Impact of Urinary Tract Infections in Kidney Transplant Recipients: A 4-Year Single-Center Experience.

BACKGROUND: Urinary tract infection (UTI) is the most frequent bacterial infection in kidney transplant recipients (KTRs), yet little is known about the impact of severe UTIs. We aimed to explore the burden of severe UTIs post renal transplant on both graft function and health care resources. METHODS: We conducted a retrospective review of KTRs with severe UTI warranting hospital admission at our center between January 1, 2012, and December 31, 2015. RESULTS: We identified 198 UTI-related hospital admissions in 83 KTRs representing 7.4% of transplant admissions; 44.6% were men and 45 (54.2%) had recurrent admissions. The most commonly isolated pathogens were E coli (47.5%) and Klebsiella (16.2%): extended-spectrum ß-lactamase-producing organisms were detected in 31.3% of Klebsiella and in 25.5% of E coli. During UTI, the median serum creatinine increased from 126 to 196.5 µmol/L, then decreased to 149 and 161 µmol/L 3 months and 1 year after UTI, respectively. Acute kidney injury complicated 40.9% of UTIs (23.7% stage 1, 12.1% stage 2, 5.1% stage 3), with no significant difference between single and recurrent admission groups (χ2 = 0.36, P = .5). The 1-year mortality and death-censored graft loss were 1.2% and 3.6%, respectively. The median length of hospital stay was 4 days (286 days per annum) and the estimated annual cost was £87,665 ($117,347). CONCLUSIONS: UTI post renal transplant represents a substantial burden on health care resources and patient morbidity in terms of acute kidney injury and deterioration in graft function. Thus, applying proper preventative and management strategies is paramount.

Improving outcomes in patients with Acute Kidney Injury: the impact of hospital based automated AKI alerts.

BACKGROUND: Acute kidney injury (AKI) is a significant cause of morbidity and mortality. Early identification may improve the outcome and in 2012 our hospital introduced an automated AKI alert system for early detection and management of AKI. OBJECTIVES: Using an automated AKI alert system we analysed whether early review and intervention by the Critical Care and Outreach (CCOT) team improved patient outcomes in AKI and whether serum bicarbonate was useful in predicting outcomes in patients with AKI. METHODS: In a retrospective analysis we identified patients who triggered an AKI alert from 20 April 2012 to 20 September 2013 and collected data on mortality, length of stay, need for intensive care admission and renal replacement therapy (RRT). RESULTS: 994 AKI alerts were generated and analysed. Patients with bicarbonate outside the normal range had significantly higher mortality. Bicarbonate <22 mmol/L was associated with a mortality of 25.7% (49/191) compared with 16.9% (39/231) when 22-29 mmol/L (p=0.047, χ(2)). Those patients reviewed ≥1 day after AKI alert by CCOT compared with those seen on the day of the alert had a 2.4 times increase in mortality and were 7 times more likely to require RRT acutely. CONCLUSIONS: Electronically identified AKI alerts identify patients at high risk of morbidity and mortality. In this group AKI alerts preceded CCOT review by a mean of 2 days. This represents a window for supportive interventions, which may explain improved outcomes in those reviewed earlier. The addition of serum bicarbonate offers a further method of risk stratifying patients at greater risk of death.

Managing latent tuberculosis in UK renal transplant units: how does practice compare with published guidance?

Renal transplantation significantly increases the risk of active tuberculosis (TB) in individuals with latent TB infection (LTBI). UK transplant recipients are often born in TB endemic areas. Using a self-completed questionnaire, we evaluated how the 23 UK renal transplant units' LTBI management compared with recently published national guidance. Three-quarters had a management protocol, but only one-third of these were in line with the guidance. Interferon-gamma release assays were rarely used to confirm LTBI. Almost half of the units prescribed LTBI treatment at the wrong dose or duration. We conclude that units should develop local protocols in line with evidence-based guidance. This must be in a format that enables national audit programmes and quality improvement to be routinely performed.

A prospective study comparing contamination rates between a novel mid-stream urine collection device (Peezy) and a standard method in renal patients.

INTRODUCTION: It is imperative that laboratories receive uncontaminated urine samples to avoid giving false-positive results and reduce antimicrobial use. AIM: The aim of the study was to investigate a novel urine collection device (Peezy) in a renal outpatient clinic to determine whether it reduced contamination of urine samples. METHODS: The novel device was used in 420 renal transplant recipients and the results were compared with 424 matched historical controls, who used the standard method of urine collection. High epithelial cell counts on microscopy and mixed urine cultures were used to identify contaminated samples. RESULTS: Peezy increased the rates of both epithelial cells and mixed growths in the urine samples when compared with the historical controls. CONCLUSIONS: Further randomised studies in other more generalisable populations need to be performed.

Protein composition of endurance trained human skeletal muscle.

Evidence suggests that myofibers from endurance trained skeletal muscle display unique contractile parameters. However, the underlying mechanisms remain unclear. To further elucidate the influence of endurance training on myofiber contractile function, we examined factors that may impact myofilament interactions (i. e., water content, concentration of specific protein fractions, actin and myosin content) or directly modulate myosin heavy chain (MHC) function (i. e., myosin light chain (MLC) composition) in muscle biopsy samples from highly-trained competitive (RUN) and recreational (REC) runners. Muscle water content was lower (P<0.05) in RUN (73±1%) compared to REC (75±1%) and total muscle and myofibrillar protein concentration was higher (P<0.05) in RUN, which may indicate differences in myofilament spacing. Content of the primary contractile proteins, myosin (0.99±0.08 and 1.01±0.07 AU) and actin (1.33±0.09 and 1.27±0.09 AU) in addition to the myosin to actin ratio (0.75±0.04 and 0.80±0.06 AU) was not different between REC and RUN, respectively, when expressed relative to the amount of myofibrillar protein. At the single-fiber level, slow-twitch MHC I myofibers from RUN contained less (P<0.05) MLC 1 and greater (P<0.05) amounts of MLC 3 than REC, while MLC composition was similar in fast-twitch MHC IIa myofibers between REC and RUN. These data suggest that the distinctive myofiber contractile profile in highly-trained runners may be partially explained by differences in the content of the primary contractile proteins and provides unique insight into the modulation of contractile function with extreme loading -patterns.

Influence of aerobic cycle exercise training on patellar tendon cross-sectional area in older women.

Nine to 12 weeks of resistance exercise training in young individuals induces quadriceps muscle (∼6%) and region-specific patellar tendon (4-6%) hypertrophy. However, 12 weeks of resistance exercise training (∼1 h total exercise time) in older individuals (60-78 years) induces quadriceps muscle hypertrophy (9%) without impacting patellar tendon size. The current study examined if a different loading paradigm using cycle exercise would promote patellar tendon hypertrophy or alter the internal tendon properties, measured with magnetic resonance imaging signal intensity, in older individuals. Nine women (70 ± 2 years) completed 12 weeks of aerobic upright cycle exercise training (∼28 h total exercise time). Aerobic exercise training increased (P < 0.05) quadriceps muscle size (11 ± 2%) and VO2max (30 ± 9%). Mean patellar tendon cross-sectional area (CSA) (2 ± 1%) and signal intensity (-1 ± 2%) were unchanged (P > 0.05) over the 12 weeks of training. Region-specific CSA was unchanged (P > 0.05) at the proximal (-1 ± 3%) and mid regions (2 ± 2%) of the tendon but tended (P = 0.069) to increase at the distal region (5 ± 3%). Region-specific signal intensity differed along the tendon but was unchanged (P > 0.05) with training. Although more studies are needed, exercise-induced patellar tendon hypertrophy, compared with skeletal muscle, appears to be attenuated in older individuals, while the loading pattern associated with aerobic exercise seems to have more impact than resistance exercise in promoting patellar tendon hypertrophy.

Cytomegalovirus replication kinetics in solid organ transplant recipients managed by preemptive therapy.

After allotransplantation, cytomegalovirus (CMV) may be transmitted from the donor organ, giving rise to primary infection in a CMV negative recipient or reinfection in one who is CMV positive. In addition, latent CMV may reactivate in a CMV positive recipient. In this study, serial blood samples from 689 kidney or liver transplant recipients were tested for CMV DNA by quantitative PCR. CMV was managed using preemptive antiviral therapy and no patient received antiviral prophylaxis. Dynamic and quantitative measures of viremia and treatment were assessed. Median peak viral load, duration of viremia and duration of treatment were highest during primary infection, followed by reinfection then reactivation. In patients who experienced a second episode of viremia, the viral replication rate was significantly slower than in the first episode. Our data provide a clear demonstration of the immune control of CMV in immunosuppressed patients and emphasize the effectiveness of the preemptive approach for prevention of CMV syndrome and end organ disease. Overall, our findings provide quantitative biomarkers which can be used in pharmacodynamic assessments of the ability of novel CMV vaccines or antiviral drugs to reduce or even interrupt such transmission.

Fulminant hepatitis following primary herpes simplex virus infection.

Fulminant hepatic failure (FHF) is a rare but well-recognized complication of primary herpes simplex virus (HSV) infection in immunocompromised patients. Here, we report two cases of acute hepatitis and FHF secondary to primary HSV type 1 infection following renal transplantation in the absence of any mucocutaneous manifestation. High levels of HSV type-1 DNA were detected in the blood. Both patients were seronegative for HSV 1 and HSV 2 immunoglobulin G (IgG) before transplantation, whereas the donor of patient 1 was HSV 1 IgG-positive but had no viremia and the donor of patient 2 was HSV-seronegative. Patient 1 recovered with acyclovir and immunoglobulin whereas patient 2 did not respond and succumbed to death. HSV-seronegative patients are potentially at risk of developing severe primary HSV disease following transplantation, particularly in the absence of routine anti-viral prophylaxis. HSV infection should always be excluded in transplant patients with hepatic dysfunction.

The influence of acute resistance training and body composition on coagulation and fibrinolytic activity in low-risk women.

This study explored the coagulation and fibrinolytic responses to acute resistance training in young women and aimed to determine the influence of body composition on these variables. Healthy young women aged 23+/-5 yrs participated in the study. Body fat and fat distribution were assessed using DEXA. Each subject performed 6 sets of 10 leg extension repetitions at an intensity associated with 70% of 1-repetition maximum. Markers of coagulation (TAT), fibrinolytic stimulation (tPA) and inhibition (PAI-1) were assessed before and immediately after exercise. tPA activity increased in response to acute resistance exercise (p<0.05), however, there was no change in TAT or PAI-1 activity. Percent body fat was negatively correlated to the tPA response to exercise (r=-0.44), and positively related to PAI-1 at baseline (r=0.47) and post-exercise (r=0.47), and to post-exercise TAT (r=0.44). Android/gynoid fat ratio was negatively related to post-exercise tPA (r=-0.43), positively related to PAI-1 at baseline (r=0.61) and post-exercise (r=0.62) and to post-exercise TAT (r=0.43). These physiological responses suggest women with elevated body fat may be at increased risk of an adverse thrombosis-related event both at rest and during exercise compared to leaner women.

A new method to study in vivo protein synthesis in slow- and fast-twitch muscle fibers and initial measurements in humans.

The aim of this study was to develop an approach to directly assess protein fractional synthesis rate (FSR) in isolated human muscle fibers in a fiber type-specific fashion. Individual muscle fibers were isolated from biopsies of the vastus lateralis (VL) and soleus (SOL) obtained from eight young men during a primed, continuous infusion of [5,5,5-(2)H3]leucine performed under basal conditions. To determine mixed protein FSR, a portion of each fiber was used to identify fiber type, fibers of the same type were pooled, and the [5,5,5-(2)H3]leucine enrichment was determined via GC-MS. Processing isolated slow-twitch [myosin heavy chain (MHC) I] and fast-twitch (MHC IIa) fibers for mixed protein bound [5,5,5-(2)H3]leucine enrichment yielded mass ion chromatographic peaks that were similar in shape, abundance, and measurement reliability as tissue homogenates. In the VL, MHC I fibers exhibited a 33% faster (P<0.05) mixed protein FSR compared with MHC IIa fibers (0.068+/-0.006 vs. 0.051+/-0.003%/h). MHC I fibers from the SOL (0.060+/-0.005%/h) and MHC I fibers from the VL displayed similar (P>0.05) mixed protein FSR. Feasibility of processing isolated human muscle fibers for analysis of myofibrillar protein [5,5,5-(2)H3]leucine enrichment was also confirmed in non-fiber-typed pooled fibers from the VL. These methods can be applied to the study of fiber type-specific responses in human skeletal muscle. The need for this level of investigation is underscored by the different contributions of each fiber type to whole muscle function and the numerous distinct adaptive functional and metabolic changes in MHC I and MHC II fibers originating from the same muscle.

Resistance exercise reduces muscular substrates in women.

The purpose of this investigation was to examine the influence of an acute bout of resistance exercise (RE) on intramuscular triglyceride (IMTG) and muscle glycogen concentrations and intracellular signaling in women with high body fat content. Six overweight women with a high percent body fat (age 29+/-3 yr; BMI 28+/-3 kg/m(2), body fat 38+/-4%) performed 6 sets of 10 repetitions of knee extension exercise at 70% 1RM. Muscle biopsies were obtained from the vastus lateralis before, 1 min after (POST1), and 2 h after (POST2) exercise. Acute RE reduced (p<0.05) IMTG content approximately 40% at POST1 and POST2 (75+/-5; 45+/-6; 50+/-10 mmol/kg/dry wt). Muscle glycogen was also reduced (p<0.05) approximately 25% at POST1 and remained lower at POST2 (317+/-14; 241+/-30; 235+/-26 mmol/kg/dry wt). ERK1/2, SAPK/JNK, and p38 phosphorylation were increased (p<0.05) approximately 2-3-fold at POST1 and ERK1/2 remained elevated and POST2 whereas SAPK/JNK and p38 returned to basal levels. AMPKalpha phosphorylation was unchanged in response to RE. These results show that both IMTG and muscle glycogen stores serve as an important energy source during RE in overweight women and the MAP kinase signaling response to RE is not compromised by high levels of body fat.

Resistance exercise and cyclooxygenase (COX) expression in human skeletal muscle: implications for COX-inhibiting drugs and protein synthesis.

We have shown that ibuprofen and acetaminophen block cyclooxygenase (COX) synthesis of prostaglandin PGF(2alpha) and the muscle protein synthesis increase following resistance exercise. Confusingly, these two drugs are purported to work through different mechanisms, with acetaminophen apparently unable to block COX and ibuprofen able to nonspecifically block COX-1 and COX-2. A recently discovered intron-retaining COX, now known to have three variants, has been shown to be sensitive to both drugs. We measured the expression patterns and levels of the intron 1-retaining COX-1 variants (-1b1, -1b2, and -1b3), COX-1, and COX-2 at rest and following resistance exercise to help elucidate the COX through which PGF(2alpha), ibuprofen, and acetaminophen regulate muscle protein synthesis. Skeletal muscle biopsy samples were taken from 16 individuals (8M, 8F) before, 4, and 24 h after a bout of resistance exercise and analyzed using real-time RT-PCR. Relatively few individuals expressed the intron 1-retaining COX-1b variants (COX-1b1, -1b2, and -1b3) at any time point, and when expressed, these variants were in very low abundance. COX-1 was the most abundant COX mRNA before exercise and remained unchanged (P > 0.05) following exercise. COX-2 was not expressed before exercise, but increased significantly (P < 0.05) at 4 and 24 h after exercise. The inconsistent and low levels of expression of the intron 1-retaining COX-1 variants suggest that these variants are not likely responsible for the inhibition of PGF(2alpha) production and skeletal muscle protein synthesis after resistance exercise by ibuprofen and acetaminophen. Skeletal muscle-specific inhibition of COX-1 or COX-2 by these drugs should be considered.

Effects of 84-days of bedrest and resistance training on single muscle fibre myosin heavy chain distribution in human vastus lateralis and soleus muscles.

AIM: This investigation determined the effects of 84 days of bedrest on the composition of myosin heavy chain (MHC) in single skeletal muscle fibres with and without a resistance-training countermeasure programme. METHODS: Muscle biopsies were obtained from the m. vastus lateralis (VL) and m. soleus (SOL) before and after 84 days of bedrest. While control (BR) subjects (VL n = 9; SOL n = 3) refrained from exercise, BRE subjects (VL n = 8; SOL n = 3) performed knee extensor and plantar flexor resistance exercise every third day. Approximately 110 fibres per sample were analysed for MHC composition using SDS-PAGE. RESULTS: BR-VL had 16 and 14% decreases (P < 0.05) in MHC I and IIa fibres, respectively. There were 10% increases (P < 0.05) in MHC I/IIa, IIa/IIx, I/IIa/IIx, and a approximately 30% increase (P < 0.05) in total hybrid fibres. BRE-VL showed a 15% reduction (P < 0.05) in MHC I fibres, no change in MHC IIa fibres, and a 13% increase (P < 0.05) in total hybrids. BR-SOL had a 19% decrease (P < 0.05) in MHC I fibres with a 22% increase in total hybrids. BRE-SOL showed no change in MHC composition across all fibre types. CONCLUSION: These data suggest that the exercise countermeasures programme prevented MHC shifts in the SOL and mitigated MHC shifts in the VL. Furthermore, in the VL it appears that the resistance training programme employed in this investigation during bedrest, emphasized the use of MHC IIa phenotype muscle fibres.

Single muscle fiber contractile properties during a competitive season in male runners.

The purpose of this investigation was to examine the contractile properties of individual myofibers in response to periodized training periods throughout a collegiate cross-country season in male runners. Muscle biopsies of the gastrocnemius were taken after a summer base training phase (T1), an 8-wk intense training period (T2), and a 4-wk taper phase (T3). Five runners (n = 5; age = 20 +/- 1 yr; wt = 65 +/- 4 kg; ht = 178 +/- 3 cm) completed all three time points. A total of 328 individual muscle fibers [myosin heavy chain (MHC) I = 66%; MHC IIa = 33%; hybrids = 1%] were isolated and studied at 15 degrees C for their contractile properties. Diameter of MHC I fibers was 3% smaller (P < 0.05) at T2 compared with T1 and an additional 4% smaller (P < 0.05) after the taper. Cell size was unaltered in the MHC IIa fibers. MHC I and IIa fiber strength increased 18 and 11% (P < 0.05), respectively, from T1 to T2. MHC I fibers produced 9% less force (P < 0.05) after the taper, whereas MHC IIa fibers were 9% stronger (P < 0.05). Specific tension increased 38 and 26% (P < 0.05) for MHC I and IIa fibers, respectively, from T1 to T2 and was unchanged with the taper. Maximal shortening velocity (Vo) of the MHC I fibers decreased 23% (P < 0.05) from T1 to T2 and 17% (P < 0.05) from T2 to T3, whereas MHC IIa Vo was unchanged. MHC I peak power decreased 20% (P < 0.05) from T1 to T2 and 25% (P < 0.05) from T2 to T3, whereas MHC IIa peak power was unchanged. Power corrected for cell size decreased 15% (P < 0.05) from T2 to T3 and was 24% (P < 0.05) lower at T3 compared with T1 for the MHC I fibers only. These data suggest that changes in run training alter myocellular physiology via decreases in fiber size, Vo, and power of MHC I fibers and through increases in force per cross-sectional area of slow- and fast-twitch muscle fibers.

Mitogen-activated protein kinase (MAPK) pathway activation: effects of age and acute exercise on human skeletal muscle.

The purpose of this investigation was to examine the activation (phosphorylation) and total protein content of MAPK signalling cascade proteins (ERK 1/2, p90RSK, Mnk 1, eIF4E, p38 MAPK, JNK/SAPK, MKP 1) at rest and following exercise, in sedentary young and old men. Eight young (22 +/- 1 years; YM) and eight old (79 +/- 3 years; OM) men underwent a resting muscle biopsy of the vastus lateralis; they then performed a knee extensor resistance exercise session (29 contractions at approximately 70 % of max), followed by a post-exercise biopsy. Western immunoblot analysis demonstrated that the OM had higher resting phosphorylation of ERK 1/2, p90RSK, Mnk 1, p38 MAPK and JNK/SAPK proteins versus YM (P < 0.05). The resistance exercise bout caused an increase in phosphorylation of the ERK 1/2, p90RSK and Mnk 1 proteins (P < 0.05) in the YM. Conversely, the OM had a decrease in ERK 1/2, p90RSK, Mnk 1, p38 MAPK and JNK/SAPK phosphorylation (P < 0.05) after the exercise bout. Neither group showed a change in eIF4E phosphorylation. The total amount of protein expression of the MAPK signalling proteins was not different between the YM and OM, except that there was a higher (P < 0.05) MKP 1 protein content in the OM. This investigation is the first to provide evidence that MAPK proteins are differentially activated at rest and in response to a bout of resistance exercise in skeletal muscle of young and old men. These findings may have implications for other processes (e.g. transcription and translation) involved in skeletal muscle type and growth, when examining the changes occurring with ageing muscle before and after resistance exercise/training.

Myosin heavy chain composition of single muscle fibers in male distance runners.

The purpose of this study was to characterize the myosin heavy chain (MHC) composition of single muscle fibers from the gastrocnemius of male collegiate distance (DIST; n = 7), middle-distance (MID; n = 6), and recreational runners (REC; n = 6). Additionally, mATPase histochemistry was used to serve as a comparison to previous studies and the single fiber MHC technique. SDS-PAGE of single muscle fibers revealed a higher proportion of MHC I in DIST compared to MID and REC (74.9 +/- 4.3 vs 54.4 +/- 2.8 vs 56.2 +/- 2.9 %, respectively; p < 0.05), less MHC IIa/IIx in DIST compared to MID and REC (0.0 +/- 0.0 vs 6.0 +/- 2.4 vs 15.9 +/- 4.2 %, respectively; p < 0.05), and more total hybrids (I/IIa+IIa/IIx+I/IIa/IIx) in REC than both run groups, DIST and MID (23.0 +/- 3.3 vs 6.2 +/- 1.1 vs 13.2 +/- 2.6 %, respectively; p < 0.05). ATPase histochemistry (pH 4.54) revealed a higher percentage of type I fibers in DIST compared to MID and REC (71.1 +/- 3.1 vs 56.3 +/- 2.5 vs 59.8 +/- 2.3 %, respectively; p < 0.05), a higher percentage of type IIa in MID compared to DIST and REC (43.3 +/- 2.7 vs 28.5 +/- 3.1 vs. 30.2 +/- 3.1 %, p < 0.05), and a higher distribution of type IIb in REC than both run groups (10.0 +/- 2.7 vs 0.4 +/- 0.2 vs 0.4 +/- 0.2 %, p < 0.05). These results suggest that distance running leads to an increase in MHC I expression, training for mid-distance events leads to a prevalence of MHC IIa, and run training leads to a decrease in hybrid fibers.

Determinants of erythropoietin release in response to short-term hypobaric hypoxia.

We measured blood erythropoietin (EPO) concentration, arterial O(2) saturation (Sa(O(2))), and urine PO(2) in 48 subjects (32 men and 16 women) at sea level and after 6 and 24 h at simulated altitudes of 1,780, 2,085, 2,454, and 2,800 m. Renal blood flow (Doppler) and Hb were determined at sea level and after 6 h at each altitude (n = 24) to calculate renal O(2) delivery. EPO increased significantly after 6 h at all altitudes and continued to increase after 24 h at 2,454 and 2,800 m, although not at 1,780 or 2,085 m. The increase in EPO varied markedly among individuals, ranging from -41 to 400% after 24 h at 2,800 m. Similar to EPO, urine PO(2) decreased after 6 h at all altitudes and returned to baseline by 24 h at the two lowest altitudes but remained decreased at the two highest altitudes. Urine PO(2) was closely related to EPO via a curvilinear relationship (r(2) = 0.99), although also with prominent individual variability. Renal blood flow remained unchanged at all altitudes. Sa(O(2)) decreased slightly after 6 h at the lowest altitudes but decreased more prominently at the highest altitudes. There were only modest, albeit statistically significant, relationships between EPO and Sa(O(2)) (r = 0.41, P < 0.05) and no significant relationship with renal O(2) delivery. These data suggest that 1) the altitude-induced increase in EPO is "dose" dependent: altitudes > or =2,100-2,500 m appear to be a threshold for stimulating sustained EPO release in most subjects; 2) short-term acclimatization may restore renal tissue oxygenation and restrain the rise in EPO at the lowest altitudes; and 3) there is marked individual variability in the erythropoietic response to altitude that is only partially explained by "upstream" physiological factors such as those reflecting O(2) delivery to EPO-producing tissues.

The role of cytokines in immunological tolerance: potential for therapy.

Current immunosuppression protocols, although often effective, are nonspecific and therefore hazardous. Consequently, immunological tolerance that is antigen specific and does not globally depress the patient's immune system has become one of the Holy Grails of immunology. Since the discovery that cytokines have immunomodulatory effects, extensive research has investigated the potential of these molecules to induce and maintain specific immunological tolerance in the context of transplantation, allergy and autoimmunity. In this article, we review the possible mechanisms by which cytokines can modulate the immune response and the animal models that frequently confound the theory that a single cytokine, or group of cytokines, can induce tolerance in a predictable manner. Finally, we discuss the role of cytokines at a paracrine level, particularly in the context of inducing and maintaining antigen-specific, regulatory T cells with the clinical potential to suppress specific immune responses.

Cognitive impairment in patients with renal failure is associated with multiple-infarct dementia.

PURPOSE: Patients undergoing long-term renal replacement therapy (such as dialysis) have an increased risk for significant cognitive impairment, which may result in memory problems and subsequently missed attendance at dialysis. The aim of this study was to try to identify any abnormalities of cerebral perfusion that could explain a patient's cognitive impairment and to determine if the pattern of these abnormalities would suggest a cause. MATERIALS AND METHODS: 17 patients (13 men; mean age, 60 years; age range, 29-74 years) in end-stage renal failure or on dialysis had SPECT imaging 10 minutes after injection of 550 MBq (15 mCi) Tc-99m HMPAO. Two of the patients had a history of previous stroke. Other risk factors for stroke were noted in most of the patients (hypertension in 10 patients, smoking or former smoking in 10 patients, and cardiac atherosclerosis in 7 patients). In all patients, attenuation correction was applied and the images were reconstructed into three sets of orthogonal slices. Activity in the frontal and temporal lobes was compared by quantification against the ipsilateral and contralateral cerebellum. RESULTS: Discrete cortical defects consistent with infarcts were seen in 14 patients. The mean right and left frontal-to-cerebellar ratio was 0.837 (SD, 0.09) and 0.837 (SD, 0.08), respectively. This was not significantly different from the right and left temporal-to-cerebellar ratios of 0.843 (SD, 0.07) and 0.848 (SD, 0.07), respectively. Both were within normally accepted ranges. CONCLUSIONS: Patients in end-stage renal failure who also had cognitive impairment appear to have a high number of cortical defects consistent with infarcts (suggesting a multiple-infarct type of dementia). There was no evidence of Alzheimer-type dementia.