Community-Acquired Acute Renal Failure James Kaufman, MD, Madhavendra Dhakal, MD, Balubhai Patel, MD, and Robert Hamburger, MD • Acute renal failure usually occurs during hospitalization, but may also be present on admission to the hospital. To define the causes and outcomes of community-acquired acute renal failure, we undertook a prospective study of patients admitted to the hospital with acute elevations in serum creatinine concentrations. Over a 17-month period, all admission serum creatinine determinations were screened for patients with values greater than 177 JLmollL (2 mg/dL). These values were compared with baseline creatinines to select patients with an acute elevation in serum creatinine occurring outside the hospital. One hundred patients were entered into the study, with an overall incidence of 1% of hospital admissions. Seventy percent of the patients had prerenal azotemia, 11 % had intrinsic acute renal failure, 17% had obstruction, and 2% could not be classified. Mean peak serum creatinine (318 ± 18 JLmollL [3.6 ± 0.2 mg/dL]) and mortality (7%) was lowest In the group with prerenal azotemia. In this group, volume contraction due to vomiting, decreased fluid intake, diarrhea, fever, glucosuria, or diuretics was the most common underlying cause. The group with Intrinsic acute renal failure had the most severe renal failure and the highest mortality (55%). Although ischemic acute tubular necrosis is the most common cause of hospitalacquired intrinsic acute renal failure, this etiology was seen in only one patient. Drug-induced nephrotoxicity and Infection-related causes were the most common underlying etiologies of intrinsic acute renal failure. "Obstructive renal failure had a mortality of 24% and was most commonly due to benign prostatic hypertrophy. Almost 90% of the patients admitted to the hospital with an acute increase in serum creatinine concentration have a potentially reversible cause, either volume contraction or obstruction. Nevertheless, the overall mortality in these patients is 15%, and the risk of dying is increased In those patients with intrinsic acute renal failure and those with higher peak serum creatinine concentrations. © 1991 by the National Kidney Foundation, Inc. INDEX WORDS: Acute renal failure; outpatient; prerenal azotemia; obstruction.
S
EVERAL STUDIES have documented the causes of hospital-acquired renal insufficiency. 1.2 The most common etiologies include decreased renal perfusion, major surgery, and nephrotoxic drugs, in particular aminoglycosides and radiocontrast agents. Acute renal failure also occurs outside the hospital. The major causes are likely to be different from those of hospital-acquired acute renal failure due to the infrequent use of nephrotoxic antibiotic drugs and the absence of major surgery in this setting. In this study, we examined the causes and outcomes of acute renal failure occurring outside the hospital. METHODS Using a daily computer search of serum creatinine determinations performed in the hospital laboratory, patients with values greater than 177 JLmollL (2 mg/dL) on admission to the hospital were identified. Acute renal failure was defined as a serum creatinine greater than 177 JLmollL (2 mg/dL) and (I) an increase of serum creatinine of at least 44 JLmollL (0.5 mg/dL) for patients with a baseline serum creatinine of less than 168 JLmollL (1.9 mg/dL) , or (2) an increase of greater than 88 JLmollL (1.0 mg/dL) for patients with a baseline creatinine of 177 to 433 JLmollL (2.0 to 4.9 mg/dL), or (3) an increase of greater than 133 JLmollL (1.5 mg/dL) for patients with a baseline serum creatinine level of 442 JLmollL (5 mg/dL) or greater.
These criteria are similar to those used by Hou et al in a study of acute renal failure in hospitalized patients. 2 Baseline serum creatinine was the most recent value obtained within the previous 6 months. For patients not having a creatinine determination in the prior 6 months , but having an admission value greater than 177 JLmollL (2 mg/dL), the presence of acute renal failure was retrospectively defined by a decrease in serum creatinine of 50% within 1 month of admission. Hospital charts were reviewed and patients interviewed to identify demographic data, admission and discharge diagnoses, risk factors at the time of admission to the study, and outcomes. Patients were classified into the three general pathophysiologic categories of prerenal, intrinsic, and postrenal acute renal failure . Prerenal azotemia was considered to be present when there was evidence for intravascular volume depletion, heart failure, or drug-induced renal hypoperfusion and improvement in creatinine was noted with correction of volume disturbance or discontinuation of the drug . 3 Intravascular volume depletion was defined as the presence of orthostatic hypotension (defined From the Renal Section, Boston li!terans Affairs Medical Center, Boston, MA. Current address of Dr Dhakal is the Renal Section, WilkesBarre li!terans Affairs Medical Center, Wilkes-Barre, PA , and that of Dr Patel is 9500-H Prince George Lane, Raleigh, NC. Address reprint requests to James Kaufman, MD , Renal Section, Boston 1\4 Medical Center, 150 S Huntington Ave, Boston, MA 02130. © 1991 by the National Kidney Foundation, Inc. 0272-638619111702-00J9$3. 00/0
American Journal of Kidney Diseases, Vol XVII, No 2 (February), 1991: pp 191-198
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as a decrease > 10 mm Hg in diastolic blood pressure or a pulse rate increase > 10 bpm on standing) or weight loss of greater than 5 % of baseline body weight (documented within 2 months of admission value) in an appropriate clinical setting. Congestive heart failure was defined as the presence of cardiomegaly with vascular redistribution or pulmonary edema on chest x-ray, or third heart sound and rales on physical examination. Gastrointestinal blood loss was defined as the presence of orthostatic hypotension with guaiac positive stools or gastric aspirate. Sepsis was considered to be present when there were positive blood cultures in an appropriate clinical setting. Nonsteroidal antiinflammatory drug or antihypertensive drug use was noted within 48 hours of entry into the study. Hepatorenal syndrome was defined as the presence of acute renal failure in the setting of severe liver failure with ascites and urine sodium concentration less than 10 mEq/L without other causes for the renal failure. Intrinsic acute renal failure was considered to be present when the urine sediment contained muddy brown granular casts and renal tubular epithelial cells, or there was no response in clinical course to volume repletion. Prolonged hypotension and prerenal azotemia may lead to structural renal damage and intrinsic acute renal failure. 3 Under these circumstances, restoration of blood pressure does not result in reversal of the renal failure, and these patients are classified as intrinsic acute renal failure. Urinary tract obstruction was determined by physical and radiologic examination, usually renal ultrasound. Patients were observed daily until their serum creatinine reverted to baseline or until discharge. At that time, a final cause of the renal failure was assigned according to the definitions above. Additional variables recorded included age, sex, baseline creatinine, entry creatinine, peak creatinine, discharge creatinine, duration of elevated creatinine (defined as the time before return to baseline, initiation of dialysis or hospital discharge), and survival outcome. Table 1.
Statistics were performed between groups using analysis of variance and post hoc testing using Newman-Keuls multiple range test for parametric data and Kruskal-Wallis test for nonparametric data. Within-group testing was done using a paired Student's t test. All statistical analyses were performed using Prophet, a statistical resource of the Division of Research Resources, National Institutes of Health. Results are expressed as the mean ± SE.
RESULTS
In the period January 1, 1988 to May 30, 1989, 100 patients meeting our inclusion criteria were entered into the study. During this same period, there were 10,924 admissions to our hospital, an acute care referral hospital serving a predominantly elderly, male population. The patients were divided into three groups according to the category of acute renal failure, either prerenal, intrinsic, or obstruction (Table 1). Two patients had renal failure that could not be classified. Most of the patients had pre renal azotemia as the cause of their renal failure. The three groups were similar in their baseline creatinines. Twenty-two patients did not have a baseline serum creatinine determination within 6 months of entry into the study, 17 in the pre renal group, none in the intrinsic group, four in the obstruction group, and one of the unclassified patients. Of the 78 patients with baseline creatinine measurements, 40 (51 %) had baseline values
Renal Function Data for Patients With Acute Renal Failure Category of Renal Failure Prerenal (n = 70)
Baseline Cr Baseline Cr range Peak Cr Peak Cr range Increase in Cr >265 ILmollL (no.) Peak Cr >442 ILmoi/L (no.) Discharge Cr Discharge Cr range Duration of renal failure (d)
Intrinsic (n = 11)
Obstruction (n = 17)
159 ± 9 (1.8 ± 0.1) 62-398 (0.7-4.5) 318 ± 18 (3.6 ± 0.2) 177-831 (2.0-9.4)
203 ± 44 (2.3 ± 0.5) 71-504 (0.8-5.7) 690 ± 115* (7.8 ± 1.3) 212-1317 (2.4-14.9)
177 ± 35 (2.0 ± 0.4) 71-539 (0.8-6.1) 575 ± 71 * (6.5 ± 0.8) 177-1131 (2.0-12.8)
13 (19%)
8(72%)
10 (58%)
11 (16%) 168 ± 8 (1.9 ± 0.1)
6 (55%) 362 ± 88t (4.1 ± 1.0)
10 (58%) 212 ± 177 (2.4 ± 2.0)
62-530 (0.7-6.0)
115-937 (1.2-10.6)
97-610 (1.1-6.9)
4.1 ± 0.5 (1-27)
10.0 ± 3.0* (1-30)
6.6 ± 2.0 (1-36)
NOTE. Cr indicates serum creatinine concentration in ILmoi/L with the values in parentheses in mg/dL. Discharge Cr is the serum creatinine concentration at the time of death or discharge. Duration of renal failure is the interval of time from hospital admission until either the serum creatinine concentration had decreased to its minimum value or until the patient had died or been discharged, with the range of values given in parentheses. *Significantly different from prerenal group (P < 0.01). tSignificantly different from prerenal and obstruction group (P < 0.01).
COMMUNITY-ACQUIRED ACUTE RENAL FAILURE
greater than 124 p.mollL (1.4 mg/dL), the upper limit of normal for our laboratory. Of these, 25 were in the prerenal group, seven in the intrinsic group, and seven in the obstruction group, and one unclassified. The mean peak serum creatinine concentration was significantly greater (P < 0.01) in the intrinsic and obstruction groups than in the prerenal group. Patients in the former groups were more likely to experience an increase in their serum creatinine concentration of greater than 265 p.mollL (3 mg/dL) and to have a peak serum creatinine concentration of greater than 442 p.moll L (5 mg/dL) compared with the group with prerenal azotemia. The serum creatinine at death or discharge from the hospital was significantly greater (P < 0.01) in the intrinsic group than in the prerenal or obstruction groups. The duration of renal failure was significantly greater (P < 0.01) in the intrinsic group compared with the prerenal group, but not compared with the obstruction group. In the intrinsic group, two patients required institution of chronic hemodialysis, and their data were not included in the analysis of duration of renal failure. The mean age was similar in all three groups,61.9 ± 1.5,60.3 ± 2.4, and 66.0 ± 3.1 years in the prerenal, intrinsic, and obstruction groups, respectively, similar to the average age of 60.0 ± 1.9 for our general hospital popUlation. All patients were males, although during this same time period 3.5% of admissions to our hospital were female. We attempted to define specific etiologies for the renal failure in the individual patients. The data for the prerenal group are shown in Table 2. Multiple Table 2.
Cause of Prerenal Azotemia
Vomiting Poor intake Diarrhea Fever Glycosuria GI bleeding Angiotensin-converting enzyme inhibitors Diuretics Congestive heart failure Antihypertensive drugs Demeclocycline Hepatorenal Sulindac Sepsis
Contributing Cause
Primary Cause
20 14
9
18 12 7
8 8
7
5
5
3
6
4
4 4 1 2 2
3 4 1 2 2
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causes were seen in 15 patients, usually decreased fluid intake associated with vomiting. Drugs were involved in 14 cases of prerenal azotemia. Angiotensin-converting enzyme inhibitors were associated with acute renal failure in six patients, four in which it was thought to be the primary cause. These patients either had hypotension, known renovascular disease, or congestive heart failure. In all six patients, the serum creatinine decreased after discontinuing the converting enzyme inhibitors, usually within 2 to 4 days. Two patients receiving demeclocyline for the syndrome of inappropriate antidiuretic hormone developed prerenal azotemia associated with polyuria, vomiting, and hypernatremia that remitted with reductions in their doses of demeclocycline. One patient with a baseline serum creatinine of 283 p.mollL (3.2 mg/ dL) developed acute renal failure after the institution of sulindac therapy. Although some of these drugs are known to cause intrinsic acute renal failure due to interstitial nephritis, all these patients were thought to have prerenal azotemia because of the presence of orthostatic hypotension, the lack of a urine sediment characteristic of acute tubular necrosis or acute interstitial nephritis, and the reversal of renal failure on discontinuation of the drugs. The causes of the renal failure in the group with intrinsic renal disease were varied. Four patients had renal failure related to infection. One patient with underlying xanthogranulomatous pyelonephritis diagnosed by renal biopsy developed acute renal failure secondary to Escherichia coli pyelonephritis. A second patient presented with septic shock and a urine sediment showing renal tubular epithelial cells and muddy brown granular casts. Two patients had infective endocarditis and renal failure. Four patients had renal failure related to drugs, two due to cisplatinum, one due to rifampin, and one due to glyburide. In these patients with drug-induced intrinsic acute renal failure, the urinalysis showed either renal tubular epithelial cells and muddy brown granular casts or eosinophils and the renal failure did not reverse within 4 days of discontinuing the drug. One patient had spontaneous cholesterol embolization confirmed by renal biopsy. A patient with underlying membranous nephropathy developed acute flank pain and an increase in creatinine, and a diagnosis of renal vein thrombosis was made by renal venography. He was treated with anticoagu-
194
KAUFMAN ET AL
lants and his creatinine returned to baseline. One patient with focal glomerulosclerosis, diagnosed by renal biopsy 1 year previously, progressed from a creatinine of 442 p.mol/L (5.0 mg/dL) to 1,308 p.mollL (14.8 mg/dL) in 2 months, with no apparent cause other than progression of the disease. Reflecting the elderly male population of our hospital, most of the patients with obstruction had benign prostatic hypertrophy (n = 11) or prostatic carcinoma (n = 2) as the cause of their obstruction. One patient with lymphoma and known right hydronephrosis, presented with anuria and an ultrasound showed bilateral hydronephrosis. Two patients had ureteral stones, one a patient with an ileal loop bladder and bilateral stones, and the other a patient with a unilateral stone complicated by pyohydronephrosis. In addition, there was a patient with a large obstructing bladder stone. The overall mortality in patients admitted with acute renal failure was 15 %, compared with a mortality rate of 3.9 % among all hospital admissions. There was a significant (P < 0.01) relationship between the category of acute renal failure and mortality by chi-square analysis with Yates correction. The highest mortality, 6 of 11 (55 %), was observed in the group with intrinsic acute renal failure. In this group, four deaths were due to infection, one to progressive cardiorespiratory failure, and one to complications of an ischemic bowel. The 7% mortality (11 = 5) in the group with prerenal azotemia included two patients with hepatorenal syndrome, a patient with end-stage liver disease and gastrointestinal bleeding, and two patients with widely metastatic carcinoma. In the group with obstruction, the mortality was 24% (n = 4), including two patients with benign prostatic Table 3.
hypertrophy, where the cause of death could not be precisely determined. A patient with prostatic cancer and the patient with ureteral obstruction secondary to lymphoma both died of complications of their advanced cancer. Three patients, all in the group with intrinsic acute renal failure, required dialysis. Two of these patients required chronic maintenance hemodialysis, while one recovered to his baseline renal function. The characteristics of the patients who survived or died are summarized in Table 3. Their ages were not different and the number having a baseline creatinine greater than 177 p.mollL (2 mg/dL) also was not different. The patients that died had a higher mean peak and discharge creatinines, reflecting the greater proportion of patients with intrinsic acute renal failure in this group. . Eight patients in the group with prerenal azotemia had a persistent increase in serum creatinine at discharge greater than 88 p.mollL (1 mg/dL) above their prior baseline values, including four patients who died. Of the four survivors, two patients had congestive heart failure and may still have had some degree of renal hypoperfusion, one patient left against medical advice 48 hours after an admission for alcohol withdrawal and vomiting, and one patient had a baseline serum creatinine of 283 p.mollL (3.2 mg/dL) that increased to 477 p.mollL (5.4 mg/dL) after treatment with sulindac and furosemide, and decreased to only 380 p.mollL (4.3 mg/dL) 9 days after discontinuing the drugs. Therefore, in surviving patients with prerenal azotemia, renal functional recovery was complete unless the underlying condition (ie, congestive heart failure) could not be reversed or drug nephrotoxicity was implicated (ie, sulindac).
Characteristics of Survivors Survivors (n = 85)
Initial Cr Initial Cr range Peak Cr Peak Cr range Discharge Cr Discharge Cr range Duration (d) Age (yr) Baseline Cr > 177 ILmoi/L (2 mg/dL) Increase in Cr >265 ILmoi/L (3 mg/dL) NOTE. Definitions are as given in Table 1. *Significantly different from survivors (P < 0.005).
159 ± 9 (1.8 ± 0.1) 62-442 (0.7-5.0) 362 ± 27 (4.1 ± 0.3) 177-1308 (2.0-14.8) 159 ± 9 (1.8 ± 0.1) 62-513 (0.7-5.8) 4.8 ± 0.6 (1-36) 62.5 ± 1.3 13/64 (20%) 15 (17%)
Deaths (n = 15)
186 ± 44 (2.1 ± 0.5) 71-539 (0.8-6.1) 628 ± 80* (7.1 ± 0.9) 186-1317 (2.1-14.9) 398 ± 53* (4.5 ± 0.6) 97-937 (1.1-10.6) 8.6 ± 2.9 (1-36) 62.2 ± 2.9 4/15 (27%) 10 (67%)
COMMUNITY-ACQUIRED ACUTE RENAL FAILURE
In the group with intrinsic renal failure, recovery of renal function was uncommon. Although eight of the 11 patients had baseline creatinines less than 177 p.mollL (2 mgJdL), four of these eight died and only two survived with creatinines less than 177 p.mollL (2 mgJdL) , one with cisplatinum-induced renal failure and one with renal vein thrombosis. Of the three patients with baseline creatinines greater than 177 p.mollL (2 mgJ dL), one progressed to chronic maintenance hemodialysis, one died of overwhelming infection with a creatinine of 884 p.mollL (10.0 mgJdL), and one patient with endocarditis recovered to his baseline renal function, but died of heart failure . In the obstruction group complete recovery of renal function was the rule. Only two of the 17 patients had a significant increase in their creatinine above baseline at discharge, one who died from the complications of metastatic prostatic carcinoma, and the other who died from the complications of widespread lymphoma. DISCUSSION
Although several studies have examined the etiologic factors involved in hospital-acquired renal insufficiency, 1.2 we are unaware of similar studies of out-of-hospital or community-acquired acute renal failure. Decreased renal perfusion, postoperative renal insufficiency, and the administration of aminogycosides or radiographic contrast agents account for 80% of the episodes of acute renal failure occurring in the hospital. 2 Although reduced renal perfusion may also be an important factor in community-acquired renal failure, the other major causes cited would not be expected to occur outside the hospital setting. We have prospectively examined the causes of community-acquired acute renal failure over a 17 -month period by screening admission laboratory data. Patients who were admitted with elevated creatinines were selected on the basis of prior creatinine determinations and their clinical course. The incidence of acute renal failure on admission to the hospital in our study was approximately 1 %, compared with an incidence of 4.9 % in hospitalized patients. 2 Decreased renal perfusion or prerenal azotemia was the most common cause of acute renal failure, occurring in 70% of the patients, with volume contraction due to vomiting, diarrhea, decreased fluid intake, osmotic diuresis due to glycosuria, and fever as common precipitating factors. Eleven per-
195
cent had intrinsic renal failure, 17 % obstruction, and 2 % could not be classified. Therefore, more than 80 % of patients entering the hospital with an acute elevation of serum creatinine will have a potentially reversible cause for their renal failure. A recent study of hospital-acquired renal insufficiency 2 examined the specific etiologies, but did not use the same categorization we have employed. Of the 129 episodes, 54 were due to decreased renal perfusion and five due to hepatorenal syndrome, both of which we would classify as prerenal azotemia, yielding a minimal incidence of prerenal acute renal failure of 46%. 1Wenty-three (18%) of the episodes occurred after major surgery, but it was not stated how many of these events were due to volume depletion. There were only three (2 %) episodes of obstruction, compared with our incidence of 17 % in community-acquired acute renal failure . Eleven (8 %) were unclassified , and the remainder (26 %) had intrinsic renal failure due to either drugs, vasculitis, renal embolus, or were multifactorial. Therefore, prerenal azotemia is the most common cause of acute renal failure, both community- and hospital-acquired. In hospital-acquired renal insufficiency, drugs are responsible for 20 % of the episodes, with contrast media and aminoglycosides the principal offending agents. 2 Drugs were implicated in 19% of our patients . Captopril was the most common offending agent in our study and is the most commonly prescribed converting enzyme inhibitor in our hospital. Renal failaure is a well-known complication of therapy with converting-enzyme inhibitors. We have classified these patients with renal failure secondary to the administration of converting enzyme inhibitors as prerenal azotemia, since the pathophysiology is thought to be due to a decrease in glomerular perfusion pressure,3 occuring in the setting of bilateral renal artery stenoses or renal artery stenosis in a solitary kidneY,4 congestive heart failure,5 or systemic hypotension. Although the converting enzyme inhibitors may cause intrinsic renal injury, the relatively rapid reversal of renal insufficiency in most of the patients is consistent with hemodynamic, rather than structural alterations. In our patients, renal function returned to baseline 1,2,2,4, 8, and 16 days after stopping the drug, the longest duration being in the patient with congestive heart failure. Besides the converting enzyme inhibitors , several other drugs were noted as causes of prere-
196
nal acute renal failure in our series, including four patients receiving diuretics , one receiving other antihypertensive agents, one receiving sulindac, and two receiving demeclocycline. These patients were thought to have prerenal acute renal failure because the renal failure reversed rapidly after discontinuing the drugs or administering fluid. Although nonsteroidal antiinflammatory agents, such as sulindac, may cause allergic interstitial nephritis 6 or acute tubular necrosis,? in most cases the renal failure is thought to be due to hemodynamic alterations secondary to inhibition of prostaglandin synthesis and has been classified as a form of prerenal azotemia. 3 Similarly, renal functional impairment has previously been reported after treatment with demeclocycline, and is thought to be due to volume depletion secondary to the impairment of urine concentrating ability, although more direct nephrotoxicity has also been suggested. 8 In the patients with intrinsic aucte renal failure, four were thought to have drug nephrotoxicity, including two receiving cisplatinum and one receiving rifampin. Both drugs have well-described nephrotoxicity.9-11 One patient developed Stevens-Johnson syndrome and allergic interstitial nephritis secondary to glyburide, diagnosed by a positive Hansel's stain of his urine sediment demonstrating eosinophiluria.1 2 We are aware of only one other report of glyburide-induced allergic interstitial nephritis. 13 Therefore, in our study, a variety of drugs were responsible for the community-acquired acute renal failure, either as direct nephrotoxins or by resulting in decreases in renal perfusion. Infection was also an important factor associated with renal failure in our population . Thirteen patients had evidence for infection at the time of admission. In the group with intrinsic acute renal failure , in four patients it was a direct cause of the renal failure and an additional patient had antibiotic-induced nephrotoxicity due to rifampin. In the obstruction group, one patient had ureteral obstruction with accompanying pyohydronephrosis. In the remaining seven patients, fever secondary to infection was thought to result in increased insensible fluid loss and contribute to intravascular volume depletion and pre renal azotemia. The patients with intrinsic acute renal failure in our study differ from those in studies of hospitalacquired renal insufficiency. I 2 In those studies, contrast media, aminoglycosides, and ischemia,
KAUFMAN ET AL
often related to surgery, accounted for the majority of the patients. In the current study, only one patient had typical acute tubular necrosis, a patient with sepsis and prolonged hypotension. In our patients, drugs and infections were common precipitants of intrinsic acute renal failure . Infectious causes have previously been cited as etiologies of acute renal failure. 14.15 Besides the patients with drug- or infection-related intrinsic acute renal failure, there were two patients that might be classified as having vascular causes, one with acute renal vein thrombosisl 6 and one with cholesterol emboli.17 The remaining patient with intrinsic acute renal failure had biopsy-proven focal segmental glomerulosclerosis, and rapid progression of his renal failure in 2 months without an obvious cause. Progression to renal fail~lfe in less than 1 year has previously been described in focal glomerulosclerosis.1 8 In the absence of other causes, rapid progression of the glomerular disease appears to be the etiology of the acute renal failure in this patient. Therefore, in our patients with intrinsic acute renal failure , the causes were varied, but often were drug- or infection-related, or due to preexisting renal pathology. In accordance with the study design , not all patients had baseline creatinines within 6 months of entry into the study. Of the 78 patients that did, 40 had baseline serum creatinines greater than 124 /LmollL (1.4 mg/dL), the upper limit of normal for our laboratory, and 18 were greater than 177 /LmollL (2 mg/dL). This finding suggests that patients with underlying renal disease are at increased risk for developing acute renal failure outside the hospital, an observation that has also been made for hospital-acquired renal insufficiency. 19 The prognosis for both patient and renal survival in our study depended on the category of acute renal failure . Patients with prerenal azotemia had the best survival, with only a 7% mortality rate. In a series of patients with hospital-acquired renal insufficiency, 35 % of the patients with acute renal failure due to decreased renal perfusion died. Most of these deaths were in patients with cardiogenic or septic shock or severe congestive heart failure, and only 9 % of those with volume contraction died. 2 In our study, the group with obstruction had a relatively high mortality rate of 24 %, probably reflecting the age of the patients and the nature of the obstruction. In a study of hospital-acquired renal insufficiency, obstruction accounted for only
197
COMMUNITY-ACQUIRED ACUTE RENAL FAILURE
three of 129 episodes of acute renal failure and there were no deaths in this group.2 However, in patients with widespread cancer and bilateral ureteral obstruction, previously reported mortality at two months was 49 %, even after nephrostomy drainage. 2o The worst prognosis in our series was in the intrinsic group , where the mortality was six of 11 (55%); an additional patient required maintenance hemodialysis, and only two patients were discharged without significant renal impairment. This mortality is relatively high for patients with nonsurgical intrinsic acute renal failure, where the mortality is usually cited as 30% to 40%.3 The high mortality of intrinsic acute renal failure in our series probably reflects the age of the patients, the severity of the underlying illnesses, and the relatively small sample size. Other than the category of acute renal failure, the patients who lived did not differ significantly from those who died. Baseline creatinines and ages were similar. The patients who died had a higher peak creatinine, probably reflecting the greater proportion of patients with intrinsic acute renal failure, as well as the contribution of the acute renal failure to mortality. Previous studies have also demonstrated that mortality is related to the magnitude of the increase in serum creatinine, with a 64 % mortality in those with an increase in serum creatinine concentration of greater than 265
JLmollL (3 mg/dL), but only a 15% mortality with a lesser increase in serum creatinine. 2 The comparable figures in our population are 40 % and 6 %, which are significantly different by Fischer's exact test (P < 0.0005). Therefore, the major predictor of mortality of out-of-hospital acquired acute renal failure appears to be the category of acute renal failure, which is further reflected in the severity of the renal disease. In conclusion, we have found an incidence of acute renal failure at the time of admission to the hospital of 1 %. Most of these patients have a reversible cause for their renal failure, either volume contraction or obstruction. Drugs were important precipitating factors in 19 % of the patients and infection played a role in 13 %. Patients classified as having prerenal azotemia were the largest etiologic category, had the least severe renal failure, and the lowest mortality. Patients with intrinsic acute renal failure had the most severe renal failure and a mortality of 55 %, comparable to that reported for hospital acquired renal insufficiency. The patients with obstruction were intermediate between these other groups. Even though prerenal azotemia and obstruction should be rapidly reversible, these groups still had mortality rates of 8 % and 24 %, which reflected the severity of the .underlying disease, rather than deaths due to renal failure.
REFERENCES I. Shusterman N, Strom BL, Murray TG, et al: Risk factors and outcome of hospital-acquired acute renal failure. Am I Med 83:65-71, 1987 2. Hou S, Bushinsky D, Wish IB, et al : Hospital-acquired renal insufficiency: A prospective study. Am I Med 74:243248, 1983 3. Anderson RJ, Schrier RW: Acute tubular necrosis, in Schrier RW, Gottschalk CW (eds): Diseases of the Kidney. Boston, MA, Little Brown, 1988, pp 1413-1445 4. Hricik DE, Browning PI , Kopelman R, et al: Captoprilinduced functional renal insufficiency in patients with bilateral renal-artery stenoses or renal-artery stenosis in a solitary kidney. N Engl I Med 308:373-376, 1983 5. Packer M, Lee WH, Medina N, et al: Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure. Ann Intern Med 106:346354, 1987 6. Corwin HL, Bonventre IV: Renal insufficiency associated with nonsteroidal anti-inflammatory agents. Am I Kidney Dis 4 :147-152, 1984 7. Kleinknecht D, Landais P, Goldfarb B: Analgesic and non-steroidal anti-inflammatory drug-associated acute renal failure: A prospective collaborative study. Clin Nephrol 25:275-281, 1986
8. De Troyer A: Demeclocycline: Treatment for syndrome of inappropriate antidiuretic hormone secretion. lAMA 237:2723-2726, 1977 9 . Madias NE, Harrington IT: Platinum toxicity. Am I Med 65 :307-314, 1978 10. Hirsch DI, Bia FI, Kashgarian M, et a1: Rapidly progressive glomerulonephritis during antituberculous therapy. Am I Nephrol 3:7-10, 1983 11. Soffer 0, Nassar VH, Campbell WG, et al: Light chain cast nephropathy and acute renal failure associated with rifampin therapy: Renal disease akin to myeloma kidney. Am I Med 82: 1052-1056, 1987 12 . Nolan CR, Anger MS, Kelleher SP: Eosinophiluria-A new method of detection and definition of the clinical spectrum. N Engl I Med 315:1516-1519, 1986 13 . Kant KS, Weiss MA: Sulfonamide induced acute interstitial nephritis: Role of mUltiple drug and cell mediated immunity. Kidney Intern 35:210, 1989 (abstr) 14. Thompson C, Verani R, Evanoff G, et al : Suppurative bacterial pyelonephritis as a cause of acute renal failure. Am I Kidney Dis 4:271-273, 1986 15 . Neugarten I, Gallo GR, Baldwin DS: Glomerulonephritis in bacterial endocarditis. Am I Kidney Dis 3:371379, 1984
198 16. L1ach F, Papper S, Massry SG: The clinical spectrum of renal vein thrombosis: Acute and chronic. Am J Med 69:819827, 1980 17. Smith MC, Ghose MK, Henry AR: The clinical spectrum of renal cholesterol embolization . Am J Med 71:174-180, 1981 18. Claris-Appiani A, Galato R, Marra G, et al: Prediction of the progression of renal failure in adult and in pediatric pa-
KAUFMAN ET AL tients with malignant focal glomerulosclerosis. Clin Nephrol 26:87-90, 1986 19 . Rasmussen HH, Pill EA, Theis LS , et al: Prediction of outcome in acute renal failure by discriminant analysis of clinical variables. Arch Intern Med 145:2015-2018 , 1985 20. Holden S, McPhee M, Grabstald H: The rationale of urinary diversion in cancer patients . J Urol 121:19-21 , 1979
S
EVERAL STUDIES have documented the causes of hospital-acquired renal insufficiency. 1.2 The most common etiologies include decreased renal perfusion, major surgery, and nephrotoxic drugs, in particular aminoglycosides and radiocontrast agents. Acute renal failure also occurs outside the hospital. The major causes are likely to be different from those of hospital-acquired acute renal failure due to the infrequent use of nephrotoxic antibiotic drugs and the absence of major surgery in this setting. In this study, we examined the causes and outcomes of acute renal failure occurring outside the hospital. METHODS Using a daily computer search of serum creatinine determinations performed in the hospital laboratory, patients with values greater than 177 JLmollL (2 mg/dL) on admission to the hospital were identified. Acute renal failure was defined as a serum creatinine greater than 177 JLmollL (2 mg/dL) and (I) an increase of serum creatinine of at least 44 JLmollL (0.5 mg/dL) for patients with a baseline serum creatinine of less than 168 JLmollL (1.9 mg/dL) , or (2) an increase of greater than 88 JLmollL (1.0 mg/dL) for patients with a baseline creatinine of 177 to 433 JLmollL (2.0 to 4.9 mg/dL), or (3) an increase of greater than 133 JLmollL (1.5 mg/dL) for patients with a baseline serum creatinine level of 442 JLmollL (5 mg/dL) or greater.
These criteria are similar to those used by Hou et al in a study of acute renal failure in hospitalized patients. 2 Baseline serum creatinine was the most recent value obtained within the previous 6 months. For patients not having a creatinine determination in the prior 6 months , but having an admission value greater than 177 JLmollL (2 mg/dL), the presence of acute renal failure was retrospectively defined by a decrease in serum creatinine of 50% within 1 month of admission. Hospital charts were reviewed and patients interviewed to identify demographic data, admission and discharge diagnoses, risk factors at the time of admission to the study, and outcomes. Patients were classified into the three general pathophysiologic categories of prerenal, intrinsic, and postrenal acute renal failure . Prerenal azotemia was considered to be present when there was evidence for intravascular volume depletion, heart failure, or drug-induced renal hypoperfusion and improvement in creatinine was noted with correction of volume disturbance or discontinuation of the drug . 3 Intravascular volume depletion was defined as the presence of orthostatic hypotension (defined From the Renal Section, Boston li!terans Affairs Medical Center, Boston, MA. Current address of Dr Dhakal is the Renal Section, WilkesBarre li!terans Affairs Medical Center, Wilkes-Barre, PA , and that of Dr Patel is 9500-H Prince George Lane, Raleigh, NC. Address reprint requests to James Kaufman, MD , Renal Section, Boston 1\4 Medical Center, 150 S Huntington Ave, Boston, MA 02130. © 1991 by the National Kidney Foundation, Inc. 0272-638619111702-00J9$3. 00/0
American Journal of Kidney Diseases, Vol XVII, No 2 (February), 1991: pp 191-198
191
192
KAUFMAN ET AL
as a decrease > 10 mm Hg in diastolic blood pressure or a pulse rate increase > 10 bpm on standing) or weight loss of greater than 5 % of baseline body weight (documented within 2 months of admission value) in an appropriate clinical setting. Congestive heart failure was defined as the presence of cardiomegaly with vascular redistribution or pulmonary edema on chest x-ray, or third heart sound and rales on physical examination. Gastrointestinal blood loss was defined as the presence of orthostatic hypotension with guaiac positive stools or gastric aspirate. Sepsis was considered to be present when there were positive blood cultures in an appropriate clinical setting. Nonsteroidal antiinflammatory drug or antihypertensive drug use was noted within 48 hours of entry into the study. Hepatorenal syndrome was defined as the presence of acute renal failure in the setting of severe liver failure with ascites and urine sodium concentration less than 10 mEq/L without other causes for the renal failure. Intrinsic acute renal failure was considered to be present when the urine sediment contained muddy brown granular casts and renal tubular epithelial cells, or there was no response in clinical course to volume repletion. Prolonged hypotension and prerenal azotemia may lead to structural renal damage and intrinsic acute renal failure. 3 Under these circumstances, restoration of blood pressure does not result in reversal of the renal failure, and these patients are classified as intrinsic acute renal failure. Urinary tract obstruction was determined by physical and radiologic examination, usually renal ultrasound. Patients were observed daily until their serum creatinine reverted to baseline or until discharge. At that time, a final cause of the renal failure was assigned according to the definitions above. Additional variables recorded included age, sex, baseline creatinine, entry creatinine, peak creatinine, discharge creatinine, duration of elevated creatinine (defined as the time before return to baseline, initiation of dialysis or hospital discharge), and survival outcome. Table 1.
Statistics were performed between groups using analysis of variance and post hoc testing using Newman-Keuls multiple range test for parametric data and Kruskal-Wallis test for nonparametric data. Within-group testing was done using a paired Student's t test. All statistical analyses were performed using Prophet, a statistical resource of the Division of Research Resources, National Institutes of Health. Results are expressed as the mean ± SE.
RESULTS
In the period January 1, 1988 to May 30, 1989, 100 patients meeting our inclusion criteria were entered into the study. During this same period, there were 10,924 admissions to our hospital, an acute care referral hospital serving a predominantly elderly, male population. The patients were divided into three groups according to the category of acute renal failure, either prerenal, intrinsic, or obstruction (Table 1). Two patients had renal failure that could not be classified. Most of the patients had pre renal azotemia as the cause of their renal failure. The three groups were similar in their baseline creatinines. Twenty-two patients did not have a baseline serum creatinine determination within 6 months of entry into the study, 17 in the pre renal group, none in the intrinsic group, four in the obstruction group, and one of the unclassified patients. Of the 78 patients with baseline creatinine measurements, 40 (51 %) had baseline values
Renal Function Data for Patients With Acute Renal Failure Category of Renal Failure Prerenal (n = 70)
Baseline Cr Baseline Cr range Peak Cr Peak Cr range Increase in Cr >265 ILmollL (no.) Peak Cr >442 ILmoi/L (no.) Discharge Cr Discharge Cr range Duration of renal failure (d)
Intrinsic (n = 11)
Obstruction (n = 17)
159 ± 9 (1.8 ± 0.1) 62-398 (0.7-4.5) 318 ± 18 (3.6 ± 0.2) 177-831 (2.0-9.4)
203 ± 44 (2.3 ± 0.5) 71-504 (0.8-5.7) 690 ± 115* (7.8 ± 1.3) 212-1317 (2.4-14.9)
177 ± 35 (2.0 ± 0.4) 71-539 (0.8-6.1) 575 ± 71 * (6.5 ± 0.8) 177-1131 (2.0-12.8)
13 (19%)
8(72%)
10 (58%)
11 (16%) 168 ± 8 (1.9 ± 0.1)
6 (55%) 362 ± 88t (4.1 ± 1.0)
10 (58%) 212 ± 177 (2.4 ± 2.0)
62-530 (0.7-6.0)
115-937 (1.2-10.6)
97-610 (1.1-6.9)
4.1 ± 0.5 (1-27)
10.0 ± 3.0* (1-30)
6.6 ± 2.0 (1-36)
NOTE. Cr indicates serum creatinine concentration in ILmoi/L with the values in parentheses in mg/dL. Discharge Cr is the serum creatinine concentration at the time of death or discharge. Duration of renal failure is the interval of time from hospital admission until either the serum creatinine concentration had decreased to its minimum value or until the patient had died or been discharged, with the range of values given in parentheses. *Significantly different from prerenal group (P < 0.01). tSignificantly different from prerenal and obstruction group (P < 0.01).
COMMUNITY-ACQUIRED ACUTE RENAL FAILURE
greater than 124 p.mollL (1.4 mg/dL), the upper limit of normal for our laboratory. Of these, 25 were in the prerenal group, seven in the intrinsic group, and seven in the obstruction group, and one unclassified. The mean peak serum creatinine concentration was significantly greater (P < 0.01) in the intrinsic and obstruction groups than in the prerenal group. Patients in the former groups were more likely to experience an increase in their serum creatinine concentration of greater than 265 p.mollL (3 mg/dL) and to have a peak serum creatinine concentration of greater than 442 p.moll L (5 mg/dL) compared with the group with prerenal azotemia. The serum creatinine at death or discharge from the hospital was significantly greater (P < 0.01) in the intrinsic group than in the prerenal or obstruction groups. The duration of renal failure was significantly greater (P < 0.01) in the intrinsic group compared with the prerenal group, but not compared with the obstruction group. In the intrinsic group, two patients required institution of chronic hemodialysis, and their data were not included in the analysis of duration of renal failure. The mean age was similar in all three groups,61.9 ± 1.5,60.3 ± 2.4, and 66.0 ± 3.1 years in the prerenal, intrinsic, and obstruction groups, respectively, similar to the average age of 60.0 ± 1.9 for our general hospital popUlation. All patients were males, although during this same time period 3.5% of admissions to our hospital were female. We attempted to define specific etiologies for the renal failure in the individual patients. The data for the prerenal group are shown in Table 2. Multiple Table 2.
Cause of Prerenal Azotemia
Vomiting Poor intake Diarrhea Fever Glycosuria GI bleeding Angiotensin-converting enzyme inhibitors Diuretics Congestive heart failure Antihypertensive drugs Demeclocycline Hepatorenal Sulindac Sepsis
Contributing Cause
Primary Cause
20 14
9
18 12 7
8 8
7
5
5
3
6
4
4 4 1 2 2
3 4 1 2 2
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causes were seen in 15 patients, usually decreased fluid intake associated with vomiting. Drugs were involved in 14 cases of prerenal azotemia. Angiotensin-converting enzyme inhibitors were associated with acute renal failure in six patients, four in which it was thought to be the primary cause. These patients either had hypotension, known renovascular disease, or congestive heart failure. In all six patients, the serum creatinine decreased after discontinuing the converting enzyme inhibitors, usually within 2 to 4 days. Two patients receiving demeclocyline for the syndrome of inappropriate antidiuretic hormone developed prerenal azotemia associated with polyuria, vomiting, and hypernatremia that remitted with reductions in their doses of demeclocycline. One patient with a baseline serum creatinine of 283 p.mollL (3.2 mg/ dL) developed acute renal failure after the institution of sulindac therapy. Although some of these drugs are known to cause intrinsic acute renal failure due to interstitial nephritis, all these patients were thought to have prerenal azotemia because of the presence of orthostatic hypotension, the lack of a urine sediment characteristic of acute tubular necrosis or acute interstitial nephritis, and the reversal of renal failure on discontinuation of the drugs. The causes of the renal failure in the group with intrinsic renal disease were varied. Four patients had renal failure related to infection. One patient with underlying xanthogranulomatous pyelonephritis diagnosed by renal biopsy developed acute renal failure secondary to Escherichia coli pyelonephritis. A second patient presented with septic shock and a urine sediment showing renal tubular epithelial cells and muddy brown granular casts. Two patients had infective endocarditis and renal failure. Four patients had renal failure related to drugs, two due to cisplatinum, one due to rifampin, and one due to glyburide. In these patients with drug-induced intrinsic acute renal failure, the urinalysis showed either renal tubular epithelial cells and muddy brown granular casts or eosinophils and the renal failure did not reverse within 4 days of discontinuing the drug. One patient had spontaneous cholesterol embolization confirmed by renal biopsy. A patient with underlying membranous nephropathy developed acute flank pain and an increase in creatinine, and a diagnosis of renal vein thrombosis was made by renal venography. He was treated with anticoagu-
194
KAUFMAN ET AL
lants and his creatinine returned to baseline. One patient with focal glomerulosclerosis, diagnosed by renal biopsy 1 year previously, progressed from a creatinine of 442 p.mol/L (5.0 mg/dL) to 1,308 p.mollL (14.8 mg/dL) in 2 months, with no apparent cause other than progression of the disease. Reflecting the elderly male population of our hospital, most of the patients with obstruction had benign prostatic hypertrophy (n = 11) or prostatic carcinoma (n = 2) as the cause of their obstruction. One patient with lymphoma and known right hydronephrosis, presented with anuria and an ultrasound showed bilateral hydronephrosis. Two patients had ureteral stones, one a patient with an ileal loop bladder and bilateral stones, and the other a patient with a unilateral stone complicated by pyohydronephrosis. In addition, there was a patient with a large obstructing bladder stone. The overall mortality in patients admitted with acute renal failure was 15 %, compared with a mortality rate of 3.9 % among all hospital admissions. There was a significant (P < 0.01) relationship between the category of acute renal failure and mortality by chi-square analysis with Yates correction. The highest mortality, 6 of 11 (55 %), was observed in the group with intrinsic acute renal failure. In this group, four deaths were due to infection, one to progressive cardiorespiratory failure, and one to complications of an ischemic bowel. The 7% mortality (11 = 5) in the group with prerenal azotemia included two patients with hepatorenal syndrome, a patient with end-stage liver disease and gastrointestinal bleeding, and two patients with widely metastatic carcinoma. In the group with obstruction, the mortality was 24% (n = 4), including two patients with benign prostatic Table 3.
hypertrophy, where the cause of death could not be precisely determined. A patient with prostatic cancer and the patient with ureteral obstruction secondary to lymphoma both died of complications of their advanced cancer. Three patients, all in the group with intrinsic acute renal failure, required dialysis. Two of these patients required chronic maintenance hemodialysis, while one recovered to his baseline renal function. The characteristics of the patients who survived or died are summarized in Table 3. Their ages were not different and the number having a baseline creatinine greater than 177 p.mollL (2 mg/dL) also was not different. The patients that died had a higher mean peak and discharge creatinines, reflecting the greater proportion of patients with intrinsic acute renal failure in this group. . Eight patients in the group with prerenal azotemia had a persistent increase in serum creatinine at discharge greater than 88 p.mollL (1 mg/dL) above their prior baseline values, including four patients who died. Of the four survivors, two patients had congestive heart failure and may still have had some degree of renal hypoperfusion, one patient left against medical advice 48 hours after an admission for alcohol withdrawal and vomiting, and one patient had a baseline serum creatinine of 283 p.mollL (3.2 mg/dL) that increased to 477 p.mollL (5.4 mg/dL) after treatment with sulindac and furosemide, and decreased to only 380 p.mollL (4.3 mg/dL) 9 days after discontinuing the drugs. Therefore, in surviving patients with prerenal azotemia, renal functional recovery was complete unless the underlying condition (ie, congestive heart failure) could not be reversed or drug nephrotoxicity was implicated (ie, sulindac).
Characteristics of Survivors Survivors (n = 85)
Initial Cr Initial Cr range Peak Cr Peak Cr range Discharge Cr Discharge Cr range Duration (d) Age (yr) Baseline Cr > 177 ILmoi/L (2 mg/dL) Increase in Cr >265 ILmoi/L (3 mg/dL) NOTE. Definitions are as given in Table 1. *Significantly different from survivors (P < 0.005).
159 ± 9 (1.8 ± 0.1) 62-442 (0.7-5.0) 362 ± 27 (4.1 ± 0.3) 177-1308 (2.0-14.8) 159 ± 9 (1.8 ± 0.1) 62-513 (0.7-5.8) 4.8 ± 0.6 (1-36) 62.5 ± 1.3 13/64 (20%) 15 (17%)
Deaths (n = 15)
186 ± 44 (2.1 ± 0.5) 71-539 (0.8-6.1) 628 ± 80* (7.1 ± 0.9) 186-1317 (2.1-14.9) 398 ± 53* (4.5 ± 0.6) 97-937 (1.1-10.6) 8.6 ± 2.9 (1-36) 62.2 ± 2.9 4/15 (27%) 10 (67%)
COMMUNITY-ACQUIRED ACUTE RENAL FAILURE
In the group with intrinsic renal failure, recovery of renal function was uncommon. Although eight of the 11 patients had baseline creatinines less than 177 p.mollL (2 mgJdL), four of these eight died and only two survived with creatinines less than 177 p.mollL (2 mgJdL) , one with cisplatinum-induced renal failure and one with renal vein thrombosis. Of the three patients with baseline creatinines greater than 177 p.mollL (2 mgJ dL), one progressed to chronic maintenance hemodialysis, one died of overwhelming infection with a creatinine of 884 p.mollL (10.0 mgJdL), and one patient with endocarditis recovered to his baseline renal function, but died of heart failure . In the obstruction group complete recovery of renal function was the rule. Only two of the 17 patients had a significant increase in their creatinine above baseline at discharge, one who died from the complications of metastatic prostatic carcinoma, and the other who died from the complications of widespread lymphoma. DISCUSSION
Although several studies have examined the etiologic factors involved in hospital-acquired renal insufficiency, 1.2 we are unaware of similar studies of out-of-hospital or community-acquired acute renal failure. Decreased renal perfusion, postoperative renal insufficiency, and the administration of aminogycosides or radiographic contrast agents account for 80% of the episodes of acute renal failure occurring in the hospital. 2 Although reduced renal perfusion may also be an important factor in community-acquired renal failure, the other major causes cited would not be expected to occur outside the hospital setting. We have prospectively examined the causes of community-acquired acute renal failure over a 17 -month period by screening admission laboratory data. Patients who were admitted with elevated creatinines were selected on the basis of prior creatinine determinations and their clinical course. The incidence of acute renal failure on admission to the hospital in our study was approximately 1 %, compared with an incidence of 4.9 % in hospitalized patients. 2 Decreased renal perfusion or prerenal azotemia was the most common cause of acute renal failure, occurring in 70% of the patients, with volume contraction due to vomiting, diarrhea, decreased fluid intake, osmotic diuresis due to glycosuria, and fever as common precipitating factors. Eleven per-
195
cent had intrinsic renal failure, 17 % obstruction, and 2 % could not be classified. Therefore, more than 80 % of patients entering the hospital with an acute elevation of serum creatinine will have a potentially reversible cause for their renal failure. A recent study of hospital-acquired renal insufficiency 2 examined the specific etiologies, but did not use the same categorization we have employed. Of the 129 episodes, 54 were due to decreased renal perfusion and five due to hepatorenal syndrome, both of which we would classify as prerenal azotemia, yielding a minimal incidence of prerenal acute renal failure of 46%. 1Wenty-three (18%) of the episodes occurred after major surgery, but it was not stated how many of these events were due to volume depletion. There were only three (2 %) episodes of obstruction, compared with our incidence of 17 % in community-acquired acute renal failure . Eleven (8 %) were unclassified , and the remainder (26 %) had intrinsic renal failure due to either drugs, vasculitis, renal embolus, or were multifactorial. Therefore, prerenal azotemia is the most common cause of acute renal failure, both community- and hospital-acquired. In hospital-acquired renal insufficiency, drugs are responsible for 20 % of the episodes, with contrast media and aminoglycosides the principal offending agents. 2 Drugs were implicated in 19% of our patients . Captopril was the most common offending agent in our study and is the most commonly prescribed converting enzyme inhibitor in our hospital. Renal failaure is a well-known complication of therapy with converting-enzyme inhibitors. We have classified these patients with renal failure secondary to the administration of converting enzyme inhibitors as prerenal azotemia, since the pathophysiology is thought to be due to a decrease in glomerular perfusion pressure,3 occuring in the setting of bilateral renal artery stenoses or renal artery stenosis in a solitary kidneY,4 congestive heart failure,5 or systemic hypotension. Although the converting enzyme inhibitors may cause intrinsic renal injury, the relatively rapid reversal of renal insufficiency in most of the patients is consistent with hemodynamic, rather than structural alterations. In our patients, renal function returned to baseline 1,2,2,4, 8, and 16 days after stopping the drug, the longest duration being in the patient with congestive heart failure. Besides the converting enzyme inhibitors , several other drugs were noted as causes of prere-
196
nal acute renal failure in our series, including four patients receiving diuretics , one receiving other antihypertensive agents, one receiving sulindac, and two receiving demeclocycline. These patients were thought to have prerenal acute renal failure because the renal failure reversed rapidly after discontinuing the drugs or administering fluid. Although nonsteroidal antiinflammatory agents, such as sulindac, may cause allergic interstitial nephritis 6 or acute tubular necrosis,? in most cases the renal failure is thought to be due to hemodynamic alterations secondary to inhibition of prostaglandin synthesis and has been classified as a form of prerenal azotemia. 3 Similarly, renal functional impairment has previously been reported after treatment with demeclocycline, and is thought to be due to volume depletion secondary to the impairment of urine concentrating ability, although more direct nephrotoxicity has also been suggested. 8 In the patients with intrinsic aucte renal failure, four were thought to have drug nephrotoxicity, including two receiving cisplatinum and one receiving rifampin. Both drugs have well-described nephrotoxicity.9-11 One patient developed Stevens-Johnson syndrome and allergic interstitial nephritis secondary to glyburide, diagnosed by a positive Hansel's stain of his urine sediment demonstrating eosinophiluria.1 2 We are aware of only one other report of glyburide-induced allergic interstitial nephritis. 13 Therefore, in our study, a variety of drugs were responsible for the community-acquired acute renal failure, either as direct nephrotoxins or by resulting in decreases in renal perfusion. Infection was also an important factor associated with renal failure in our population . Thirteen patients had evidence for infection at the time of admission. In the group with intrinsic acute renal failure , in four patients it was a direct cause of the renal failure and an additional patient had antibiotic-induced nephrotoxicity due to rifampin. In the obstruction group, one patient had ureteral obstruction with accompanying pyohydronephrosis. In the remaining seven patients, fever secondary to infection was thought to result in increased insensible fluid loss and contribute to intravascular volume depletion and pre renal azotemia. The patients with intrinsic acute renal failure in our study differ from those in studies of hospitalacquired renal insufficiency. I 2 In those studies, contrast media, aminoglycosides, and ischemia,
KAUFMAN ET AL
often related to surgery, accounted for the majority of the patients. In the current study, only one patient had typical acute tubular necrosis, a patient with sepsis and prolonged hypotension. In our patients, drugs and infections were common precipitants of intrinsic acute renal failure . Infectious causes have previously been cited as etiologies of acute renal failure. 14.15 Besides the patients with drug- or infection-related intrinsic acute renal failure, there were two patients that might be classified as having vascular causes, one with acute renal vein thrombosisl 6 and one with cholesterol emboli.17 The remaining patient with intrinsic acute renal failure had biopsy-proven focal segmental glomerulosclerosis, and rapid progression of his renal failure in 2 months without an obvious cause. Progression to renal fail~lfe in less than 1 year has previously been described in focal glomerulosclerosis.1 8 In the absence of other causes, rapid progression of the glomerular disease appears to be the etiology of the acute renal failure in this patient. Therefore, in our patients with intrinsic acute renal failure , the causes were varied, but often were drug- or infection-related, or due to preexisting renal pathology. In accordance with the study design , not all patients had baseline creatinines within 6 months of entry into the study. Of the 78 patients that did, 40 had baseline serum creatinines greater than 124 /LmollL (1.4 mg/dL), the upper limit of normal for our laboratory, and 18 were greater than 177 /LmollL (2 mg/dL). This finding suggests that patients with underlying renal disease are at increased risk for developing acute renal failure outside the hospital, an observation that has also been made for hospital-acquired renal insufficiency. 19 The prognosis for both patient and renal survival in our study depended on the category of acute renal failure . Patients with prerenal azotemia had the best survival, with only a 7% mortality rate. In a series of patients with hospital-acquired renal insufficiency, 35 % of the patients with acute renal failure due to decreased renal perfusion died. Most of these deaths were in patients with cardiogenic or septic shock or severe congestive heart failure, and only 9 % of those with volume contraction died. 2 In our study, the group with obstruction had a relatively high mortality rate of 24 %, probably reflecting the age of the patients and the nature of the obstruction. In a study of hospital-acquired renal insufficiency, obstruction accounted for only
197
COMMUNITY-ACQUIRED ACUTE RENAL FAILURE
three of 129 episodes of acute renal failure and there were no deaths in this group.2 However, in patients with widespread cancer and bilateral ureteral obstruction, previously reported mortality at two months was 49 %, even after nephrostomy drainage. 2o The worst prognosis in our series was in the intrinsic group , where the mortality was six of 11 (55%); an additional patient required maintenance hemodialysis, and only two patients were discharged without significant renal impairment. This mortality is relatively high for patients with nonsurgical intrinsic acute renal failure, where the mortality is usually cited as 30% to 40%.3 The high mortality of intrinsic acute renal failure in our series probably reflects the age of the patients, the severity of the underlying illnesses, and the relatively small sample size. Other than the category of acute renal failure, the patients who lived did not differ significantly from those who died. Baseline creatinines and ages were similar. The patients who died had a higher peak creatinine, probably reflecting the greater proportion of patients with intrinsic acute renal failure, as well as the contribution of the acute renal failure to mortality. Previous studies have also demonstrated that mortality is related to the magnitude of the increase in serum creatinine, with a 64 % mortality in those with an increase in serum creatinine concentration of greater than 265
JLmollL (3 mg/dL), but only a 15% mortality with a lesser increase in serum creatinine. 2 The comparable figures in our population are 40 % and 6 %, which are significantly different by Fischer's exact test (P < 0.0005). Therefore, the major predictor of mortality of out-of-hospital acquired acute renal failure appears to be the category of acute renal failure, which is further reflected in the severity of the renal disease. In conclusion, we have found an incidence of acute renal failure at the time of admission to the hospital of 1 %. Most of these patients have a reversible cause for their renal failure, either volume contraction or obstruction. Drugs were important precipitating factors in 19 % of the patients and infection played a role in 13 %. Patients classified as having prerenal azotemia were the largest etiologic category, had the least severe renal failure, and the lowest mortality. Patients with intrinsic acute renal failure had the most severe renal failure and a mortality of 55 %, comparable to that reported for hospital acquired renal insufficiency. The patients with obstruction were intermediate between these other groups. Even though prerenal azotemia and obstruction should be rapidly reversible, these groups still had mortality rates of 8 % and 24 %, which reflected the severity of the .underlying disease, rather than deaths due to renal failure.
REFERENCES I. Shusterman N, Strom BL, Murray TG, et al: Risk factors and outcome of hospital-acquired acute renal failure. Am I Med 83:65-71, 1987 2. Hou S, Bushinsky D, Wish IB, et al : Hospital-acquired renal insufficiency: A prospective study. Am I Med 74:243248, 1983 3. Anderson RJ, Schrier RW: Acute tubular necrosis, in Schrier RW, Gottschalk CW (eds): Diseases of the Kidney. Boston, MA, Little Brown, 1988, pp 1413-1445 4. Hricik DE, Browning PI , Kopelman R, et al: Captoprilinduced functional renal insufficiency in patients with bilateral renal-artery stenoses or renal-artery stenosis in a solitary kidney. N Engl I Med 308:373-376, 1983 5. Packer M, Lee WH, Medina N, et al: Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure. Ann Intern Med 106:346354, 1987 6. Corwin HL, Bonventre IV: Renal insufficiency associated with nonsteroidal anti-inflammatory agents. Am I Kidney Dis 4 :147-152, 1984 7. Kleinknecht D, Landais P, Goldfarb B: Analgesic and non-steroidal anti-inflammatory drug-associated acute renal failure: A prospective collaborative study. Clin Nephrol 25:275-281, 1986
8. De Troyer A: Demeclocycline: Treatment for syndrome of inappropriate antidiuretic hormone secretion. lAMA 237:2723-2726, 1977 9 . Madias NE, Harrington IT: Platinum toxicity. Am I Med 65 :307-314, 1978 10. Hirsch DI, Bia FI, Kashgarian M, et a1: Rapidly progressive glomerulonephritis during antituberculous therapy. Am I Nephrol 3:7-10, 1983 11. Soffer 0, Nassar VH, Campbell WG, et al: Light chain cast nephropathy and acute renal failure associated with rifampin therapy: Renal disease akin to myeloma kidney. Am I Med 82: 1052-1056, 1987 12 . Nolan CR, Anger MS, Kelleher SP: Eosinophiluria-A new method of detection and definition of the clinical spectrum. N Engl I Med 315:1516-1519, 1986 13 . Kant KS, Weiss MA: Sulfonamide induced acute interstitial nephritis: Role of mUltiple drug and cell mediated immunity. Kidney Intern 35:210, 1989 (abstr) 14. Thompson C, Verani R, Evanoff G, et al : Suppurative bacterial pyelonephritis as a cause of acute renal failure. Am I Kidney Dis 4:271-273, 1986 15 . Neugarten I, Gallo GR, Baldwin DS: Glomerulonephritis in bacterial endocarditis. Am I Kidney Dis 3:371379, 1984
198 16. L1ach F, Papper S, Massry SG: The clinical spectrum of renal vein thrombosis: Acute and chronic. Am J Med 69:819827, 1980 17. Smith MC, Ghose MK, Henry AR: The clinical spectrum of renal cholesterol embolization . Am J Med 71:174-180, 1981 18. Claris-Appiani A, Galato R, Marra G, et al: Prediction of the progression of renal failure in adult and in pediatric pa-
KAUFMAN ET AL tients with malignant focal glomerulosclerosis. Clin Nephrol 26:87-90, 1986 19 . Rasmussen HH, Pill EA, Theis LS , et al: Prediction of outcome in acute renal failure by discriminant analysis of clinical variables. Arch Intern Med 145:2015-2018 , 1985 20. Holden S, McPhee M, Grabstald H: The rationale of urinary diversion in cancer patients . J Urol 121:19-21 , 1979
