A Multicenter Case-control Study of the Effect of Acute Rejection and Cytomegalovirus Infection on Pneumocystis Pneumonia in Solid Organ Transplant Recipients.

BACKGROUND: Pneumocystis pneumonia (PCP) is associated with morbidity and mortality in solid organ transplant (SOT) recipients. In this case-control study, we determined the association between posttransplant PCP and 3 variables: cytomegalovirus (CMV) infection, allograft rejection, and prophylaxis. METHODS: Eight transplant centers participated. For each case (SOT recipient with PCP), 3-5 controls (SOT recipients without PCP) were included. Controls were matched to the cases based on transplant center, type of allograft, and date of transplantation (±6 months). RESULTS: We enrolled 53 cases and 209 controls. Transplant types included kidney (n = 198), heart (n = 30), liver (n = 15), kidney-pancreas (n = 14), and lung (n = 5). PCP occurred beyond 12 months after transplantation in 43 (81.1%) cases. Thirty-four cases (64.1%) required admission to the intensive care unit, and 28 (52.8%) had mechanical ventilation. Allograft failure occurred in 20 (37.7%) cases, and 14 (26.9%) died. No patient developed PCP prophylaxis breakthrough. The proportion of female sex (P = .009), kidney dysfunction (P = .001), cardiac diseases (P = .005), diabetes mellitus (P = .03), allograft rejection (P = .001), CMV infection (P = .001), and severe lymphopenia (P = .001) were significantly higher in cases. In the logistic regression model, CMV infection (adjusted odds ratio [aOR], 4.6 [95% confidence interval {CI}, 2.0-10.5]) and allograft rejection (aOR, 3.0 [95% CI, 1.5-6.1]) significantly increased the likelihood of PCP. CONCLUSIONS: PCP was mostly a late-onset disease occurring after complete course of prophylaxis, particularly among patients with CMV infection or allograft rejection. PCP is associated with significant allograft loss. Extended prophylaxis targeting recipients with allograft rejection or CMV infection may reduce the risk of PCP.

Myocardial Perfusion Scans and Mortality in Asymptomatic Patients Awaiting Renal Transplantation.

Cardiac risk assessment for asymptomatic patients awaiting renal transplantation is controversial. Patients awaiting renal transplantation in Southern Saskatchewan from 2005 to 2015 were retrospectively reviewed. Patients underwent cardiac risk stratification with stress myocardial perfusion scan. Baseline clinical characteristics, nuclear scan results, all-cause mortality, and cardiovascular events were analyzed. Abnormal scans were defined as studies with reversible defects, wall motion abnormalities, lung uptake, or transient ischemic dilation. Descriptive statistics and survival analysis were calculated. Charts from 285 consecutive patients with 608 nuclear scans were analyzed. Mean age was 55.2 ± 11.7 years and 34.7% were female. Forty-three (15.1%) patients were transplanted and 99 (40.9%) patients died while awaiting renal transplantation. One hundred fifty-three patients (63.2%) had at least one abnormal scan. The mean follow-up period was 5.47 ± 3.11 years. An abnormal scan was not associated with decreased survival and/or coronary events (hazard ratio: 0.94, P = .77; 95% confidence intervals: 0.62 to 1.43). Patients awaiting renal transplantation in Saskatchewan with abnormal myocardial perfusion scans were not at greater risk of death or coronary events.

Health Literacy, Knowledge, and Patient Satisfaction Before Kidney Transplantation.

BACKGROUND: Poor health literacy is associated with inferior outcomes in kidney transplant recipients, and knowledge remains suboptimal in this population. The goal of this study was to characterize the health literacy, kidney transplant knowledge, medication beliefs, and education satisfaction in a cohort of patients waiting to undergo kidney transplantation. METHODS: All patients on the wait-list in 1 Canadian center were invited to participate in the study. A research assistant administered the Short Test of Functional Health Literacy in Adults and its numeracy section, the Beliefs about Medicines Questionnaire, the Kidney Transplant Understanding Tool, and questions regarding satisfaction. Descriptive and univariate statistics were calculated between demographic variables and the assessments. RESULTS: Thirty-nine percent of patients (41 of 106) patients participated in the study. Overall, 95% and 86% were defined as having adequate health literacy and numeracy, respectively. The mean score on the Kidney Transplant Understanding Tool was 79%, and the majority (97.4%) had strong beliefs regarding the necessity of medication and little concern about adverse effects (73.8%). Participants with higher literacy scores had increased knowledge (r = 0.52; P = .05), understanding of why antirejection pills are necessary (r = 0.38; P = .05), and confidence about taking posttransplant medications (r = 0.32; P = .05). Overall, 30.7% were unsatisfied with their education regarding medications, and 22.5% were unsatisfied with what to expect after the transplant. CONCLUSIONS: Before transplantation, health literacy, transplant knowledge, and scores on the Beliefs about Medicines Questionnaire were high in this cohort of patients. However, patient satisfaction regarding educational content remained suboptimal.

Peritoneal dialysis versus hemodialysis in patients with delayed graft function.

Delayed graft function (DGF) in kidney transplantation affects adverse outcomes. It remains unclear whether the post-transplant dialysis modality alters perioperative or long-term graft outcomes. We performed a retrospective observational quality initiative at two Canadian renal transplant centers, in which DGF occurred in the recipient, necessitating one of peritoneal dialysis (PD) or hemodialysis (HD). There was no difference in baseline factors between patients with post-transplant PD (n = 14) or HD (n = 63). The use of PD was associated with an increased risk of wound infection/leakage (PD 5/14 vs. HD 6/63, p = 0.024), shorter length of hospitalization (13.7 vs. 18.7 d, p = 0.009) and time requiring dialysis post-operatively (6.5 vs 11.0 d, p = 0.043). There were no differences in readmission to hospital within 6 months (4/14 vs. 23/63, p = 0.759), graft loss (0/14 vs. 2/63, p = 1.000) or acute rejection episodes (1/14 vs. 4/63, p = 1.000) at one yr, and GFR did not differ between the PD or HD groups at 30 d (35.7 vs. 33.8 mL/min/m(2), p = 0.731), six months (46.9 vs. 45.5 mL/min/m(2), p = 0.835) or one yr (46.6 vs. 44.5 mL/min/m(2), p = 0.746). Further research is needed to determine which transplant patients are most appropriate to undergo PD catheter removal at the time of transplantation.

Severe antibody-mediated rejection following IVIG infusion in a kidney transplant recipient with BK-virus nephropathy.

Intravenous immune-globulin (IVIG) use in renal transplantation has increased, with common uses including desensitization, treatment of antibody mediated rejection and adjunctive therapy for BK virus nephropathy. Although considered generally safe, potential side effects can occur in up to 23% of patients including acute kidney injury. We present a case of an unexpected cause of acute kidney injury in a renal transplant recipient following IVIG infusion. A 48-year-old nonsensitized female with end stage renal disease secondary to polycystic kidney disease received a deceased donor kidney transplant. The initial post-transplant period was unremarkable however at three years post-transplant the patient develops BK virus nephropathy. Despite a reduction in immunosuppression, graft function worsened and IVIG infusion was commenced. Immediately following the IVIG infusion, the patient develops anuric acute kidney injury necessitating hemodialysis. Renal transplant biopsy performed before and after the IVIG infusion revealed the de novo development of acute antibody mediated rejection and donor specific antibodies in the serum. Anti-HLA and donor-specific antibodies were also confirmed in a diluted sample of the IVIG preparation. We argue that the anti-HLA antibodies present in the IVIG caused an acute antibody mediated rejection in this previously nonsensitized female.

A retrospective study of the Framingham cardiovascular risk scores in a liver transplant population.

OBJECTIVE: Evaluate the relationship between Framingham cardiovascular risk scores (FRS) and transplant-related factors, particularly renal function, in a stable liver transplant population. METHODS: Single-center retrospective study of 54 post-liver transplant patients followed in one outpatient clinic. Demographics and laboratory data were assessed using the modified FRS (2009). Standard statistical analyses were performed between FRS and transplant-related factors; patient demographics, new-onset diabetes after transplant (NODAT), immunosuppressives, and estimated glomerular filtration rate (eGFR) measured by isotope dilution mass spectrometry (IDMS) and Cockcroft-Gault (CG) equations. RESULTS: Forty percent of patients were classified as low FRS, 29.6% as moderate FRS, and 29.6% as high FRS (of whom 50% had NODAT). Immunosuppressant use was similar between the high- and low-risk groups. FRS inversely correlated with eGFR (P = .0001) measured by either equation. eGFR measured by IDMS in the high-risk group (60.4 ± 22.1 mL/min/1.73 m(2)) was significantly lower than that in the low-risk group (97.1 ± 54 mL/min/1.73 m(2); P = .0001). In the multivariate analysis, age, eGFR and NODAT were significantly different between the low- and high-risk FRS groups. Receiving operational characteristic (ROC) analysis identified eGFR measured by IDMS at 42.7 mL/min/1.73 m(2) with a sensitivity of 92%, specificity of 19%, and positive predictive value of 72% to identify high-risk patients. Box-plot analysis of variance between eGFRs in the three risk groups showed a P value of .001. CONCLUSIONS: In this study one-third of liver transplant patients had a high FRS, and 14.8% had an eGFR below 40 mL/min/1.73 m(2). Low eGFR predicts those with high FRS. Liver transplant patients particularly those with NODAT, with low eGFR should undergo close management of cardiovascular risk factors.

Morphological Characterization of the Polyflux 210H Hemodialysis Filter Pores.

Background. Morphological characterization of hemodialysis membranes is necessary to improve pore design. Aim. To delineate membrane pore structure of a high flux filter, Polyflux 210H. Methods. We used a Joel JSM-6010LV scanning electron microscope (SEM) and a SU6600 Hitachi field emission scanning electron microscope (FESEM) to characterize the pore and fiber morphology. The maximal diameters of selected uremic toxins were calculated using the macromolecular modeling Crystallographic Object-Oriented Toolkit (COOT) software. Results. The mean pore densities on the outermost and innermost surfaces of the membrane were 36.81% and 5.45%, respectively. The membrane exhibited a tortuous structure with poor connection between the inner and outer pores. The aperture's width in the inner surface ranged between 34 and 45 nm, which is 8.76-11.60 times larger than the estimated maximum diameter of ß2-microglobulin (3.88 nm). Conclusion. The results suggest that the diameter size of inner pore apertures is not a limiting factor to middle molecules clearance, the extremely diminished density is. Increasing inner pore density and improving channel structure are strategies to improve clearance of middle molecules.

Similar lipid profile but improved long-term outcomes with sirolimus after cyclosporine withdrawal compared to sirolimus with continuous cyclosporine.

Renal transplant recipients show an increased risk of cardiovascular disease compared with a nontransplant population. Herein we have shown an analysis of a randomized controlled trial wherein 525 patients receiving a first or second (9.7%) renal allograft from a deceased (89.1%), a living-related (7.8%), or a living-unrelated donor (3.1%) received sirolimus (SRL), cyclosporine (CsA), and steroids (ST) at the time of transplantation with randomization at 3 months after transplantation of 430 eligible patients to continue on SRL-CsA-ST or to have CsA withdrawn with increased SRL trough targets (SRL-ST group). Graft survival, patient survival, and renal function at 5 years were analyzed by average fasting total cholesterol (200 mg/dL) and triglyceride (240 mg/dL) subgroups. At 5 years, total, high-density lipoprotein (HDL), and low-density lipoprotein [LDL] cholesterol and triglyceride values were similar between the groups. Statins ( approximately 80% of patients of both groups) were most effective to lower cholesterol ( approximately 50 mg/dL; P < .001; both groups), and fibrates ( approximately 25% of patients of both groups) were most effective to decrease triglycerides ( approximately 100 mg/dL; P < .001; both groups). Renal function and blood pressure were significantly better with SRL-ST. Hypercholesterolemia and hypertriglyceridemia were associated with reduced graft survival, patient survival, and calculated GFR, but the only significant difference was lower graft survival among SRL-CsA-ST patients with hypertriglyceridemia. Cardiovascular-related deaths were reported in 3.7% and 2.8% of patients in the SRL-CsA-ST and SRL-ST groups, respectively. In conclusion, when compared with continuous SRL-CsA-ST, CsA withdrawal at 3 months followed by SRL-ST significantly improved glomerular filtration rate (GFR) and blood pressure without a further increase in lipid parameters or an incidence of untoward effects from hyperlipidemia, despite a 2-fold higher SRL exposure.

Prediabetes: a must to recognise disease state.

UNLABELLED: Prediabetes mellitus (PDM) is defined as a state of abnormal glucose homeostasis in which deficiency or resistance to insulin is the hallmark. PDM precedes the development of overt type 2 DM. It is associated with increased mortality and morbidity and thus fits well with the criteria of a disease condition. Framing PDM as a disease and not a risk or a 'pre' stage for diabetes is needed to facilitate early management. AIM: This review aims therefore to increase awareness of PDM as a disease state. METHODS: To do so, we shall preview guidelines for its diagnosis. Its prevalence and hazards will be then discussed. Finally, we shall elaborate on the current treatment guidelines. RESULT: Enough evidence support the notion that PDM is a curable disease state. CONCLUSIONS: The current recommendations for the treatment of PDM should be adhered. In addition, there is a room for the use of other pharmacological agents.

Lack of benefit of early protocol biopsies in renal transplant patients receiving TAC and MMF: a randomized study.

We conducted a randomized, multicenter study to determine whether treatment of subclinical rejection with increased corticosteroids resulted in beneficial outcomes in renal transplant patients receiving tacrolimus (TAC), mycophenolate mofetil (MMF) and prednisone. One hundred and twenty-one patients were randomized to biopsies at 0,1,2,3 and 6 months (Biopsy arm), and 119 to biopsies at 0 and 6 months only (Control arm). The primary endpoint of the study was the prevalence of the sum of the interstitial and tubular scores (ci + ct)> 2 (Banff) at 6 months. Secondary endpoints included clinical and subclinical rejection and renal function. At 6 months, 34.8% of the Biopsy and 20.5% of the Control arm patients had a ci + ct score >or= 2 (p = 0.07). Between months 0 and 6, clinical rejection episodes were 12 in 10 Biopsy arm patients and 8 in 8 Control arm patients (p = 0.44). Overall prevalence of subclinical rejection in the Biopsy arm was 4.6%. Creatinine clearance at 6 months was 72.9 +/- 21.7 in the Biopsy and 68.90 mL/min +/- 18.35 mL/min in the Control arm patients (p = 0.18). In conclusion, we found no benefit to the procurement of early protocol biopsies in renal transplant patients receiving TAC, MMF and prednisone, at least in the short term. This is likely due to their low prevalence of subclinical rejection.

Performance of creatinine clearance equations on the original Cockcroft-Gault population.

BACKGROUND: Prediction of endogenous creatinine clearance by mathematical equations such as the Cockcroft-Gault formula is used in clinical practice in spite of the reported concern for their limited predictability. The aim of this study is to determine whether the measured creatinine clearance can be predicted accurately by a number of published equations including the recently modified Cockcroft-Gault formula = Cockcroft-Gault formula x 1.73 m2/body surface area from the original Cockcroft-Gault population. METHODS: The performance of the mathematical equations in patients with different creatinine clearance and body mass indices was assessed by computing accuracy at different percentiles, bias and precision from the original Cockcroft-Gault data. RESULTS: Refitting the modified formula to the Cockcroft-Gault data gave superior results compared to the original Cockcroft-Gault formula with an overall accuracy in the general and subgroup analysis above 70% agreement within 30% estimate of the measured creatinine clearance. On the other hand, analysis of the other equations, including the original Cockcroft-Gault, demonstrated a limited accuracy to predict creatinine clearance particularly in patients with creatinine clearance below 50 ml/min with an overall accuracy in less than 1/3 of the calculated creatinine clearance within 30% range from the measured creatinine clearance. CONCLUSION: The current creatinine clearance equations and even the original Cockcroft-Gault formula did not accurately predict the measured creatinine clearance. Normalization for body surface area in the original Cockcroft-Gault formula demonstrated more accuracy to estimate creatinine clearance, particularly in patients with diminished renal function and is recommended to physicians who wish to use the Cockcroft-Gault formula in their practice until more credible formulas are developed.

Prevalence of weight gain in patients with better renal transplant function.

AIMS: This study investigates the association between renal function and change in weight after kidney transplantation. METHODS: Retrospective analyses of 165 transplant patients on maintenance steroids who were followed-up for 6.2 +/- 2.4 years. RESULTS: 101 males and 64 females participated in the study. Results are expressed as mean +/- SD. At the first post-transplant outpatient visit (time 0), BMI was 25.3 +/- 4.8 kg/m2. It increased significantly by 7.7 +/- 10.8% and 10.9 +/- 12.6% at 1 and 5 years. 18 and 29% of patients had a BMI > 30 kg/m2 at times 0 and 5 years, respectively. Thereafter, diminishing glomerular filtration rate (GFR) was associated with the loss of the excess weight. Multivariate analysis showed that GFR, but not age, race, sex, source of graft, number of HLA mismatches or length of dialysis was significant to post-transplant weight gain. 38 patients gained weight > 1 SD above the mean of the population and were designated the high weight gain (HWG) group. 41 patients gained weight < the mean - 1 SD of the population and were designated the low weight gain (LWG) group. GFR in the high and low weight gain groups at time 0 was 71.8 +/- 20.3 ml/min/1.73 m2 and 66.4 +/- 23.1 ml/min/1.73 m2, respectively (p = NS), as compared to 77.4 +/- 23.3 ml/min/1.73 m2 and 61.5 +/- 24.5 ml/min/ 1.73 m2 at 6 months, respectively (p < 0.01) and continued to be significant thereafter (72.7 +/- 17.2 ml/min/1.73 m2 and 58.9 +/- 19.8 ml/min/1.73 m2, p < 0.05 at 6 years). CONCLUSIONS: Patients with relatively better renal transplant function gained more weight, suggesting a pivotal role of improved appetite on weight gain post transplantation. Most of the weight gain occurred during the first year.

Prevention of CAN graft loss in the medium term without HLA disparity reduction.

INTRODUCTION: This study compares the incidence of cadaveric graft failure from chronic allograft nephropathy in the medium term (1 to 5 years) using older and newer immunosuppressive regimens. The older regimen was established triple therapy and the newer regimen, almost universal replacement of azathioprine by mycophenolate. MATERIALS AND METHODS: In the older series, 76 (71 after death censoring) cadaveric renal grafts done from 1990 to mid-1996 in patients who survived for more than 1 year were analyzed. In the newer series, 49 (45 after death censoring) cadaveric grafts done 5 or more years ago in patients surviving 1 year were analyzed. In the older series, immunosuppression was combined steroids, cyclosporine, and azathioprine. In the newer series, mycophenolate replaced azathioprine in 85%, historically conventional immunosuppression was used in 7.5%, and miscellaneous in 7.5%. RESULTS: Cumulative deaths in years 1 to 5 with renal graft function were as follows: older series, 6.6% (5/76), newer 8.2% (4/49) (P = NS). In the older series, death-censored 1- to 5-year cumulative graft failure was 35.2% (24/71), newer series 4.4% (2/45) (chi-square 13.5, relative risk reduction 0.87 [0.51 to 0.97], P =.00021). ACE-inhibitor antihypertensive therapy was used in 25% (18/71) of the patients in the older series and in 53% (24/45) of patients in the newer series (chi-square 6.1, relative risk 1.8 [1.1 to 2.9], P =.01). CONCLUSION: Replacement of azathioprine with mainly myocophenolate in triple immunosuppression and enhanced use of ACE inhibitors are associated with near complete prevention (87%) of medium-term CAN graft failure, making death with graft function now the major cause of graft loss in this time.

Improvement of experimental allergic encephalomyelitis (EAE) by thymoquinone; an oxidative stress inhibitor.

UNLABELLED: Experimental Allergic Encephalomyelitis (EAE) is an autoimmune demyelinating disease of the central nervous system that is widely accepted as an animal model for the human multiple sclerosis. Oxidative stress appears to play a role in the onset and progression of EAE. We reasoned that decreasing oxidative stress might ameliorate symptoms and signs of EAE. Thymoquinone is reported to inhibit oxidative stress. One way of decreasing oxidative stress is to induce glutathione (GSH). We tested the impact of Thymoquinone (1 mg/kg, injected at tail vein) in our EAE model. We induced (EAE) in female Lewis rats using myelin basic protein emulsified with complete Freund's adjuvant. 24 animals were placed into three groups: A) Rats with EAE B) EAE rats with concomitant five day injection of Thymoquinone days 1-5, C) EAE rats with five doses of Thymoquinone injected at day 12-17. Twenty-eight days later, animals were sacrificed; spinal cord tissues collected for glutathione (GSH). RESULTS: 63% of animals in group "A" developed hind limb weakness and/or paralysis while 37% developed mild tail weakness, perivascular inflammation and low spinal cord GSH level. 25% of animals in group "B" exhibited mild tail and hind limb weakness and 75% animals had no symptoms, no perivascular inflammation and high spinal cord GSH level. 63% of animals of group "C" showed improving symptoms following Thymoquinone injections, no perivascular inflammation and higher GSH level while 37% of animals showed no symptoms prior and post Thymoquinone injections. Clinical symptoms correlated well with perivascular inflammation and GSH level. Animals received Thymoquinone at day 12-17 had higher GSH level, no perivascular inflammation and no symptoms compared with other groups. CONCLUSION: Thymoquinone inhibited oxidative stress which leads into improvement in our EAE animals. Thymoquinone may have a role in treatment of Multiple Sclerosis.

Pre-column derivatization high-performance liquid chromatographic method for determination of cysteine, cysteinyl-glycine, homocysteine and glutathione in plasma and cell extracts.

A sensitive high-performance liquid chromatographic method for quantification of sulphydryl and disulfide amino acids in human plasma using ultra violet spectrophotometric detection was developed. Precolumn derivatization with 5,5'-dithio-bis-nitrobenzoic acid (DTNB) and an optional pre-derivatization reaction with dithiothreitol allowed both quantitative reduction of disulfides for measurement of total amino acid levels and the measurement of the reduced forms. A dynamic range of 500 nmol/l-750 micromol/l allowed the major analytes of interest to be quantified in plasma without sample dilution. The assay is a sensitive and precise method for the determination of sulphydryl and disulfide amino acids in plasma and cell extracts.

Analysis of the CD40/CD40L role in the sustenance of alloreactive antibody production.

CD40 ligand (CD40L) is important for T/B lymphocyte interaction. To understand the cellular basis of humoral allosensitization we, therefore: (1) measured CD40L protein and gene expression in sensitized and non-sensitized uremic unactivated peripheral CD4+ T lymphocytes; (2) studied the impact of blocking the CD40/CD40L pathway on alloreactive antibody (allo-Ab) production by engrafted sensitized PBLs into severe combined immunodeficient (SCID) mice after in vitro preactivation with IL2/LPs/HLA class II allopeptides and adjuvants as a potent stimulus to produce allo-Ab (Shoker et al. Transplantation 1999;68;1188); and (3) studied the modifying effect of CD40/CD40L blockade on T helper type I and II cytokine gene expression in the respective mice spleen. The CD40L protein was measured by flow cytometry and the gene expression was measured by quantitative RT-PCR. Alloreactive antibodies (alo-Abs) produced by sensitized PBLs engrafted into SCID mice with and without blockade of the CD40 receptor were measured by the PRA-STAT ELISA method. The modifying effects of CD40 blocking on allo-Ab production and cytokine gene expression by the engrafted cells measured by RT-PCR were then compared. There was no detectable CD40L protein expression in either the uremic or the control groups. The CD40L gene expression of 0.04 +/- 0.02 attomoles (aM) in the sensitized group was significantly higher than in the non-sensitized patients (0.009 +/- 0.007 aM, P < 0.0001) or the control CD4+ T cells (0.016 +/- 0.004 aM, P < 0.001). Blockade of the CD40 receptor abrogated the production of allo-Ab antibodies by the engrafted sensitized cells in 60% of the tested mice (n = 10); decreased the mean +/- S.D. optic density of allo-Ab to 0.1 +/- 0.13 and the mean +/- S.D. PRA to 12 + 16). In the presence of the control Ab, allo-Ab production in SCID sera was present in 100% of the 10 SCID mice tested; the mean +/- S.D. PRA was 75 +/- 20, and the mean + S.D. OD activity was 0.412 +/- 0.17. All cytokine genes were, otherwise, expressed in the presence or absence of CD40 blockade. The results suggest a potential role of an enhanced CD40/CD40L interaction in the sustenance of alloreactive antibody production without significant deviation to T helper-like I or II responses. Blocking the CD40/CD40L pathway may have a potential therapeutic benefit to treat sensitized uremic patients.