Mechanisms of portal hypertension-induced alterations in renal hemodynamics, renal water excretion, and renin secretion.

Clinical states with portal venous hypertension are frequently associated with impairment in renal hemodynamics and water excretion, as well as increased renin secretion. In the present investigation, portal venous pressure (PVP) was increased in anesthetized dogs undergoing a water diuresis. Renal arterial pressure was maintained constant in all studies. As PVP was increased from 6 to 20 mm Hg, decreases in cardiac output (2.5-2.0 liter/min, P less than 0.05) and mean arterial pressure (140-131 mm Hg, P less than 0.05) were observed. Increases in PVP were also associated with decreases in glomerular filtration rate (GFR, 40-31 ml/min, P less than 0.001), renal blood flow (RBF, 276-193 ml/min, P less than 0.001), and increases in renin secretion (232-939 U/min, P less than 0.025) in innervated kidneys. No significant change in either GFR or RBF and a decrease in renin secretion occurred with increases in PVP in denervated kidneys. To dissociate the changes in cardiac output and mean arterial pressure induced by increase PVP from the observed decreases in GFR and RBF, studies were performed on animals undergoing constriction of the thoracic inferior vena cava. In these studies, similar decreases in cardiac output and mean arterial pressure were not associated with significant changes in GFR or RBF. Increases in PVP also were associated with an antidiuresis as urine osmolality increased from 101 to 446 mosmol/kg H2O (P less than 0.001). This antidiuresis was significantly blunted but not abolished by acute hypophysectomy. In hypophysectomized animals, changes in free water clearance and urine flow were linearly correlated as PVP was increased. These studies indicate that increases in PVP result in decreases in GFR and RBF and increases in renin secretion mediated by increased renal adrenergic tone. Increased PVP is also associated with antidiuresis; this antidiuresis is mediated both by vasopressin release and by diminished tubular fluid delivery to the distal nephron.

Dissociation of systemic and renal effects in endotoxemia. Prostaglandin inhibition uncovers an important role of renal nerves.

To elucidate the mechanisms responsible for systemic and renal hemodynamic changes in early endotoxemia, the roles of prostaglandins (PG) and renal nerves were investigated. Endotoxin (E, 3 micrograms/kg i.v.) was given to two groups of anesthetized dogs that had undergone unilateral renal denervation: Group I (n = 9) E only; Group II (n = 11) E + indomethacin (10 mg/kg i.v.) or meclofenamate (5 mg/kg i.v.). A third group of dogs (Group III, n = 5) received indomethacin (10 mg/kg i.v.) only. 1 h after E group I dogs, mean arterial pressure (MAP) decreased from 126 to 94 mm Hg (P less than 0.001), and prostacyclin (6-keto-Fl alpha metabolite, PGI2) increased (from 0.64 to 2.08 ng/ml, P less than 0.005). Glomerular filtration rate (GFR) and renal blood flow (RBF) declined comparably both in innervated and denervated kidneys. In marked contrast, group II dogs had a stable MAP (136-144 mm Hg, NS) and no increase in PGI2 levels. Plasma renin activity (0.7-2.5 ng/ml per h, P less than 0.005) increased, and renin secretion was greater in innervated compared with denervated kidneys (255 vs. 74 U/min, P less than 0.01) in these PG-inhibited dogs. In addition, denervated kidneys in group II dogs had a greater GFR (42 vs. 34 ml/min, P less than 0.01) and RFB (241 vs. 182 ml/min, P less than 0.01) than innervated kidneys after E. Group III animals had no significant changes in systemic or renal hemodynamics, plasma renin activity or PGI2 during the study. These results suggest that PGI2 mediates the systemic hypotension of early endotoxemia in the PG-intact animal. Moreover, PG inhibition uncovers an important effect of E to increase efferent renal nerve activity with a consequent decline in GFR and RBF independent of changes in MAP. Finally, the results demonstrate that renal nerves are important stimuli to renin secretion in early endotoxemia via pathways that are PG-independent.

Dexamethasone modulates rat renal brush border membrane phosphate transporter mRNA and protein abundance and glycosphingolipid composition.

Glucocorticoids are important regulators of renal phosphate transport. This study investigates the role of alterations in renal brush border membrane (BBM) sodium gradient-dependent phosphate transport (Na-Pi cotransporter) mRNA and protein abundance in the dexamethasone induced inhibition of Na-Pi cotransport in the rat. Dexamethasone administration for 4 d caused a 1.5-fold increase in the Vmax of Na-Pi cotransport (1785 +/- 119 vs. 2759 +/- 375 pmol/5 s per mg BBM protein in control, P < 0.01), which was paralleled by a 2.5-fold decrease in the abundance of Na-Pi mRNA and Na-Pi protein. There was also a 1.7-fold increase in BBM glucosylceramide content (528 +/- 63 vs. 312 +/- 41 ng/mg BBM protein in control, P < 0.02). To determine whether the alteration in glucosylceramide content per se played a functional role in the decrease in Na-Pi cotransport, control rats were treated with the glucosylceramide synthase inhibitor, D-threo-1-phenyl-2-decanoyl-amino-3-morpholino-1-propanol (PDMP). The resultant 1.5-fold decrease in BBM glucosylceramide content (199 +/- 19 vs. 312 +/- 41 ng/mg BBM protein in control, P < 0.02) was associated with a 1.4-fold increase in Na-Pi cotransport activity (1422 +/- 73 vs. 1048 +/- 85 pmol/5 s per mg BBM protein in control, P < 0.01), and a 1.5-fold increase in BBM Na-Pi protein abundance. Thus, dexamethasone-induced inhibition of Na-Pi cotransport is associated with a decrease in BBM Na-Pi cotransporter abundance, and an increase in glucosylceramide. Since primary alteration in BBM glucosylceramide content per se directly and selectively modulates BBM Na-Pi cotransport activity and Na-Pi protein abundance, we propose that the increase in BBM glucosylceramide content plays an important role in mediating the inhibitory effect of dexamethasone on Na-Pi cotransport activity.

Recovery from rapidly progressive glomerulonephritis. Improvement after plasmapheresis and immunosuppression.

Two patients with rapidly advancing renal insufficiency underwent biopsy and were found to have crescentic glomerulonephritis. Patient 1 demonstrated findings compatible with Goodpasture's syndrome. Crescents were present in 100% of his glomeruli. Patient 2 had findings of immune complex-mediated glomerulonephritis and crescents in greater than 90% of his glomeruli. Both patients were treated with high-dose prednisone, cyclophosphamide, and plasmapheresis. Patient 2 additionally required hemodialysis for a brief period. Renal function improved in both patients and has not deteriorated after follow-up of 14 and 18 months, respectively. Repeated renal biopsies were performed in each patient. Our findings suggest that clinical improvement and histologic healing are possible in rapidly progressive glomerulonephritis despite the initial presence of crescents in every glomerulus.

Renal cell carcinoma: unusual systemic manifestations.

A series of cases is presented which illustrates unusual aspects in the presentation, diagnosis, and management of renal cell carcinoma. The entire "classic triad" of flank pain, gross hematuria, and palpable mass was not present at the time of diagnosis in any of the patients. Moreover, in only three patients did the initial clinical findings raise the suspicion of renal cell carcinoma. A diagnosis of polycystic kidney disease, cardiac failure, glomerulonephritis, analgesic abuse, and perirenal hemorrhage obscured the primary diagnosis in the other five patients. In four patients the tumor was probably present from 3 to 12 years before detection. These findings emphasize that knowledge of the hematologic, humoral, immunologic and vascular abnormalities induced by this tumor may provide a clue to early diagnosis. The systematic use of excretion urography, nephrotomography, ultrasonography, renal scanning, renal arteriography and cyst puncture then may allow the accuracy of radiologic diagnosis of this tumor to approach 100%. Lastly, the therapy of choice for this tumor is radical nephrectomy. Excision of apparently solitary metastases also may sometimes be feasible. However, partial nephrectomy to remove tumor in a solitary kidney was performed in one patient to avoid the need for end-stage kidney treatment. Where nephrectomy renders the patient anephric, chronic hemodialysis and renal transplantation should be considered as potential measures to sustain life. While hormonal agents, chemotherapy, and radiation therapy sometimes provide palliation, their use generally has been disappointing.

Aminoglycoside nephrotoxicity: pathogenesis and prevention.

Nephrotoxicity resulting from aminoglycoside antibiotics is a serious clinical problem and the incidence is probably increasing. The mechanism of renal toxicity is unclear but these agents affect several nephron functions including glomerular filtration, proximal tubular reabsorption, and urinary concentration. The degree of toxicity appears to correlate with the level of renal tissue concentration of aminoglycoside. Clinical nephrotoxicity is most likely to occur in the presence of volume depletion, advancing age, preexisting renal dysfunction and exposure to other nephrotoxins. Despite the use of dosing nomograms, nephrotoxicity still occurs in some patients and the decline in renal function may only become apparent after completion of the antibiotic course. Subclinical nephrotoxic effects from aminoglycosides probably occur in all patients treated with these agents and only the most severely affected have clinically apparent nephrotoxicity.

Southwestern Internal Medicine Conference: bone disease in kidney failure: diagnosis and management.

Recent technologic and therapeutic advances have improved the life of the patient with end-stage renal disease. High efficiency and high-flux hemodialyzer membranes have shortened the time required to dialyze, and recombinant erythropoietin has all but eliminated anemia as a major cause of morbidity, but the problem of renal osteodystrophy remains. The following discussion examines the spectrum of bone and joint disease in the patient with end-stage renal disease. The diagnostic and therapeutic strategies currently being tried in the management of these disorders are discussed.

Renal cell carcinoma.

Renal cell carcinoma accounts for 3% of all adult cancers and has many unusual features in its presentation, diagnosis, and management. It develops in a significant number of patients with acquired renal cystic disease, a disorder found almost exclusively in chronic hemodialysis patients. Abnormalities of chromosome 3 are frequently found in sporadic and familial forms. Radical nephrectomy remains the only potentially curative therapy for this tumor.

Drug therapy in the management of acute renal failure.

Pharmacologic intervention aimed at altering the natural history of acute renal failure is a routine practice without scientific support of efficacy. Oliguria has become a separate disease entity with an apparent disregard for the underlying condition that caused it. Volume expansion is clearly beneficial in preventing many volume depleted patients from progressing to acute renal failure. While mannitol and furosemide have been used to "convert" oliguric acute renal failure to the more easy to manage non-oliguric acute renal failure, published reports suggest that responders were not as ill as non-responders. The use of dopamine to increase urine flow in patients with established acute renal failure is the current fashion, but there is little evidence that this drug raises the glomerular filtration rate or shortens the course of acute renal failure. These pharmacologic therapies increase the complexity and cost of care with little tangible evidence of benefit to the patient or the physician caring for the patient.

Renal failure following radiologic procedures.

Radiologic procedures that employ intravascular contrast material with or without angiography may lead to renal failure. In procedures that use intravenous contrast alone, the mechanism of renal injury is not precisely known, but direct toxicity to renal tubular cells is likely to be a major factor. Ionic and nonionic contrast agents are both capable of causing this adverse reaction. Renal failure occurring during angiography may also be secondary to the effects of radiocontrast, but the additional possibility that micro cholesterol emboli have been dislodged from atheroma located on the intima of large vessels must be considered. The acute or subacute development of renal failure in the presence of skin changes (livido reticularis), hypertension, multiple organ failure or dysfunction, and a fatal outcome favors the later diagnosis.

Psychogenic polydipsia with hyponatremia: report of eleven cases.

Psychogenic polydipsia is an uncommon clinical disorder characterized by excessive water-drinking in the absence of a physiologic stimulus to drink. The excessive water-drinking is well tolerated unless hyponatremia supervenes. This report describes 11 patients with psychogenic polydipsia and hyponatremia (ten men and one woman) who were collectively hospitalized a total of 70 times for treatment of complications of this disorder. This group differs from the classical patient with psychogenic polydipsia, ie, a hospitalized schizophrenic, in that none was institutionalized and there was a high incidence of chronic alcoholism (10), intractable hiccups (7), self-induced vomiting (6), and laboratory evidence for rhabdomyolysis (5).

Heterogeneity in gentamicin clearance between high-efficiency hemodialyzers.

Gentamicin is frequently prescribed for treatment of gram-negative infections in patients on dialysis. The amino-glycoside is renally excreted; therefore, dosage modifications are required in patients on hemodialysis. The introduction of short-duration dialysis using high-efficiency hemodialyzers requires that the dialysance of gentamicin be re-examined. We recently demonstrated that high-efficiency dialyzers have a superior gentamicin clearance as compared with conventional dialyzers. In this study we examined the dialysance of gentamicin in two high-efficiency dialyzers using a randomized, controlled, cross-over design. Despite a comparable amount of dialysis (Kt/V urea), rate of dialysis (K/V urea), and ultrafiltration, there were significant differences noted in gentamicin removal between the high-efficiency cuprammonium rayon and polysulfone dialyzers. Furthermore, the amount of dialysis (Kt/V urea) could predict the fractional gentamicin clearance for the TAF 175L dialyzer (Terumo Corp, Somerset, NJ) and may be useful in the initial planning of gentamicin therapy. In addition, since gentamicin is a middle molecule (molecular weight, 500 to 2,000 d), the study suggests a superior middle molecule clearance of cuprammonium rayon dialyzer compared with a high-efficiency polysulfone dialyzer. The substantial heterogeneity in gentamicin clearance, even between dialyzers of the same class, emphasizes the importance of monitoring drug levels in hemodialysis patients receiving this drug.

Role of potassium in the pathogenesis of acute renal failure.

Potassium depletion can potentiate several experimental models of acute renal failure. It causes renal vasoconstriction, probably under the influence of vasoconstrictor prostaglandins and angiotensin II, and causes a reduction in vasodilatory prostaglandins. Aminoglycoside nephrotoxicity in experimental animals and in man causes a reduction in serum potassium and in animals it enhances the functional and histological damage produced by aminoglycosides. Chronic potassium loading protects against mercuric chloride, uranyl nitrate, and gentamicin models of acute renal failure. In the gentamicin model, protection is associated with a stimulation of renal cortical Na-K-ATPase activity and a reduction in the level of gentamicin accumulated in cortical tissue. In the clinical setting, potassium deficiency should be avoided in patients at risk for acute renal failure. However, potassium loading should also be avoided, since a falling glomerular filtration rate in the presence of a potassium load could result in potentially serious hyperkalemia.

Protective effect of thyroxine but not parathyroidectomy on gentamicin nephrotoxicity.

Gentamicin nephrotoxicity increases renal cortex calcium and sodium and decreases renal cortex Na-K-ATPase activity. Human acute renal failure is accompanied by an increase in parathyroid hormone (PTH), a hormone that stimulates calcium uptake by tissues, and by a decrease in thyroid hormone, a hormone that increases renal cortex Na-K-ATPase activity. This study evaluated the role of extracellular calcium, PTH, and thyroxine in the pathogenesis of gentamicin nephrotoxicity. Chronically parathyroidectomized hypocalcemic rats (PTXG) given gentamicin (30 mg/kg s.c. twice daily for 8 days) were not protected from renal failure when compared with intact rats given gentamicin (NG), serum creatinine being 4.4 +/- 1.0 and 3.7 +/- 0.7 mg/dl, respectively, compared with normals (N), 1.2 +/- 0.1 mg/dl. Rats given thyroxine (10 micrograms/100 g body wt for 10 days) before and during gentamicin (PTXT4G) had a serum creatinine not significantly different from normals, 2.1 +/- 0.4 mg/dl. Plasma T4 was reduced in PTXG, NG, and PTXT4G compared with N, but the value for PTXT4G was significantly higher than for either PTXG or NG. Renal cortex Na-K-ATPase activity (mumol Pi X mg prot-1 X h-1) was lower in PTXG (2.3 +/- 0.2) and NG (2.4 +/- 0.5) compared with N (3.7 +/- 0.1), but activity was not reduced in PTXT4G (3.2 +/- 0.2) Thyroxine was protective also against gentamicin nephrotoxicity in intact rats. Clearance and excretion studies indicated that this protection did not result from an increase in glomerular filtration rate, filtered load of calcium, or urinary calcium excretion.(ABSTRACT TRUNCATED AT 250 WORDS)

Early selective effects of gentamicin on renal brush-border membrane Na-Pi cotransport and Na-H exchange.

Gentamicin nephrotoxicity is associated with impairments in proximal tubular function. This study determined whether gentamicin administration to the rat, before a reduction in glomerular filtration rate (GFR), causes early and selective alterations in renal cortical brush-border membrane (BBM) enzyme and transport activity, lipid composition, and fluidity. Three days of gentamicin administration caused significant decreases in the Vmax of alkaline phosphatase, the Vmax of sodium gradient-dependent phosphate transport (Na-Pi cotransport), and the Vmax of pH gradient-dependent sodium transport (Na-H exchange). Gentamicin did not affect BBM-bound maltase or leucine aminopeptidase activities and sodium gradient-dependent glucose or proline transport activities. Gentamicin also caused a significant decrease in BBM sphingomyelin, significant increases in BBM phosphatidylcholine and phosphatidylinositol, a significant decrease in the phospholipid fatty acid saturation index, and a significant increase in BBM fluidity, i.e., decrease in the fluorescence anisotropy of diphenylhexatriene. These BBM functional and compositional effects of gentamicin were independent of endogenous parathyroid hormone activity. We conclude that gentamicin causes early and specific alterations in BBM enzyme and transport activity and also lipid composition, which may play an important role in the progression of renal cell injury.

Effect of potassium depletion on tubular morphology in gentamicin-induced acute renal failure in dogs.

Potassium deprivation has recently been reported to potentiate the degree of functional impairment in a gentamicin-induced model of acute renal failure. The present study investigated the effects of two different states of potassium homeostasis on the development of cellular injury in the early stage of gentamicin nephrotoxicity in dogs. Gentamicin (15 mg. per kg. intramuscularly twice daily) was administered for 4 and 7 days to potassium-depleted or potassium-supplemented animals. The results show that potassium supplementation markedly lessens the severity of pathologic alterations induced by gentamicin. In both groups of animals, the S1 and S2 segments of the proximal tubule were the most consistently damaged regions of of the nephron. Potassium-supplemented dogs had a significantly higher number of normal proximal tubule cells than did the animals deprived of potassium and viewed 7 days after gentamicin treatment (77.3 versus 36.9 per cent; p less than 0.025). The degree of total injury to the proximal tubule was significantly higher in potassium-depleted animals than in those supplemented with potassium (59.9 versus 21.9 per cent; p less than 0.05). Only those dogs depleted of potassium prior to the administration of gentamicin had a markedly elevated plasma creatinine level of proximal tubular injury and functional impairment (r = 0.81; p less than 0.005). Potassium supplementation appears to lessen the extent of structural alterations seen in this model of gentamicin-induced acute renal failure in dogs.

Glomerular architectural changes after a two-hour infusion of norepinephrine.

Alterations in glomerular architecture have been suggested to play a role in the pathogenesis of several models of acute renal failure. In this study, mongrel dogs were subjected to an intrarenal infusion of norepinephrine for 2 hours. Light microscopy and scanning and transmission electron microscopy were used to describe glomerular architecture 2 days after the initial norepinephrine infusion. In addition, scanning electron microscopy was used to quantitate the percentage of "abnormal areas" in glomerular capillary-loop morphology in both norepinephrine-infused kidneys and the contralateral control kidneys. Alterations in glomerular structure in these experiments appeared to be much less extensive than previously reported. A variable amount of glomerular pedical shape simplification was seen, which involved about 15% of the capillary loop. Quantitative evaluation revealed abnormal morphology of 15.2% +/- 0.6% of the glomerular capillary loop in the norepinephrine-infused kidneys, compared to 2.9% +/- 0.4 abnormal loop structure in the contralateral control kidneys (P less than 0.001). It is concluded that alterations in glomerular structure are not extensive in this model.

Protection by thyroxine in nephrotoxic acute renal failure.

Thyroxine (T4) protects against ischemic and nephrotoxic experimental acute renal failure (ARF). This study examined functional, biochemical, and morphological markers of uranyl nitrate (UN)-induced renal injury in the rat to determine the cellular site at which T4 exerts its protective effect. In experimental group UNT4, 1-thyroxine (10 micrograms/100 g body wt) was given for 10 days prior to and for 4 days following a single subcutaneous injection of UN (0.5 mg/kg body wt). Group UN received only UN, and group CT4 received only T4 for 14 days. Five days after UN administration, plasma creatinine rose from base line in group UNT4 (0.52 +/- 0.30 to 0.84 +/- 0.08 mg/dl, P less than 0.025) and group UN (0.52 +/- 0.03 to 1.64 +/- 0.13 mg/dl, P less than 0.001) but not in group CT4 (0.47 +/- 0.02 to 0.48 +/- 0.04 mg/dl, NS). However, plasma creatinine in group UNT4 was significantly lower than group UN (0.84 +/- 0.08 vs. 1.64 +/- 0.13 mg/dl, P less than 0.001). T4 administration stimulated the basolateral membrane-bound enzyme Na-K-ATPase in the renal cortex homogenate in group UNT4 (13.9 +/- 0.5 micron X mg protein-1 X h-1, P less than 0.005) and group CT4 (16.3 +/- 0.6 micron X mg protein-1 X h-1, P less than 0.001) when compared with controls (11.7 +/- 0.5 micron X mg protein-1 X h-1). Na-K-ATPase activity fell in group UN to 10.0 +/- 0.6 micron X mg protein-1 X h-1 (P less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)