Postoperative Chronic Renal Failure - NCBI

Postoperative Chronic Renal Failure: A New Syndrome? GEORGE E. MERINO, THEODORE J. BUSELMEIER, CARL M. KJELLSTRAND

Of 125 patients with postsurgical acute tubular necrosis, 87 died, 34 regained clinical normal renal function, and 4 survivors (9.5%) were left with severe permanent renal failure, two of whom required chronic dialysis and transplantation. Preoperatively these 4 patients had normal renal function. The 4 patients were above age 60, two had undergone methoxyflurane anesthesia, and nephrotoxic antibiotics were used in all. The incidence of permanent renal failure is much higher than ever reported and may reflect the survival of patients who previously died because of less ideal dialysis. We believe that the cause of this permanent lesion is multifactorial, including age (over 60 years), nephrotoxic antibiotics (particularly cephalothin and gentamicin sulfate), and nephrotoxic anesthetic (methoxyflurane) agents. This combination of factors should be avoided whenever possible.

A CUTE TUBULAR NECROSIS (ATN) following surgery has a mortality of 50 to 70%*.35 8'30 The patients who survive the acute episode recover clinical complete renal function within 2 to 8 weeks, although some cases of functional disturbances can be detected by dilution tests, concentration tests, and glomerular filtration rates.1427 Recently there have been reports of incomplete clinical function recovery after methoxyflurane (Penthrane) anesthesia.9"15 In our earlier experiences, and that of others,35"14'27 clinical complete renal function returned in all patients who survived ATN following operation. Since 1968, however, we encountered a 10o incidence of severe chronic renal failure complicating operative procedures in patients with previous normal renal function. These patients represent a previously unobserved postoperative condition. This paper describes these patients and our search for contributing etiological factors. Between January 1968 and August 1974, 187 patients

From the Dialysis Unit, Departments of Medicine and Surgery, University of Minnesota Hospital, Minneapolis, Minnesota

needed dialysis because of acute renal failure associated with a catastrophic illness (Table 1). Fifty-one of these patients had their complication as a consequence of a medical disease, 8 were obstetrical complications, and three cases of ATN followed severe burns. The remaining 125 patients developed ATN after different types of operative procedures. Eighty-seven (70%) of these ATN patients died, and 34 recovered enough renal function to maintain a creatinine level below 2 mg/100 ml, usually within one month. However, two patients have required continuous chronic hemodialysis or transplantation and two others have creatinine levels of approximately 4 mg/100 ml, one and 6 years after their acute renal failure episode. These last 4 patients represent 109o of the surviving post-surgical group and their case reports follow. Case Reports Case I (Fig. 1). A 70-year-old man was admitted in May 1970 for the removal of a right colonic polyp. He had a 10-year

history of mild diabetes mellitus which was controlled with diet. On admission he had a blood pressure reading of 150/80, a BUN of 20 mg/100 ml, glucose of 210 mg/100 ml, and uric acid of 3.8 mg/100 ml. Urinalysis, electrolytes, total proteins, cholesterol, alkaline phosphatase and SGOT readings were normal. Six days after admission, following colonic preparation with low residue diet and sulphathalidine therapy, a segmental resection of his right colon was performed. He was anesthetized with pentothal sodium (250 mg) and methoxyflurane (Penthrane) 0.7 vol %. During the 3½ hour-long operation the patient's blood pressure, 160 mm systolic immediately preoperation, remained at approximately 120 mmHg, but it decreased to 100 mmHg in Submitted for publication March 27, 1975. the recovery room. This was promptly corrected with intravenReprint requests: Dr. Carl Kjelistrand, Box #123, Department ous fluids and metaraminol (Aramine). On the day of his operaof Surgery, Mayo Memorial Building, University of Minnesota, Min- tion the patient produced 1000 cc of urine, but oliguria ensued neapolis, Minnesota 55455. (200 and 400 cc of urine per day) in spite of treatment with 37

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MERINO, BUSELMEIER AND KJELLSTRAND

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DIALYSIS ii it ;4 ;H tii it I I ii IMMiM4i MMMMM4 441it MM I IW444 200

20 0

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(METHOXYFLUORANE) mannitol and ethacrynic acid. He received cephalothin (Keflin), 1 gm every 6 hours, for 14 days. Seventeen days after surgery his creatinine was 15.2 mg/100 ml, BUN 106 mg/100 ml, HCO3 14, uric acid 14.0 mg/100 ml, serum potassium 6.2 mEq and serum phosphorus 9.5 mg/100 ml. Calcium oxalate crystals were found in two repeated urinalysis tests. The result of a renogram (131 I Hippuran) was compatible with acute tubular necrosis and hemodialysis was started. Over the next 5 months, the patient received approximately 40 dialyses. His urine output remained between 56 and 200 cc per day the entire time. He then received a cadaver donor kidney transplant that functioned well at first, but three rejection episodes ensued, which were treated with local radiation and large doses of prednisone. Subsequently, pulmonary infection developed that necessitated the lowering of his immunosuppression dosage, and irreversible kidney rejection followed. Candida albicans was cultured from his sputum and urine at that time. The patient refused further dialysis treatment. He died 5 months after transplantation, 10 months after the onset of renal failure. The postmorten examination of the patient's own kidneys showed fibrosis of the renal cortex, with multiple small abscesses that contained candida organisms and oxalate crystals (Fig. 2). Case 2 (Fig. 3). The patient was a 60-year-old man with a history of peptic ulcer that had been treated by antrectomy and a Billroth II gastroenterostomy. In March 1973 he was gastroscoped under Diazepam sedation for removal of a polyp in the duodenal stump. At that time the patient had a BUN of 18, the urinalysis and electrolyte study results were normal. Twenty-four hours following endoscopy acute peritonitis developed. An exploratory laparotomy revealed an accidental perforation of the duodenal stump. Closure of the perforation and lavage were completed in two hours under Halothane (fluothane) anesthesia. The following day he became febrile and was given cephalothin (Keflin), 2 gm every 4 hours, intravenously for 6 days. An intraperitoneal abscess developed and a 2 hour long

9/l/70

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exploratory laparotomy for drainage of a sub-hepatic abscess was done on the 16th postoperative day with fentanyldroperidol (Innovar) anesthesia. Before surgery the patient's serum creatinine was 1.7 mg/100 ml and the BUN was 17 mg/ml. The procedure was complicated by 20 minutes of hypotension (BP 80/40 mm Hg), which was corrected with 2000 cc of fluid. Gentamycin sulfate therapy was started (80 mg) during surgery and continued for 11 days, with ampicillin, 1 gm 4 times a day, for 6 days. His urine output remained at about 2000 ml daily for 6 days, then dropped to less than 100 cc/day. Sixteen days after laparotomy his serum creatinine was 11.3, and the BUN was 100 mg/100 ml. At that time the patient was transferred to the University of Minnesota Hospital to begin periodic hemodialysis, which he still requires. Chloramphenicol therapy replaced gentamycin. On the 46th postoperative day a colocutaneous fistula was discovered draining through the surgical wound. A fistulogram demonstrated its continuity with a subphrenic abscess. Under halothane (Fluothane) anesthesia, the colonic fistula was closed and terminal loop ileostomy performed. Pseudomonas aeruginosa was cultured from the wound three days later, and gentamycin (70 mg after each dialysis) therapy was reinstituted for a 22 day period. The patient has remained oliguric (less than 400 cc/urine/day) since then. Four months later his ileostomy was successfully taken down. At the present time he requires three dialyses per week and produces about 200 cc of urine a day. His predialysis serum creatinine ranges from 6-9 mg/100 ml. Case 3 (Fig. 4). A 71-year-old man had a three month history of intermittent hematuria when he entered his local hospital in October 1968. At that time an IVP revealed an incomplete filling of the upper pole calices of the left kidney. Retrograde pyelogram and renal arteriograms confirmed neoplasia of the left kidney. His BUN was 23.5, creatinine 0.6 mg/100 ml and electrolyte studies were normal. There was microscopic evidence of hematuria, but no proteinuria. Methoxyflurane (Penthrane) (0.7 vol %) was used during the nephrectomy, which was compli-

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POSTOPERATIVE CHRONIC RENAL FAILURE

FIG. 2. Macroscopic and microscopic views of Case 1 kidneys. The third kidney .seen on the right was transplanted from a cadaver donor. Microscopic sections, from the patients own kidneys show cortical fibrosis, microabscess and dense oxalate crystals depositions.

cated by left pneumothorax. A brief hypotensive and hypoxic episode occurred before a chest tube was inserted to relieve the pneumothorax. The urine output fell progressively to 300-600 cc/day during 8 postoperative days and the serum creatinine level rose rapidly

sodium was 67 mEq/L and the serum potassium 18.1 mEq/L., 10 days after unilateral nephrectomy, complicated by a staphylococcal infection of the wound and a pulmonary embolism. He was treated with Chloramphenicol (500 mg) twice daily, and subsequently he received bo.th ampicillin (500 mg) and methicillin (500 mg) 4 times a day for 3 weeks. On the 15th

to 13 mg/100 ml, and the BUN to 188 mg/100 ml. Urinary DIAL YS/S

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MERINO, BUSELMEIER AND KJELLSTRAND DIAL YS/S

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postoperative day the patient was started on hemodialysis. Over the next 57 days he received 16 hemodialyses. His urine output increased to about 1000 cc/day and he was then discharged on a Giovennetti diet. At that time his creatinine was 8.4 and BUN was 43 mg/100 ml. Since then the patient has been hospitalized twice for a mild cerebrovascular accident and a rectal polypectomy. Using a protein restricted diet combined with 20-40 mg of furosemide per day, his creatinine is now stable around 4 mg/100 ml, and his BUN is at 48-60 mg/100 ml, 6 years after acute renal failure. Case 4 (Fig. 5). A 74-year-old woman was admitted to this hospital in September 1973 with a two-year history of intermittent jaundice. One year prior to admission on oral cholecystogram had DIAL YS/S

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shown a non-functioning gall badder but the patient had declined surgery. Since then she had been on phenothiazine derivatives as treatment for agitation. She had an enlarged liver, bilirubin 8.8mg/ 100 ml, BUN 16 mgl 100 ml, serum creatinine 0.8 mg/ 100 ml, alkaline phosphorus 1221 U., SGOT 56 U. A urinalysis revealed bilirubinuria. Phentothiazine therapy was discontinued but the jaundice persisted, and after a week she developed fever, chills, and an elevated WBC, interpreted as acute cholangitis. She was started on cephalexin monohydrate (Keflex) therapy, 1 gm every 6 hours. Three days later a cholecystectomy and cholodocholithotomy were performed and a T tube was left in place. Anesthesia was induced with pentothal sodium and maintained with halothane (0.7 Vol %) for 31/4 hours.

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Postoperatively the patient received 4 gm of cephalothin and 600 cc of dextran (Rheomacrodex) daily for 8 days. On the fourth day the urine output had decreased, and over the next two days the patient developed anuria. By the ninth postoperative day, the creatinine was 12.2 mg/100 ml, BUN 64 K+ 6.5 mEq/L., and the pH was 7.27. Repeated 131 Iodine renal scans indicated acute tubular necrosis. Over the next 56 days the patient received 21

hemodialyses.

On the 22nd postoperative day she became febrile, the WBC rose to 20,000 and the blood cultures grew out gram negative rods of the Alkaligenes species. She was treated with 80 mg of gentamycin for 8 days, followed by Chloramphenicol 1 gm every 6 hours for 31 days until the infection was cleared. On the 54th postoperative day the urine output increased to 720 cc/day. Since then the urine output has remained at 1000 cc/day. At discharge from the hospital the patient's BUN was 62 mg/100 ml, serum creatinine 4.6 mg/100 ml, creatinine clearance was 10 cc/minute for 1.73 in2. Recent BUN and creatinine readings taken 10 months after discharge were 82 and 4.2 mg/100mI respectively.

Methods

Diagnostic Methods The diagnosis of acute tubular necrosis was based on falling urinary output, isosthenuria and a rise in serum creatinine and BUN levels. Prerenal failure was ruled out by urine electrolytes, and by appropriate fluid replacement and the use of mannitol and furosemide or ethacrynic acid. All four patients with permanent lesions received 131 1 Hippuran renograms, and two of them also received a retrograde pyelography. Only one patient (Case 1) underwent renal biopsy (Fig. 1). One patient (Case 3) had only one kidney, and the other two patients refused biopsies.

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these 4 patients died 10 months later, 5 months after kidney transplantation. He had required dialysis until the time of transplantation. Another patient is on chronic dialysis two years after his episode of acute renal failure. The other two patients no longer require dialysis but they are managed on moderate protein restriction and diuretics, one and 6 years after their acute renal failure episode. Both patients have a serum creatinine in the range of 4 mg/100 ml.

Surgical Procedures Forty-eight abdominal, 11 urological, and 49 cardiovascular operative procedures, and 17 episodes of trauma, were the origins of the 125 postoperative ATN patients treated with dialysis (Table 1). Twenty-one per cent of these procedures were performed in other hospi-

tals. Three of the four cases of permanent renal damage occurred after abdominal surgery, and one after a unilateral nephrectomy for hypernephroma. Each of the four procedures lasted more than three hours. There were no major intra-operative complication but two patients (Cases 2 and 3) experienced moderate hypotensive episodes (less than 15 minutes) which were corrected with fluids, and in one case (Case 1), with vasoactive amines.

Age and Sex The youngest of the 125 patients with postoperative ATN were two premature babies, and the oldest patient was age 83 (Table 2). The patients who required abdominal or cardiovascular surgery tended to be older. There were 104 males, and 21 females (one of the patients with permanent lesions was a woman).

Medical Treatment and Dialysis Regimen Broad spectrum antibiotics were used immediately following operation in these four patients. Three of the four patients with permanent lesions (Cases 1, 2, 4) received cephalothin, the two (Cases 3 and 4) received ChloramComplete 1 Permanent T Mortality 1 phenicol early in their course. In addition, gentamicin _ _ _ Pt _ No. No Recovery J Damage _%__ was given to patients 2 and 4, and ampicillin and/or methicillin to patients 2 and 3. Post - Surgical All patients received oral aluminum hydroxide, for Abdominal 48 7 3 79 phosphate binding, and intramuscular injections of l Urological 10 0 anabolic steroids and 90% of them received broad specCardiovascular 49 10 79 trum antibiotics. Hyperalimentation with intravenous Trauma 17 7 58 amino acids and 50o glucose was used in 50% of the 125 Total 125 [ 34 |4 (3.2%)f 69 patients. Two of the patients with irreversible failure (Cases 1, 3) were hyperalimentated from 15 days to 2 Obstetrical 8 6 months. Seven-hour-long hemodialyses were performed Medical 51 18 three to seven times weekly. Regional heparinization was Burns 3 used according to a previously described technique,18 and antibiotic doses were adjusted according to the standard hemodialysis criteria.6 | Overall Total 187 58 4 (2.1 %) 68 Results Table 1. One hundred and twenty-five of the 187 patients treated for ATN were postoperative patients. Thirty-eight survived, but 4 of them Of the 38 patients who survived postoperative ATN, 4 (9.5%) had permanent renal damage (3.2% of all postoperative ATN (9.5%) developed severe chronic renal failure. One of patients).


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Damage

Ann. Surg.

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the time of surgery. There was no evidence of septicemia Mortality] J in Patient 1 until after a cadaver kidney was transplanted (%) and immunosuppressive treatment was started. 77

Anesthesia Two of the four patients with permanent lesions re20-29 10 5 50 ceived methoxyflurane, the other two had halothane anesthesia. At our institution, nitrous oxide and an IV 4 1 30-39 75 narcotic agent are used for approximately 60o of the 6 67 40-49 2 general anesthesia inductions and halothane is used in 20%. Ten per cent of the operations are performed under 50-59 33 10 70 local anesthesia, and less than 1% of the patients receive 35 8 1 60-69 74 methoxyflurane antibiotics. Cephalothin was used early 70-83 4 24 3 70 after surgery in three cases and gentamicin was used in two. Two patients were treated with chloramphenicol I Total 4 I 125 34 and two with ampicillin and methicillin sodium. Almost all of our postoperative patients with ATN received Table 2. Sixteen of 38 survivors were over 60 years of age. The 4 broad spectrum antibiotics during their course. patients with residual chronic renal failure were all over 60 and 3 of them were actually over 70 years old. Cephalothin is most commonly used, but one-third of the patients also received gentamicin. Table 2 illustrates that age influenced the renal funcDiscussion tional recovery. Of 16 surviving patients above age 60, In spite of great improvements in dialysis techniques, four (25%) never recovered good renal function. None of vascular access, postoperative care, the understanding of the 22 patients younger than age 60, who survived, exfluid balance and parental alimentation, and the electrolyte perienced permanent damage. development of new antibiotics, the survival rate of paOliguric Period tients with postoperative ATN has remained unchanged Oliguria (urine output less than 400 cc per day) lasted over the last three decades. Apparently the technical for an average of 12.7 days in the 34 patients that had full improvements have been offset by an increased patient recovery of renal function. Of the 4 patients with perma- age and an increased severity of the basic disease comnent lesions, one remained oliguric indefinitely and one plicated by acute renal failure.3'5'8'16'30 intermittently for over 2 years. The other 2 patients A high incidence (9.5%) of severe chronic renal failure (Cases 3 and 4) remained intermittently oliguric for 52 in the survivors of postoperative ATN, however, is at and 55 days. As expected, there was no correlation be- variance with earlier descriptions. Several previous large tween the rapidity of creatinine and BUN elevation in the series have reported that such patients achieve clinical 34 patients who recovered complete renal function, and normalcy, although subclinical abnormalities were found the four who did not. in 60-70o of the cases.1427 The most common abnormalities seem to be a reduction in the glomerular filtraComplications tion rate and renal blood flow. The tubular function tests Infectious complications occurred in nearly all of the were abnormal in a smaller per cent of patients (3 1%).14,27 125 ATN patients. Eighty per cent had positive urine What specifically inhibited the regenerative of cultures and pathogenic bacteria was cultured from their the kidneys in our four patients is unknown.capacity These pasputum. During the first postoperative month 60o of the tients may represent a group that would have died when 87 patients who died had positive blood cultures that prolonged dialysis, in the pre-Scribner shunt era, was usually grew gram negative rods. technically impossible. Several factors, alone, or more Three of the four patients who required dialysis (Cases likely, combined must be considered. 2, 3, 4), grew positive blood cultures in the immediate postoperative period, and two of them (Cases 2 and 4) Age probably had sepsis before surgery. Patient 2 had an Age was the common factor among the four patients intraperitoneal infection at the time of the operative pro- with permanent lesions. Each was above age 60 at the cedure coincidental with the onset of renal failure, and time their acute renal failure developed. Davies and gram-negative septicemia was documented at least twice Shock10 have reported decreases in renal function with during the first postoperative month. Patient 4 presented aging. They reported that innulin and PAH clearance with a picture of ascending colangitis and more than decreased to 46% and 53%, respectively, between the 100,000 colonies/ml of E. coli were grown from the bite at ages of 20 and 90 years. Kumar et al.20 found that the 10-19

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older patient who experienced acute renal failure has a longer period of aliguria and a slower recovery period. Hall et al.14 observed that in spite of complete clinical recovery after postoperative acute renal failure, the average "functional" recovery was only 75% in patients over 45 years of age. Vascular changes of benign nephrosclerosis is the most common abnormality of the senescent kidney, which probably accounts for the atrophic and degenerative changes evident as focal areas of diminished uptake on the 1311 Hippuran renal scan. In the older patient, this may predispose the kidneys to less than complete recovery. However, Skov and Hansen29 observed no difference in the functional hypertrophy of the remaining kidney in either elderly or young kidney donors. The 25% failure to achieve clinically normal function in our surviving patients above age 60 remains our single most impressive finding.

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prolonged acute renal failure.32 Cases of prolonged renal failure after methoxyflurane anesthesia may thus be a reaction to oxalate crystals with interstital fibrosis.6 To our knowledge there have been no reports of nephrotoxicity following halothane anesthesia. Nephrotoxic Antibiotics All of our patients received antibiotics that have been associated with renal failure. Patients 1, 2 and 4 received cephalothin immediately after their operation. Although cephalothin does not appear to be toxic in healthy kidneys, several cases of aggravation of pre-existing impaired kidney function have been attributed to its use

7,19,26

Gentamicin was used in two of four patients (Cases 2 and 4); one patient (Case 2) received it repeatedly. Because gentamicin is usually given to only severely ill patients it is difficult to make a conclusion regarding its clinical nephrotoxicity.31 These same two patients (Cases 2 and 4) also received cephalothin therapy. There are several reports of enhanced nephrotoxicity when cephalothin and gentamicin are used concomitantly.11'19 Ampicillin and methicillin, used in 2 of our patients (Cases 2 and 3), have both been associated with acute and chronic renal failure.1'4'13 Chlorampenicol was used in Patients 2, 3 and 4 but we know of no reports associating it with nephrotoxicity. It has also been suggested that certain antibiotics potentiate the nephrotoxicity of

Operative Procedure Three of the four instances of permanent renal damage occurred among ten patients who survived abdominal surgery. This group of patients is also the oldest in our series (mean age 62.1 years), in spite of two premature babies who were also included. It is difficult to conceive how the type of surgery, alone, could prevent complete functional recovery. It is more likely that the failure for this group of patients to recover normal function is demethoxyflurane.21'24 pendent on their age.

Anesthesia Two of the four patients who did not recover from their acute renal failure had methoxyflurane (Penthrane) anesthesia, and two had halothane (Fluothane) anesthesia. Acute postoperative renal dysfunction has been attributed to methoxyflurane anesthesia in at least 104 patients, 31 of whom died.2'9'17 Most patients had a polyuric type of renal dysfunction but a smaller number developed oliguria that required hemodialysis treatment. Most patients had only transient renal abnormalities but at least 7 failed to recover normal renal function. Chronic renal failure following methoxyflurane anesthesia seems to represent a separate syndrome, but methoxyflurane was used only in two of our four patients. Two possible mechanisms of methoxyflurane nephrotoxicity have been proposed, related to fluoride and oxalic acid respectively, thought to be metabolities of methoxy-

flurane.'2'23 Halpren et al. report that an autopsy examination revealed extensive oxalate deposition in a patient who had died with renal failure after 14 months of hemodialysis.15 A similar finding was noticed in the microscopic pathology of our Patient 1 (Fig. 2). In patients with metabolic disorders leading to increased oxalate production, renal insufficiency develops slowly, but acute poisoning with oxalic acid can induce

Sepsis Infection plays a dominant role in the outcome of patients with reversible intrinsic renal failure. Montgomery, Kalmanson and Guze25 recognized infection as the most common cause of death in oliguric patients. They calculated that 22% of the patients with traumatic or surgical renal failure died from an infection that was introduced at the time of injury or developed after admission to the hospital. In the Kennedy report,16 sepsis was either present before the onset of acute renal failure or it developed during the acute phase. Kennedy considered sepsis to be the major cause of death in 25% of the surgical and traumatic group. All of our four patients with irreversible damage had positive urine cultures at one time during their postoperative course, and three of them had documented septicemia. To our knowledge, no data are available on the negative effects of sepsis on the reversibility of acute tubular necrosis, however, it is possible that acute pyelonephritis contributed to the destruction of kidneys in our patients. Conclusion With the exception of the few cases of irreversible renal failure following methoxyflurane anesthesia, none


44

of the factors discussed in this paper seem to be responsible, alone, for irreversible acute renal failure. It is more likely that a conglomerate of factors existed. For example, all of our patients were in the older age range and had urinary tract infections. Patient 1 was exposed to both methoxyflurane and cephalothin. Patient 2 received cephalothin, and repeated treatments with gentamicin and ampicillin. Neither of these patients ever regained enough kidney function to allow them freedom from dialysis. Patient 3 received methoxyflurane anesthesia, a unilateral nephrectomy, methicillin and ampicillin. Patient 4 was treated with a combination of cephalothin and gentamicin after renal failure became apparent. The latter two patients were left with severe renal failure, but they did not need continued dialysis. However, what specifically inhibited the regenerative capacity of the kidneys in these particular patients remains unclear because other patients with similar operations, age, septicemia, complications and drug treatment have had adequate and prompt recovery. To our knowledge, only two comparable cases have previously been reported. Levin et al.22 described one case of prolonged renal insufficiency, accompanied by severe complications, and one of 5 patients described by Siegler and Bloomer28 had a similar course. References 1. Aerenlung, J. H., Halveg, A. B. and Saunamaiki, K. I.: Permanent Impairment of Renal Function After Methicillin Nephropathy. Br. Med. J., 4:406, 1971. 2. Albert, P. S., Kane, L. H. and Davis, J. E.: Methoxyflurane-Induced Renal Failure. Urology, 11:553, 1973. 3. Alwall, N. and Kjellstrand, C. M.: "Acute Renal Failure." A Study of 639 Cases Involving 1,073 Treatments with the Artificial Kidney over the Period 1946-1961. In Therapeutic and Diagnostic Problems in Severe Renal Failure. Sweden, Bonniers Stockholm, 1963; p. 335. 4. Baldwin, D. S., Levine, B. B., McCluskey, R. T. and Gallo, G. R.: Renal Failure and Interstital Nephritis Due to Penicillin and Methicillin. N. Engl. J. Med., 279:1245, 1968. 5. Balsl0v, J. T. and J0rgensen, H. E.: A Survey of 499 Patients with Acute Anuric Renal Insufficiency. Am. J. Med., 34:753, 1963. 6. Bennett, W. M., Singer, I. and Coggins, C. J.: A Guide to Drug Therapy in Renal Failure. JAMA, 230:1544, 1974. 7. Bobrow, S. M., Jaffe, E. and Young, R. C.: Anuric and Acute Tubular Necrosis Associated with Gentamicin and Cephalothin. JAMA, 222:1546, 1972. 8. Casali, R., Simmons, R. L., Najarian, J. S., et al.: Acute Renal Insufficiency Complicating Major Cardiovascular Surgery. Ann. Surg., 181:370, 1975. 9. Churchill, D., Knaack, J., Chirito, E., et al.: Persisting Renal Insufficiency After Methoxyflurane Anesthesia: Report of Two Cases and Review of Literature. Am. J. Med., 56:575, 1974.

Ann. Surg. * July 1975

10. Davis, D. F. and Shock, N. W.: Age Changes in G.F.R. Effective Plasma Flow and Tubular Secretory Capacity in Adult Males. J. Clin. Invest., 29:495, 1950. 11. Fillastre, J. P., Laumonier, R., Humbert, G., et al.: Acute Renal Failure Associated with Combined Gentamicin and Cephalothin, Therapy, Br. Med. J., 2:396, 1973. 12. Frascino, J. A.: Effect of Inorganic Fluoride on the Renal Concentrating Mechanism. Possible Nephrotoxicity in Man. J. Lab. Clin. Med., 79:192, 1972. 13. Gilbert, D. N., Gourley, R., d'Agostine, A., et al.: Interstitial Nephritis Due to Methicillin, Penicillin and Ampicillin. Ann. Allergy, 28:378, 1970. 14. Hall, J. W., Johnson, W. J., Maher, F. T. and Hunt, J. C.: Immediate and Long-term Prognosis in Acute Renal Failure. Ann. Intern. Med., 73:515, 1970. 15. Halpren, B. A., et al.: Intestitial Fibrosis and Chronic Renal Failure Following Methoxyflurane Anesthesia. JAMA, 223:1239, 1973. 16. Kennedy, A. C., Burton, J. A., Luke, R. G., et al.: Factors Affecting the Prognosis in Acute Renal Failure: A Survey of 251 Cases. Quart. J. Med., XLII: 165, 1972. 17. Kiefer, L., Amboy, P. and Paegle, R. D.: Partial Recovery from Renal Failure Following Methoxyflurane Anesthesia. JAMA, 227:201, 1974. 18. Kjellstrand, C. M. and Buselmeier, T. J.: A Simple Method for Anticoagulation During Pre- and Postoperative Hemodialysis Avoiding Rebound Phenomenon. Surgery, 72:630, 1972. 19. Kleinknecht, D. et al.: Acute Renal Failure After High Doses of Gentamicin and Cephalothin, Lancet, I:1129, 1973. 20. Kumar, R., Hill, C. M. and MqGeown, M. G.: Acute Renal Failure in the Elderly. Lancet, 1:90, 1973. 21. Kuzucu, E. Y.: Methoxyflurane, Tetracycline and Renal Failure. JAMA, 211:1162, 1970. 22. Levin, M. L., Simon, N. M., Herdson, P. B. and Del Greco, F.: Acute Renal Failure Followed by Protracted Slowly Resolving Chronic Uremia. J. Chron. Dis., 25:645, 1972. 23. Mazze, R. I., Trudell, J. R., and Cousins, M. J.: Methoxyflurane Metabolism and Renal Dysfunction: Clinical Correlation in Man. Anesthesiology, 35:247, 1971. 24. Mazze, R. I. and Cousins, M. J.: Combined Nephrotoxicity of Gentamicin and Methoxyflurane Anesthesia in Man: A Case Report. Br. J. Anesth., 45:394, 1973. 25. Montgomery, J. Z., Kalmanson, G. M. and Guze, L. B.: Renal Failure and Infection. Medicine (Baltimore), 47:1-32, 1968. 26. Pickering, M. J., et al.: Declining Renal Function Associated with Administration of Cephalothin, South. Med. J., 63:426, 1970. 27. Sewers, D. T., Mathew, T. H., Maher, J. F., et al.: Long-term Follow-up of Renal Function and Histology After Acute Tubular Necrosis. Ann. Intern. Med., 73:523, 1970. 28. Siegler, R. L. and Bloomer, H. A.: Acute Renal Failure with Prolonged Oliguria: An Account of Five Cases. JAMA, 225:133, 1973. 29. Skov, P. E. And Hansen, H. E.: Glomerular Filtration Rate, Renal Flow, and Filtration Fraction in Living Donors Before and After Nephrectomy. Acta Med., 195:97, 1974. 30. Stott, R. B., Cameron, J. S., Ogg, C. S. and Bewick, M.: Why the Persistently High Mortality in Acute Renal Failure? Lancet, 11:75, 1972. 31. Wilfert, J. N., Burke, J. P., Bloomer, H. A. and Smith, C. B.: Renal Insufficiently Associated with Gentamycin Therapy. J. Infect. Dis. 124:S148, 1971. 32. Williams, H. E. and Smith, L. H.: Disorders of Oxalate Metabolism. Am. J. Med., 45:715, 1968.