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 whomrequired chronic dialysis and transplantation. Preoperativelythese 4 patients had normal renal function. The 4 patients wereabove age 60, two had undergone methoxyflurane anesthesia, andnephrotoxic antibiotics were used in all. The incidence of perma-nent renal failure is much higher than ever reported and mayreflect the survival of patients who previously died because ofless ideal dialysis. We believe that the cause of this permanentlesion is multifactorial, including age (over 60 years), nephrotoxicantibiotics (particularly cephalothin and gentamicin sulfate), andnephrotoxic anesthetic (methoxyflurane) agents. This combina-tion of factors should be avoided whenever possible.

A CUTE TUBULAR NECROSIS (ATN) following surgeryhas a mortality of 50 to 70%*.35 8'30 The patients who

survive the acute episode recover clinical complete renalfunction within 2 to 8 weeks, although some cases offunctional disturbances can be detected by dilution tests,concentration tests, and glomerular filtration rates.1427Recently there have been reports of incomplete clinicalfunction recovery after methoxyflurane (Penthrane)anesthesia.9"15 In our earlier experiences, and that ofothers,35"14'27 clinical complete renal function returned inall patients who survived ATN following operation.Since 1968, however, we encountered a 10o incidence ofsevere chronic renal failure complicating operative pro-cedures in patients with previous normal renal function.These patients represent a previously unobserved post-operative condition. This paper describes these patientsand our search for contributing etiological factors.Between January 1968 and August 1974, 187 patients

From the Dialysis Unit, Departments of Medicine andSurgery, University of Minnesota Hospital,

Minneapolis, Minnesota

needed dialysis because of acute renal failure associatedwith a catastrophic illness (Table 1). Fifty-one of thesepatients had their complication as a consequence of amedical disease, 8 were obstetrical complications, andthree cases of ATN followed severe burns. The remain-ing 125 patients developed ATN after different types ofoperative procedures. Eighty-seven (70%) of these ATNpatients died, and 34 recovered enough renal function tomaintain a creatinine level below 2 mg/100 ml, usuallywithin one month. However, two patients have requiredcontinuous chronic hemodialysis or transplantation andtwo others have creatinine levels of approximately 4mg/100 ml, one and 6 years after their acute renal failureepisode. These last 4 patients represent 109o of the sur-viving post-surgical group and their case reports follow.

Case ReportsCase 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-yearhistory of mild diabetes mellitus which was controlled with diet.On admission he had a blood pressure reading of 150/80, a BUNof 20 mg/100 ml, glucose of 210 mg/100 ml, and uric acid of 3.8mg/100 ml. Urinalysis, electrolytes, total proteins, cholesterol,alkaline phosphatase and SGOT readings were normal. Six daysafter admission, following colonic preparation with low residuediet and sulphathalidine therapy, a segmental resectionof his right colon was performed. He was anesthetized withpentothal sodium (250 mg) and methoxyflurane (Penthrane) 0.7vol %. During the 3½ hour-long operation the patient's bloodpressure, 160 mm systolic immediately preoperation, remainedat approximately 120 mmHg, but it decreased to 100 mmHg inthe recovery room. This was promptly corrected with intraven-ous fluids and metaraminol (Aramine). On the day of his opera-tion the patient produced 1000 cc of urine, but oliguria ensued(200 and 400 cc of urine per day) in spite of treatment with

37

Submitted for publication March 27, 1975.Reprint requests: Dr. Carl Kjelistrand, Box #123, Department

of Surgery, Mayo Memorial Building, University of Minnesota, Min-neapolis, Minnesota 55455.

MERINO, BUSELMEIER AND KJELLSTRAND Ann. Surg. July 1975

FIG. 1. Clinical course anddrug regimen of Case 1.

5/1/70 6/1/70 7/1/70 8/1/70 9/l/70

DateR. SEGMIENTALCOLECTOM Y

(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/100ml. Calcium oxalate crystals were found in two repeatedurinalysis tests. The result of a renogram (131 I Hippuran) wascompatible with acute tubular necrosis and hemodialysis wasstarted. Over the next 5 months, the patient received approxi-mately 40 dialyses. His urine output remained between 56 and200 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 ofprednisone. Subsequently, pulmonary infection developed thatnecessitated the lowering of his immunosuppression dosage,and irreversible kidney rejection followed. Candida albicanswas cultured from his sputum and urine at that time. The patientrefused further dialysis treatment. He died 5 months aftertransplantation, 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 ab-scesses 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 anda Billroth II gastroenterostomy. In March 1973 he was gastro-scoped under Diazepam sedation for removal of a polyp in theduodenal stump. At that time the patient had a BUN of 18, theurinalysis and electrolyte study results were normal.

Twenty-four hours following endoscopy acute peritonitis de-veloped. An exploratory laparotomy revealed an accidentalperforation of the duodenal stump. Closure of the perforationand 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 6days. An intraperitoneal abscess developed and a 2 hour long

RENALTRANSPLANT

exploratory laparotomy for drainage of a sub-hepatic abscesswas done on the 16th postoperative day with fentanyl-droperidol (Innovar) anesthesia. Before surgery the patient'sserum 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 surgeryand 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 afterlaparotomy his serum creatinine was 11.3, and the BUN was100 mg/100 ml.At that time the patient was transferred to the University of

Minnesota Hospital to begin periodic hemodialysis, which hestill requires. Chloramphenicol therapy replaced gentamycin.On the 46th postoperative day a colocutaneous fistula wasdiscovered draining through the surgical wound. A fistulogramdemonstrated its continuity with a subphrenic abscess. Underhalothane (Fluothane) anesthesia, the colonic fistula was closedand terminal loop ileostomy performed. Pseudomonas aeru-ginosa was cultured from the wound three days later, andgentamycin (70 mg after each dialysis) therapy was reinstitutedfor a 22 day period.

The patient has remained oliguric (less than 400 cc/urine/day)since then. Four months later his ileostomy was successfullytaken down. At the present time he requires three dialyses perweek and produces about 200 cc of urine a day. His predialysisserum 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 inOctober 1968. At that time an IVP revealed an incomplete fillingof the upper pole calices of the left kidney. Retrograde pyelo-gram and renal arteriograms confirmed neoplasia of the left kid-ney. His BUN was 23.5, creatinine 0.6 mg/100 ml and electro-lyte studies were normal. There was microscopic evidence ofhematuria, but no proteinuria. Methoxyflurane (Penthrane) (0.7vol %) was used during the nephrectomy, which was compli-

38

20020

BUN0 -0

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UrineVolume(cc)

0

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

i

Vol. 182 * No. I POSTOPERATIVE CHRONIC RENAL FAILURE

FIG. 2. Macroscopic andmicroscopic views of Case1 kidneys. The third kidney.seen on the right wastransplanted from acadaver donor. Micro-scopic sections, from thepatients own kidneys showcortical fibrosis, micro-abscess and dense oxalatecrystals depositions.

cated by left pneumothorax. A brief hypotensive and hypoxicepisode occurred before a chest tube was inserted to relieve thepneumothorax.The urine output fell progressively to 300-600 cc/day during 8

postoperative days and the serum creatinine level rose rapidlyto 13 mg/100 ml, and the BUN to 188 mg/100 ml. Urinary

DIAL YS/S

BUN* -0

Creatinine(mg/100 ml0-c

FIG. 3. Clinical course anddrug regimen of Case 2.

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

141111 1111111114441111111iM411111111111111

-'V

UrineVolume 000(cc)

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ARCESS(FENTVAHYL -

DRCPER/DOL )

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I |I I l

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ILEOSTOMY TAKE DOWN(HALOTHANE) (FENTAHYL - DROPER/DOL)

39

20020 F

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2000 ^ _'oromphen/co/

0

40

20020

BUN_ * 100

Creatinine 10(mg /l Oml)o---o

DIAL YS/S

MERINO, BUSELMEIER AND KJELLSTRAND Ann. Surg. * July 1975

44l44 i4 '' M 4 i

Chioromphenlcol AmpIciiini

Methlcl//llA

UrineVolume

(cc)

1 1 /110/1/68 11/1/68 12/1/68 1/l/69 i)/1/70 12/1/70 11/4/72 4/1/74

FIG. 4. Clinical course anddrug regimen of Case 3.

L. IVEPHRECTOMY(METHOX YFLWORANE )

postoperative day the patient was started on hemodialysis.Over the next 57 days he received 16 hemodialyses. His urineoutput increased to about 1000 cc/day and he was then dis-charged on a Giovennetti diet. At that time his creatinine was8.4 and BUN was 43 mg/100 ml. Since then the patient has beenhospitalized twice for a mild cerebrovascular accident and arectal polypectomy. Using a protein restricted diet combinedwith 20-40 mg of furosemide per day, his creatinine is nowstable around 4 mg/100 ml, and his BUN is at 48-60 mg/100 ml, 6years 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 ofintermittentjaundice. One year prior to admission on oral cholecystogram had

DIAL YS/S

shown a non-functioning gall badder but the patient had declinedsurgery. Since then she had been on phenothiazine derivatives astreatment for agitation. She had an enlarged liver, bilirubin8.8mg/ 100 ml, BUN 16 mgl100 ml, serum creatinine 0.8 mg/ 100 ml,alkaline phosphorus 1221 U., SGOT 56 U. A urinalysis revealedbilirubinuria. Phentothiazine therapy was discontinued but thejaundice persisted, and after a week she developed fever, chills,and an elevated WBC, interpreted as acute cholangitis. She wasstarted on cephalexin monohydrate (Keflex) therapy, 1

gm every 6 hours. Three days later a cholecystectomy andcholodocholithotomy were performed and a T tube was left inplace. Anesthesia was induced with pentothal sodium and main-tained with halothane (0.7 Vol %) for 31/4 hours.

i O Mi111 i iI i i

20020

100_-I10

O _

BUN0-

Creotinine(mg/lOOmI )

o---o___-0

2000

UrineVolume(cc)

FIG. 5. Clinical course anddrug regimen of Case 4.1004

8/1/73 9/1/73 10/1/73lI

11/1/73 12/1/73 4/1/74 5/1/74

Date

C.D. EXPLORA TION(HALOTHANE)

Date

POSTOPERATIVE CHRONIC RENAL FAILURE

Postoperatively the patient received 4 gm of cephalothin and600 cc of dextran (Rheomacrodex) daily for 8 days. On the fourthday the urine outputhad decreased, and over the nexttwo days thepatient developed anuria. By the ninth postoperative day, thecreatinine was 12.2 mg/100 ml, BUN 64 K+ 6.5 mEq/L., and thepH was 7.27. Repeated 131 Iodine renal scans indicated acutetubular necrosis. Over the next 56 days the patient received 21hemodialyses.On the 22nd postoperative day she became febrile, the WBC

rose to 20,000 and the blood cultures grew out gram negative rodsof the Alkaligenes species. She was treated with 80 mg ofgentamycin for 8 days, followed by Chloramphenicol 1 gm every 6hours for 31 days until the infection was cleared. On the 54thpostoperative day the urine output increased to 720 cc/day. Sincethen the urine output has remained at 1000 cc/day.At discharge from the hospital the patient'sBUN was 62 mg/100

ml, serum creatinine 4.6 mg/100 ml, creatinine clearance was 10cc/minute for 1.73 in2. Recent BUN and creatinine readings taken10 months after discharge were 82 and 4.2 mg/100mI respectively.

MethodsDiagnostic MethodsThe diagnosis of acute tubular necrosis was based on

falling urinary output, isosthenuria and a rise in serumcreatinine and BUN levels. Prerenal failure was ruled outby urine electrolytes, and by appropriate fluid replace-ment and the use of mannitol and furosemide or ethac-rynic acid. All four patients with permanent lesions re-ceived 131 1 Hippuran renograms, and two of them alsoreceived 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 patientsrefused biopsies.

Medical Treatment and Dialysis RegimenBroad spectrum antibiotics were used immediately fol-

lowing operation in these four patients. Three of the fourpatients with permanent lesions (Cases 1, 2, 4) receivedcephalothin, the two (Cases 3 and 4) received Chloram-phenicol early in their course. In addition, gentamicinwas given to patients 2 and 4, and ampicillin and/ormethicillin to patients 2 and 3.

All patients received oral aluminum hydroxide, forphosphate binding, and intramuscular injections ofanabolic steroids and 90% of them received broad spec-trum antibiotics. Hyperalimentation with intravenousamino acids and 50o glucose was used in 50% of the 125patients. Two of the patients with irreversible failure(Cases 1, 3) were hyperalimentated from 15 days to 2months. Seven-hour-long hemodialyses were performedthree to seven times weekly. Regional heparinization wasused according to a previously described technique,18and antibiotic doses were adjusted according to the stan-dard hemodialysis criteria.6

ResultsOf the 38 patients who survived postoperative ATN, 4

(9.5%) developed severe chronic renal failure. One of

these 4 patients died 10 months later, 5 months afterkidney transplantation. He had required dialysis until thetime of transplantation. Another patient is on chronicdialysis two years after his episode of acute renal failure.The other two patients no longer require dialysis but theyare managed on moderate protein restriction and di-uretics, one and 6 years after their acute renal failureepisode. Both patients have a serum creatinine in therange of 4 mg/100 ml.

Surgical ProceduresForty-eight abdominal, 11 urological, and 49 car-

diovascular operative procedures, and 17 episodes oftrauma, were the origins of the 125 postoperative ATNpatients treated with dialysis (Table 1). Twenty-one percent 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 unilat-eral nephrectomy for hypernephroma. Each of the fourprocedures lasted more than three hours. There were nomajor intra-operative complication but two patients(Cases 2 and 3) experienced moderate hypotensiveepisodes (less than 15 minutes) which were correctedwith fluids, and in one case (Case 1), with vasoactiveamines.

Age and SexThe youngest of the 125 patients with postoperative

ATN were two premature babies, and the oldest patientwas age 83 (Table 2). The patients who required abdomi-nal or cardiovascular surgery tended to be older. Therewere 104 males, and 21 females (one of the patients withpermanent lesions was a woman).

Pt No. Complete 1 Permanent T Mortality 1_ _ _ _ No Recovery J Damage _%__Post - Surgical

Abdominal 48 7 3 79Urological l 10 0Cardiovascular 49 10 - 79Trauma 17 7 - 58

Total 125 [ 34 |4 (3.2%)f 69

Obstetrical 8 6 -

Medical 51 1 8 -

Burns 3 -

| Overall Total 187 58 4 (2.1 %) 68

Table 1. One hundred and twenty-five of the 187 patients treated forATN were postoperative patients. Thirty-eight survived, but 4 of them(9.5%) had permanent renal damage (3.2% of all postoperative ATNpatients).

41Vol. 182 No. I

MERINO, BUSELMEIER AND KJELLSTRAND

Ageq1 No. T Complete 1 Permanent Mortality]Age j Patients j Recovery J Damage (%) J

[ 0-9 9 2 77

10-19 4 2 50

20-29 10 5 50

30-39 4 1 75

40-49 6 2 67

50-59 33 10 70

60-69 35 8 1 74

70-83 24 4 3 70

Total 125 34 I 4 I

Table 2. Sixteen of 38 survivors were over 60 years of age. The 4patients with residual chronic renal failure were all over 60 and 3 ofthem were actually over 70 years old.

Table 2 illustrates that age influenced the renal func-tional recovery. Of 16 surviving patients above age 60,four (25%) never recovered good renal function. None ofthe 22 patients younger than age 60, who survived, ex-perienced permanent damage.

Oliguric PeriodOliguria (urine output less than 400 cc per day) lasted

for an average of 12.7 days in the 34 patients that had fullrecovery of renal function. Of the 4 patients with perma-nent lesions, one remained oliguric indefinitely and oneintermittently for over 2 years. The other 2 patients(Cases 3 and 4) remained intermittently oliguric for 52and 55 days. As expected, there was no correlation be-tween the rapidity of creatinine and BUN elevation in the34 patients who recovered complete renal function, andthe four who did not.

ComplicationsInfectious complications occurred in nearly all of the

125 ATN patients. Eighty per cent had positive urinecultures and pathogenic bacteria was cultured from theirsputum. During the first postoperative month 60o of the87 patients who died had positive blood cultures thatusually grew gram negative rods.Three of the four patients who required dialysis (Cases

2, 3, 4), grew positive blood cultures in the immediatepostoperative period, and two of them (Cases 2 and 4)probably had sepsis before surgery. Patient 2 had anintraperitoneal infection at the time of the operative pro-cedure coincidental with the onset of renal failure, andgram-negative septicemia was documented at least twiceduring the first postoperative month. Patient 4 presentedwith a picture of ascending colangitis and more than100,000 colonies/ml ofE. coli were grown from the bite at

the time of surgery. There was no evidence of septicemiain Patient 1 until after a cadaver kidney was transplantedand immunosuppressive treatment was started.

AnesthesiaTwo of the four patients with permanent lesions re-

ceived methoxyflurane, the other two had halothaneanesthesia. At our institution, nitrous oxide and an IVnarcotic agent are used for approximately 60o of thegeneral anesthesia inductions and halothane is used in20%. Ten per cent of the operations are performed underlocal anesthesia, and less than 1% of the patients receivemethoxyflurane antibiotics. Cephalothin was used earlyafter surgery in three cases and gentamicin was used intwo. Two patients were treated with chloramphenicoland two with ampicillin and methicillin sodium. Almostall of our postoperative patients with ATN receivedbroad spectrum antibiotics during their course.Cephalothin is most commonly used, but one-third of thepatients also received gentamicin.

DiscussionIn spite of great improvements in dialysis techniques,

vascular access, postoperative care, the understanding ofelectrolyte fluid balance and parental alimentation, and thedevelopment of new antibiotics, the survival rate of pa-tients with postoperative ATN has remained unchangedover the last three decades. Apparently the technicalimprovements have been offset by an increased patientage and an increased severity of the basic disease com-plicated by acute renal failure.3'5'8'16'30A high incidence (9.5%) of severe chronic renal failure

in the survivors of postoperative ATN, however, is atvariance with earlier descriptions. Several previous largeseries have reported that such patients achieve clinicalnormalcy, although subclinical abnormalities were foundin 60-70o of the cases.1427 The most common abnor-malities seem to be a reduction in the glomerular filtra-tion rate and renal blood flow. The tubular function testswere abnormal in a smaller per cent of patients (31%).14,27What specifically inhibited the regenerative capacity ofthe kidneys in our four patients is unknown. These pa-tients may represent a group that would have died whenprolonged dialysis, in the pre-Scribner shunt era, was

technically impossible. Several factors, alone, or more

likely, combined must be considered.

AgeAge was the common factor among the four patients

with permanent lesions. Each was above age 60 at thetime their acute renal failure developed. Davies andShock10 have reported decreases in renal function withaging. They reported that innulin and PAH clearancedecreased to 46% and 53%, respectively, between theages of 20 and 90 years. Kumar et al.20 found that the

42 Ann. Surg. - July 1975

POSTOPERATIVE CHRONIC RENAL FAILURE

older patient who experienced acute renal failure has alonger period of aliguria and a slower recovery period.Hall et al.14 observed that in spite of complete clinicalrecovery after postoperative acute renal failure, the av-erage "functional" recovery was only 75% in patientsover 45 years of age.

Vascular changes of benign nephrosclerosis is the mostcommon abnormality of the senescent kidney, whichprobably accounts for the atrophic and degenerativechanges evident as focal areas of diminished uptake onthe 1311 Hippuran renal scan. In the older patient, thismay predispose the kidneys to less than complete recov-ery. However, Skov and Hansen29 observed no differ-ence in the functional hypertrophy of the remaining kid-ney in either elderly or young kidney donors. The 25%failure to achieve clinically normal function in our surviv-ing patients above age 60 remains our single most impres-sive finding.

Operative ProcedureThree of the four instances of permanent renal damage

occurred among ten patients who survived abdominalsurgery. This group of patients is also the oldest in ourseries (mean age 62.1 years), in spite of two prematurebabies who were also included. It is difficult to conceivehow the type of surgery, alone, could prevent completefunctional recovery. It is more likely that the failure forthis group of patients to recover normal function is de-pendent on their age.

AnesthesiaTwo of the four patients who did not recover from their

acute renal failure had methoxyflurane (Penthrane) anes-thesia, and two had halothane (Fluothane) anesthesia.Acute postoperative renal dysfunction has been attrib-

uted to methoxyflurane anesthesia in at least 104 pa-tients, 31 of whom died.2'9'17 Most patients had a polyurictype of renal dysfunction but a smaller number developedoliguria that required hemodialysis treatment. Most pa-tients had only transient renal abnormalities but at least 7failed to recover normal renal function. Chronic renalfailure following methoxyflurane anesthesia seems torepresent a separate syndrome, but methoxyflurane wasused only in two of our four patients. Two possiblemechanisms of methoxyflurane nephrotoxicity havebeen proposed, related to fluoride and oxalic acid re-spectively, thought to be metabolities of methoxy-flurane.'2'23

Halpren et al. report that an autopsy examination re-vealed extensive oxalate deposition in a patient who haddied with renal failure after 14 months of hemodialysis.15A similar finding was noticed in the microscopic pathol-ogy of our Patient 1 (Fig. 2).In patients with metabolic disorders leading to in-

creased oxalate production, renal insufficiency developsslowly, but acute poisoning with oxalic acid can induce

43prolonged acute renal failure.32 Cases of prolonged renalfailure after methoxyflurane anesthesia may thus be areaction to oxalate crystals with interstital fibrosis.6 Toour knowledge there have been no reports of nephro-toxicity following halothane anesthesia.

Nephrotoxic AntibioticsAll of our patients received antibiotics that have been

associated with renal failure. Patients 1, 2 and 4 receivedcephalothin immediately after their operation. Althoughcephalothin does not appear to be toxic in healthy kid-neys, several cases of aggravation of pre-existing im-paired kidney function have been attributed to itsuse 7,19,26

Gentamicin was used in two of four patients (Cases 2and 4); one patient (Case 2) received it repeatedly. Be-cause gentamicin is usually given to only severely illpatients it is difficult to make a conclusion regarding itsclinical nephrotoxicity.31 These same two patients (Cases2 and 4) also received cephalothin therapy. There areseveral reports of enhanced nephrotoxicity whencephalothin 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 acuteand chronic renal failure.1'4'13 Chlorampenicol was usedin Patients 2, 3 and 4 but we know of no reports associat-ing it with nephrotoxicity. It has also been suggested thatcertain antibiotics potentiate the nephrotoxicity ofmethoxyflurane.21'24

SepsisInfection plays a dominant role in the outcome of pa-

tients with reversible intrinsic renal failure. Montgomery,Kalmanson and Guze25 recognized infection as the mostcommon cause of death in oliguric patients. They calcu-lated that 22% of the patients with traumatic or surgicalrenal failure died from an infection that was introduced atthe time of injury or developed after admission to thehospital.

In the Kennedy report,16 sepsis was either presentbefore the onset of acute renal failure or it developedduring the acute phase. Kennedy considered sepsis to bethe major cause of death in 25% of the surgical andtraumatic group.

All of our four patients with irreversible damage hadpositive urine cultures at one time during their postopera-tive course, and three of them had documented sep-ticemia.To our knowledge, no data are available on the nega-

tive effects of sepsis on the reversibility of acute tubularnecrosis, however, it is possible that acute pyelonephritiscontributed to the destruction of kidneys in our patients.

ConclusionWith the exception of the few cases of irreversible

renal failure following methoxyflurane anesthesia, none

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44 MERINO, BUSELMEIER AND KJELLSTRAND Ann. Surg. * July 1975

of the factors discussed in this paper seem to be respon-sible, alone, for irreversible acute renal failure. It is morelikely that a conglomerate of factors existed. For exam-ple, all of our patients were in the older age range and hadurinary tract infections. Patient 1 was exposed to bothmethoxyflurane and cephalothin. Patient 2 receivedcephalothin, and repeated treatments with gentamicinand ampicillin. Neither of these patients ever regainedenough kidney function to allow them freedom fromdialysis. Patient 3 received methoxyflurane anesthesia, aunilateral nephrectomy, methicillin and ampicillin. Pa-tient 4 was treated with a combination of cephalothin andgentamicin after renal failure became apparent. The lattertwo patients were left with severe renal failure, but theydid not need continued dialysis.However, what specifically inhibited the regenerative

capacity of the kidneys in these particular patients re-mains unclear because other patients with similar opera-tions, age, septicemia, complications and drug treatmenthave had adequate and prompt recovery.To our knowledge, only two comparable cases have

previously been reported. Levin et al.22 described onecase of prolonged renal insufficiency, accompanied bysevere complications, and one of 5 patients described bySiegler and Bloomer28 had a similar course.

References1. 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-In-duced Renal Failure. Urology, 11:553, 1973.

3. Alwall, N. and Kjellstrand, C. M.: "Acute Renal Failure." A Studyof 639 Cases Involving 1,073 Treatments with the Artificial Kid-ney over the Period 1946-1961. In Therapeutic and DiagnosticProblems in Severe Renal Failure. Sweden, Bonniers Stock-holm, 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 andMethicillin. N. Engl. J. Med., 279:1245, 1968.

5. Balsl0v, J. T. and J0rgensen, H. E.: A Survey of 499 Patients withAcute Anuric Renal Insufficiency. Am. J. Med., 34:753, 1963.

6. Bennett, W. M., Singer, I. and Coggins, C. J.: A Guide to DrugTherapy in Renal Failure. JAMA, 230:1544, 1974.

7. Bobrow, S. M., Jaffe, E. and Young, R. C.: Anuric and AcuteTubular Necrosis Associated with Gentamicin and Cephalothin.JAMA, 222:1546, 1972.

8. Casali, R., Simmons, R. L., Najarian, J. S., et al.: Acute RenalInsufficiency Complicating Major Cardiovascular Surgery. Ann.Surg., 181:370, 1975.

9. Churchill, D., Knaack, J., Chirito, E., et al.: Persisting RenalInsufficiency After Methoxyflurane Anesthesia: Report of TwoCases and Review of Literature. Am. J. Med., 56:575, 1974.

10. Davis, D. F. and Shock, N. W.: Age Changes in G.F.R. EffectivePlasma 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 RenalFailure Associated with Combined Gentamicin and Cephalothin,Therapy, Br. Med. J., 2:396, 1973.

12. Frascino, J. A.: Effect of Inorganic Fluoride on the Renal Concen-trating Mechanism. Possible Nephrotoxicity in Man. J. Lab.Clin. Med., 79:192, 1972.

13. Gilbert, D. N., Gourley, R., d'Agostine, A., et al.: InterstitialNephritis 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.: Im-mediate 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 FailureFollowing Methoxyflurane Anesthesia. JAMA, 223:1239, 1973.

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