Pathology of the digestive organs and systemic endotoxinemia

The intestine being a natural depot of the gram-negative bacteria, may be the source of the systemic endotoxinemia in various pathologic processes followed by the increase of bacteria death, mucous membrane damage, pancreas endocrine function deficiency, liver barrier function depression, decrease of the portal circulation speed or its shunting. At the same time, the systemic endotoxinemia in itself may be one of the most important etiological factors of the various digestive organs injury. The authors observations and the literature suggest an important role of the endotoxin-positive granulocytes in the pathogenesis of the haemorrhagic infarct of the intestine, mesenteric vein thrombosis, destructive appendicitis and cholecystitis.     

Cutaneous complications in renal transplant recipients

Systematic review of the histologic characteristics of skin lesions biopsied and/or resected in a group of 580 renal transplant recipients collected over a 16-year period showed a total of 170 specimens from 120 patients. In this group there were 41 benign tumors, 22 infections, 35 inflammatory dermatoses, and 13 miscellaneous lesions. Fifty-nine lesions were malignant, and half of these were squamous cell carcinomas (SCCs). None were lethal or metastasized, although deeply invasive local recurrences and multiple lesions were common. Comparison with SCCs from a control group showed no clearcut differences with respect to level of invasion, grade, pattern, or presence of actinic change. Most of these lesions were found in sun-exposed areas, were associated with actinic changes, and with actinic keratoses. Problems in differentiating SCC from keratoacanthoma and the clinical implications of these difficulties are discussed in conjunction with a review of the literature.     

Cardiovascular pathology in renal transplant recipients

Various cardiovascular complications are among the major causes of mortality in renal transplant recipients. The authors examined the cardiovascular findings from necropsy of 18 renal transplant patients. All but three of the patients showed one or more pathological abnormalities. Five patients exhibited severe coronary arteriosclerosis with acute myocardial infarction with a history of myocardial infarction noted in four patients. In addition, one patient showed moderate and two showed mild coronary arteriosclerosis. Also prevalent were left ventricular (LV) hypertrophy (10/18), right ventricular (RV) hypertrophy (7/18), LV dilatation (4/18), RV dilatation (8/18), left atrial dilatation (3/18), and right atrial dilatation (6/18). Valvular abnormalities consisted of dilatations of mitral ring (1/18), pulmonic valve (2/18), and tricuspid valve (3/18). Pericarditis was found in two patients and aortic atherosclerosis in ten patients. Findings on routine chest roentgenograms and electrocardiograms did not always correspond with the anatomical findings noted on necropsy examination. The results demonstrate a marked increase in the incidence of various cardiac abnormalities in renal transplant recipients.     

Cytomegalovirus infection in renal transplant recipients

Cytomegalovirus (CMV) belongs to the family of human herpes viruses. It is also known as the human herpes virus 5 (HHV-5). In immunocompromised host it becomes significant pathogen, causing the spectrum of different symptoms and affecting different tissues and organs. Epidemiologic forms of CMV infection include primary infection, reactivation or secondary infection, and superinfection or reinfection. CMV infection has direct and indirect effects. Direct effects occur at the time of highest viraemia with severe clinical presentation. To the contrast, indirect effects occur at the time of asymptomatic viraemia as the consequence of immunologic response. Indirect effects are mediated by cytokines, chemokines and growth factors. Diagnosis of CMV infection is based on virus detection in body fluids and tissues. There are several diagnostic methods for detection of CMV, and their use is primarily determined by the possibilities of the specific transplantation center. Regarding the risk of CMV infection, several categories of renal transplant recipients may be identified. The main factor for estimation of risk for development of CMV infection is donor and recipient serological status. The highest risk is associated with combination of CMV seropositive donor and CMV seronegative recipient (D+/R-). CMV infection was often fatal before introduction of potent antiviral drugs in therapeutic protocols. Contemporary treatment has significantly decreased mortality rate from the CMV infection. Several drugs are used for prevention and treatment of CMV infection: hyper immune gamma globulin, gancyclovir, valgancyclovir, valacyclovir and acyclovir, depending on the kind of treatment (prophylaxis or preemptive treatment). In the case of CMV disease, the best results may currently be achieved with the combination of hyper immune gamma globulin and intravenous gancyclovir.     

Gastrointestinal complications in renal transplant recipients

In a 16-year study, 101 gastrointestinal (GI) lesions (16 fatal) developed in 580 renal transplant recipients seen in the authors' institution. Lesions were seen at all levels of the GI tract, but colonic lesions were the most common (42 patients) and were fatal in 8. Segmental ischemic colitis was the single most common morphologic diagnosis (14 patients). Seven of these patients had an unusual syndrome that clinically, at surgery, and on gross examination resembled inflammatory bowel disease. Lesions were segmental; involved bowel was thickened and erythematous with creeping peritoneal fat. Histologically, mucosa adjacent to the frank necrosis showed simplification and striking epithelial atypia. Specific identifiable viral infections caused 28% of the GI complications in this series. This incidence is higher than that in other reported series. Most of these infections can be diagnosed from endoscopically obtained material. These findings have therapeutic implications.     

Neurological complications in renal transplant recipients

Renal transplantation is method of choice for treatment of patients with end-stage renal disease without contraindications for immunosuppressive therapy. Neurological complications occur frequently in renal transplant recipients. They may be the consequence of immunosuppressive treatment, but more often evolve as the consequence of previous disturbances which developed during the state of uraemia and treatment with dialysis. The most pronounced neurotoxic effect has calcineurin inhibitors tacrolimus and cyclosporine. The spectrum of neurological disturbances caused by calcineurin inhibitors range from very mild symptoms as paraesthesiae, tremor, headache or flushing, to severe changes that may cause lethal outcome. Peripheral neuropathies in renal transplant recipients may occur in the form of mononeuropathy or polyneuropathy. Cerebrovascular diseases are consequence of changes on blood vessels caused by uraemia, dialysis and side effects of immunosuppressive drugs. They cause death in 8% of renal transplant recipients. Central nervous system (CNS) infections usually occur during the first posttransplant year. Unclear symptomatology frequently postpones the diagnosis. Diagnostic evaluation should include magnetic resonance imaging for localization of the process, as well as lumbal puncture in cases without contraindications for the procedure, in order to determine the causative agent. Regarding the ominous prognosis of CNS infections in the immunocompromised host, only timely diagnosis may improve survival. The most common causative agents are Cryptococcus neoformans, Listeria monocytogenes and Aspergillus funigatus. Viral infections also occur, and are commonly caused by herpes virideae, varicella-zoster virus and papova virus. CNS infections clinically present as meningitis, progressive dementia or focal neurological defect. The most common primary brain tumors are B-cell lymphomas, but glioblastoma, hemangioblastoma, leiomyosarcoma or glioma may also occur. In cases of neurological posttransplant complications, optimal treatment should be guided by neurologist, nephrologist and infectologist, in some cases also by neurosurgeons.     

Pulmonary pathology in renal transplant recipients

Studies of the lungs have revealed multiple functional and histopathological abnormalities in patients with chronic renal failure, but data following renal transplantation are extremely limited. We examined postmortem data from 20 transplant patients and found pulmonary abnormalities in most patients. The number of pulmonary abnormalities noted in patients with poor transplantation, averaged 5.3 per patient. The corresponding number was significantly less (3.4 per patient) in the group with good transplant renal function, surviving more than one year after transplantation. Pulmonary calcification, fibrosis, and hemosiderosis were found in several patients in the former group but in none of the latter group. This observation suggests reversibility of these pulmonary abnormalities with successful renal transplantation.     

Arterial hypertension in renal transplant recipients

Arterial hypertension develops in up to 80% of renal transplant recipients. Uncontrolled hypertension induces left ventricular hypertrophy, heart failure and death, but also promotes deterioration of allograft function. Cadaveric transplantation, delayed graft function, renal artery stenosis, presence of native kidneys, increased body weight and therapy with calcineurin inhibitors and steroids have been associated with an increased incidence of hypertension after kidney transplantation. Cyclosporine increases both systemic and renal vascular resistance, enhances sympathetic activation, endothelin production and, possibly, decreases vascular relaxation by decreasing the generation of nitric oxide. Tacrolimus has less pronounced prohypertensive role after renal transplantation. Corticosteroids contribute to the development of hypertension, since their withdrawal results in a significant decrease of blood pressure in the majority of patients. Renal artery stenosis occurs in almost 12% of hypertensive renal transplant recipients. It is a correctable cause of hypertension, and for this reason should be investigated in all suspected patients. Doppler ultrasonography is used as the screening method that is highly sensitive and specific in the hands of a well-experienced investigator. However, dependence of the method on the experience of the investigator is its major drawback. Magnetic resonance angiography and spinal computed tomography angiography are useful noninvasive methods, but arteriography remains a method for establishing the definitive diagnosis. Percutaneous balloon angioplasty, with or without placement of the stent, is successful in the majority of patients, but with a high incidence of restenoses (20%). Surgery is indicated for stenoses that cannot be treated with angioplasty or that recur. Auto-transplantation of the kidney with complex stenoses of graft arteries is useful in selected cases. Posttransplant hypertension should be aggressively treated to prevent the development of end-organ damage. Every effort should be invested in reducing immunosuppression when appropriate, together with salt restriction and weight reduction. Calcium channel blockers have good antihypertensive properties accompanied with minimization of cyclosporine-induced renal vasoconstriction. Angiotensin-converting enzyme inhibitors (ACEi) should be used in patients with proteinuria. Renal function should be carefully monitored after their introduction since they may cause transitory deterioration of glomerular filtration and/or hyperkaliemia. ACEi can induce anemia in renal transplant recipients, side effect that is often used in the treatment of posttransplant erythrocytosis. All other antihypertensive drugs could be used, with minoxidil being the most potent one. Patients with resistant hypertension should be investigated for the presence of renal artery stenosis. After exclusion of rejection, renal artery stenosis and recurrent disease, in cases of severe hypertension, native kidneys laparoscopic nephrectomy should be considered.     

Lymphoproliferative disorders in Oxford renal transplant recipients

BACKGROUND: Increased cancer incidence, particularly lymphoproliferative disease, is a complication of immunosuppression in organ transplantation. Non-Hodgkin's lymphomas (NHLs) occur frequently during the first year after transplantation, more so in North America than in Europe. METHODS: This study audited and correlated the demographic, clinical, pathological, and outcome features of post-transplant lymphoproliferative disorders (PTLDs) in a large centre in Oxford, and assessed whether the time of onset fitted more with the European or North American pattern. RESULTS: There were 1383 renal transplants in the study period and 27 patients developed lymphoma: 26 NHLs and one Hodgkin's disease (1.95%). Four of the patients never received cyclosporin. The mean time of diagnosis after transplant was 46 months. Most tumours (21/27) presented extranodally. Management included reduction of immunosuppression, surgical excision, antiviral treatment, radiotherapy, and chemotherapy. Three patients presented in the first post-transplant year-0.34% of cyclosporin managed patients-similar to the North American incidence, although the incidence of extranodal late PTLDs was also high (mean onset, 36 months v 15 months international mean). Post-transplant lymphomas were the most common malignancy associated with death in transplant patients. CONCLUSIONS: PTLDs occurred in 2% of renal transplant patients, presenting both in the first year in association with cyclosporin use, as in North America, but also in subsequent years, giving an overall presentation time later than the international mean. The disease usually presented extranodally, accounting for the wide range of symptoms and signs. Despite awareness and active management, the disease contributed to death in more that 50% of patients with PTLDs.     

Neutrophil functions in renal transplant recipients.

Neutrophils obtained from peripheral blood of renal allograft recipients were studied for their ability to kill Gram-positive and Gram-negative bacteria as well as to enhance intracellular metabolism measured by the reduction of NBT salts. In addition, the influence of sera these patients on normal cells was investigated. At the same time, these cells were also tested for candidacidal activity. The data derived from these studies indicate that phagocytic cells from these patients are impaired with respect to their capacity to fight the pathogenic microorganisms as well as their sera do not promote normal killing of microorganisms, while the NBT reaction is not changed significantly. Large doses of steroids and rejection crises do not appear to affect dramatically these functions, while an ATG therapy abolishes neutrophil killing ability.     

Viral infections in renal transplant recipients.

Cytomegalovirus (CMV) infections are common in renal transplant recipients. We studied 23 recipients prospectively to determine whether infections by other herpes-group and non-herpes-group viruses were also present. Sera, obtained at the time of surgery and periodically thereafter, were tested for antibody to CMV, herpes simplex virus (HSV), Epstein-Barr virus (EBV), parainfluenza viruses types 1, 2, and 3, and the viruses of measles and rubella. We found no evidence of an unusual incidence of primary or secondary infection by the non-herpesviruses tested. Rises to CMV, HSV, and EBV antibody titers occurred in 43, 38, and 32% of patients, respectively. All serological rises to herpes-group viruses occurred in patients seropositive at the time of transplantation, with the exception of three patients who experienced primary CMV infections. We conclude that reactivation of all herpes-group viruses tested may occur in transplant recipients. Morbidity was associated only with primarly CMV infection.     

Clinical outcomes of tuberculosis in renal transplant recipients

Tuberculosis (TB) is an important cause of morbidity and mortality in renal transplant recipients. Rifampin has a potent sterilizing activity, but it reduces the serum concentrations of the immunosuppressive agents. Moreover, the possible contribution made by mycobacterial infection to the incidence of graft rejection or renal dysfunction remains unclear. In this study, we investigated the recurrence of TB and graft survival duration according to rifampin usage, and we evaluated the factors that could influence the duration time until the recurrence of TB. Seventy-eight TB patients diagnosed after kidney transplantation were studied. Pulmonary TB was diagnosed in 26 of the 78 patients (33.3%), pleural TB in 23 (29.5%), combined pulmonary and pleural TB in 5 (6.4%), miliary TB in 19 (24.4%), and intestinal TB in 2 patients. In the pulmonary (pulmonary TB and pleural TB) TB group, no differences in graft survival and the TB free duration period were observed between the rifampin usage subgroup and the non- rifampin usage subgroup. In the extrapulmonary TB group, no difference was found in mean graft survival time between the rifampin usage subgroup and the non-rifampin usage subgroup, but the rifampin usage subgroup showed that the TB had a tendency to recur later than for the non-rifampin usage subgroup (87 +/- 8 vs. 44 +/- 7 months, respectively, p=0.30). The factor affecting the duration period until the recurrence of TB was the treatment duration (RR=0.761, p=0.030). This study suggests that rifampin does not affect graft survival in renal transplant recipients in whom immunosuppression is carefully monitored. Also, the study results indicate that rifampin may prevent a recurrence of extrapulmonary tuberculosis. Prolonged treatment appears to be appropriate for renal transplant recipients with TB.     

Donor non-specific MICA antibodies in renal transplant recipients

Despite recent advances in solid organ transplantations, an antibody mediated rejection caused by donor specific antibodies is still a major problem in kidney graft survival. Besides HLA-induced humoral response, antibodies against MICA antigens have recently attracted attention because of their possible role in graft rejection.     

Prostaglandin E2 in renal transplant recipients.

Prostaglandin E2 (PGE2), sodium, potassium and creatinine were determined in the blood and urine of 50 renal transplant recipients treated for at least one year post transplantation with cyclosporine A or azathioprine as immunosuppressive agent. Fourteen healthy subjects were used as a control group. The urinary PGE2 excretion was significantly decreased in the renal transplant recipients on azathioprine therapy while it was unchanged in the patients treated with cyclosporine A. At the same time, a significant decrease in urinary excretion of sodium and potassium was found. On the other hand, a high elevation of blood PGE2 concentration was observed while no significant changes were seen in sodium and potassium in the blood of these renal transplant recipients. It is suggested that an association exists between urinary PGE2 reduction and immunosuppressive treatments in renal transplant recipients and that PGE2 may regulate intrarenal haemodynamics and influence renal tubular electrolyte excretion. Finally, urinary PGE2 can be used as an indicator of successful renal transplantation.     

Erythropoiesis and erythropoietin levels in renal transplant recipients

Summary Moderately increased blood levels of endogenous erythropoietin (Epo) usually induce complete restoration of renal anemia after successful kidney transplantation. With good graft function erythropoiesis is maintained by normal Epo serum levels. Persistent anemia can be related to iron deficiency, low excretory graft function, and high dosage of immunosuppressive agents leading to marrow suppression or nephrotoxicity. Acute early rejection is associated with a fall in serum Epo and abrogation of reticulocytosis. About 15% of recipients fail to exhibit the normal feedback regulation and develop a mostly transient post-transplant erythrocytosis. Both an increased sensitivity of erythrocytic progenitors to Epo and inappropriate Epo secretion by the native kidneys may account for this overshooting reaction.Abbreviations Epo erythropoietin - rHuEpo recombinant human erythropoietin - RIA radioimmunoassay - ELISA enzyme-linked immunosorbent assay - RTx renal transplantation - CAPD continuous ambulatory peritoneal dialysis - PTE posttransplant erythrocytosis - Aza azathioprine - CsA cyclosporine A - ALG antilymphoblast globulin     

Infections with atypical mycobacteria in renal transplant recipients

Infections due to atypical mycobacteria are infrequent in renal transplant recipients but they cause serious morbidity. These pathogens are common in patients with acquired immune deficiency syndrome (AIDS). We report four proven cases of infections caused with atypical mycobacteriae from 1997 to 2003, by different organisms namely, M. chelonei, M.fortuitum, M. abcessus and M. terrae in renal transplant recipients. Infection with M. terrae documented here is the first occurrence in a renal transplant patient. Histopathological examination of aspirates or biopsy specimens from involved areas and staining and culture for mycobacteriae are essential for diagnosis. Treatment involves antimycobacterial therapy, reduction in immunosuppression and surgery, if indicated. Atypical mycobacterial infections, though currently uncommon, are significant and could prove to be an emerging pathogen in renal transplant recipients in the context of the AIDS epidemic in India.     

B19 virus infection in renal transplant recipients.

BACKGROUND: B19 virus infection with persistent anaemia has been reported in organ transplant recipients. Detection of B19 virus DNA in serum is the best direct marker of active infection. OBJECTIVE: The present study evaluated the incidence and clinical role of active B19 virus infection in renal transplant recipients presenting with anaemia. STUDY DESIGN: Forty-eight such recipients were investigated by nested PCR on serum samples. The controls were 21 recipients without anaemia. Active HCMV infection was also investigated as a marker of high immunosuppression. RESULTS AND CONCLUSIONS: In 11/48 (23%) patients B19 virus DNA was demonstrated in serum versus only 1/21 (5%) of the controls. Ten of these 11 patients had already been seropositive at transplantation and active infection occurred in eight of them during the first 3 months after transplantation. The remaining patient experienced a primary infection 9 months after transplantation. Eight (73%) of these 11 patients displayed a concomitant HCMV infection and four (36%) showed increasing serum creatinine levels but none developed glomerulopathy; 3/11 (27%) recovered spontaneously from anaemia whereas 8/11 (73%) needed therapy. In conclusion, the relatively high occurrence (23%) of B19 virus infection in patients presenting with anaemia, suggests that it should be considered in the differential diagnosis of persistent anaemia in renal transplant recipients. Presence of the viral DNA should be assessed early from transplantation and the viral load should be monitored to follow persistent infection and better understand the relation between active infection and occurrence of anaemia, and to assess the efficacy of IVIG therapy and/or immunosuppression reduction in clearing the virus.     

Human cytomegalovirus glycoprotein B genotypes in renal transplant recipients

Based on sequence variation of the glycoprotein B (gB) gene, human cytomegalovirus (HCMV) strains can be classified into four gB genotypes. In a previous study of bone marrow transplant recipients, infection with the gB type 1 correlated with a more favorable clinical outcome than infection with the gB types 2, 3, or 4. The gB type was determined in 60 renal transplant and in 47 bone marrow transplant recipients using PCR and restriction analysis. All HCMV variants in patient specimens could be assigned to one of the four previously described gB types. Two or more specimens obtained from 39 patients were analysed; in 31 of these patients the gB type was the same in all samples. The gB type did not correlate with the clinical outcome or the level of viremia in renal transplant recipients. © 1996 Wiley-Liss, Inc.