Infection In Renal Transplant Patients Research Articles

Antigenemia, immunoblotting, and enzyme immunoassay for early diagnosis of cytomegalovirus infection in renal transplant patients

Abstract Timely and rapid diagnosis of cytomegalovirus (CMV) infection is important for the management of transplant patients. We compared three serological assays, IgM immunoblot and IgG/IgM enzyme immunoassay (EIA), as well as the detection of CMV antigens in polymorphonuclear blood leukocytes (antigenemia), for their value in the early diagnosis of CMV infection. Thirty-one patients were monitored longitudinally for 3 months after renal transplantation. Laboratory documented CMV infection occurred in 20 patients. All of these cases showed a positive IgM immunoblot result that was confirmed by at least one of the other test assays (IgG EIA 19/20, antigenemia assay 13/20, and IgM EIA 12/20). All of the ten patients whose clinical picture was compatible with symptomatic CMV disease were positive for CMV infection according to IgM immunoblot and IgG EIA, nine were positive according to the antigenemia assay, and seven were positive according to IgM EIA. With reference to the temporal pattern, the antigenemia assay indicated CMV infection significantly earlier than the serological tests (P≪ 0.05). In symptomatic patients CMV antigen-positive leukocytes were, on the average, detected on the day of onset of symptoms, whereas detection by IgM immunoblot, IgG EIA, and IgM EIA followed 8, 13, and 14 days later, respectively. These results show that: (1) the CMV antigenemia assay is very useful for the early diagnosis of symptomatic CMV infections; (2) CMV antibodies, as an indicator of CMV infection, are detectable earlier and more frequently by IgM immunoblot than by IgG/IgM EIA; (3) compared to CMV antigenemia, the IgM immunoblot indicated CMV infection more often but significantly later; and (4) only a combination of several diagnostic methods allows optimal detection of CMV infections in renal transplant patients.

Risk Factors for Nosocomial Urinary Tract and Postoperative Wound Infections in Renal Transplant Patients: A Matched-Pair Case-Control Study

A matched-pair case-control study was done on 4 groups of renal transplant patients who acquired nosocomial infections: 1) urinary tract infection, 2) postoperative wound infection, 3) urinary tract plus postoperative wound infection and 4) the entire group of patients. For urinary tract infection patients a prolonged period of hemodialysis before hospitalization was considered a risk factor. Renal transplantation with an HLA-1 (identical) donor graft was a characteristic related to the control group. High levels of plasma creatinine and prolonged vesical catheterization were risk factors for acquiring postoperative wound infection. The latter was also considered to be a risk factor for both infections, as well as the inadequate use of antibiotic prophylaxis and the number of antibiotics used. For the entire group of patients surgical wall hematoma was a risk factor. In this group the independent risk factors analyzed by multivariate logistic regression were renal transplantation with a cadaver donor graft, prolonged vesical catheterization and prolonged use of antibiotics. Careful management of the cadaver donor allograft, decreasing the chances of contamination, decreasing the interval of urinary catheter maintenance and use of antibiotics in the postoperative period are measures that can contribute to lessen the incidence of these nosocomial infections in renal transplant recipients.

Immunoglobulin G subclasses and lymphocyte stimulatory responses to cytomegalovirus in transplant patients with primary cytomegalovirus infections.

The early activation of T- and B-cell responses to cytomegalovirus was studied in immunosuppressed patients. Primary lymphocyte stimulation to cytomegalovirus (CMV) antigen, a measure of T-helper activity, and anti-CMV IgG subclass responses were analyzed. Ten patients suffering from primary CMV infection following renal transplantation were studied. Of the ten, nine became positive for CMV induced lymphocyte proliferation 5-40 weeks after transplantation. Nine showed an almost simultaneous appearance of anti-CMV IgG1 and three at 3-32 weeks after transplantation, while one patient synthesized only low levels of anti-CMV IgG1. The lymphocyte proliferation assays have limited diagnostic value for primary CMV infection in renal transplant patients. The humoral and cellular immune responses seemed to be independent of each other.

Tubulointerstitial nephritis caused by the antiviral agent foscarnet

The antiviral agent foscarnet has long been used in our unit to treat cytomegalovirus (CMV) infections in renal transplant patients. The clinical effect has been convincing and, apart from changes in serum calcium levels, very few side effects have been noted. We have, however, observed a nephrotoxic reaction in a series of patients with initially good renal function who therefore received high doses of foscarnet. Transplant biopsies performed in five of those patients revealed degenerative changes in the tubular epithelial cells as well as tubular calcium deposits and an infiltration of the interstitium by mixed mononuclear and polymorphonuclear leucocytes. Renal insufficiency was accompanied by high fever. After withdrawal of the drug, the temperature rapidly normalized, whereas serum creatinine continued to rise for about 3 days and then fell back towards previous levels. We conclude that transplant biopsies are of great value in distinguishing between a foscarnet nephrotoxic effect and CMV nephritis, various forms of rejection, and other causes of impaired renal function.

Infections in Renal Transplant Patients Treated with Cyclosporine or Azathioprine

The incidence and severity of infectious complications were retrospectively investigated in 80 renal transplant patients who had been selected randomly to receive either cyclosporine (CsA) or azathioprine (Aza) in combination with low doses of corticosteroids. In the first 3 months, the incidence of infections was twice as high in the Aza-treated patients (p less than 0.05) which was due to an increase of predominantly minor infections. This increased incidence of infections was related to the increased number of anti-rejection treatments in the Aza-treated group. The types of infections were not different between the 2 treatment groups nor did the incidence of CMV infections differ. In the CsA-treated group, patients were randomly assigned at 3 months after transplantation to either continuation of CsA therapy or conversion to Aza. After conversion a small but not significant increase in predominantly minor infections was observed, which may be attributable to increased doses of corticosteroids given during the conversion. We conclude that in the first 3 months following transplantation, CsA therapy is associated with significantly less infections than Aza therapy; following conversion of CsA to Aza at 3 months only a small increase in the infection incidence is found.

Tubulointerstitial nephritis caused by the antiviral agent foscarnet

Abstract. The antiviral agent foscarnet has long been used in our unit to treat cytomegalovirus (CMV) infections in renal transplant patients. The clinical effect has been convincing and, apart from changes in serum calcium levels, very few side effects have been noted. We have, however, observed a nephrotoxic reaction in a series of patients with initially good renal function who therefore received high doses of foscarnet. Transplant biopsies performed in five of those patients revealed degenerative changes in the tubular epithelial cells as well as tubular calcium deposits and an infiltration of the interstitium by mixed mononuclear and polymor-phonuclear leucocytes. Renal insufficiency was accompanied by high fever. After withdrawal of the drug, the temperature rapidly normalized, whereas serum creatinine continued to rise for about 3 days and then fell back towards previous levels. We conclude that transplant biopsies are of great value in distinguishing between a foscarnet nephrotoxic effect and CMV nephritis, various forms of rejection, and other causes of impaired renal function.

Promising new antiviral drugs

We now have a basis for a more rational approach to rapid evaluation and development of antiviral drugs by screening for activity in vitro, testing for toxicity and efficacy in animals, and clinical testing in humans. Acyclovir is a prototype of this improved process. Interferon has a beneficial effect against CMV infection in renal transplant patients and has promising results in the treatment of papillomas and rhinovirus infections. It does not seem to be as effective against genital herpes or varicella zoster as acyclovir. Ribavirin is effective against respiratory syncytial virus infections and Lassa fever. Varicella-zoster virus is highly sensitive to bromovinyl deoxyuridine in vitro. Phosphonoformate is effective in herpes simplex in animals but of little clinical benefit topically in human recurrent A2 herpes. Zidovudine may decrease mortality rates and infectious complications in patients with acquired immunodeficiency syndrome. DHPG (9-(1,3-dihydroxy-2-propoxymethyl]guanine is useful in treatment of cytomegalovirus and infection in immunocompromised patients. The prodrug of acyclovir results in high blood levels of acyclovir and shows promise in the treatment of varicella-zoster infections. Many halogenated pyrimidine nucleoside analogs are being developed. Buciclovir is another acyclic guanosine analog effective against herpes simplex virus in vitro. 2'-nor-cyclic guanosine monophosphate has a broad antiviral spectrum of action. Interleukin-2 is being investigated. Combined therapies of two or more antiviral drugs or antiviral drugs and other treatments are being studied.

Incidence of Cytomegalovirus Infections in Renal Transplant Patients Treated With Conventional or Cyclosporin Therapy

The incidence and severity of cytomegalovirus (CMV) infection was examined in groups of consecutive renal transplant patients: group A (50 patients) transplanted from August 1984 to October 1985 received cyclosporin (from the day of transplantation) and steroid therapy; group B (50 patients) transplanted between June and July 1984 received conventional therapy (azathioprine and steroids, and antilymphocyte globulin for 14 days). In groups A and B there were respectively 5 (10%) and 14 (28%) seronegative patients prior to transplantation (CMV antibody titre less than 128 by ELISA); the overall incidence of CMV was 38% vs 74% (P less than 0.001); the incidence of primary infection was 0% (0 of 5) vs 36% (5 of 14) (NS); the incidence of secondary infection was 42% (19 of 45) vs 89% (32 of 36) (P less than 0.00001); and the total incidence of symptomatic infection was 10% vs 26% (P = 0.04). Thus we conclude that initial cyclosporin therapy leads to a reduction in CMV infection.

Urinary tract infection in renal transplant patients.

The incidence of urinary tract infections (UTI) in 299 renal graft transplantations (281 patients) was analyzed. UTI episodes were demonstrated in 185 grafts (62%), most frequently in the first month after transplantation. The infectious episodes were mostly recurrent. Persistent infection, detected in 11% of grafts, was associated with urologic complications in almost all cases. No significant correlation between the primary renal disease and the UTI rate was found, and there was no significant correlation between UTI and sex. In grafts with recurrent infectious episodes, vesicoureteral reflux was more common. No significant difference was observed in the residual bladder volume, irrespective of whether infection was present or not. The urine was infected by a number of hospital strains, particularly Klebsiella, Enterobacter and indole-positive Proteus strains. An overwhelming majority of UTI episodes (96%) were asymptomatic. Antibody-coated bacteria in urinary sediment were present in only 19% of infectious episodes. Clinically severe courses were observed in infections associated with urologic complications (especially urinary fistulae); these were difficult to treat and were often a source of sepsis and a risk factor in graft loss.

Complement activation associated with active cytomegalovirus infection in renal transplant patients, and its absence in transplant rejection episodes.

In 20 patients with a cadaveric renal allograft, serial measurements were made of the serum complement factors C3, C4, factor B (FB), and C3d, the stable conversion product of C3. Measurements were started immediately before transplantation and continued thereafter once a week to investigate whether these assays help to differentiate between acute allograft rejection (R) and an active cytomegalovirus (CMV) infection. Fifteen patients had one or more R episodes, and 9 patients suffered from an active CMV infection. Six patients had an R episode and subsequently a CMV infection 13-64 days after R. No significant changes were found in the levels of C3, C4, and FB during R or CMV infection. C3d levels remained unchanged or decreased slightly during R. However, there was a 43-500% increase in the C3d level during CMV infection. This difference in the behavior of levels of C3d during R and CMV infection is significant (P less than 0.01), and suggests that serial measurements of C3d may be useful in differentiating CMV infection from R after renal transplantation.

Association of concurrent herpes simplex virus and cytomegalovirus with detrimental effects after renal transplantation.

Herpes simplex virus (HSV) and cytomegalovirus (CMV) infections occur frequently after renal transplantation. To determine the effect of these infections on long-term prognosis, we reviewed the charts of 558 patients who underwent primary renal transplantation between Jan 1, 1974 and Dec 31, 1978, at the University of Minnesota Hospitals, Minneapolis, for cultural evidence of these infections. The presence of HSV alone appeared to have a minimal effect on either patient or allograft survival. Positive CMV cultures were associated with decreased patient and allograft survival. Patients with HSV and CMV infections had further reduced patient and allograft survival. Lethal CMV syndrome and associated severe bacterial and fungal infections were common and frequently were the immediate cause of death in patients who had concomitant positive HSV and CMV cultures. Concurrent HSV and CMV infections in renal transplant patients may be a grave prognostic indicator, being associated with enhanced mortality and renal allograft loss.

Single-dose treatment with netilmicin for different clinical forms of urinary tract infections.

A group of 44 patients with various clinical forms of urinary tract infections received a single dose of 300 mg netilmicin i.m. The treatment was efficacious in all patients with infections which were negative in the antibody-coated bacteria test and not complicated by anatomic and/or functional abnormalities of the kidneys and urinary tract. After three weeks the recurrence rate was only 19%. Single-dose treatment also proved very effective against urinary tract infections in renal transplant patients whose infection is almost always located in the lower urinary tract. In contrast, the short-term results of treatment were much poorer in complicated infections and particularly in urinary tract infections which were positive in the anti-body-coated bacteria test; here, the recurrence rate was 67%.

Non-typhoid salmonella infections after renal transplantation. A serious clinical problem.

A retrospective study of 410 renal transplant recipients showed that 1.96% (8/410) of patients had developed severe non-typhoid salmonella infections. The clinical features seen were fever, leucopenia, pneumonia, diarrhoea, abscesses, pyelonephritis, venous thrombosis and pleural effusion. Neither uraemia nor repeated high doses of steroids seemed to be major precipitating events. All isolates were strains of Salmonella enteritidis. All 8 patients were cured and none became permanent carriers. Salmonella infections cause severe, life-threatening infections in renal transplant patients and require vigorous treatment often with a long-term low-dose regimen. Patients seemed to respond best to chloramphenicol, but ampicillin and co-trimoxazole were useful in some. Bilateral nephrectomy should be performed before the transplantation if the organism is grown from the urine.

Terminal infections in renal transplant patients in a tropical environment.

Infections were a major cause of death in 84% of 38 autopsied renal allograft recipients in a south Indian hospital. Pyogenic bacteria and fungi were the most common etiological agents encountered, being present in 50 and 47% of cases, respectively. Tuberculosis and hepatitis B virus infection were more prevalent and Pneumocystis carinii and cytomegalovirus disease rarer than in comparable series from non-tropical countries. 1 case each of amoebiasis, strongyloidiasis and filariasis were the parasitic infections encountered.

A trial of vidarabine for cytomegalovirus infection in renal transplant patients

A trial of vidarabine for cytomegalovirus infection in renal transplant patients

A Trial of Vidarabine for Cytomegalovirus Infection in Renal Transplant Patients

Vidarabine was evaluated in renal transplant patients as a potential therapeutic agent in cytomegalovirus (CMV) infection. Four patients received vidarabine on an open protocol, then ten additional patients were enrolled in a double-blind protocol. Among the nine patients who received vidarabine, no notable clinical improvement occurred in either the vidarabine- or placebo-treated groups. Thus, vidarabine showed no therapeutic effect in the treatment of CMV infections at the dosages used. Four patients showed dramatic CNS deterioration within several days of the onset of vidarabine therapy. Tremors and myoclonus were common, and one patient had unusual brain pathologic changes with widespread neuronal chromatolysis. The pathologic findings in the brain in the other three patients were complex and included intracerebral hemorrhage, Fabry's disease, coccidioidomycosis meningitis, and cerebral vascular occlusion. Thus, there was no conclusive proof that vidarabine contributed to the sudden neurologic deterioration of these patients.

PROSPECTIVE STUDY OF THE PREVALENCE AND SYMPTOMATOLOGY OF CYTOMEGALOVIRUS INFECTION IN RENAL TRANSPLANT RECIPIENTS

SUMMARY To determine the incidence and symptomatology of cytomegalovirus (CMV) infection in renal transplant recipients, we followed 40 patients prospectively for 5 to 24 months after operation. As judged by the serological change and virus isolation from blood and/or urine, the infection rate for the entire group was 82% (33 of 40 patients). Two types of infection were recognized: primary infection that occurred in 3 patients, and reactivation infection that occurred in 30 patients. Twenty-one patients were asymptomatic and 12 were mildly symptomatic. Four had mild hepatic dysfunction; two had the CMV mononucleosis syndrome associated with mild to moderate deterioration of renal function. Two patients had hyperglycemia. One patient who reached a CMV antibody titer of 1:32,768 was totally asymptomatic other than fever of short duration. CMV-induced pneumonitis or retinitis was not noted, and there was no mortality from CMV infection in our patients. Factors which may be associated with the absence of severe manifestations of active CMV infection in these patients are discussed Many virus diseases have a wide spectrum of clinical manifestations, with mild subclinical infection at one extreme and severe life-threatening illness at the other. This is true of CMV infection in renal transplant recipients. The high incidence of CMV infection in renal transplant patients is well documented (1-4). The incidence has variously been reported from 52 to 96%. We have previously reported, from another center, an incidence of 96% (1). In seronegative patients with no prior evidence of infection with CMV, infection is thought to be transmitted exogenously, i.e., from the allograft itself or from blood transfusions. Immunosuppressive drugs may contribute to infection by facilitating reactivation or primary infection, but their relative importance in these two types of infection is unknown. The common and incidental finding of CMV in asymptomatic patients after transplantation has led many to believe that this ubiquitous infection is just an incidental finding of no consequence. Contrary to this view, there are reports of severe hepatitis, retinitis, pneumonitis, and even death (3). We studied our patients prospectively to determine the incidence and severity of CMV infection and have analyzed the results in an attempt to discover reasons for the differences in incidence and severity that have been observed at other centers

Risk of Pneumococcal Infections in Renal Transplant Patients

Because of the recent licensing of pneumococcal vaccine, the risk of pneumococcal infections on a renal transplant service was determined. The overall risk of infection was 7% (14 of 197 patients) over a six-year period, or 1% per year. In patients with functioning allografts, this represented a risk of 28 infections per 1,000 patient-years of follow-up. Clinically, the major presentations of pneumococcal infection were pneumonia in the patient who was rejecting his kidney and pneumococcemia of sudden onset that was often fatal. Five of the pneumococci isolated from bacteremic patients were typed; three of the isolates were types that are in the vaccine. The frequency and seriousness of pneumococcal infections in renal transplant patients suggest that pneumococcal vaccine should be given to these patients, probably before transplantation.

Risk of pneumococcal infections in renal transplant patients

Risk of pneumococcal infections in renal transplant patients

Epidemiology of cytomegalovirus infection in end stage renal disease

Since primary cytomegalovirus (CMV) infection is a cause of morbidity among renal transplant recipients, we undertook a prospective study of our maintenance hemodialysis patients and personnel to determine whether these sources posed a risk for transmission of CMV. Our study of 85 patients and 49 personnel showed that CMV was detected in eight nontransplanted, older dialysis patients and 13 patients who had lost their allograft. In spite of the presence of CMV on the unit, no patient or staff member developed primary infection from interpersonal transmission or from transfused frozen red blood cells. All primary infections in renal transplant patients could be accounted for by acquisition from the transplanted kidney, thus eliminating the dialysis unit or frozen blood as a risk to either patients or personnel.