is greater in young animals. The mechanism for enhanced compensatory renal growth in young animals does not involve glomerular neogenesis since there was no evidence for formation of additional nephrons following nephrectomy either in weanling or neonatal animals.

The present in vivo studies were performed in the rat to determine whether the colon was capable of net potassium absorption, as well as secretion, and to further elucidate the process responsible for net potassium movement. Both the proximal and distal lumina of the colon of control, potassium-deficient, and potassium-loaded animals were perfused with solutions containing either 140 or 20 mmol/l sodium. Net potassium secretion was present in both proximal and distal colon of control animals during perfusion with the 140 mmol/l sodium solution. The rate of net potassium secretion was reduced in the potassium-deficient animals. During perfusion with the 20 mmol/l sodium solution, the rate of potassium secretion was also reduced (compared with control perfusion solution) in both the control and potassium-deficient animals. As a result, there was net potassium absorption (0.94 +/- 0.14 mueq.1-1.g dry wt-1) and zero net potassium movement in the distal and proximal segments, respectively, of the potassium-deficient animals perfused with the low-sodium solution. Additional studies were performed to determine whether net potassium secretion was saturable and showed that, during progressive increases in the plasma potassium level, net secretion was constant at plasma potassium levels above 11-13 meq/l. These data, therefore, demonstrate that the mammalian colon regulates intestinal transport of potassium by both absorptive and secretory mechanisms and that a carrier-mediated process probably regulates both transport processes.

The present report documents the occurrence of lupus nephropathy as the sole initial manifestation of systemic lupus erythematosus (SLE). Despite the absence of initial systemic signs characteristic of SLE, the diagnosis was confirmed on the basis of the renal histopathologic features and serological studies. Subsequent follow-up demonstrated systemic features of the disease in each of the four patients. The report shows that the diagnostic criteria for SLE proposed by the American Rheumatology Association may not be fulfilled at the time of the initial evaluation in all cases, and that some patients may exhibit signs attributable to primary renal disease. These data emphasize the importance of careful assessment of the pattern of glomerular ultrastructural changes and usefulness of appropriate serological studies.

Recent studies of relatively large numbers of gravidas with primary renal disease indicate that pregnancy probably does not affect the underlying disease in the absence of overt renal insufficiency or hypertension. Women with renal disease and near normal function have a moderate risk for encountering a rise in blood pressure and decline in renal function during pregnancy, complications that are usually manageable and reversible after delivery. There is a substantial risk, however, that heavy proteinuria and edema formation may occur toward the latter stages of pregnancy, especially in women with preexisting proteinuria, although this complication also usually reverses after delivery and does not affect the underlying renal disease. The question of the effect of pregnancy on renal disease in women with moderate renal insufficiency at the start of pregnancy is unanswerable on the basis of available data. Published reports indicate that severe hypertension is a major complicating factor during pregnancy in many of these women and, on theoretical grounds, may play an important role in aggravating the renal lesion. To resolve this question, studies are required in which prepregnancy levels of GFR are carefully monitored, a specific diagnosis of the underlying renal disease is established, and elevated blood pressure levels are normalized during pregnancy.

Studies were performed in the rat to determine the transepithelial potential difference (PD) of the medullary collecting duct (MCD). With the microcatheter as an exploring electrode the PD from duct lumen to the reference electrode, placed in peritoneal fluid, was approximatley 1 mV, lumen positive, in the MCD. It was unlikely that the polarity and small magnitude of PD was due to an artifact created by the microcatheter, since essentially similar results were obtained by transmural puncture of the inner third of the duct using Ling-Gerard glass electrodes and glass microelectrodes, tip OD 3-5 micron. Moreover, a PD of a few millivolts, lumen positive, was observed in experimental states characterized by marked increases in potassium and hydrogen ion secretion and sodium absorption. Further studies showed that the diffusion potential existing within the interstitial fluid compartment, between papilla and reference electrode, was approximately +2 mV, owing to the higher NaCl concentration in the papillary area. These data demonstrate, therefore, that the transepithelial PD in MCD approaches zero in control animals, and is not substantially altered by marked changes in net electrolyte transport.

An experimental model of hyperparathyroidism was developed in the rat to simulate primary hyperparathyroidism in humans. In this model thyroparathyroidectomized (TPTX) or parathyroidectomized (PTX) animals were infused for 6 days with an amount of bovine synthetic parathyroid hormone (PTH)-(1-34) fragment to restore plasma calcium levels to normal (0.7 U X h-1) or with PTH at twofold (1.4 U X h-1) or threefold (2.1 U X h-1) this basal level. Animals infused with 2.1 U X h-1 of bovine PTH-(1-34) exhibited hypercalcemia, hypophosphatemia, a reduction in theoretical renal threshold for phosphate and an increase in 1,25-dihydroxyvitamin D plasma levels that were approximately threefold the control value. In addition, these animals demonstrated nephrocalcinosis and changes of bone histology that were typical of the findings in patients with primary hyperparathyroidism. In contrast, in animals infused at 1.4 U X h-1, plasma calcium, phosphate, and theoretical renal threshold for phosphate remained within normal limits, but plasma 1,25-dihydroxyvitamin D was increased above control, suggesting that increased activity of 1 alpha-hydroxylase may be the most sensitive index of increased PTH levels. This animal model permits sustained elevation of PTH plasma levels at basal or pathologically elevated levels and should provide an effective means by which to evaluate the consequences of chronic hyperparathyroidism on epithelial function, bone, and other organ systems.