Evaluation of PEG-coated iron oxide nanoparticles as blood pool tracers for preclinical magnetic particle imaging.

Superparamagnetic iron oxide (SPIO) nanoparticles with optimized and well-characterized properties are critical for Magnetic Particle Imaging (MPI). MPI is a novel in vivo imaging modality that promises to integrate the speed of X-ray CT, safety of MRI and sensitivity of PET. Since SPIOs are the source of MPI signal, both the core and surface properties must be optimized to enable efficient in vivo imaging with pharmacokinetics tailored for specific imaging applications. Existing SPIOs like Resovist (ferucarbotran) provide a suboptimal MPI signal, and further limit MPI's in vivo utility due to rapid systemic clearance. An SPIO agent with a long blood half-life (t1/2) would be a versatile MPI tracer with widespread applications. Here we show that a long circulating polyethylene glycol (PEG)-coated SPIO tracer, LS-008, provides excellent colloidal stability and a persistent intravascular MPI signal, showing its potential as the first blood pool tracer optimized for MPI. We evaluated variations of PEG coating and found that colloidal stability of tracers improved with the increasing PEG molecular weight (keeping PEG loading constant). Blood circulation in mice, evaluated using Magnetic Particle Spectrometry (MPS), showed that the t1/2 of SPIO tracers varied with both PEG molecular weight and loading. LS-008, coated with 20 kDa PEG at 18.8% loading capacity, provided the most promising long-term colloidal stability with a t1/2 of about 105 minutes in mice. In vivo MPI imaging with LS-008 using a 7 T/m/µ0 3D x-space MPI mouse scanner revealed a prolonged intravascular signal (3-5 hours) post-injection. Our results show the optimized magnetic properties and long systemic retention of LS-008 making it a promising blood pool MPI tracer, with potential to enable MPI imaging in cardio- and cerebrovascular disease models, and solid tumor quantification and imaging via enhanced permeation and retention.

Drive-field Frequency Dependent MPI Performance of Single-Core Magnetite Nanoparticle Tracers.

The drive-field frequency of Magnetic Particle Imaging (MPI) systems plays an important role for system design, safety requirements and tracer selection. Because the commonly utilized MPI drive-field frequency of 25 kHz might be increased in future system generations to avoid peripheral nerve stimulation, a performance evaluation of tracers at higher frequencies is desirable. We have studied single-core magnetite nanoparticles that were optimized for MPI applications, utilizing Magnetic Particle Spectrometers (MPS) with drive-field frequencies in the range from 1 kHz up to 100 kHz. The particles have core diameters of 25 nm and a hydrodynamic size of 77 nm. Measurements in the frequency range above 5 kHz were carried out with a newly designed MPS system. In addition, to exclude possible particle interaction, samples of different concentrations were characterized and compared.

Slew-rate dependence of tracer magnetization response in magnetic particle imaging.

Magnetic Particle Imaging (MPI) is a new biomedical imaging technique that produces real-time, high-resolution tomographic images of superparamagnetic iron oxide nanoparticle tracers. Currently, 25 kHz and 20 mT/µ0 excitation fields are common in MPI, but lower field amplitudes may be necessary for patient safety in future designs. Here, we address fundamental questions about MPI tracer magnetization dynamics and predict tracer performance in future scanners that employ new combinations of excitation field amplitude (Ho ) and frequency (ω). Using an optimized, monodisperse MPI tracer, we studied how several combinations of drive field frequencies and amplitudes affect the tracer's response, using Magnetic Particle Spectrometry and AC hysteresis, for drive field conditions at 15.5, 26, and 40.2 kHz, with field amplitudes ranging from 7 to 52 mT/µ0. For both fluid and immobilized nanoparticle samples, we determined that magnetic response was dominated by Néel reversal. Furthermore, we observed that the peak slew-rate (ωHo) determined the tracer magnetic response. Smaller amplitudes provided correspondingly smaller field of view, sometimes resulting in excitation of minor hysteresis loops. Changing the drive field conditions but keeping the peak slew-rate constant kept the tracer response almost the same. Higher peak slew-rates led to reduced maximum signal intensity and greater coercivity in the tracer response. Our experimental results were in reasonable agreement with Stoner-Wohlfarth model based theories.

Size-dependent ferrohydrodynamic relaxometry of magnetic particle imaging tracers in different environments.

PURPOSE: Magnetic particle imaging (MPI) is a recently developed imaging technique that seeks to provide ultrahigh resolution and tracer sensitivity with positive contrast directly originated from superparamagnetic iron oxide nanoparticles (NPs). MPI signals can be generated from a combination of Néel relaxation, Brownian rotational diffusion, and hysteretic reversal mechanisms of NPs in response to applied magnetic fields. When specific targeting of organs, such as carcinoma and endothelial cardiovascular cells, is needed, different behavior may be expected in immobilized NPs, due to complete or partial elimination of the Brownian motion. Here, the authors present an experimental investigation of the MPI spatial resolution and signal intensities as a function of a wide range of median core sizes of NPs under four representative conditions, including after immobilization in a tissue equivalent medium. METHODS: Monodisperse hydrophobic NPs with median core diameters (d0) ranging from 7 to 22 nm were synthesized in organic media and subsequently dispersed in aqueous solution after a facile surface modification. Morphology, median size, size distribution, and magnetic properties of the NPs were investigated. Hydrophobic and hydrophilic NPs with various core sizes were immobilized in trioctyl phosphine oxide and agarose gel, respectively. Their size-dependent performance as MPI tracers for system matrix and x-space image reconstruction was evaluated using magnetic particle spectrometry (MPS) and compared with the free rotating counterparts. RESULTS: Immobilized NPs with core diameters smaller than ≈ 20 nm have similar spatial resolution, but lower signal intensities when compared with their free rotating counterparts. Compared to their performance in solution, spatial resolution was improved, but signal intensity was lower, when larger NPs with core size of 22 nm were immobilized in agarose. Same trends were observed in signal intensities, when considering either system matrix or x-space approaches. The harmonic and dm/dH signal intensities changed linearly and the spatial resolution did not change with decreasing NP concentration up to 15 µg/ml. CONCLUSIONS: The results show that the MPI signal is very sensitive to both NP size and environment. The authors' calculations show that Brownian rotational diffusion is slower than the field switching cycle and, therefore, it has minimal influence on MPS signals. dm/dH analyses show that Néel relaxation is the dominant mechanism determining MPI response in smaller NPs (d0 < ≈ 20 nm). Larger NPs show hysteretic reversal when the applied field amplitude is large enough to overcome the coercivity. Linear variation of the MPS signal intensity with iron concentration but with uniform spatial resolution enables quantitative imaging for a range of applications, from high-concentration bolus chase imaging to low-concentration molecular imaging (while the authors' instrument is noise-limited to ≈ millimolar iron concentrations, nanomolar sensitivity is expected for MPI, theoretically). These results pave the way for future application of the authors' synthesized tracers for immobilized or in vivo targeted MPI of tissues.

The effect of Pediococcus acidilactici on the gut microbiota and immune status of on-growing red tilapia (Oreochromis niloticus).

AIM: To assess Pediococcus acidilactici as a dietary supplement for on-growing red tilapia (Oreochromis niloticus). METHODS AND RESULTS: Tilapia were fed either a control diet or control diet supplemented with Ped. acidilactici at 10(7) CFU g(-1) for 32 days. Ped. acidilactici colonized the intestinal tract and significantly affected the intestinal microbial communities. PCR-DGGE revealed direct antagonism of gastric Ped. acidilactici with an endogenous uncultured bacterium during a period of reverting to nonsupplemented feeding. Light microscopy revealed that gut integrity and leucocyte levels were unaffected by Ped. acidilactici; however, blood leucocyte levels and serum lysozyme activity were elevated after 14-days' feeding. No significant improvements in growth performance were observed at the end of the trial (day 32), but survival was significantly higher in the probiotic group. CONCLUSIONS: The study demonstrates that oral supplementation of Ped. acidilactici modulates intestinal bacterial communities in on-growing red tilapia and also stimulates some aspects of the nonspecific immune response. SIGNIFICANCE AND IMPACT OF THE STUDY: To our knowledge this is the first study assessing the effects of probiotics on the gut microbiota of tilapia using culture-independent methods. Such methods are crucial to understand the mechanisms which underpin and mediate host benefits.

Clinical outcomes of renal transplant recipients treated with enteric-coated mycophenolic acid vs. mycophenolate mofetil as a switch agent using a primary steroid-free rapamune and microemulsion cyclosporine protocol.

Since 2002 our transplant program has utilized a steroid free, cyclosporine (CSA)- and rapamycin (RAPA)-based maintenance immunosuppression regimen. In cases where it has been desirable to avoid the potential nephrotoxicity with this regimen we have used mycophenolic acid (MPA) as our "switch" drug of choice. Both mycophenolate mofetil (MMF) (Roche Inc., Nutley, NJ, USA) and enteric-coated MPA (ECM) (Novartis, East Hanover, NJ, USA) have been used. In this study, we retrospectively compared the tolerability of the two formulations of MPA. Thus we compared 103 recipients switched to RAPA/MMF (RMM group) to 114 switched to RAPA/ECM (REC group). There was a significantly higher incidence of patients requiring dose changes and drug discontinuation in the RMM group, as well as an increased frequency of dose changes. There were significantly more acute rejection episodes and kidney losses in the dose adjustment vs. no dose adjustment patients. However, when comparing the incidence of acute rejection and kidney loss between the RMM and REC groups, there was no significant difference. We conclude that in this cohort of recipients, the ECM formulation of MPA was better tolerated than the MMF formulation, resulting in fewer patients requiring dose adjustments or drug discontinuation.

Impact of mycophenolate mofetil (MMF)-related gastrointestinal complications and MMF dose alterations on transplant outcomes and healthcare costs in renal transplant recipients.

Mycophenolate mofetil (MMF), a mycophenolic acid prodrug, is a highly effective adjunct immunosuppressive agent in transplant therapy. Although MMF is generally well tolerated, optimal therapy may be limited by adverse effects, in particular gastrointestinal (GI) toxicity, which has been reported to occur in up to 45% of MMF-treated patients. MMF dose changes resulting from these adverse events may lead to sub-therapeutic dosing and impaired clinical outcomes. This retrospective study analyzed clinical records from 772 renal transplant patients from 10 US transplant centers who were initiated on MMF. The analysis revealed that 49.7% (n = 382) of patients experienced at least one GI complication within the first 6 months post-transplant, with 66.8% (n = 255) of these having multiple GI complications. Of the patients with GI complications, 39.0% experienced MMF dose adjustments or discontinuation of MMF therapy. Patients with GI complications who experienced MMF dose adjustments/discontinuation had a significantly increased incidence of acute rejections compared with patients without GI complications (30.2% vs. 19.4%; p = 0.005). Mean treatment costs were higher in patients with GI complications than in those with no GI complications, particularly in those who experienced MMF dose adjustments/discontinuation (p = 0.0001). The mean incremental cost for patients experiencing GI complications was US$3700 per patient during the 6 months post-transplant (p < 0.001), which was mainly attributable to hospitalization costs. In summary, GI complications and MMF dose adjustments/discontinuations are associated with a significant negative impact on transplant outcomes and markedly increase short-term treatment costs.

A randomized prospective trial of OKT3 induction in the current immunosuppression era.

Recent improvements in immunosuppression and subsequent decreases in the incidence of acute rejection have brought into question the benefit of the use peri-transplant antibody therapy (i.e. induction therapy). In the current era of immunosuppression that includes mycophenolate mofetil (MMF) and cyclosporine emulsion (Neoral, Novartis, Basle, Switzerland), we designed and have completed a prospective, randomized trial to address this question. Cadaveric and living donor renal allograft recipients were randomized to receive either OKT3/MMF/delayed Neoral/prednisone or MMF/immediate Neoral/prednisone without OKT3. The incidence of rejection episodes was the primary end point. Patients with delayed graft function were excluded. All rejection episodes were biopsy proven and all patients have been followed for a minimum of 2 yr. Fifty-four patients received OKT3 induction, of which 6 patients suffered a rejection episode (11%), while 13 patients (27%) not receiving OKT3 (p=0.04) had a rejection episode. Four patients in the no OKT3 group suffered multiple rejections, while there were only 2 with more than one episode in the OKT3 group. There was no increased incidence of infectious complications in the group receiving OKT3. Hospital costs tended to be higher in the OKT3-treated group, but were not significantly different. The low incidence of rejection in the OKT3-treated group was intriguing and validates the use of antibody therapy in the early post-operative periods even in the era of improved baseline immunosuppression.

Life satisfaction in renal transplant recipients: preliminary results from the transplant learning center.

The Transplant Learning Center (TLC) was designed to improve quality of life (QOL) and preserve graft function in solid-organ transplant recipients. To meet the specific goals of the program, the Life Satisfaction Index and Transplant Care Index were designed to serve as composite measures for measuring transplant-specific QOL and the ability to care for a transplant, respectively. In this study, we analyzed self-reported health information to examine relationships between comorbidities and individual posttransplantation side effects, life satisfaction, and transplant care, defined by renal transplant recipients. Patients entered the TLC through self-referral or referral by a health professional. Included in the analysis were 3,676 TLC enrollees with a mean time since transplantation of 4.8 years. Comorbidities and adverse effects were common, with high blood pressure reported by 89% of respondents and unusual hair growth reported by 70%. Sexual dysfunction and headache had a greater impact on QOL than more common adverse effects, such as changes in body and facial shape, hirsutism, and tremor. Regression modeling was used to identify the most significant associations between QOL indices and structural (nonmedical), medical, and psychosocial factors. Greater life satisfaction was most strongly associated with being in control of one's health and living a normally active life with satisfying emotional relationships. Management of such clinical problems as adverse effects of medication and nonadherence should be informed by the patient's perspective. Clinicians should actively solicit information about physical activity, appearance concerns, side effects of medications, nonadherence, and sexual and relationship issues when evaluating renal transplant recipients.

Elevated blood pressure predicts the risk of acute rejection in renal allograft recipients.

BACKGROUND: Acute rejection (AR) is a strong predictor of renal allograft survival. Recent advances in immunosuppression have reduced considerably the incidence of AR. Still, approximately 25% of patients have AR early post-transplant, and the factors that predispose to AR have not been fully clarified. METHODS: The study includes 1641 adults, recipients of first cadaveric (CAD, N = 1195) or living related renal grafts (LRD, N = 446), transplanted in one institution. The variables associated with the occurrence of AR during the first year post-transplant were identified. RESULTS: By univariate analyses, AR was associated with the following variables: younger (P < 0.001); heavier (P = 0.003); and African American recipients (P = 0.002); CAD transplants (P = 0.001); higher number of HLA mismatches (P = 0.001); delayed graft function (DGF, P = 0.001); higher levels of serum creatinine post-transplant (P = 0.003); and higher levels of systolic and/or diastolic blood pressure (BP) post-transplant (P < 0.001). Higher BP levels were also associated with earlier AR episodes (P < 0.0001). By multivariable analysis AR was significantly associated with recipient age, number of HLA mismatches, DGF, pre-PRA and systolic BP. Analysis of BP measured weekly post-transplant indicated that elevated BP levels, even three weeks prior to the AR episode, were significantly associated with AR. For every level of BP, the use of BP medications was associated with a lower incidence of AR (P < 0.0001). Furthermore, the use of calcium channel blockers was also associated with lower incidence of AR (P = 0.001). Of note, 81% of recipients whose BP increased after the transplant had AR. In contrast, 22% of patients whose BP declined post-transplant had AR. CONCLUSIONS: Elevated BP levels post-transplant identify patients at high risk of AR independently of graft function. Treatment of BP and reduction of BP levels appears to be associated with a decreased risk of AR. We hypothesize that high BP may be an indicator of a particular type of allograft damage, perhaps ischemic, that may predispose to AR.

Post-transplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) is a serious complication of transplantation caused by immunosuppressive drugs. In this study, we assessed the incidence of PTDM and the factors that are associated with the development of this complication. METHODS: The study population included 2078 non-DM renal allograft recipients, transplanted since 1983 in one institution. PTDM was diagnosed by the requirement of hypoglycemic medications, starting more than 30 days after transplantation. Post-transplant, all patients received cyclosporine (CsA) and prednisone, but none of these patients received tacrolimus. RESULTS: At 1, 3, 5, and 10 years after transplantation, 7, 10, 13, and 21% of patients developed PTDM. By multivariate Cox, the following variables correlated with a more rapid increase in the number of PTDM cases: (1) older age (RR = 2.2 comparing patients younger or older than 45 years, P < 0.0001), (2) transplant done after 1995 (RR = 1.7, P = 0.003), (3) African American race (RR = 1.6, P = 0.003), and (4) higher body weight at transplant (RR = 1.4, P < 0.0001). Compared with before 1995, since 1995, the percentage of patients with PTDM has increased from 5.9 to 10.5% at one year and from 8.8 to 16.9% at three years. This increase was statistically independent from all other variables tested. However, since 1995, recipients have become significantly heavier (P < 0.0001) and older (P < 0.0001), and the average CsA level has increased significantly (P < 0.0001). Also, since 1995, the cumulative dose of corticosteroids has declined (P < 0.0001); patients received a newer, better absorbed preparation of CsA and received mycophenolate mofetil. CONCLUSIONS: The risk of PTDM increases continuously with time post-transplant. There has been an increase in the incidence of PTDM in patients transplanted recently, and that increase can be explained only partially by changes in the recipients' characteristics. We postulate that this increase may be due to the introduction of better absorbed CsA formulations that result in higher blood levels and higher cumulative exposure to this diabetogenic drug.

Evidence for a genetic predisposition towards acute rejection after kidney and simultaneous kidney-pancreas transplantation.

BACKGROUND: In vitro production of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), interleukin 10 (IL-10), and transforming growth factor-beta (TGF-beta) correlate with their respective genetic polymorphisms. We analyzed the relationship between these genetic polymorphisms and posttransplant outcome. METHODS: Using DNA polymerase chain reaction (PCR) technology, polymorphisms for TNF-alpha, IFN-gamma, IL-10, and TGF-beta were determined for 82 kidney (K) and 19 simultaneous kidney-pancreas (SKP) recipients. These results were analyzed with regard to the incidence of acute rejection (AR), and the timing and severity of the first AR episode. RESULTS: A high TNF-alpha production phenotype correlated with recurrent acute rejection (AR) episodes (P<0.026). Compared with the low TNF-alpha production phenotype, more patients with the high production phenotype had a post-AR serum creatinine >2.0 mg/dl, but this was not statistically significant (64 vs. 35%, P=0.12). There was no relationship between TNF-alpha genotype and the time to first AR episode or incidence of graft loss. IFN-gamma production phenotype showed no correlation with any of these clinical outcome parameters. There was an increase in AR incidence as the IL-10 production phenotype increased (low, intermediate, high), but only in low TNF-alpha producer phenotypes (P=0.023). CONCLUSIONS: Patients with a polymorphic cytokine genotype putatively encoding for high in vivo TNF-alpha production, and to a lesser extent IL-10 cytokine genotypes putatively encoding for higher levels of in vivo IL-10 production, had a worse clinical outcome regarding AR episodes. These data support the hypothesis that the strength of alloimmune responsiveness after transplantation in part is genetically determined.

Pulmonary Rhizopus infection in a diabetic renal transplant recipient.

Infectious complications after renal transplantation remain a major cause of morbidity and mortality. Mucormycosis is a rare infection in renal transplant recipients; however, mortality is exceedingly high. Risk factors predisposing to this disease include prolonged neutropenia, diabetes, and patients who are immunosuppressed (Singh N, Gayowski T, Singh J, Yu LV. Invasive gastrointestinal zygomycosis in a liver transplant recipient: case report and review of zygomycosis in solid-organ transplant recipients, Clin Infect Dis 1995: 20: 617). Life-threatening infections can occur, as this fungus has the propensity to invade blood vessel endothelium, resulting in hematological dissemination. We report a case of cavitary Rhizopus lung infection, 2 months after renal transplantation, where the patient was treated successfully with Amphotericin B and surgical resection of the lesions with preservation of his allograft function. In this era of intensified immunosuppression, we may see an increased incidence of mucormycosis in transplant population. Invasive diagnostic work-up is mandatory in case of suspicion; Amphotericin B and, in selected cases, surgical resection are the mainstays of therapy.

Obese living kidney donors: short-term results and possible implications.

BACKGROUND: Living kidney donation has increased recently as the shortage of cadaveric organs continues. This increase has occurred in part, due to expanded donor criteria, including obese patients. This is a potential concern because obesity is associated with surgical complications, possibly death, and chronic medical problems. To address this concern, we examined the outcome of a large group of obese (ObD) and nonobese living kidney donors (NObD). METHODS: A total of 107 obese (body mass index> or =27 kg/m2) and 116 nonobese (body mass index<27 kg/m2) living kidney donors donating at a single institution between 1990 and 1996 were studied. Surgical complications, operative duration, and hospital length of stay were assessed. Preoperative blood pressure, serum creatinine, creatinine clearance, protein excretion, fasting glucose, and hemoglobin A1C were measured and first degree relatives with diabetes were identified. RESULTS: Overall complications were significantly more common in ObD, 16.8 vs. 3.4% (P=0.0012). The majority of complications in the entire cohort, 56%, were wound related and were significantly more common in ObD (P=0.016). There was no significant increase in nonwound-related infections, bleeding, or cardiopulmonary events. There were no deaths or major complications. Operative time was significantly longer in ObD 151+/-30 vs. 141+/-29 min (P<0.05) but hospital duration was no different. Predonation, blood pressure in ObD was significantly higher, (P<0.05) and they more often had a family history of diabetes, 46 vs. 30% (P<0.05) than nonobese donors. Renal function, proteinuria, fasting glucose, or hemoglobin A1C were no different. CONCLUSION: With prudent selection, the use of obese living kidney donors appears safe in the short term. They experience more minor complications, usually wound related, and slightly longer operations. Given a higher baseline blood pressure and family history of diabetes, the long-term effect on the remaining solitary kidney in ObD needs to be examined.

Renal allograft survival following acute rejection correlates with blood pressure levels and histopathology.

BACKGROUND: Acute rejection (AR) is a strong predictor of renal graft survival, but the negative impact of AR on survival is variable, suggesting that other factors modulate this relationship. In this study, we examined the variables that correlate with graft survival after AR, particularly the impact of blood pressure (BP), graft function, and histopathology. METHODS: The study population included patients with no AR (N = 942) and patients with one (N = 407) or two (N = 156) AR during the first year post-transplant. Patients were adults who were recipients of living related (LRD, N = 410) or cadaveric grafts (CAD, N = 1095) and who were transplanted in a single institution and followed for 5.8 +/- 4 years. RESULTS: Compared with patients without AR, those with AR were significantly younger, had more human lymphocyte antigen mismatches, and included more CAD recipients. Graft survival was analyzed beyond six-months post-transplant. In patients with AR, reduced survival correlated (multivariate) with (a) younger recipients (P = 0.01), (b) AR occurring later during the first-year post-transplant (P = 0.0006), (c) elevated serum creatinine (Cr) before (P = 0.05), at the time (P = 0.0001) of, or after AR (P = 0.0004), and (d) average BP levels after AR [systolic BP (P = 0.003 logistic, P < 0.0001 by Cox), diastolic BP (P = 0.007), mean arterial pressure (P < 0.0001)]. This latter correlation was independent of graft function and recipient race. Thus, post-AR BP levels correlated with graft survival in patients with post-AR creatinine

Focal segmental glomerulosclerosis in renal allografts with chronic nephropathy: implications for graft survival.

De novo focal segmental glomerulosclerosis (FSGS) in renal allografts most often is diagnosed in association with chronic allograft nephropathy (CN). In this study, we assessed the clinical and pathological variables that correlate with the presence of de novo FSGS and the implications of FSGS for the survival of grafts with CN. The study population included 293 renal allograft recipients (52 living related donor, 241 cadaveric donor) diagnosed with CN by biopsy more than 6 months after transplantation. Patients with recurrent FSGS or FSGS associated with other glomerulopathies were excluded. FSGS was present in 87 patients with CN (30%). FSGS was diagnosed more commonly in the following groups of patients: young (P = 0.04), black (P = 0.02), and those with elevated serum cholesterol levels (P = 0.002) and/or high-grade proteinuria (P < 0. 0001, all univariate analysis). FSGS was diagnosed later after transplantation than CN without FSGS (P < 0.0001), and FSGS correlated with the presence of arteriolar hyalinosis in the biopsy specimen (P = 0.04). Compared with CN without FSGS, FSGS was associated with significantly worse death-censored graft survival (P = 0.008, univariate Cox). In addition, when we analyzed all patients with CN, graft survival correlated by multivariate analysis with the following parameters: serum creatinine level (P < 0.0001) and proteinuria (P = 0.004) at the time of diagnosis, presence of FSGS (P = 0.03), and degree of interstitial fibrosis and tubular atrophy (CN score; P < 0.0001, Cox). Of interest, the use of lipid-reducing agents was also associated with improved graft survival in patients with CN (P = 0.0002, univariate Cox), although total lipid levels were not significantly less in patients receiving these drugs. In conclusion, de novo FSGS presents late after transplantation and in association with arteriolar hyalinosis, suggesting these lesions may be related to chronic cyclosporine toxicity. In CN, the presence of FSGS and the severity of interstitial fibrosis are negative independent predictors of graft survival. The possible relationship between lipid-reducing agents and graft survival clearly needs to be examined carefully in future studies.

Patient survival after renal transplantation: II. The impact of smoking.

Renal transplant recipients have significantly higher mortality than individuals without kidney disease and the excess mortality is mainly due to cardiovascular causes. In this study, we sought to determine the impact of smoking, a major cardiovascular risk factor, on patient and renal graft survival. The study population included all adult recipients of first cadaveric kidney transplants done in our institution from 1984 to 1991. By selection, all patients were alive and had a functioning graft for at least 1 yr after transplantation. Smoking history was gathered prior to transplantation. The follow-up period was 84.3 + 41 months and during this time 28%, of the patients died and 21%, lost their graft. By univariate and multivariate analysis, patient survival, censored at the time of graft loss, correlated with these pre-transplant variables: age (p < 0.0001); diabetes (p = 0.0002); history of cigarette smoking (p = 0.004); time on dialysis prior to the transplant (p = 0.0005); and cardiomegaly by chest X-ray (p = 0.0005). Post-transplant variables did not correlate with patient mortality. By Cox regression, patient survival time was significantly shorter in diabetics (p < 0.0001), smokers (p = 0.0005), and recipients older than 40 yr. However, there were no significant differences between the survival of smokers, non-diabetics, diabetics, and older recipients. Patient death was the most common cause of renal transplant failure in smokers, in patients older than 40 yr, and in diabetics, but these patient characteristics did not correlate with graft survival. The prevalence of different causes of death was not significantly different between smokers and non-smokers. In conclusion, a history of cigarette smoking correlates with decreased patient survival after transplantation, and the magnitude of the negative impact of smoking in renal transplant recipients is quantitatively similar to that of diabetes.

Medication compliance following renal transplantation.

BACKGROUND: There appears to be general consensus that a relationship exists between noncompliance and clinical outcomes in health care, including renal transplantation. This study investigated variables associated with medication noncompliance after renal transplantation. METHODS: A mail survey containing objective and subjective variables was sent to individuals who met eligibility criteria. Medication compliance was measured by two items: 1) Frequency of forgetting to take medications and 2) Frequency of not taking medications exactly as prescribed. Descriptive and multivariate analyses were utilized to examine the data. RESULTS: Individuals who were older and those who perceived less pain were less likely to forget medications. The belief that health outcomes were controlled by chance and feeling bothered by part of the transplant experience were associated with greater likelihood of forgetting medications. Individuals who perceived a higher level of social functioning and those who believed that health outcomes were controlled by powerful others were more likely to take medications exactly as prescribed. An internal locus of control for health outcomes and feeling bothered by part of the transplant experience were associated with less likelihood of taking medication exactly as prescribed. CONCLUSIONS: The finding of this study suggest that compliance with medications after renal transplant is associated with subjective, not objective variables. Positive feelings regarding their physicians and the transplant experience increased compliance. Combining consistent measurement of compliance, examination of its relationship to clinical outcomes, and appreciation for the patient perspective should result in increased levels of compliance and better clinical outcomes.

Pathologic classification of chronic allograft nephropathy: pathogenic and prognostic implications.

BACKGROUND: After transplantation renal allografts frequently develop interstitial fibrosis and tubular atrophy, and these pathologic changes are the hallmarks of chronic allograft nephropathy (CN). However, the diagnosis of CN has no specific pathogenic implications. In this study we sought to determined whether a subclassification of CN according to vascular pathology correlates with posttransplant events, particularly acute rejection, and graft survival. METHODS: A total of 419 patients with moderate to severe CN were subdivided into: (1) transplant arteriopathy (TA, n=233, 56%); (2) arteriolar hyalinosis (AH, n=89, 21%); and (3) no characteristic vascular pathology (IFb, n=97, 23%). RESULTS: Patients with AH differed significantly from patients with TA or IFb in the following parameters: (1) AH was diagnosed later after transplantation (P=0.001); (2) fewer patients with AH had acute rejection (AR) before the diagnosis of CN (P<0.0001). For example, 44% of AH and 75% of TA had AR before CN; (3) patients with AH also had fewer AR episodes than the other two groups (P<0.0001); finally, (4) graft survival was better in patients with AH than in patients with TA (P=0.01 by chi2, P=0.001 by Cox). In contrast, there were no significant differences between patients with TA and IFb. By multivariate analysis the survival of grafts with CN correlated with: (1) serum creatinine at diagnosis (P<0.0001), (2) recipient's weight (P=0.004); (3) presence of FGS or level of proteinuria (P=0.03); and (4) the occurrence of AR after the diagnosis of CN (P<0.0001). Regarding the latter, AR were more common (P=0.007) and more numerous (P=0.005) in patients with TA or IFb than in AH. CONCLUSIONS: CN can be classified according to vascular pathology in the majority of cases, and this classification correlates with graft survival. Although some forms of CN are closely associated with the occurrence of AR others are not. This study also uncovered several variables that correlate with the survival of grafts with CN.