Clostridium difficile--associated diarrhea and chronic renal insufficiency.

ABSTRACT

Background. Clostridium difficile-associated diarrhea (CDAD) is a common cause of mortality and morbidity in hospitalized patients. Some case reports have implicated renal failure as a risk factor for CDAD. The aim of this study was to assess whether chronic renal insufficiency is a risk factor for CDAD and whether it increases mortality and morbidity.

Method. We reviewed charts of 385 patients with diarrhea for CDAD, chronic renal insufficiency, mortality, and recurrence of CDAD.

Results. Seventy-seven patients had infection due to C difficile. There was no difference in the chronic renal insufficiency, mortality, and other comorbid conditions between patients who had C difficile infection and those who did not. The patients with CDAD and chronic renal insufficiency had significantly higher mortality and recurrence of CDAD than patients without chronic renal insufficiency.

Conclusions. Chronic renal insufficiency is not a risk factor for CDAD, but its presence with CDAD increases mortality and recurrence of CDAD.

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CLOSTRIDIUM DIFFICILE is a gram-positive, spore-bearing anaerobic bacterium first described by Hall and O'Toole (1) in 1935, but its clinical identity as Clostridium difficile-associated diarrhea (CDAD) was not recognized until the late 1970. (2) It is estimated that 3 million new cases of diarrhea and colitis are caused by C difficile in the United States annually. Clostridium difficile-associated diarrhea is one of the leading causes of nosocomial enteric infections. (3-5) It affects as many as 10% of patients hospitalized for more than 2 days. Clostridium difficile is one of the major. causes of morbidity and mortality among elderly debilitated patients.

The most common predisposing factor for clostridial colitis is the use of antibiotics such as ampicillin, amoxicillin, cephalosporins, and clindamycin. (5,6) Increasing age, gastrointestinal surgery, malnutrition, use of laxatives/antacids/stool softeners, and gastrointestinal procedures have also been found to increase the risk of clostridial colitis. (68)

One of us (M.G.S.) sent a questionnaire to many nephrologists in the United States seeking their opinion regarding chronic renal failure as a possible risk factor for CDAD. Most of those who responded do suspect chronic renal failure to be a risk factor. From our observation of increased mortality in a few patients who had clostridial colitis and chronic renal failure, we suspected that chronic renal insufficiency might increase morbidity and mortality in such patients. The aim of this study was to assess whether chronic renal insufficiency is an additional risk factor for CDAD and whether mortality and morbidity increase from coexisting chronic renal insufficiency.

METHODS

This retrospective study was conducted at the Department of Veterans Affairs Medical Center in Dayton, Ohio. We reviewed charts of patients who presented with diarrhea from May 1997 to May 1998. Names of the patients whose stool was tested for C difficile were obtained from the microbiology laboratory. Clostridial colitis was diagnosed by the finding of C difficile toxin A on enzyme immunoassay (Immunocard Toxin A enzyme immunoassay [EIA], Meridian Diagnostics Inc, Cincinnati, Ohio). Study patients included both inpatients and outpatients. We assessed their renal status by looking at the creatinine level before the onset of diarrhea, during resolution, and 3 months after resolution of diarrhea. We defined chronic renal insufficiency as persistently elevated (for 3 months or longer) serum creatinine level of 1.5 mg/dL or more. We excluded the patients with transient elevation of creatinine during the episode of diarrhea. We evaluated for the presence of other comorbid conditions such as diabetes mellitus, hypo thyroidism, advanced malignancy (cancer of colon, lung or prostate with regional or distant metastasis), human immunodeficiency virus infection, and cirrhosis of liver. In addidon, we evaluated for the recurrence of CDAD and mortality rates. If the diarrhea improved from the initial treatment but returned within a month after the completion of treatment, it was considered as a recurrence of CDAD. Patients with diarrhea and suspected C difficile colitis but who had tests negative for C difficile toxin served as control subjecs. Data were analyzed using chisquare method.

RESULTS

A total of 385 patients' charts were reviewed. Of these 385 patients tested for C difficile, 77 patients (20%) were toxin-positive. The remaining 308 patients were toxin-negative and served as controls. In the toxin-positive group 34% (n = 26) were younger than 60 years, and 66% (n = 51) were aged 60 or older. In the toxin-negative group, 29% (n = 91) were younger than 60 years, and 71% (n = 217) were aged 60 or older. Twenty-four (31%) of the 77 patients with CDAD had chronic renal insufficiency, whereas 73/308 (24%) had chronic renal insufficiency in the toxin-negative group (P = .177). Diabetes mellitus was present in 39% (n = 30) of toxin-positive patients and 33% (n = 102) of toxin-negative patients. Table 1 shows the prevalence of hypothyroidism and other conditions such as cirrhosis and advanced malignancy. Of 24 patients with persistently elevated creatinine level in the toxin-positive group, 7 were receiving renal dialysis. Mortality among patients with CDAD and chronic renal insufficiency was 67% (1 6/24), whereas in patients without chronic renal insufficiency it was 25% (13/53). Eight (33%) of the 24 patients with clostridial colitis and chronic renal insufficiency had recurrence of CDAD, as opposed to only 2 of 53 patients (4%) without chronic renal insufficiency (Table 2).

DISCUSSION

The etiologic link between clostridial colitis and antibiotic use is well established. Other factors such as advanced age, gastrointestinal procedures, and abdominal surgery are also recognized as risk factors for colitis due to C difficile.(6-8) Renal failure was incriminated as a risk factor for clostridial colitis in a report in 1985 by Leung et al.(9) Their study of five male patients receiving dialysis showed that uremic patients were predisposed to C difficile infection and suggested that the disease might run a more severe course in such patients. Cunney et al(10) reported that the number of patients who were admitted to their nephrology unit and who had C difficile colitis was four times higher than in the rest of the hospital, and mortality in patients with CDAD and renal failure was high.

The aims of our study were (1) to assess the prevalence, morbidity, and mortality of C difficile in our patients, (2) to determine whether chronic renal insufficiency is a risk factor for CDAD, and (3) to learn whether its presence with CDAD increases mortality and morbidity.

Contrary to our expectation, our data show that patients with chronic renal insufficiency do not have a higher incidence of C difficile colitis (Table 1). Our study included more patients with mild chronic renal insufficiency, and only six patients were receiving renal dialysis. This may account for our findings being different from those of other studies.(9-13)

In our study, mortality and recurrence in CDAD-positive patients with chronic renal insufficiency were almost three times higher than in patients who had CDAD but did not have renal insufficiency. Similar findings were reported in 1982 by Gokal et al.(12) We did not find diabetes mellitus, hypothyroidism, or other immunosupressive conditions such as advanced malignancy, cirrhosis, or human immunodeficiency virus infection to be a significant risk factor for development of CDAD. Similar observation was made in an earlier study. (13)

The limitations of our study are that it is retrospective and has a small number of patients with CDAD who also had chronic renal insufficiency. However, the differences in mortality of all causes and recurrence of CDAD (Table 2) are so striking that one cannot ignore it. Prospective studies are needed to confirm our findings.

In conclusion, patients with chronic renal insufficiency may not have any higher risk for clostridial diarrhea, but those who have CDAD as well as renal insufficiency have higher mortality and higher recurrence rates. Physicians taking care of patients with CDAD and chronic renal insufficiency should be aware of higher morbidity and mortality in this subset of patients and be aggressive in treating CDAD.

TABLE 1

Clostridium difficile--Associated Diarrhea and Chronic Renal
Insufficiency

                                   C difficile     C difficile
                                  Toxin-negative  Toxin-Positive

No. of patients                        308              77
Age
 <60                                    91              26
 >60                                   217              51
Chronic renal insufficiency             73              24
Diabetes mellitus                      102              30
Hypothyroidism                          25               7
Advanced malignancy                     46              12
Other conditions                        28               5
 (HIV infection, cirrhosis, etc)

                                    P
                                  Value *

No. of patients
Age
 <60
 >60                              .471
Chronic renal insufficiency       .177
Diabetes mellitus                 .334
Hypothyroidism                    .782
Advanced malignancy               .887
Other conditions                  .466
 (HIV infection, cirrhosis, etc)

* Chi-square test.
TABLE 2

Mortality and Recurrence of Clostridium difficile-Associated Diarrhea
(CDAD)

               CDAD         CDAD        P
             With CRI    Without CRI  Value *

Mortality   16/24 (67%)  13/53 (25%)  < .001
Recurrence   8/24 (33%)   2/53 (4%)   < .001

* Chi-square test.

CRI = Chronic renal insufficiency.

References

(1.) Hall JC, O'Toole E: Intestinal flora in newborn infants with a description of a new pathogenic anaerobe, Bacillus difficilus. Am J Dis Child 1935; 9:390-402

(2.) Barlett JG, Chang TW, Gurwith M, et al: Antibiotic-associated pseudomembranous colitis due to toxin-producing clostridia. N Engl J Med 1978; 298:531-534,581

(3.) Seigel DL, Edelstein PH, Nachamakin I: Inappropriate testing for diarrheal diseases in the hospital. JAMA 1990; 263:979-982

(4.) Yanelli B, Gurevich I, Schoch PE, et al: Yield of stool cultures, ova and parasite tests, and Clostridium difficile determination in nosocomial diarrheas. Am J Infect Control 1988; 16:246-249

(5.) McFarland LV, Surawicz CM, Stamm WE: Risk factors for Clostridium difficile carriage and C. difficile-associated diarrhea in cohort of hospitalized patients. J Infect Dis 1990; 162:678-684

(6.) Pierce PF Jr, Wilson R, Silva J Jr, et al: Antibiotic-associated pseudomembranous colitis, an epidemiologic investigation of a cluster of cases. J Infect Dis 1982; 145:269-274

(7.) Nolan NPM, Kelly CP, Humphreys JFH, et al: An epidemic of psetidomembranous colitis: importance of person to person spread. Cut 1987; 28:1467-1473

(8.) Hirschhorn LR, Trnka Y, Onderdonk A, et al: Epidemiology of community-acquired Clostridium difficile-associated diarrhoea. J Infect Dis 1994; 169:127-133

(9.) Leung ACT, Orange G, McLay A, et al: Clostridium difficile-associated colitis in uremic patients. Clin Nephrol 1985; 24:242-248

(10.) Cunney RJ, Magge C, McNamara E, et al: Clostridium difficile colitis associated with chronic renal failure. Nephrol Dial Transplant 1998; 13:2842-2846

(11.) Aronsson B, Barany P, Nord CE, et al: Clostridium difficile-associated diarrhoea in uremic patients. Eur J Clin Microbiol 1987;6:352-356

(12.) Gokal R, Ramos JM, Francis DMA, et al: Peritonitis in continuous ambulatory peritoneal dialysis. Lancet 1982; 2:1388-1398

(13.) Barany P. Stenvinkel P, Nord CE, et al: Clostridiun difficile infection: a poor prognostic sign in uremic patients? Clin Nephrol 1992; 38:53-57

RELATED ARTICLE: KEY POINTS

* Clostridium difficile-associated diarrhea (CDAD) is one of the leading causes of nosocomial enteric infections.

* In our study, mortality and recurrence were significantly higher in CDAD-positive patients with chronic renal insufficiency (almost three times higher than in patients who had CDAD but did not have renal insufficiency).

* Patients with chronic renal insufficiency do not have a higher risk for CDAD.

* Physicians taking care of patients with GOAD and chronic renal insufficiency should be aware of higher morbidity and mortality in this subset of patients and be aggressive in treating CDAD.

From the Veterans Affairs Medical center and the Department of Medicine, Wright State University, Dayton, Ohio.

Reprint requests to N. Gopalswamy, MD, Veterans Affairs Medical center (111), 4100 W Third St, Dayton, OH 45428.