URINARY INFECTION J. N. KRIEGER,
IN KIDNEY TRANSPLANTATION
M.D.
L. TAPIA, M.D. W. T. STUBENBORD, K. H. STENZEL, A. L. RUBIN,
M.D.
M.D.
M.D.
From the Rogosin Kidney Center, The New York HospitalCornell Medical Center, New York, New York
ABSTRACT - Urinary tract infection is the most frequent complication following renal transplantation and is important in the etiology of post-transplantation sepsis. The 87 renal homografts done in 1974 at The New York Hospital-Cornell Medical Center were reviewed retrospectively, with at least one year follow-up, in all cases, with particular attention to factors relating urinary tract infection to ultimate success or failure of the renal graft. The over-all incidence of urinary tract infection was 61 per cent. Early infection was associated with a particularly poor prognosis for graft survival. Most patients with urinary infections after successful transplantation experience a combination of both early and late infections. Anatomic factors constitute a remediable cause of urinary infections after transplantation and should be searched for in cases of multiple, recurrent infections, de novo hypertension, or deterioration of previously stable graft function. There were signijcant differences in the bacteriologic spectrum of urinary tract infections associated with successful transplants as opposed to unsuccessful transvlants.
Urinary tract infection is the most frequent complication following renal transplantation. l-’ The etiologic role of urinary infection in posttransplantation sepsis has been described.*,’ Since sepsis constitutes a leading cause of death following kidney transplantation, the crucial importance of urinary tract infection in this group of patients is apparent. lo-l3 Although previous studies have been useful in establishing the importance of urinary infection after transplantation, there are several deficiencies.‘,14 All studies to date have reviewed cases from several years of clinical experience, frequently representing a variety of surgical techniques and regimens of medical management. For this reason a retrospective review of the 87 renal homografts performed at The New York Hospital-Cornell Medical Center during 1974 was done from the standpoint of urinary infections. Criteria for patient selection, surgical
130
immunosuppression, and general technique, medical management were well established and reasonably uniform for this group of patients. Adequate postoperative follow-up was possible in all instances. Particular attention is paid to the determination of specific factors relating urinary tract infection to ultimate success of the renal graft. Material and Methods Patient population and period of study The 87 renal transplants included in this study were done between January 1 and December 31, 1974. During this period 83 patients, 51 male and 32 female, each had one graft, while 2 patients, 1 male and 1 female, each had two grafts. The patients are classified by underlying etiology of their end-stage renal disease. that chronic It is apparent glomerulonephritis remains the most frequent
UROLOGY
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/ VOLUMEIX,
NUMBER2
TABLE I.
Patient
Group1
creatinine values one year after transplantation are detailed in Table I. It is apparent that graft function is good with serum creatinine less than or equal to 2 mg. per 100 ml. in most instances. If a patient dies of causes unrelated to his renal failure, for example, myocardial infarction, with a functioning graft, the patient was considered in the unsuccessful transplant group.
renal transplants*
Successful
Serum Creatinine -(milligrams per 100 ml.)l-2 2-3 3-4 4-S 5-6 O-l
Cadaver grafts 4 (26) Living related donor grafts (7) 4
14
5
2
0
1
2
0
0
0
1
Clinical
*Functioning graft in living patient twelve months after transplantation. t Figures in parentheses represent total number of patients in group.
Preoperative evaluation of all patients was done at the Rogosin Kidney Center. This evaluation consisted of antigen determination and matching as well as urologic assessment, including a cystogram. All patients with vesicoureteral reflux underwent preliminary bilateral nephroureterectomy prior to transplantation. In the operating room a Foley catheter was inserted immediately prior to surgery, and 100 to 150 cc. of sterile neomycin sulfate solution (1 per cent in saline) was instilled in the bladder. The catheter was then clamped until the ureteroneocystotomy was done. This indwelling catheter was routinely left in place for one week after surgery. In all instances a sterile, closed, drainage system was meticulously maintained. Immunosuppression consisted of a combination of corticosteroids and azathioprine. Methylprednisolone sodium succinate (Solumedrol), 100 mg. twice a day, was given for the first three days after transplantation. On the fourth postoperative day, prednisone, 100 mg., was given, then tapered by 10 mg. per day to a maintenance dosage of 30 mg. per day. Azathioprine, 5 mg. per kilogram, was started the day before surgery and was tapered by 1 mg. per kilogram per day to a maintenance dose of 100 to 150 mg. a day. Azathioprine was decreased or discontinued in the presence of leukopenia. Rejection episodes were treated with methylprednisolone sodium succinate, 250 mg. intravenously, twice a day for three days. This immunosuppression regimen was not modified for uncomplicated urinary tract infections. Urine cultures were routinely taken every other day during hospitalization. After hospital discharge, cultures were obtained every other week for three months and at every clinic visit thereafter. More frequent cultures were obtained in the presence of urinary tract infection. Cultures were obtained using aseptic technique, namely during midstream micturition after cleansing with povidone-iodine (Betadine) solution. Specimens were either sent immediately to the microbiology laboratory or were refriger-
cause of renal failure in our patient population. In total there were 75 cadaver transplants and 12 living related donor transplants. All patients were followed up for at least twelve months after surgery, and no patient who received a renal homotransplant in 1974 was excluded from this study. Definition
of terms
The most widely used definition of urinary tract infection after renal transplantation is the presence of more than 100,000 organisms per milliliter or a single bacterial strain in two, consecutive, urine specimens. 1,3~13~15 However, as stressed by Hinman, Schaelzie, and Belzer,2 “Colony counts of washout specimens may be quite low but still be significant.” Our experience is in accord with this. Therefore, we also consider significant urinary tract infection to be present after transplantation in the presence of repeated counts of less than 100,000 of the same organism. Urinary tract infections occurring during the first month after transplantation were considered to be early infections, whereas infections occurring later than the first postoperative month were considered late infections. This type of classification is in accord with several No attempt was made previous studies. 3*8~15~16 to differentiate recurrent infection from reinfection, and the term recurrence is used for either. Persistent infection was operationally defined as presence of continuous urinary tract infection for longer than one month despite numerous attempts to eradicate the. infection with appropriate antibiotics. Rigorous criteria for success of the renal graft were employed in this study. Only patients surviving one year with adequate graft function to obviate the need for dialysis were considered to have successful renal transplants. Serum
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TABLE
II.
Urinary tract infection after renal transplantation: 1974 experience (total of 87 transplants)
Patient Group (n = 75) Successful (n=26) Male (n=17) Female (n=9) Unsuccessful (n=49) Male (n=32) Female (n= 17)
CADAVER GRAFTS
Urinary Tract Infection*
No Urinary Tract Infection*
45 (60)
30 (40) 18 11 7 27 14 8
(65.4) (64.7) (77.8) (55.1) (59.4) (47.1)
4 2 2 4 2 2
(57.1) (66.7) (50) (80) (100) (66.7)
8 6 2 22 13 9
(34.6) (35.3) (22.2) (44.9) (40.6) (52.9)
3 1 2 1 0 1
(42.9) (33.3) (50) (20) (0) (33.3)
LIVING RELATED DONOR
(n= 12) Successful (n=7) Male (n=3) Female (n=4) Unsuccessful (n=5) Male (n=2) Female (n=3)
GRAFTS
TOTALS
4 (33.3)
8 (66.7)
53 (60.9)
34 (39.1)
*Figures in parenthesesindicatepercentages
ated. Urine aliquots were plated, using calibrated loops on blood agar as well as on MacConkey agar plates. The plates were incubated at 35” C. overnight and then counted. Appropriate biochemical tests were used to identify organisms present in significant numbers. Routine antibiotic prophylaxis was not done in any case. Graft function was closely monitored by following daily urine output and by daily serum creatinine and creatinine clearance determinations. In addition, serial renal scans were done using hippurate I-131 as well as technetium-%. Prior to discharge all patients with functioning grafts had cystograms as well as intravenous pyelograms taken. Statistical analysis results were analyzed using either the chi-square test or Fisher’s exact test, where appropriate. Results Between January 1 and December 31, 1974, a total of 87 kidney transplants were done at this medical center. Urinary tract infections occurred in 53 cases (61 per cent) (Table II). There were no statistically significant differences between urinary tract infection rates following cadaver grafts or living related donor grafts. Significant differences in urinary tract infection rates did not occur between recipients of successful or unsuccessful transplants. The relationship between etiology of endstage renal disease and urinary tract infection
132
after transplantation is indicated in Table III. Glomerulonephritis was by far the most frequent disease (37 patients), followed by nephrosclerosis (11 patients) and pyelonephritis (10 patients). Of the 37 patients in the glomerulonephritis group 22 (59 per cent) had significant bacteriuria. Further analysis of this group reveals that successful transplants in patients with glomerulonephritis were associated with a higher incidence of urinary infection, 10 of 14 patients (71 per cent) than the unsuccessful group, 12 of 23 (52 per cent). This difference does not reach statistical significance (0.30 < p < 0.20) and is probably to some extent an artifact reflecting the longer period of time which the successful group was at risk for development of a urinary infection. It should be noted that 57 per cent of the unsuccessful grafts were removed during the first eight weeks after surgery. Of the patients with hypertensive nephrosclerosis 2 of 3 (67 per cent) in the successful group and 5 of 8 (62 per cent) in the unsuccessful group had significant bacteriuria. Urinary infection occurred in 3 of 4 (75 per cent) of successful grafts in the patients with pyelonephritis and in 4 of 6 (67 per cent) patients with unsuccessful grafts. There are no statistically significant differences among these groups. Urinary tract infections after renal transplantation may be classified as either early infections, occurring in the first postoperative weeks, or late infections, occurring after the first four
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III. Relationship of etiology of end-stage renal disease to urinary tract infection (UTZ) after renal transplantation
TABLE
Etiology of EndStage Renal Disease*
Successful Grafts UT1 No UT1
Local causes Glomerulonephritis Pyelonephritis Interstitial nephritis Polycystic disease
10 3
2 1
1
3
- 2 11
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- 2 31
10 87
23
Textbook of Medicine, 14th Ed.,
weeks (Table IV). Occurrence of early infection only is more common in unsuccessful cases (19 of 31 patients, 61 per cent) than in successful cases (3 of 22, 14 per cent). This is a statistically significant difference (p < 0.05). The total number of isolated late infections is small (6 of 53, 11 per cent). Most patients with successful grafts associated with urinary tract infection experience a combination of early and late infections (15 of 22 patients, 68 per cent). The relationship of early urinary tract infection to urine flow after transplantation is analyzed in Table V. Almost half of the early infections (23 of 47) began when urine volume was greater than 1,500 cc. per twenty-four hours. It should be noted, however, that early infections associated with good urine flow almost always occurred early in the diuretic phase. Continuation of good urine output was frequently associated with resolution of bacteriuria. During the period of oliguria, when urine flow was less than 100 cc. per twenty-four hours, only 8 of 47 patients (17 per cent) experienced onset of significant bacteriuria. Most patients with urinary tract infection after renal transplantation experienced only a single episode (29 of 53 patients, 55 per cent) heavily, (Table VI). This fig ure is weighted however, in patients with unsuccessful grafts; 22
/
11
4
1 1
*Based on Beeson and McDermott, Saunders Co., 1975, p. 1093, Table 2.
UROLOGY
12
1
22
TOTALS
Total
1
Systemic diseases and intoxications Hypertensive nephrosclerosis Systemic lupus Diabetes Heavy metal poison etiology
4 1 1
2
Lower tract obstruction Urethral values Bladder neck obstruction
Undetermined
Unsuccessful Grafts UT1 No UT1
Philadelphia, W. B.
IV. Urinary tract infections after renal transplantation
TABLE
Patient Group*
-InfectionsEarly Late
Both
Successful cadaver grafts - male and female (18/26)
2
4
12
Unsuccessful cadaver grafts - male and female (27/49)
17
2
8
Successful living related donor grafts male and female (4/7)
1
0
3
Unsuccessful living related donor grafts male and female (4/5) TOTALS (W87)
_2_ 22
0
2 6
25
*Number of patients in group with urinary tract infections/ total number of patients.
of 29 patients with a single urinary infection had unsuccessful transplants. Analysis of the successful grafts alone reveals that approximately 20 to 30 per cent of patients with urinary tract infections are cured by each course of antibiotics. Only 2 of 22 patients (9 per cent) had persistent infections. Only 1 patient in our series had more
133
TABLE V. Relationship
of early urinary
to urine volume after renal transplantation
24-Hour Urine Volume at Onset of Urinary Infection (X 100 cc.) 5.0-7.5 7.5-10 10-15 1.0-2.5 2.5-5.0
~
Patient Group*
tract infection
< 1.0
> 15
Successful cadaver grafts (14)
2
0
2
0
0
1
9
Unsuccessful cadaver grafts (25)
3
3
5
2
0
3
9
Successful living related donor grafts (4)
1
0
0
0
0
0
3
0
0 0
Unsuccessful living related donor grafts (4)
TOTALS (47) *Number
0
2
0
3
8
with early infection. TABLE
VI.
Number
Patient Group*
Unsuccessful cadaver grafts male and female (27) Successful living related donor grafts - male and female (4) Unsuccessful living related donor grafts - male and female (4)
TOTALS (53) *Figures in parentheses
of episodes of urinary renal transplantation
1
Successful cadaver grafts - male and female (18)
tract infection
after
Number of Urinary Infections 4 5 2 3
Persistent
6
4
2
4
0
2
20
3
1
1
0
2
1
1
1
0
1
0
2 29
r 9
1
0
0
0
5
5
1
4
indicate number of patients in group.
than five discrete episodes of urinary and her case history is illustrative:
infection,
A twenty-year-old woman had a transplant from a sibling with full antigen match and low (< 10 per cent) reactivity in mixed lymphocyte culture. The patient’s postoperative course was characterized by good graft function despite seven, discrete, symptomatic, urinary tract infections. Each infection responded well to antibiotic therapy. Lower tract evaluation was normal. Nine months after transplantation she became hypertensive, and renal function began to deteriorate. An intravenous pyelogram’ at this time showed marked hydronephrosis, and a retrograde pyelogram revealed obstruction at the ureteroneocystotomy. For this reason the ureter was reimplanted in the bladder. After surgery hypertension subsided,
134
Y
7
renal function improved, hydronephrosis peared, and bacteriuria did not recur.
disap-
This case demonstrates that anatomic problems should be strongly suspected in cases of multiple, discrete episodes of urinary tract infection after transplantation. A total of 99 episodes of significant bacteriuria were documented in 53 patients (Table VII). Over-all the most frequent organism was Escherichia coli, followed by Streptococcus faecalis and the Klebsiella-Enterobacter group. Interesting differences become apparent when the bacteriology of urinary tract infection in the successful group is compared with infection in the unsuccessful group. E. coli caused most first infections (7 of 22, 32 per cent) as well as most
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recurrent infections (15 of 36, 42 per cent) in patients with unsuccessful grafts. S. faecalis and mixed infections were next in frequency. In contrast, S. faecalis was responsible for most first infections in the unsuccessful group (9 of 31, 29 per cent). Recurrent infections in the unsuccessful group were caused by a variety of gram-negative bacteria as well as Candida albicans. Success or failure of the graft correlates with this difference in infecting organisms (p < 0.02 for first infections and recurrent infections).
lost. The high incidence of isolated early infections, 22 of 53 patients, appears to have prognostic significance for graft survival. Of the 22 patients with early urinary tract infection only, 19 lost their graft. Although the pathology report was “acute rejection” in most cases, it is known that infection can trigger host responses and induce rejection.” Early infection of the urinary tract is also an important source of organisms causing wound infection and septicemia which result in a poor prognosis for both the graft and the patient. 1o-14~18It should be noted that septicemia itself may induce a Shwartzmantype reaction causing intravascular coagulation and loss of the graft.‘7*‘8 Most patients with urinary tract infection following successful transplantation experience a combination of both early and late infection (15 of 22 patients, 68 per cent). Most early infections are initially noted early in the diuretic phase, and continuation of good urine output was usually associated with resolution of bacteriuria. Anatomic factors constitute a remediable cause of urinary tract infection after transplantation. For this reason complete urologic evaluation is indicated in cases of multiple, recurrent
Comment Urinary tract infection is the most frequent complication after renal transplantation. This high incidence, 61 per cent in the present series, is related to multiple factors including the generalized catabolic condition of many end-stage kidney patients, immunosuppression, the trauma of surgery, and catheterization. Urinary infection is an adverse influence on both graft and patient survival after renal transplantation. The primary effect of significant bacteriuria appears to occur early in the postoperative course, the period when most grafts are TABLE VII.
Organisms causing urinary tract infection after renal transplantation* -Successful 1st Infection
Infecting Organism Gram-negative rods Escherichia coli Proteus mirabilis vulgaris Providencia stuartii Klebsiella-Enterobacter
GraftsRecur 15 (42)
7 (32)
-Unsuccessful 1st Infection 4 (13)
Graft+ Recur 2 (17)
3 (9)
1 (3)
Gram-positive cocci Streptococcus faecalis /3-hemolytic Staphylococcus epidermidis
1 (5)
1 (3)
2 (6)
2 07) I (6)
4 (4) 5 (5)
1 (5)
1 (3) 2 (6)
3 (10)
2 (17)
1 (1) 8 (8)
4 (18) 1 (5)
3 (9)
Q (29)
2 (9)
2 (6)
2 (6)
1 (3)
1 (3) 2 (6)
2 (17)
5 (15) 34
7 (23) 31
3 (25) 12
Other organisms Candida albicans Yeast-like organisms Mixed infection
4 (18) 22
TOTALS
28 (29) 3 (3) 1 (1) 1 (1)
1 (3)
2 (9)
group Serratia species Pseudomonas fluorescens aeruginosa
TotaI
16 (16) 1 (1) 6 (6) 4 (4) 2 (2) 19 (19) 99
*Numbers in parentheses represent percentages.
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urinary infections, de novo hypertension, or deterioration of graft function after transplantation. There appears to be a significant difference in the bacteriologic spectrum of urinary tract infections associated with successful transplants as compared with urinary tract infections associated with unsuccessful transplants. E. coli is the most frequent cause of both first infections and recurrent infections in the successful group. In contrast, S. faecalis was the most frequent cause of first infections in the unsuccessful group while Klebsiella-Enterobacter and mixed organisms were isolated most frequently in recurrent infections. Improvement in the results of renal transplantation ultimately depends on fundamental advances in immunology. From a clinical standthere remains room for impoint, however, provement using therapeutic modalities presently available. Diminishing the incidence and duration of urinary tract infections should improve the success rate of renal grafts. Several approaches to this problem are available including reducing steroid dose to the minimal level needed to prevent rejection, meticulous care and maintenance of a closed urine drainage system immediately after surgery, early removal of urethral catheters, specific, early antibiotic therapy, and a vigorous search for remediable anatomic defects. 525 East 68 Street New York, New York 10021 (DR. TAPIA) References 1. BENNETT, W. M., BECK, C. H., YOUNG, H. H., and RUSSELL, P. S.: Bacteriuria in the first month following renal transplantation, Arch. Surg. 101:453 (1970). 2. HINMAN, F., SCHAELZIE, J. F., and BELZER, R.
136
3.
4.
5. 6.
7.
8.
9. 10.
11.
12. 13.
14.
15.
16. 17. 18.
0.: Urinary tract infection and renal homotransplantation: II post-transplantation bacterial invasion, J. Urol. 101:673 (1969). LEIGH, D. A.: The outcome of urinary tract infection in patients after human cadaveric renal transplantation, Br. J. Urol. 41: 406 (1969). MACKINNON, K. J., OLIVER, J. A., MOREHOUSE, D. D., and TAGUCHI, Y.: Cadaver renal transplantation: emphasis on urologic aspects, J. Urol. 99: 486 (1968). MARTIN, D. C.: Urinary tract infection in clinical renal transplantation, Arch. Surg. 99: 474 (1969). PROUT, G. R., HUME, D. M., LEE, H. M., and WILLIAMS, G. M.: Some urologic aspects of 93 consecutive renal homotransplants in modified recipients, J. Urol. 97: 409 (1967). RIFKIND, D., MARCHIORO, T. L., WADDELL, W. R., and STARZL, T. E.: Infectious diseases associated with renal transplantation, J.A.M.A. 189: 397 (1964). MAHON, F. B., MALEK, G. H., and UEHLING, D. T. : Urinary tract infection after renal transplantation, Urology 1: 579 (1973). MCDONALD, J. C., et al.: Sepsis in human renal transplantation, Surgery 69: 189 (1971). KELLY, W. D., et al.: Kidney transplantation: experiences at the University of Minnesota Hospitals, ibid. 62: 764 (1967). MOORE, T. C., and HUME, D. M.: The period and nature of hazard in clinical renal transplantation: I the hazard to patient survival, Ann. Surg. 170: 1 (1969). PLETKA, P., et al.: Cadaveric renal transplantation, an analysis of 65 cases, Lancet 1: 1 (1969). SUSSMAN, M., and RUSSELL, R. B.: Infection after cadaver+ renal transplantation, Proc. Roy. Sot. Med. 65: 471 (1973). ANDERSON,R. J., SCHAFER, L. A., OLIN, D. B., and EICKHOFF, T. C.: Septicemia in renal transplant recipients, Arch. Surg. 166: 692 (1973). HANSHERE, R. J., CHISOLM, G. D., and SHACKMAN, R.: Late urinary-tract infection after renal transplantation, Lancet 2: 793 (1974). DOUGLAS, J. F., et al.: Late urinary-tract infection after renal transplantation, ibid. 2: 1015(1974). SIMMONS, R. L., et al. : Do mild infection trigger the rejection of renal allografts? Trans. Proc. 2: 419 (1970). MYEROWITZ, R. L., MEDEIROS, A. A., and O’BRIEN, T. R.: Bacterial infection in renal homotransplant recipients, Am. J. Med. 53: 308 (1972).
UROLOGY / FEBRUARY 1977 / VOLUME IX, NUMBER 2
IN KIDNEY TRANSPLANTATION
M.D.
L. TAPIA, M.D. W. T. STUBENBORD, K. H. STENZEL, A. L. RUBIN,
M.D.
M.D.
M.D.
From the Rogosin Kidney Center, The New York HospitalCornell Medical Center, New York, New York
ABSTRACT - Urinary tract infection is the most frequent complication following renal transplantation and is important in the etiology of post-transplantation sepsis. The 87 renal homografts done in 1974 at The New York Hospital-Cornell Medical Center were reviewed retrospectively, with at least one year follow-up, in all cases, with particular attention to factors relating urinary tract infection to ultimate success or failure of the renal graft. The over-all incidence of urinary tract infection was 61 per cent. Early infection was associated with a particularly poor prognosis for graft survival. Most patients with urinary infections after successful transplantation experience a combination of both early and late infections. Anatomic factors constitute a remediable cause of urinary infections after transplantation and should be searched for in cases of multiple, recurrent infections, de novo hypertension, or deterioration of previously stable graft function. There were signijcant differences in the bacteriologic spectrum of urinary tract infections associated with successful transplants as opposed to unsuccessful transvlants.
Urinary tract infection is the most frequent complication following renal transplantation. l-’ The etiologic role of urinary infection in posttransplantation sepsis has been described.*,’ Since sepsis constitutes a leading cause of death following kidney transplantation, the crucial importance of urinary tract infection in this group of patients is apparent. lo-l3 Although previous studies have been useful in establishing the importance of urinary infection after transplantation, there are several deficiencies.‘,14 All studies to date have reviewed cases from several years of clinical experience, frequently representing a variety of surgical techniques and regimens of medical management. For this reason a retrospective review of the 87 renal homografts performed at The New York Hospital-Cornell Medical Center during 1974 was done from the standpoint of urinary infections. Criteria for patient selection, surgical
130
immunosuppression, and general technique, medical management were well established and reasonably uniform for this group of patients. Adequate postoperative follow-up was possible in all instances. Particular attention is paid to the determination of specific factors relating urinary tract infection to ultimate success of the renal graft. Material and Methods Patient population and period of study The 87 renal transplants included in this study were done between January 1 and December 31, 1974. During this period 83 patients, 51 male and 32 female, each had one graft, while 2 patients, 1 male and 1 female, each had two grafts. The patients are classified by underlying etiology of their end-stage renal disease. that chronic It is apparent glomerulonephritis remains the most frequent
UROLOGY
/ FEBRUARY1977
/ VOLUMEIX,
NUMBER2
TABLE I.
Patient
Group1
creatinine values one year after transplantation are detailed in Table I. It is apparent that graft function is good with serum creatinine less than or equal to 2 mg. per 100 ml. in most instances. If a patient dies of causes unrelated to his renal failure, for example, myocardial infarction, with a functioning graft, the patient was considered in the unsuccessful transplant group.
renal transplants*
Successful
Serum Creatinine -(milligrams per 100 ml.)l-2 2-3 3-4 4-S 5-6 O-l
Cadaver grafts 4 (26) Living related donor grafts (7) 4
14
5
2
0
1
2
0
0
0
1
Clinical
*Functioning graft in living patient twelve months after transplantation. t Figures in parentheses represent total number of patients in group.
Preoperative evaluation of all patients was done at the Rogosin Kidney Center. This evaluation consisted of antigen determination and matching as well as urologic assessment, including a cystogram. All patients with vesicoureteral reflux underwent preliminary bilateral nephroureterectomy prior to transplantation. In the operating room a Foley catheter was inserted immediately prior to surgery, and 100 to 150 cc. of sterile neomycin sulfate solution (1 per cent in saline) was instilled in the bladder. The catheter was then clamped until the ureteroneocystotomy was done. This indwelling catheter was routinely left in place for one week after surgery. In all instances a sterile, closed, drainage system was meticulously maintained. Immunosuppression consisted of a combination of corticosteroids and azathioprine. Methylprednisolone sodium succinate (Solumedrol), 100 mg. twice a day, was given for the first three days after transplantation. On the fourth postoperative day, prednisone, 100 mg., was given, then tapered by 10 mg. per day to a maintenance dosage of 30 mg. per day. Azathioprine, 5 mg. per kilogram, was started the day before surgery and was tapered by 1 mg. per kilogram per day to a maintenance dose of 100 to 150 mg. a day. Azathioprine was decreased or discontinued in the presence of leukopenia. Rejection episodes were treated with methylprednisolone sodium succinate, 250 mg. intravenously, twice a day for three days. This immunosuppression regimen was not modified for uncomplicated urinary tract infections. Urine cultures were routinely taken every other day during hospitalization. After hospital discharge, cultures were obtained every other week for three months and at every clinic visit thereafter. More frequent cultures were obtained in the presence of urinary tract infection. Cultures were obtained using aseptic technique, namely during midstream micturition after cleansing with povidone-iodine (Betadine) solution. Specimens were either sent immediately to the microbiology laboratory or were refriger-
cause of renal failure in our patient population. In total there were 75 cadaver transplants and 12 living related donor transplants. All patients were followed up for at least twelve months after surgery, and no patient who received a renal homotransplant in 1974 was excluded from this study. Definition
of terms
The most widely used definition of urinary tract infection after renal transplantation is the presence of more than 100,000 organisms per milliliter or a single bacterial strain in two, consecutive, urine specimens. 1,3~13~15 However, as stressed by Hinman, Schaelzie, and Belzer,2 “Colony counts of washout specimens may be quite low but still be significant.” Our experience is in accord with this. Therefore, we also consider significant urinary tract infection to be present after transplantation in the presence of repeated counts of less than 100,000 of the same organism. Urinary tract infections occurring during the first month after transplantation were considered to be early infections, whereas infections occurring later than the first postoperative month were considered late infections. This type of classification is in accord with several No attempt was made previous studies. 3*8~15~16 to differentiate recurrent infection from reinfection, and the term recurrence is used for either. Persistent infection was operationally defined as presence of continuous urinary tract infection for longer than one month despite numerous attempts to eradicate the. infection with appropriate antibiotics. Rigorous criteria for success of the renal graft were employed in this study. Only patients surviving one year with adequate graft function to obviate the need for dialysis were considered to have successful renal transplants. Serum
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TABLE
II.
Urinary tract infection after renal transplantation: 1974 experience (total of 87 transplants)
Patient Group (n = 75) Successful (n=26) Male (n=17) Female (n=9) Unsuccessful (n=49) Male (n=32) Female (n= 17)
CADAVER GRAFTS
Urinary Tract Infection*
No Urinary Tract Infection*
45 (60)
30 (40) 18 11 7 27 14 8
(65.4) (64.7) (77.8) (55.1) (59.4) (47.1)
4 2 2 4 2 2
(57.1) (66.7) (50) (80) (100) (66.7)
8 6 2 22 13 9
(34.6) (35.3) (22.2) (44.9) (40.6) (52.9)
3 1 2 1 0 1
(42.9) (33.3) (50) (20) (0) (33.3)
LIVING RELATED DONOR
(n= 12) Successful (n=7) Male (n=3) Female (n=4) Unsuccessful (n=5) Male (n=2) Female (n=3)
GRAFTS
TOTALS
4 (33.3)
8 (66.7)
53 (60.9)
34 (39.1)
*Figures in parenthesesindicatepercentages
ated. Urine aliquots were plated, using calibrated loops on blood agar as well as on MacConkey agar plates. The plates were incubated at 35” C. overnight and then counted. Appropriate biochemical tests were used to identify organisms present in significant numbers. Routine antibiotic prophylaxis was not done in any case. Graft function was closely monitored by following daily urine output and by daily serum creatinine and creatinine clearance determinations. In addition, serial renal scans were done using hippurate I-131 as well as technetium-%. Prior to discharge all patients with functioning grafts had cystograms as well as intravenous pyelograms taken. Statistical analysis results were analyzed using either the chi-square test or Fisher’s exact test, where appropriate. Results Between January 1 and December 31, 1974, a total of 87 kidney transplants were done at this medical center. Urinary tract infections occurred in 53 cases (61 per cent) (Table II). There were no statistically significant differences between urinary tract infection rates following cadaver grafts or living related donor grafts. Significant differences in urinary tract infection rates did not occur between recipients of successful or unsuccessful transplants. The relationship between etiology of endstage renal disease and urinary tract infection
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after transplantation is indicated in Table III. Glomerulonephritis was by far the most frequent disease (37 patients), followed by nephrosclerosis (11 patients) and pyelonephritis (10 patients). Of the 37 patients in the glomerulonephritis group 22 (59 per cent) had significant bacteriuria. Further analysis of this group reveals that successful transplants in patients with glomerulonephritis were associated with a higher incidence of urinary infection, 10 of 14 patients (71 per cent) than the unsuccessful group, 12 of 23 (52 per cent). This difference does not reach statistical significance (0.30 < p < 0.20) and is probably to some extent an artifact reflecting the longer period of time which the successful group was at risk for development of a urinary infection. It should be noted that 57 per cent of the unsuccessful grafts were removed during the first eight weeks after surgery. Of the patients with hypertensive nephrosclerosis 2 of 3 (67 per cent) in the successful group and 5 of 8 (62 per cent) in the unsuccessful group had significant bacteriuria. Urinary infection occurred in 3 of 4 (75 per cent) of successful grafts in the patients with pyelonephritis and in 4 of 6 (67 per cent) patients with unsuccessful grafts. There are no statistically significant differences among these groups. Urinary tract infections after renal transplantation may be classified as either early infections, occurring in the first postoperative weeks, or late infections, occurring after the first four
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III. Relationship of etiology of end-stage renal disease to urinary tract infection (UTZ) after renal transplantation
TABLE
Etiology of EndStage Renal Disease*
Successful Grafts UT1 No UT1
Local causes Glomerulonephritis Pyelonephritis Interstitial nephritis Polycystic disease
10 3
2 1
1
3
- 2 11
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weeks (Table IV). Occurrence of early infection only is more common in unsuccessful cases (19 of 31 patients, 61 per cent) than in successful cases (3 of 22, 14 per cent). This is a statistically significant difference (p < 0.05). The total number of isolated late infections is small (6 of 53, 11 per cent). Most patients with successful grafts associated with urinary tract infection experience a combination of early and late infections (15 of 22 patients, 68 per cent). The relationship of early urinary tract infection to urine flow after transplantation is analyzed in Table V. Almost half of the early infections (23 of 47) began when urine volume was greater than 1,500 cc. per twenty-four hours. It should be noted, however, that early infections associated with good urine flow almost always occurred early in the diuretic phase. Continuation of good urine output was frequently associated with resolution of bacteriuria. During the period of oliguria, when urine flow was less than 100 cc. per twenty-four hours, only 8 of 47 patients (17 per cent) experienced onset of significant bacteriuria. Most patients with urinary tract infection after renal transplantation experienced only a single episode (29 of 53 patients, 55 per cent) heavily, (Table VI). This fig ure is weighted however, in patients with unsuccessful grafts; 22
/
11
4
1 1
*Based on Beeson and McDermott, Saunders Co., 1975, p. 1093, Table 2.
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1
22
TOTALS
Total
1
Systemic diseases and intoxications Hypertensive nephrosclerosis Systemic lupus Diabetes Heavy metal poison etiology
4 1 1
2
Lower tract obstruction Urethral values Bladder neck obstruction
Undetermined
Unsuccessful Grafts UT1 No UT1
Philadelphia, W. B.
IV. Urinary tract infections after renal transplantation
TABLE
Patient Group*
-InfectionsEarly Late
Both
Successful cadaver grafts - male and female (18/26)
2
4
12
Unsuccessful cadaver grafts - male and female (27/49)
17
2
8
Successful living related donor grafts male and female (4/7)
1
0
3
Unsuccessful living related donor grafts male and female (4/5) TOTALS (W87)
_2_ 22
0
2 6
25
*Number of patients in group with urinary tract infections/ total number of patients.
of 29 patients with a single urinary infection had unsuccessful transplants. Analysis of the successful grafts alone reveals that approximately 20 to 30 per cent of patients with urinary tract infections are cured by each course of antibiotics. Only 2 of 22 patients (9 per cent) had persistent infections. Only 1 patient in our series had more
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TABLE V. Relationship
of early urinary
to urine volume after renal transplantation
24-Hour Urine Volume at Onset of Urinary Infection (X 100 cc.) 5.0-7.5 7.5-10 10-15 1.0-2.5 2.5-5.0
~
Patient Group*
tract infection
< 1.0
> 15
Successful cadaver grafts (14)
2
0
2
0
0
1
9
Unsuccessful cadaver grafts (25)
3
3
5
2
0
3
9
Successful living related donor grafts (4)
1
0
0
0
0
0
3
0
0 0
Unsuccessful living related donor grafts (4)
TOTALS (47) *Number
0
2
0
3
8
with early infection. TABLE
VI.
Number
Patient Group*
Unsuccessful cadaver grafts male and female (27) Successful living related donor grafts - male and female (4) Unsuccessful living related donor grafts - male and female (4)
TOTALS (53) *Figures in parentheses
of episodes of urinary renal transplantation
1
Successful cadaver grafts - male and female (18)
tract infection
after
Number of Urinary Infections 4 5 2 3
Persistent
6
4
2
4
0
2
20
3
1
1
0
2
1
1
1
0
1
0
2 29
r 9
1
0
0
0
5
5
1
4
indicate number of patients in group.
than five discrete episodes of urinary and her case history is illustrative:
infection,
A twenty-year-old woman had a transplant from a sibling with full antigen match and low (< 10 per cent) reactivity in mixed lymphocyte culture. The patient’s postoperative course was characterized by good graft function despite seven, discrete, symptomatic, urinary tract infections. Each infection responded well to antibiotic therapy. Lower tract evaluation was normal. Nine months after transplantation she became hypertensive, and renal function began to deteriorate. An intravenous pyelogram’ at this time showed marked hydronephrosis, and a retrograde pyelogram revealed obstruction at the ureteroneocystotomy. For this reason the ureter was reimplanted in the bladder. After surgery hypertension subsided,
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Y
7
renal function improved, hydronephrosis peared, and bacteriuria did not recur.
disap-
This case demonstrates that anatomic problems should be strongly suspected in cases of multiple, discrete episodes of urinary tract infection after transplantation. A total of 99 episodes of significant bacteriuria were documented in 53 patients (Table VII). Over-all the most frequent organism was Escherichia coli, followed by Streptococcus faecalis and the Klebsiella-Enterobacter group. Interesting differences become apparent when the bacteriology of urinary tract infection in the successful group is compared with infection in the unsuccessful group. E. coli caused most first infections (7 of 22, 32 per cent) as well as most
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recurrent infections (15 of 36, 42 per cent) in patients with unsuccessful grafts. S. faecalis and mixed infections were next in frequency. In contrast, S. faecalis was responsible for most first infections in the unsuccessful group (9 of 31, 29 per cent). Recurrent infections in the unsuccessful group were caused by a variety of gram-negative bacteria as well as Candida albicans. Success or failure of the graft correlates with this difference in infecting organisms (p < 0.02 for first infections and recurrent infections).
lost. The high incidence of isolated early infections, 22 of 53 patients, appears to have prognostic significance for graft survival. Of the 22 patients with early urinary tract infection only, 19 lost their graft. Although the pathology report was “acute rejection” in most cases, it is known that infection can trigger host responses and induce rejection.” Early infection of the urinary tract is also an important source of organisms causing wound infection and septicemia which result in a poor prognosis for both the graft and the patient. 1o-14~18It should be noted that septicemia itself may induce a Shwartzmantype reaction causing intravascular coagulation and loss of the graft.‘7*‘8 Most patients with urinary tract infection following successful transplantation experience a combination of both early and late infection (15 of 22 patients, 68 per cent). Most early infections are initially noted early in the diuretic phase, and continuation of good urine output was usually associated with resolution of bacteriuria. Anatomic factors constitute a remediable cause of urinary tract infection after transplantation. For this reason complete urologic evaluation is indicated in cases of multiple, recurrent
Comment Urinary tract infection is the most frequent complication after renal transplantation. This high incidence, 61 per cent in the present series, is related to multiple factors including the generalized catabolic condition of many end-stage kidney patients, immunosuppression, the trauma of surgery, and catheterization. Urinary infection is an adverse influence on both graft and patient survival after renal transplantation. The primary effect of significant bacteriuria appears to occur early in the postoperative course, the period when most grafts are TABLE VII.
Organisms causing urinary tract infection after renal transplantation* -Successful 1st Infection
Infecting Organism Gram-negative rods Escherichia coli Proteus mirabilis vulgaris Providencia stuartii Klebsiella-Enterobacter
GraftsRecur 15 (42)
7 (32)
-Unsuccessful 1st Infection 4 (13)
Graft+ Recur 2 (17)
3 (9)
1 (3)
Gram-positive cocci Streptococcus faecalis /3-hemolytic Staphylococcus epidermidis
1 (5)
1 (3)
2 (6)
2 07) I (6)
4 (4) 5 (5)
1 (5)
1 (3) 2 (6)
3 (10)
2 (17)
1 (1) 8 (8)
4 (18) 1 (5)
3 (9)
Q (29)
2 (9)
2 (6)
2 (6)
1 (3)
1 (3) 2 (6)
2 (17)
5 (15) 34
7 (23) 31
3 (25) 12
Other organisms Candida albicans Yeast-like organisms Mixed infection
4 (18) 22
TOTALS
28 (29) 3 (3) 1 (1) 1 (1)
1 (3)
2 (9)
group Serratia species Pseudomonas fluorescens aeruginosa
TotaI
16 (16) 1 (1) 6 (6) 4 (4) 2 (2) 19 (19) 99
*Numbers in parentheses represent percentages.
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urinary infections, de novo hypertension, or deterioration of graft function after transplantation. There appears to be a significant difference in the bacteriologic spectrum of urinary tract infections associated with successful transplants as compared with urinary tract infections associated with unsuccessful transplants. E. coli is the most frequent cause of both first infections and recurrent infections in the successful group. In contrast, S. faecalis was the most frequent cause of first infections in the unsuccessful group while Klebsiella-Enterobacter and mixed organisms were isolated most frequently in recurrent infections. Improvement in the results of renal transplantation ultimately depends on fundamental advances in immunology. From a clinical standthere remains room for impoint, however, provement using therapeutic modalities presently available. Diminishing the incidence and duration of urinary tract infections should improve the success rate of renal grafts. Several approaches to this problem are available including reducing steroid dose to the minimal level needed to prevent rejection, meticulous care and maintenance of a closed urine drainage system immediately after surgery, early removal of urethral catheters, specific, early antibiotic therapy, and a vigorous search for remediable anatomic defects. 525 East 68 Street New York, New York 10021 (DR. TAPIA) References 1. BENNETT, W. M., BECK, C. H., YOUNG, H. H., and RUSSELL, P. S.: Bacteriuria in the first month following renal transplantation, Arch. Surg. 101:453 (1970). 2. HINMAN, F., SCHAELZIE, J. F., and BELZER, R.
136
3.
4.
5. 6.
7.
8.
9. 10.
11.
12. 13.
14.
15.
16. 17. 18.
0.: Urinary tract infection and renal homotransplantation: II post-transplantation bacterial invasion, J. Urol. 101:673 (1969). LEIGH, D. A.: The outcome of urinary tract infection in patients after human cadaveric renal transplantation, Br. J. Urol. 41: 406 (1969). MACKINNON, K. J., OLIVER, J. A., MOREHOUSE, D. D., and TAGUCHI, Y.: Cadaver renal transplantation: emphasis on urologic aspects, J. Urol. 99: 486 (1968). MARTIN, D. C.: Urinary tract infection in clinical renal transplantation, Arch. Surg. 99: 474 (1969). PROUT, G. R., HUME, D. M., LEE, H. M., and WILLIAMS, G. M.: Some urologic aspects of 93 consecutive renal homotransplants in modified recipients, J. Urol. 97: 409 (1967). RIFKIND, D., MARCHIORO, T. L., WADDELL, W. R., and STARZL, T. E.: Infectious diseases associated with renal transplantation, J.A.M.A. 189: 397 (1964). MAHON, F. B., MALEK, G. H., and UEHLING, D. T. : Urinary tract infection after renal transplantation, Urology 1: 579 (1973). MCDONALD, J. C., et al.: Sepsis in human renal transplantation, Surgery 69: 189 (1971). KELLY, W. D., et al.: Kidney transplantation: experiences at the University of Minnesota Hospitals, ibid. 62: 764 (1967). MOORE, T. C., and HUME, D. M.: The period and nature of hazard in clinical renal transplantation: I the hazard to patient survival, Ann. Surg. 170: 1 (1969). PLETKA, P., et al.: Cadaveric renal transplantation, an analysis of 65 cases, Lancet 1: 1 (1969). SUSSMAN, M., and RUSSELL, R. B.: Infection after cadaver+ renal transplantation, Proc. Roy. Sot. Med. 65: 471 (1973). ANDERSON,R. J., SCHAFER, L. A., OLIN, D. B., and EICKHOFF, T. C.: Septicemia in renal transplant recipients, Arch. Surg. 166: 692 (1973). HANSHERE, R. J., CHISOLM, G. D., and SHACKMAN, R.: Late urinary-tract infection after renal transplantation, Lancet 2: 793 (1974). DOUGLAS, J. F., et al.: Late urinary-tract infection after renal transplantation, ibid. 2: 1015(1974). SIMMONS, R. L., et al. : Do mild infection trigger the rejection of renal allografts? Trans. Proc. 2: 419 (1970). MYEROWITZ, R. L., MEDEIROS, A. A., and O’BRIEN, T. R.: Bacterial infection in renal homotransplant recipients, Am. J. Med. 53: 308 (1972).
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