Prerenal Azotemia Research Articles

Acute renal dysfunction during interleukin-2 treatment: suggestion of an intrinsic renal lesion.

Adoptive immunotherapy with interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells has been effective in treating some advanced malignancies in animals and humans. One complication of this treatment is a reversible, oliguric, acute renal failure, which has been ascribed to renal hypoperfusion and resultant prerenal azotemia. We serially studied renal function in 10 patients receiving high-dose regimens of recombinant interleukin-2 (rIL-2) to attempt to delineate further the nature of the renal dysfunction caused by IL-2 treatment. Renal plasma flow was computed from iodine 131 (I-131 Hippuran; Mediphysics, Paramus, NJ) orthoiodohippurate, excretion curves, and glomerular filtration rate (GFR) was determined by creatinine clearance. Studies done prior to and on day 4 of treatment showed that GFR fell in nine of 10 patients, with a mean decrease of 43% +/- 8%, and renal plasma flow fell in five of the 10 patients with a mean decrease of 5% +/- 10%. The average pretherapy filtration fraction was calculated to be 23% +/- 1% and after 4 days of treatment, decreased to a mean value of 15 +/- 2%. The BUN to creatinine ratio also declined in all patients. These findings collectively suggest that IL-2 nephrotoxicity may result from an intrarenal defect in addition to the previously described prerenal azotemia. Additionally, radionuclide studies of renal function are a reliable and reproducible noninvasive method of assessing these changes in renal function.

Drug-Induced Nephropathies

Drug-induced renal disease is a common problem. Drugs cause several renal syndromes, such as prerenal azotemia, fluid and electrolyte abnormalities, acute tubular necrosis, acute interstitial nephritis, and chronic interstitial nephritis. Acute renal failure due to acute tubular necrosis is the most common syndrome and is most frequently caused by aminoglycoside antibiotics, radiographic contrast agents, and amphotericin B. Avoidance of these drugs in volume-depleted or hypotensive patients with preexisting renal disease or in those receiving multiple nephrotoxic drugs is the most effective way to reduce nephrotoxicity. Acute interstitial nephritis is an immune process that is most commonly caused by penicillins, diuretics, allopurinol, nonsteroidal anti-inflammatory drugs, cimetidine, and sulfonamides. Prompt recognition of the disease and cessation of the responsible drug are usually the only necessary therapy. Chronic interstitial nephritis is most often seen after prolonged use of several different types of analgesic agents, including aspirin, acetaminophen, and nonsteroidal anti-inflammatory drugs. These patients develop recurrent papillary necrosis and eventually chronic renal failure. They are also at risk of developing transitional cell carcinomas of the urinary collecting system. Some patients who are receiving cyclosporine also develop chronic renal failure due to interstitial fibrosis.

The Hepatorenal Syndrome

HRS occurs frequently in patients with advanced cirrhosis of the liver and fulminant hepatitis. The pathogenesis of HRS is not clearly understood; reduced effective plasma volume and intense renal cortical vasoconstriction seem to have important roles. The HRS is a diagnosis by exclusion, and it [table: see text] is often difficult to differentiate this entity from prerenal azotemia and ATN. The HRS is characterized by its relentless progression and usually fatal outcome. The essential steps in the management of HRS are to identify and correct the precipitating factors leading to HRS and avoidance of potential hepatotoxic and nephrotoxic drugs. Patients with potentially reversible liver diseases should be treated aggressively. Volume expansion is important and should be tried first, even though hypovolemia may be not clinically evident. Dialysis may benefit patients with fluid overload and electrolyte imbalance or those awaiting liver transplantation. In selective cases, peritoneovenous shunt may be of value. Liver transplantation is the only curative therapy available at present.

Changes in laboratory results for cancer patients treated with interleukin-2

The systemic administration of interleukin-2 (IL-2) can lead to significant antitumor responses in some patients with metastatic cancer in whom standard therapy has failed. A limitation of this immunotherapy is the toxicity associated with IL-2 infusion. To assess toxicity, we determined aspartate aminotransferase (AST; EC 2.6.1.1), alanine aminotransferase (ALT; EC 2.6.1.2), gamma-glutamyltransferase (GGT; EC 2.3.2.2), lactate dehydrogenase (LD; EC 1.1.1.27), alkaline phosphatase (ALP; EC 3.1.3.1), creatine kinase (CK; EC 2.7.3.2), total bilirubin (TBI), direct bilirubin (DBI), creatinine, urea nitrogen, and C-reactive protein in serum from 21 patients before and during five consecutive days of IL-2 treatment. Ten patients were followed for an additional five days after the end of IL-2 therapy. The IL-2 infusion caused liver toxicity and prerenal azotemia, as evidenced by significant increases (P less than 0.05) of all analytes except CK by day 1. There was a progressive increase in the results (except CK) for these tests until IL-2 treatment was stopped. Seven tests related to liver function (AST, ALT, GGT, LD, ALP, DBI, and TBI) showed increases, but the test results indicated significant improvement and moved toward the baseline value five days after the end of IL-2 therapy. Concentrations of creatinine and urea nitrogen in serum were normal three days after the cessation of IL-2 therapy.

Candida-associated diarrhea in hospitalized patients

Ten hospitalized patients with severe diarrhea associated with intestinal Candida overgrowth are reported. Candida-associated diarrhea is predominantly of the secretory type, characterized by frequent watery stools, usually without blood, mucus, tenesmus, or abdominal pain. The patients were elderly, malnourished, and critically ill, or suffered from chronic debilitating illness. Their hospital stays were prolonged, and the majority were being treated with multiple antibiotics or chemotherapeutic agents. Diarrhea often led to dehydration, prerenal azotemia, hyperchloremic metabolic acidosis, and electrolyte imbalance. Stool culture most frequently isolated Cand. albicans in association with decreased normal flora. Colonoscopy showed no evidence of colitis. Diagnosis was made based on the absence of diarrheaproducing medications, the continuation of diarrhea despite fasting, the exclusion of other infections, inflammatory conditions and other causes of secretory diarrhea, and a dramatic reponse to a short course of nystatin.

Decreased Fractional Excretion of Urate as an Indicator of Prerenal Azotemia

Although the fractional excretion of uric acid (FEUA) is known to reflect extracellular fluid volume changes, the diagnostic significance of decreased FEUA in dehydration has not been previously reported. We studied the possible association between low FEUA and acute prerenal azotemia, and its diagnostic value, compared with other traditional indices, in discriminating prerenal azotemia from renal parenchymal causes of acute renal failure. In 65 chronic renal disease patients, 174 FEUA measurements were obtained from 24-hour urine collections. FEUA levels increased as reciprocal serum creatinine levels decreased. All 8 patients with prerenal azotemia showed significantly decreased FEUA values compared with chronic renal disease patients with a comparable degree of serum creatinine elevation, whereas all 7 patients with acute renal failure had FEUA values higher than those of chronic renal disease patients with comparable creatinine levels. FEUA values in prerenal azotemia were distinctly lower than those in acute renal failure (p less than 0.001). Patients with prerenal azotemia showed a lower fractional excretion of sodium, a lower fractional excretion of chloride and renal failure index, and a higher urine-to-plasma creatinine ratio than those with acute renal failure (p less than 0.05). However, these traditional indices were not useful in discriminating between the two conditions. The urine-to-plasma urea nitrogen ratio and the ratio of plasma urea nitrogen to creatinine showed no statistical difference between prerenal azotemia and acute renal failure. We conclude that, in acute azotemia, a decreased FEUA value may represent a reliable indicator of prerenal azotemia in the differential diagnosis of acute renal failure.

Volume Depletion in a Patient With Cirrhosis

A 40-year-old mechanic was admitted to the medical service on January 16 because of progressively increasing jaundice and abdominal girth, malaise, and fevers. The patient had consumed one to two six-packs of beer daily for approximately 22 years. On physical examination the temperature was 100.2 OF, heart rate 104 beats per minute, blood pressure (BP) 110170 mm Hg supine and 100/65 mm Hg standing, and weight 205 pounds. Abnormal findings included gross (but not tense) ascites, + + pedal edema, spider angiomata, and enlarged liver (25 cm span) and spleen (edge palpated at 4 finger-breadths below costal margin). Skin turgor was normal. The stool was negative for occult blood. Low-grade fever persisted, but no source was identified from extensive culturing of blood, urine, and sputum. Selected laboratory values are shown in Table 1. Abdominal ultrasound and computed axial tomography scan showed hepatomegaly, splenomegaly, ascites, and normal-sized biliary ducts. A liver-spleen scan showed marked reticuloendothelial shift, with hepatosplenomegaly. The diagnostic impression of the gastrointestinal consultant was alcoholic hepatitis with a predominantly obstructive component. The patient was treated with bed rest, low-salt diet (2 g sodium/d), sucralfate, and vitamins. Over the next 2 weeks he remained stable and nonoliguric, but his plasma blood urea nitrogen (BUN) and creatinine increased. A renal consultation was requested on January 31. On January 31, the physical examination was essentially unchanged from admission. The heart rate was 100 beats per minute, the BP 110170 mm Hg supine, decreasing to 90/65 mm Hg standing, and light-headedness accompanied the postural hypotension. Weight was 208 pounds. The urine output had been 700 to 1,200 mLld. Urinalysis showed a specific gravity of 1.015 and a normal sediment. A renal ultrasound study showed no evidence of obstruction. The impression was that the patient had pre-renal azotemia from true ECF volume depletion. Between January 31 and February 4, to replete ECF volume, the patient received normal saline at 30 to 100 mLlh and 10 U of fresh frozen plasma. By February 4 his weight had increased by 20 pounds. Heart rate was 104 beats per minute, and BP was 110170 mm Hg supine, decreasing to 90/65 mm Hg when standing, and again postural light-headedness occurred. The ascites had increased and was more tense. Peripheral edema had increased to + + +. Neither BUN nor creatinine had improved. Two diagnostic tests were performed.

Acute Renal Failure in Pregnancy

Acute renal failure is a most challenging clinical problem when it occurs in pregnancy. It requires an understanding of the normal physiology of the kidney in pregnancy and the natural history of different underlying renal diseases when pregnancy occurs. Because patients with chronic renal disease may present with worsening proteinuria, hypertension, and renal function, these disorders must be excluded from those conditions that cause acute deterioration of renal failure in otherwise normal women during pregnancy. As in all patients who develop acute renal failure, prerenal and obstructive causes must be excluded. Particularly important causes of prerenal azotemia in pregnancy include hyperemesis gravidarum and uterine hemorrhage, especially if it is unsuspected as in abruptio placentae. Infectious causes of acute renal failure in the pregnant woman include acute pyelonephritis and septic abortion. The clinical presentation of both these conditions should be apparent, and appropriate diagnosis and treatment can then be promptly instituted. Renal cortical necrosis is another cause of renal failure that occurs more frequently in pregnancy, and it must be differentiated from the many causes of acute tubular necrosis that may be associated with pregnancy. Those conditions that cause renal failure unique to pregnancy must always be considered when renal function deteriorates in the last trimester or the postpartum period. Severe preeclampsia, acute fatty liver of pregnancy, and idiopathic postpartum acute renal failure may all present similar complications, but the approach to each of these clinical disorders must be individualized. By understanding the causes of renal functional deterioration in pregnancy, a logical differential diagnosis can be established, allowing appropriate therapeutic decisions to preserve both maternal and fetal well-being.

Role of diuretics, hormonal derangements, and clinical setting of hyponatremia in medical patients.

Because hyponatremia is frequently associated with preceding diuretic treatment and unrestricted fluid intake--conditions which have not been addressed sufficiently in published literature--we studied the pathophysiology and the clinical setting of such hyponatremia in a large group of internal medicine patients. We observed: a) Of an initial 310 patients with chemical hyponatremia only 204 (64%) had an associated plasma hypoosmolality. Since a normal plasma osmolality excludes a disturbance of water metabolism only the 204 patients with hypoosmolar hyponatremia were included in the study. This data shows that plasma osmolality is an essential measurement in any evaluation of hyponatremia. b) In 204 consecutive patients with hypoosmolar hyponatremia the electrolyte disturbance was related to advanced congestive cardiac failure in 25%, decompensated liver cirrhosis in 18%, volume contraction in 28%, syndrome of inappropriate antidiuretic hormone secretion in 19% and renal insufficiency in 4%. c) Plasma vasopressin was measurable in 90% of the 204 patients. It is known that radioimmunoassays to measure vasopressin fail to reliably detect low concentrations of circulating vasopressin (less than 0.5 pg/ml). It may therefore be stated that hypoosmolar hyponatremia was generally characterized by a failure of antidiuretic hormone suppression. d) Mean daily fluid intake of hyponatremic patients was 2.35 +/- 0.15 l. In the presence of stimulated vasopressin this large a fluid intake is bound to worsen the severity of hyponatremia. e) Of 204 patients 126 were treated with diuretics at the time of study. In these patients hyponatremia worsened during such treatments and was associated with evidence of prerenal azotemia. However there were no significant differences between diuretic-treated and -untreated patients with respect to plasma vasopressin stimulation and amount of fluid intake.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of asialo-GM1-positive lymphoid cells in mediating the toxic effects of recombinant IL-2 in mice.

Studies were performed to characterize the toxic effects of human rIL-2 in mice and to examine the mechanism of toxicity. Intraperitoneal administration of rIL-2 at doses greater than or equal to 2 X 10(6) U/kg twice each day for greater than or equal to 4 days led to toxicity in several strains of mice. The toxic effects of rIL-2 included the vascular leak syndrome (manifested by pulmonary edema, pleural effusions, and ascites), elevated hepatic transaminases, hyperbilirubinemia, hypoalbuminemia, pre-renal azotemia, anemia, thrombocytopenia, mild eosinophilia, and death. Marked lymphoid cell infiltration of pulmonary and hepatic vasculature was present in mice suffering from rIL-2 toxicity, and the pleural and ascitic fluids also contained high numbers of mononuclear cells. Mononuclear cells isolated from the pleural fluids and livers of these mice were 74 to 98% Thy-1+, 55 to 83% asialo-GM1+, 29 to 45% Lyt-2+, and less than 10% L3T4+. These cells possessed potent lymphokine-activated killer (LAK)-like activity in that their ability to lyse cells of the NK-resistant P815 mastocytoma line was 10- to 100-fold higher on a per cell basis than splenocytes from the same animals. A correlation was found between the dose level, duration, and frequency of dosing with rIL-2 required to induce pleural effusions and hepatotoxicity and the dosage regimens required to produce the LAK-like cells in the pleural cavities and livers, respectively, of rIL-2-treated mice. Moreover, treatment of mice with anti-asialo-GM1 (anti-ASGM-1) antiserum in vivo at the same time they were receiving toxic doses of rIL-2 abolished or greatly reduced the severity of the vascular leak syndrome and hepatotoxicity and significantly prolonged the survival of the mice. Administration of anti-ASGM-1 to mice receiving toxic doses of rIL-2 resulted in a marked reduction in the LAK-like cytolytic activity of their pleural and liver lymphoid cells and a corresponding reduction in the percentage of ASGM-1+ cells in pulmonary and hepatic lymphoid infiltrates. Nevertheless, the overall extent of pulmonary and hepatic lymphoid infiltration, as well as other consequences of rIL-2 administration, including splenomegaly, hypoalbuminemia, eosinophilia, and thrombocytopenia, were not diminished as a result of anti-ASGM-1 treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of interleukin-2 immunotherapy on renal function.

Recombinant interleukin-2 (IL-2) infusions have recently been evaluated as a new form of immunotherapy for the treatment of malignancies. This form of therapy has been complicated by the development of fluid retention, azotemia, and hypophosphatemia. To evaluate the effects of IL-2 on renal function, we prospectively studied eight patients who received IL-2 (10(5) micron/kg every eight hours intravenously [IV]) for five days as the initial phase of a treatment protocol using IL-2 plus lymphokine activated killer (LAK) cells. Dopamine and fluids were used to maintain blood pressure and all patients received indomethacin (100 mg/d). IL-2 therapy produced a syndrome similar to endotoxemia with the development of respiratory alkalosis (pH = 7.44 +/- .2, pCO2 = 30 +/- 2) and hypotension (mean BP, 71.3 mm Hg). These changes were accompanied by marked sodium avidity, edema formation, and mild elevations of BUN and creatinine. Hypophosphatemia, hypocalcemia, and hypomagnesemia were commonly seen. No defects in renal calcium, magnesium, phosphorous, net acid excretion, or glycosuria were demonstrated. We conclude: (1) IL-2 induces an increase in vascular permeability causing the development of edema, sodium avidity, and prerenal azotemia as occurs during endotoxemia; (2) IL-2 therapy induces respiratory alkalosis with the subsequent intracellular shift of phosphorous accompanied by increased renal phosphorous reabsorption; and (3) there is no evidence of renal tubular dysfunction (renal tubular acidosis [RTA], renal leak of glucose, phosphorous, or magnesium).

Urinary Doubly Refractile Lipid Bodies in Nonglomerular Renal Diseases

Urinary doubly refractile lipid bodies (DRLB) are a characteristic finding in patients with glomerular renal diseases causing heavy proteinuria. DRLB are felt to be an uncommon finding in glomerular diseases without heavy proteinuria, and a rare finding in nonglomerular renal diseases. In order to determine whether DRLB are found in nonglomerular renal diseases, we reviewed the medical records of all patients who had urinalyses performed in our laboratory from February 1975 to June 1983. Three hundred sixty one patients demonstrated less than or equal to +2 proteinuria, and at least two DRLB. Of these, 290 were identified as having a single renal diagnosis. One hundred forty eight patients (51%) had a variety of acute and chronic glomerular diseases, and 125 patients (43.2%) had nonglomerular renal diseases, including acute tubular necrosis (ATN), prerenal azotemia, chronic interstitial nephritis, polycystic kidney disease, acute interstitial nephritis, renal neoplasia, and acute myeloma kidney. Ten patients had transient proteinuria associated with acute illness, and seven patients had no renal disease at all. Only two patients with nonglomerular renal disease had more than five DRLB per 20 high power microscopic fields. The frequency of DRLB in patients with nonglomerular renal diseases was: chronic interstitial nephritis, 26%; polycystic kidney disease, 38%; prerenal azotemia, 20%; ATN, 15%; and acute interstitial nephritis, 33%. These data suggest that at lower levels of proteinuria, DRLB are found frequently in nonglomerular renal diseases, and that DRLB do not differentiate glomerular from nonglomerular renal diseases unless more than five DRLB are found on urinary sediment examination.

Relative density of urine: methods and clinical significance.

The physical properties and chemical composition of urine are highly variable and are determined in large measure by the quantity and the type of food consumed. The specific gravity is the ratio of the density to that of water, and it is dependent on the number and weight of solute particles and on the temperature of the sample. The weight of solute particles is constituted mainly of urea (73%), chloride (5.4%), sodium (5.1%), potassium (2.4%), phosphate (2.0%), uric acid (1.7%), and sulfate (1.3%). Nevertheless, urine osmolality depends only on the number of solute particles. The renal production of maximally concentrated urine and formation of dilute urine may be reduced to two basic elements: (1) generation and maintenance of a renal medullary solute concentration hypertonic to plasma and (2) a mechanism for osmotic equilibration between the inner medulla and the collecting duct fluid. The interaction of the renal medullary countercurrent system, circulating levels of antidiuretic hormone, and thirst regulates water metabolism. Renin, aldosterone, prostaglandins, and kinins also play a role. Clinical estimation of the concentrating and diluting capacity can be performed by relatively simple provocative tests. However, urinary specific gravity after taking no fluids for 12 h overnight should be 1.025 or more, so that the second urine in the morning is a useful sample for screening purposes. Many preservation procedures affect specific gravity measurements. The concentration of solids (or water) in urine can be measured by weighing, hydrometer, refractometry, surface tension, osmolality, a reagent strip, or oscillations of a capillary tube. These measurements are interrelated, not identical. Urinary density measurement is useful to assess the disorders of water balance and to discriminate between prerenal azotemia and acute tubular necrosis. The water balance regulates the serum sodium concentration, therefore disorders are revealed by hypo- and hypernatremia. The disturbances are due to renal and nonrenal diseases, mainly liver, cardiovascular, intestinal, endocrine, and iatrogenic. Fluid management is an important topic of intensive care medicine. Moreover, the usefulness of specific gravity measurement of urine lies in interpreting other findings of urinalysis, both chemical and microscopical.

Acute Renal Failure

Acute renal failure is divided into its classic parts: prerenal azotemia, postrenal azotemia (obstruction), and renal azotemia (including acute tubular necrosis). The division of acute tubular necrosis into the ischemic and toxic varieties is supplemented by an analysis of toxic varieties into those caused by antibiotics, radiologic contrast agents, chemotherapeutic-immunosuppressive agents, heavy metals, organic solvents, etc. Acute tubular necrosis caused by hemoglobin and myoglobin is described in detail. The importance of urinalysis and the urinary indices in distinguishing prerenal azotemia from acute tubular necrosis is stressed. Finally, current prognosis and treatment are reviewed.

Effects of interleukin-2 on renal function in patients receiving immunotherapy for advanced cancer.

Adoptive transfer of autologous lymphokine-activated killer cells in conjunction with recombinant interleukin-2 in patients with advanced cancer has produced significant regression of metastatic disease in selected patients. We analyzed the effects of interleukin-2 regimens on renal function in 99 consecutive patients. Interleukin-2 therapy with or without lymphokine-activated killer cells was associated with varying degrees of hypotension, fluid retention, azotemia, oliguria, and low fractional sodium excretion. After the patients completed the interleukin-2 regimens, their renal function improved promptly. Renal function values returned to baseline levels within 7 days in 62% of patients, within 14 days in 84%, and within 30 days in 95%. Pretherapy serum creatinine values above 1.4 mg/dL predicted the severity of azotemia and prolonged duration of renal functional recovery, interleukin-2 therapeutic regimens induce prerenal azotemia. Careful selection of patients and early detection of adverse physiologic changes may alleviate the side effects of interleukin-2 therapy.

Potentially Deleterious Effects of Long-term Vasodilator Therapy in Patients with Heart Failure

SUMMARY It is clear that we clinicians have accepted a philosophy of treating heart failure with vasodilator compounds, and we are fortunate to have a variety of pharmacotherapeutic agents from which we can choose. Each group has certain advantages and potentially deleterious effects, and as a general class of compounds, it is critical to remember the hemodynamic effects of these drugs. The advantages of the angiotensin-converting enzyme inhibitors include well-documented long-term efficacy with significant reduction in symptoms, improved exercise tolerance, and amelioration of detrimental hemodynamics. There is a large clinical experience with both captopril and enalarpril, with one agent, captopril, currently having the blessing of the Food and Drug Administration for use in congestive heart failure. Enalapril may have fewer side effects than captopril because of the absent sulfhydryl group and is suitable for once or twice daily dosing because of prolonged activity. The major disadvantages of the angiotensin-converting enzyme inhibitors include hypotension and pre-renal azotemia, but other potentially serious side effects such as neutropenia and proteinuria seem, fortunately, to be rare. Other vasodilators, such as hydralazine, prazosin, and nitrates, have some potential advantages, including the long-term demonstrated efficacy of nitrates in terms of hemodynamic and symptomatic improvement and relative freedom from serious side effects. Of additional importance are the recently published data from the VA cooperative study of vasodilators in heart failure, which demonstrated an attentuation of mortality in patients receiving the combination of oral isosorbide dinitrate and hydralazine (Apresoline). 8 This reduction in mortality was seen despite a complicated regimen of drug administration (300 mg of hydralazine per day and 160 mg of isosorbide dinitrate per day) and a 22 percent discontinuation of treatment in this group (usually because of deleterious effects). The major disadvantage of prazosin, which did not have the same effect on mortality as the combination of hydralazine and isosorbide dinitrate, seems to be the lack of demonstrated long-term efficacy. Still, the possibility of serious side effects from hydralazine (lupus syndrome), the requirement for frequent dosing (at least thrice daily), and the necessity of combining the agent with other vasodilators to achieve concomitant reduction in preload, remain disadvantages for hydralazine. Calcium-channel blocking agents have several physiologic properties, including peripheral and coronary vasodilation, electrophysiologic and antiarrhythmic effects, and the tendency to increase diastolic compliance, which, theoretically, make them beneficial drugs in certain patients with heart failure. The potential cardiodepressant effects and the limited clinical experience with calcium-channel blockers in congestive heart failure make for difficult titration, but, clearly, patients with ischemic heart disease and moderately depressed left ventricular function might benefit from them without developing serious deleterious consequences during long-term therapy. Also, patients who have heart failure with diastolic dysfunction such as hypertrophic cardiomyopathies would probably improve more predictably with these vasodilators than others. The use of combined vasodilator drugs may offer distinct advantages to the patient with heart failure, and the best example of this is the combination of nitrate therapy with hydralazine (Apresoline). Theoretically, nitrates and nifedipine or any of the other calcium-channel blockers would also be beneficial because the primary preload-reducing effects of nitrates would ameliorate one aspect of hemodynamic abnormality not affected by the relatively pure after-load-reducing advantage of the other. Results of combining two vasodilators effecting similar hemodynamic responses in patients with heart failure is unknown. Thus, combinations of angiotensin-converting enzyme inhibitors and prazosin or of hydralazine and nifedipine should not routinely be designed. It is possible that no additive vasodilator effects would be evident, but the patient might be exposed to an additional burden of toxic effects, particularly with respect to idiosyncratic reactions. It certainly might be appropriate to combine vasodilator drugs if the patient's condition was refractory to manipulation with one compound, but precise hemodynamic characterization of the clinical state would be mandatory. Should a decision be made to combine two or more vasodilators, choosing agents from disparate classes seems most logical. The choice of which single vasodilator agent to use clinically in patients with left ventricular dysfunction is one that must be individualized, juxtaposing the pharmacologic properties of agents with the hemodynamic, neurohumoral, and clinical characteristics of particular patients, always weighing the possibility of deleterious effects in the decision-making matrix. This demands beng cognizant of whether the patient is relatively well compensated and asymptomatic or whether symptoms are present that relate to low-output syndrome or the congestive state of heart failure.

Diagnosis of Renal Proximal Tubular Injury by Urinary Immunoassay for a Proximal Tubular Antigen, the Adenosine Deaminase Binding Protein

A sandwich ELISA assay has been formatted from two commercially available murine monoclonal antibodies, URO-4 and URO-4a, directed against a 120,000 dalton glycoprotein, the adenosine deaminase binding protein (ABP), found on the brush border of the renal proximal tubular epithelial cell. Untimed urine samples from 37 normal individuals and urinary ABP less than 0.1 AU; 37 patients with pure glomerular disease had ABP less than 0.4 AU (with 29, or 76% less than 0.2 AU); 10 patients with pre-renal azotaemia had ABP less than 0.6 (with 8, or 80% less than 0.3 AU). In contrast, 79 patients with post-ischaemic acute tubular necrosis had ABP greater than 0.6 AU. Acute renal failure due to myoglobinuria, contrast dye, and aminoglycoside toxicity were all associated with urinary ABP greater than 1.0 AU. In addition, all six patients with acute bacteraemic pyelonephritis had ABP greater than 0.7 AU, as opposed to ABP less than 0.2 AU in the urines of 12 women with acute cystitis. We conclude that this monoclonal antibody based urinary assay is a sensitive measure of renal proximal tubular injury, reliably distinguishes acute tubular from glomerular disease, and may be helpful in differentiating forms of urinary tract infection.

Peritoneovenous shunt in the management of the hepatorenal syndrome

The hepatorenal syndrome (HRS) is a terminal complication of severe liver disease associated with a mortality of 80 to 90%. Although the renal functional abnormalities in the HRS suggest prerenal azotemia, volume expansion with saline, albumin or ascitic fluid rarely results in reversal of the HRS because fluid redistributes from the vascular space. Since the peritoneovenous (PV) shunt causes sustained central volume expansion, it has been advocated for the treatment of the HRS. We prospectively compared the PV shunt (N = 10) to Medical Therapy (MED) (N = 10) on renal function and mortality in 20 patients with the HRS associated with alcoholic liver disease. The HRS was diagnosed on the basis of clinical, hemodynamic, and laboratory criteria. The insertion of a PV shunt resulted in an increase in pulmonary capillary wedge pressure (4.2 +/- 1.1 vs. -1.5 +/- 1.0 mm Hg, P less than 0.01) and in cardiac index (0.8 +/- 0.3 vs. -0.2 +/- 0.3 1/min/m2, P less than 0.05). After 48 to 72 hours, weight (+3.1 +/- 1.1 kg) and serum creatinine (3.9 +/- 0.5 to 5.5 +/- 0.7 mg/dl, P less than 0.001) were increased with MED therapy and decreased (weight: -3.7 +/- 0.7 kg; serum creatinine: 3.6 +/- 0.4 to 3.0 +/- 0.5, P less than 0.05) with the PV shunt. Despite improvement in renal function, only one patient with the PV shunt had prolonged survival (210 days). In the remainder, survival was 13.8 +/- 2.2 days compared to 4.1 +/- 0.6 days with MED therapy. We conclude that the PV shunt often stabilizes renal function, but does not prolong life in patients with the HRS.

Renal failure in children with hepatic failure undergoing liver transplantation

Over a 3 1/2 year period, 133 children with hepatic failure underwent orthotopic liver transplantation (OLT) at our center. Renal failure (creatinine clearance less than 20 ml/min/1.73 m2) was present in 19 (14.3%) of these children. In seven of the 19 children, renal failure was present before OLT, and in the other 12 after OLT. The causes of renal failure included hepatorenal syndrome in seven, postischemic acute tubular necrosis in five, severe prerenal azotemia in five, and cyclosporine nephrotoxicity in two. Eight other patients died of renal failure while awaiting emergency transplantation. Of the total of 31 deaths among 133 children who underwent OLT, nine occurred in the 19 patients with renal failure. Thus patients with OLT and renal failure had a significantly higher mortality than other patients with transplants (P less than 0.025). Dialysis was not associated with improved survival. The majority of deaths in patients with renal failure were related to severe hemorrhage, thromboembolic events, and systemic fungal infections. Our experience suggests that renal failure is common in children with hepatic failure and is associated with reduced patient survival after OLT.

Fractional Excretion of Chloride in Prerenal Azotemia

To the Editor. —The fractional excretion of filtered sodium (FENa) has been shown to be a reliably discriminating test between prerenal azotemia (PRA) and acute tubular necrosis.1However, and as was reviewed by Zarich et al2in the JanuaryArchives, exceptions for the diagnostic value of FENa have been reported repeatedly. Zarich et al limited their discussion to those categories of acute renal failure (ARF) that are associated withlowFENa values. Thus, in addition to PRA, low FENa values may be encountered in acute glomerulonephritis; early ureteral obstruction; contrast-induced ARF; pigment-induced ARF; acute interstitial nephritis; and ARF associated with burns, sepsis, cirrhosis, captopril therapy, or cardiac surgery. We wish to expand the discussion to involve those exceptions whereby ahighFENa value may be encountered. In addition to acute tubular necrosis and late urinary tract obstruction,1high FENa values are expected in PRA associated with metabolic