Boosting the IL-22 response using flagellin prevents bacterial infection in cigarette smoke-exposed mice.

The progression of chronic obstructive pulmonary disease (COPD), a lung inflammatory disease being the fourth cause of death worldwide, is marked by acute exacerbations. These episodes are mainly caused by bacterial infections, frequently due to Streptococcus pneumoniae. This susceptibility to infection involves a defect in interleukin (IL)-22, which plays a pivotal role in mucosal defense mechanism. Administration of flagellin, a Toll-like receptor 5 (TLR-5) agonist, can protect mice and primates against respiratory infections in a non-pathological background. We hypothesized that TLR-5-mediated stimulation of innate immunity might improve the development of bacteria-induced exacerbations in a COPD context. Mice chronically exposed to cigarette smoke (CS), mimicking COPD symptoms, are infected with S. pneumoniae, and treated in a preventive and a delayed manner with flagellin. Both treatments induced a lower bacterial load in the lungs and blood, and strongly reduced the inflammation and lung lesions associated with the infection. This protection implicated an enhanced production of IL-22 and involved the recirculation of soluble factors secreted by spleen cells. This is also associated with higher levels of the S100A8 anti-microbial peptide in the lung. Furthermore, human mononuclear cells from non-smokers were able to respond to recombinant flagellin by increasing IL-22 production while active smoker cells do not, a defect associated with an altered IL-23 production. This study shows that stimulation of innate immunity by a TLR-5 ligand reduces CS-induced susceptibility to bacterial infection in mice, and should be considered in therapeutic strategies against COPD exacerbations.

Clinical characteristics of non-tuberculous mycobacterial pulmonary infections in Bamako, Mali.

The global spread of non-tuberculous mycobacteria (NTM) may be due to HIV/AIDS and other environmental factors. The symptoms of NTM and tuberculosis (TB) disease are indistinguishable, but their treatments are different. Lack of research on the epidemiology of NTM infections has led to underestimation of its prevalence within TB endemic countries. This study was designed to determine the prevalence and clinical characteristics of pulmonary NTM in Bamako. A cross-sectional study which include 439 suspected cases of pulmonary TB. From 2006 to 2013 a total of 332 (76%) were confirmed to have sputum culture positive for mycobacteria. The prevalence of NTM infection was 9.3% of our study population and 12.3% of culture positive patients. The seroprevalence of HIV in NTM group was 17.1%. Patients who weighed <55 kg and had TB symptoms other than cough were also significantly more likely to have disease due to NTM as compared to those with TB disease who were significantly more likely to have cough and weigh more than 55 kg (OR 0.05 (CI 0.02-0.13) and OR 0.32 (CI 0.11-0.93) respectively). NTM disease burden in Bamako was substantial and diagnostic algorithms for pulmonary disease in TB endemic countries should consider the impact of NTM.

Tuberculosis drug resistance in Bamako, Mali, from 2006 to 2014.

BACKGROUND: Although Drug resistance tuberculosis is not a new phenomenon, Mali remains one of the "blank" countries without systematic data. METHODS: Between 2006 and 2014, we enrolled pulmonary TB patients from local TB diagnostics centers and a university referral hospital in several observational cohort studies. These consecutive patients had first line drug susceptibility testing (DST) performed on their isolates. A subset of MDR was subsequently tested for second line drug resistance. RESULTS: A total of 1186 mycobacterial cultures were performed on samples from 522 patients, including 1105 sputa and 81 blood samples, yielding one or more Mycobacterium tuberculosis complex (Mtbc) positive cultures for 343 patients. Phenotypic DST was performed on 337 (98.3%) unique Mtbc isolates, of which 127 (37.7%) were resistant to at least one drug, including 75 (22.3%) with multidrug resistance (MDR). The overall prevalence of MDR-TB was 3.4% among new patients and 66.3% among retreatment patients. Second line DST was available for 38 (50.7%) of MDR patients and seven (18.4%) had resistance to either fluoroquinolones or second-line injectable drugs. CONCLUSION: The drug resistance levels, including MDR, found in this study are relatively high, likely related to the selected referral population. While worrisome, the numbers remained stable over the study period. These findings prompt a nationwide drug resistance survey, as well as continuous surveillance of all retreatment patients, which will provide more accurate results on countrywide drug resistance rates and ensure that MDR patients access appropriate second line treatment.

Quantitative microbial risk assessment related to urban wastewater and lagoon water reuse in Abidjan, Côte d'Ivoire.

We assessed the infection risks related to the use of wastewater in Abidjan, Côte d'Ivoire, by using quantitative microbial risk assessment (QMRA). Giardia lamblia and Escherichia coli were isolated and identified in wastewater samples from the canal and lagoon. The exposure assessment was conducted using a cross-sectional survey by questionnaire with 150 individuals who were in contact with the wastewater during their daily activities of swimming, fishing, washing, and collecting materials for reuse. Risk was characterised using the Monte Carlo simulation with 10,000 iterations. Results showed high contamination of water by G. lamblia and E. coli (12.8 CFU/100 mL to 2.97 × 10(4)CFU/100 mL and from 0 cyst/L to 18.5 cysts/L, respectively). Estimates of yearly average infection risks for E. coli (90.07-99.90%, assuming that 8% of E. coli were E. coli O157:H7) and G. lamblia (9.4-34.78%) were much higher than the acceptable risk (10(-4)). These results suggest the need for wastewater treatment plants, raising awareness in the population in contact with urban wastewater and lagoon water. Our study also showed that QMRA is appropriate to study health risks in settings with limited data and budget resources.

Healthy Aging: Comparative Analysis of Local Perception and Diet in Two Health Districts of Côte d'Ivoire and Japan.

Context: Good health and longevity depend on dynamic interactions between biological, social, psychological, and environmental factors. Aging is globally a big challenge, particularly with the demographic transition, including population growth, and an emerging burden to society. Knowledge, behavior, diet, and consumption of animal source food were related to aging and emerged as the key factors modulating healthy aging. Objective: The study was designed to understand the main healthy aging factors, such as knowledge, social network, and diet of elders, and to derive mutual learning from it for healthy aging. Methods: A qualitative approach has been applied to explore health-related knowledge, attitude, and diet of elders from Ebetsu (Japan) and Tiassalé (Côte d'Ivoire) health districts, using focus group discussions and comparative context analysis between high- and low-income countries. Results: The study shows that living longer is a common feature of people in Japan compared to Côte d'Ivoire, where the life expectancy is still low. Both groups of elders have social networks that support them, and both offer their gained experience to society. While Japanese elders depend on pension and insurance for income and medical treatments, Ivorians depend mostly on their children and social network in old age. The worries of elders differ between the two regions. In Ebetsu, elder members of the community are concerned about the future burden they pose for the younger generation if they develop ill-health, making them more resilient to aging. In Taabo, elders are considered to be culturally and socially useful to the society. Elders in Ebetsu pointed out that for healthy aging, education on diet at a younger age, physical activities, and access to basic social services are the key aspects. This was not observed in Taabo's context. Being inactive and dependent on others were described as the most worrying situations for elders in Ebetsu, as it is perceived to increase the risk of non-communicable diseases and anxiety. Elders in Ebetsu have good knowledge on what constitutes a healthy diet, and they believe that diversifying their diet, reducing portions, and substituting red meat with good animal and vegetable proteins are best eating practices to maintain good health. In Côte d'Ivoire, the diet is imbalanced and the whole family consumes the same meal made mainly with high-energy staples and little protein. However, it is observed in both societies that adopting a good diet is very expensive. Conclusion: The consciousness of aging is universal, but healthy aging varies according to the social systems, education, and knowledge on diet transition. Physical activities, protein-energy balance in diet, and social networks are the key for healthy aging in both contexts. The challenge is to find ways to increase knowledge regarding healthy aging and to strengthen the support system so that healthy aging becomes affordable.

[Socio-economic impact at the household level of the health consequences of toxic waste discharge in Abidjan in 2006]. / Impact socio-économique du déversement de déchets toxiques à Abidjan en 2006 à l'échelle des ménages.

In August 2006, toxic wastes were discharged in the district of Abidjan, causing important health consequences in many households in the area. In order to appreciate the socio-economic impact of the consequences of toxic waste discharge on the households and of the measures taken by the authorities to deal with this catastrophe, and to appreciate the spatial extent of the pollution, we undertook a multidisciplinary transversal investigation at the sites of discharge of oxic waste, from October the 19th to December the 8th, 2006, using a transect sampling methodology. This paper presents the results related to the socio-economic aspects of the survey while the environmental and epidemiological results are presented in two other published papers. The socioeconomics investigation, conducted using a questionnaire, concerned 809 households across the various sites of discharge of toxic waste. More than 62% of households had at least one person who had been affected by toxic waste (affected households). 62.47% of these households were in Cocody district (with 2 sites and 4 points of discharge), 30.14% in Abobo district (with 2 sites and 3 points) and 7.39% in Koumassi district (with 1 site and 1 point). To escape the bad smell and the nuisance, 22.75% of the 501 "affected" households had left their houses. To face the health consequences generated by the toxic waste, 30.54% of the "affected" households engaged expenses. Those were on average of 92 450 FCFA (€141), with a minimum of 1 000 FCFA (€1.5) and a maximum of 1500000 FCFA (€2.287), in spite of the advertisement of the exemption from payment treatment fees made by the government. The decision of destroying cultures and farms near the points of discharge of the toxic products in a radius of 200 meters, taken by the authorities, touched 2.22% of the households. For these households, it did nothing but worsen their state of poverty, since the zone of influence of the toxic waste went well beyond the 200 meters prescribed by the authorities as the limit of the operations of destruction.

Performance of Mali's biosafety level 3 laboratory in the external quality assessment in preparedness of laboratory accreditation and support to clinical trials.

Background: The external quality assessment (EQA) or external quality control is an evaluation conducted by a certified external organization to inquire about the quality of the results provided by a laboratory. The primary role of EQA is to verify the accuracy of laboratory results. This is essential in research because research data should be published in international peer-reviewed journals, and laboratory results must be repeatable. In 2007, the University Clinical Research Center (UCRC's) biosafety level 3 (BSL-3) laboratory joined the EQA program with the College of American Pathologists in acid-fast staining and culture and identification of mycobacteria as per laboratory accreditation preparedness. Thus, after 11 years of participation, the goal of our study was to evaluate the performance of our laboratory during the different interlaboratory surveys. Methods: We conducted a descriptive retrospective study to evaluate the results of UCRC mycobacteriology laboratory from surveys conducted during 2007 and 2017. Results: Of the 22 evaluations, the laboratory had satisfactory (100% of concordance results) in 18 (81.8%) and good (80% of concordance results) in 4 (18.2%). Overall, the laboratory was above the commended/accepted limits of 75%. Conclusion: So far, UCRC's BSL-3 performed well during the first 11 years of survey participation, and efforts should be deployed to maintain this high quality in the preparedness for laboratory accreditation and support to clinical trials.

Diabetes Mellitus among new tuberculosis patients in Bamako, Mali.

INTRODUCTION: Diabetes Mellitus (DM) increases worldwide, mostly in low- and middle-income countries. In Mali, the prevalence in the adult population is estimated at 1.8%, but tuberculosis (TB) patients are not systematically screened. The goal of our study was to determine the prevalence of DM among newly diagnosed TB patients. METHODS: We conducted a cross sectional study and a pilot prospective cohort study in four health centers in Bamako. All patients underwent fasting capillary-blood glucose (FCBG) test at Day 0, and repeated after one-week of TB treatment. Venous FBG test was performed for discrepancies between the two FCBG results. Thereafter, FCBG was performed for pilot study at month-2 (M2) and M5 of TB treatment. RESULTS: Two hundred and one patients were enrolled in this study. Impaired fasting blood glucose was identified in 17 (8.5%), of whom 11 (5.5%) had DM (VFBG >7 mmol/L). Among patients with DM, seven (63.6%) had successful TB treatment outcome, versus 142 (74.7%) of those without DM (p = 0.64), and (OR: 1.69, 95%CI 0.47-6.02). CONCLUSION: The prevalence of DM among TB patients in Bamako exceeds that of the general population and screening at TB diagnosis suffices to identify those with DM. Systematic screening of both diseases will allow better treatment.

Establishing Reference Ranges of Hematological Parameters from Malian Healthy Adults.

INTRODUCTION: Measurement of immuno-hematological parameters has been historically helpful in the diagnosis and treatment monitoring of many infectious diseases and cancers. However, these parameters have not yet been established in many developing countries where patient care strongly relies on such low-cost tests. This study describes the immuno-hematological parameter ranges for Malian healthy adults. METHODS: A cross sectional study was conducted from August 2004 to May 2013. We included 213 healthy volunteers (173 male and 40 female), aged between 18-59 years. Median, 2.5 and 97.5 percentile ranges for each immuno-hematological parameter are presented. RESULTS: In our study population, the hematological parameters' ranges were mostly different to the universal established ranges. We found in our population a Median white blood cell (WBC) count of 5200 cells/µL [3237.5-11900], Red Blood Cell (RBC) count of 4.94 10^6 [3.56-6.17], hemoglobin (Hb) of 14.2 g/dL [12.2-17.38], platelet count (Plt) of 275 10^3/µL [145.4-614.4], lymphocytes 2050/µL [1200-3800], neutrophils 2200/µL [1040-6220]; monocytes 200/µL [100-660]; eosinophils 131/µL [0-1026]; CD4 902 cells/µL [444-1669] and CD8 485 cells/µL [0-1272]. We found significant gender differences in RBC, Hb level and MPV. However, RBC and Hb were higher in males median values compared to females (median values) (p<0.001), whereas the Mean platelet volume lower values (MPV) in males than females (P<0.047). The hemoglobin level for some West African countries (Mali, Burkina Faso, Togo, and Nigeria) ranged from 13.5 to 15.1 g/dL for males and 12 to 13 g/dL for females. However in East and Southern Africa, the values were anywhere from 14.1 to 16.1 for males and 11.2 to 14.4 for females. CONCLUSION: Our data may help physicians to better define hematological abnormalities in patients. They may also be used to define new "normal hematological values" in Malian population or in the whole West African population.

Performance of microscopic observation drug susceptibility for the rapid diagnosis of tuberculosis and detection of drug resistance in Bamako, Mali.

OBJECTIVES: In Mali early detection and treatment of multidrug-resistant tuberculosis (MDR-TB) are still challenging due to the cost, time and/or complexity associated with regular tests. Microscopic Observation Drug Susceptibility (MODS) is a low-cost assay validated by WHO in 2010. It is a liquid-culture-based assay to detect the 'cording' characteristic of Mycobacterium tuberculosis complex and to assess susceptibility to both isoniazid and rifampicin defining multidrug-resistant tuberculosis (MDR-TB). In this study we aimed to evaluate the performance of MODS as diagnostic tool compared with a validated method-Mycobacteria Growth Indicator Tube/Antimicrobial Susceptibility Testing/Streptomycin, Isoniazid, Rifampicin and Ethambutol (MGIT/AST/SIRE). METHODS AND RESULTS: Between January 2010 and October 2015 we included 98 patients with suspected TB in an observational cohort study. The sensitivity and specificity of MODS assay for detecting TB were respectively 94.12% and 85.71% compared with the reference MGIT/7H11 culture, with a Cohen κ coefficient of 0.78 (95% CI 0.517-1.043). The median time to culture positivity for MODS assay and MGIT (plus interquartile range, IQR) was respectively 8 days (IQR 5-11) and 6 days (IQR 5-6). In detecting patients with MDR-TB, the sensitivity and specificity of MODS assay were respectively 100% and 95.92%. The positive predictive value and negative predictive value were, respectively, 66.7% and 100%. The median turnaround times for obtaining MDR-TB results using MODS assay and MGIT/AST/SIRE was respectively 9 days and 35 days. Hence, the MODS assay rapidly identifies MDR-TB in Mali compared with the MGIT/AST/SIRE. CONCLUSION: As an easy, simple, fast and affordable method, the MODS assay could significantly improve the management of TB.

[Aneurismal bone cyst of clavicle: A case report]. / Kyste anévrismal de la clavicule: à propos d'un cas.

Aneurismal bone cyst is a rare tumour. The authors report an exceptional case in its clavicle localization. They review the diagnosis circumstances and treatment modalities of this pathology. The occurrence of the cyst is linked to vascular homodynamic disturbance and its discovery in a post-traumatic context has been assessed by the histology exam. Although numerous therapeutic trials, radical removal versus conservatory methods avoid relapse. Finally, resection of the clavicle leading to few functional consequences should be recommended for the cure of evoluted aneurismal bone cyst.

Acute renal failure following percutaneous transhepatic cholangiography. A retrospective study.

We analyzed retrospectively the incidence of potential nephrotoxic effects of radiographic contrast material associated with percutaneous transhepatic cholangiography and percutaneous biliary drainage. Of 72 consecutive patients who underwent these procedures, three developed acute renal insufficiency (defined as a rise in the serum creatinine concentration of greater than 2 mg/dL [greater than 180 mumol/L]) following administration of contrast medium. In two patients, abdominal roentgenograms taken after the procedure showed persistently opaque kidneys, indicating that contrast material had gained access to the circulation. Percutaneous transhepatic cholangiography and percutaneous biliary drainage may be associated with nephrotoxic effects of radiographic contrast material, and patients with recognized risk factors may benefit from prophylactic hydration regimens as recommended for other procedures.

Molecular biology of natriuretic peptides and nitric oxide synthases.

Natriuretic peptides and nitric oxide play important roles in cardiovascular and renal physiology and disease. The natriuretic peptides - atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide - comprise a family of proteins that participate in the integrated control of intravascular volume and arterial blood pressure. The natriuretic peptides differentially bind distinct classes of receptors that signal through different mechanisms. Membrane-bound, guanylyl cyclase-coupled natriuretic peptide receptors (A- and B-types) mediate natriuretic peptide effects through the production of 3',5'-cyclic guanosine monophosphate (cGMP). C-Type natriuretic peptide receptors, which lack the guanylyl cyclase domain, alter target cell function through G(i) protein-coupled inhibition of membrane adenylyl cyclase activity, and also serve to clear circulating natriuretic peptides. The expression of the natriuretic peptides and their receptors are subject to complex controls. Similar structural and regulatory diversity exists for the nitric oxide synthases. The three nitric oxide synthase genes are regulated by a variety of mechanisms ranging from alternative splicing and alternative promoter usage to complex post-translational controls. This review highlights the molecular diversity of the natriuretic peptides and nitric oxide synthases and explores recent insights into their regulation.

Molecular approaches to renal physiology and therapeutics.

The recent development of methods to transfer, mutate, or ablate genes in vivo has provided renal investigators and physicians with powerful tools to explore normal renal physiology, the pathophysiological basis of renal disease, and potential therapeutic interventions. The use of transgenic and knockout mice to produce gain-of-function and loss-of-function mutations, and to create animal models of human hereditary renal diseases, permits unprecedented versatility and power of experimental design. Conditional and inducible gene targeting methods to control the temporal and spatial expression of transgenes offer considerable promise in studying the impact of normal and disease genes in the kidney. In vivo gene transfer of encoding DNAs, antisense DNA and RNA, and cis-element decoys allows manipulation of specific genes in somatic cells. Liposome-mediated, virally mediated, and ex vivo transduced renal cells represent novel approaches to facilitate in vivo gene transfer to the kidney.

How will gene therapy apply to the kidney in the 21st century?

Nephrology is entering the age of genomics-based drug discovery and development. Once only a theoretical objective, gene therapy is now being tested in various diseases. New and substantially improved vector systems and related technologies are undergoing development, many have shown promise in animal studies, and some are now being used in clinical trials. Recent advances in the molecular basis for renal diseases, organ transplant rejection, and hypertension have led to preclinical tests of gene therapeutic approaches. The most impressive of these strategies will likely soon be studied in the clinic. This review details recent advances in gene therapy technology and highlights potential novel applications of gene therapy in the treatment of renal diseases and hypertension. While the manufacture and widespread use of gene therapy products as conventional pharmaceuticals for renal diseases and hypertension may seem to be a goal for the remote future, much of the needed genetic information, technology, and intellectual resources are rapidly becoming available.

Localization and regulation of nitric oxide synthase isoforms in the kidney.

Nitric oxide synthases (NOS), which comprise a multi-gene family, play important roles in a variety of physiological and pathophysiological processes in the kidney. The three major NOS isoforms are expressed in a cell type--specific manner and are subject to complex and distinct control mechanisms. Although knowledge about the intrarenal distribution and regulation of the major NOS isoforms has been expanding, recent advances in the molecular details of the structure, function, and regulation of the NOS genes and the enzymes they encode have added considerable complexity to the effort. Molecular biological studies have identified alternative splice variants of NOS1 and NOS2 that appear to be subject to unique regulation and may encode functionally distinct proteins. The renal distribution of these new variants has yet to be explored in detail. In addition, newly discovered transcriptional and posttranscriptional control mechanisms, including alternative promoter usage, protein-protein interactions, and phosphorylation events, for the three major NOS isoforms await characterization in renal cells. This review highlights the current state of knowledge about the distribution and regulation of the NOS isoforms in the kidney, and identifies new opportunities for further renal investigation.

Post-injury multiple organ failure: the role of the gut.

Despite intensive investigation, the pathogenesis of post-injury multiple organ failure (MOF) remains elusive. Laboratory and clinical research strongly suggests that the gastrointestinal tract (i.e., the gut) plays a pivotal pathogenic role. Since its inception in 1988, the Trauma Research Center (TRC) at the University of Texas-Houston Medical School (UTHMS) has focused its efforts on elucidating the role of the gut in post-injury MOF. On the basis of our observations and those of others, we believe that 1) shock with resulting gut hypoperfusion is an important inciting event, 2) the reperfused gut is a source of proinflammatory mediators that can amplify the early systemic inflammatory response syndrome (SIRS) and thus contribute to early MOF, 3) early gut hypoperfusion causes an ileus in both the stomach and small bowel that sets the stage for progressive gut dysfunction so that the proximal gut becomes a reservoir for pathogens and toxins that contribute to late sepsis-associated MOF, and 4) late infections cause further worsening of this gut dysfunction. Thus, the gut can be both an instigator and a victim of MOF. The purpose of this article is to provide the rationale behind these beliefs and to provide a brief overview of the ongoing research projects in the TRC at UTHMS.

Macrophages and chronic renal allograft nephropathy.

In a previous study we demonstrated that macrophage infiltrates stained for thromboxane A synthase (TxAS) correlated inversely with renal function six months after biopsy. We propose that macrophage based inflammation is a cofactor leading to chronic allograft nephropathy. For this study we compared four indices of renal allograft nephropathy with renal survival. The Banff Score of Inflammatory Changes (BSI) is an index of acute inflammation. The Banff Chronic Index (BCI) and Chronic Allograft Damage Index (CADI) are indexes of chronic disease. The Macrophage Index (MI) is the same as the BSI applied only to macrophages. These indices were determined on renal allograft biopsies obtained because of delayed graft function within the first week of transplantation, and for increasing plasma creatinine levels after stable function. All four indices predicted renal survival in the post-biopsy interval. MI predicted renal survival for the entire transplant period. In addition, the presence of TxAS transcripts in the renal allografts was determined using a reverse transcription-polymerase chain reaction-based assay. This confirms previous observations of TxAS in the grafts. This study supports the hypothesis that macrophage derived inflammation is a cofactor for chronic allograft nephropathy.

Potential source of human exposure to Mycobacterium bovis in Burkina Faso, in the context of the HIV epidemic.

OBJECTIVE: To identify potential sources of human Mycobacterium bovis infection in Bobo-Dioulasso, Burkina Faso. METHODS: A tuberculin survey among 174 cattle was performed. Mycobacteriologic identification in 64 samples of pooled milk, and in 199 tissue samples collected from the slaughterhouse of Bobo-Dioulasso, Burkina Faso, was also done. We retrospectively analyzed the distribution of tuberculosis (TB) cases on 1140 clinical records according to professional occupation and to ethnic group. The frequency of pulmonary and extrapulmonary TB was related to potential exposure and route of transmission of M. bovis from animals. RESULTS: Out of six herds (total 170 bovines), only one was free of any positive tuberculin test. Among 199 bovines which had been slaughtered over four consecutive nights, 38 (19%) had morphologic lesions suggestive of TB; 17 (45%) of those were positive for acid-fast bacilli by microscopic examination on one of their lesions, and 20 samples (53%) presented a positive culture for a pathogenic mycobacterium, including M. bovis and M. tuberculosis. In the retrospective analysis, Peuls more frequently had a pulmonary form of disease. This may be related to the route of transmission. CONCLUSIONS: Attention has to be paid to human TB of bovine origin in Burkina Faso. The identification of M. tuberculosis in milk and in tissue samples raises the question of the transmission of TB from humans to cattle.

Acute renal failure produced by combining cyclosporine and brief renal ischemia in the Munich Wistar rat.

To evaluate the combined effects of a brief ischemic insult and cyclosporine, four groups of male Munich Wistar rats were given: a) parenteral cyclosporine (60 mg/kg i.p.) for 4 days following 20 minutes of bilateral renal ischemia, b) the castor oil cyclosporine vehicle in a comparable volume and the same ischemic insult, c) saline in the same volume and ischemia, or d) saline and sham surgery. The cyclosporine animals ate and drank poorly, and therefore the other groups were pair-fed and watered with them. The cyclosporine-ischemia group developed significant renal failure. The other groups exhibited only a mild rise in blood urea nitrogen. Tubular vacuolization was a prominent feature in the cyclosporine and vehicle groups, but not in the saline groups. Vacuolization was correlated with severity of renal impairment. Lipid stains showed that many of the vacuoles contained lipid. Eosinophilic cytoplasmic inclusions were seen only in the cyclosporine or vehicle- (castor oil) treated animals. These findings emphasize the probable functional importance of tubular lesions in cyclosporine-induced acute renal failure, and suggest that the castor oil vehicle of parenteral cyclosporine may have renal effects of its own.