Are patient and relationship variables associated with participation of intimate partners in couples research?

BACKGROUND: Recruitment of participants for studies focusing on couples facing illness is a challenging task and participation decline may be associated with nonrandom factors creating bias. This study examines whether patient and relationship characteristics are associated with partner participation in research. METHOD: Patients invited to participate in a cross-sectional study on adaptation and quality of life after renal transplantation were asked to forward information about an add-on study to their partners. RESULTS: A total of 456 participating patients had a partner; 293 of the partners showed interest in the study and 206 actually completed the questionnaire. Backward logistic regression analyses revealed that demographic, illness, and personal characteristics of the patient were not associated with partner interest in the study nor actual partner participation. However, partners who indicated interest in the study showed more active engagement toward the patients (as reported by the patients). Furthermore, patients of partners who actually completed the questionnaire reported less negative affect and higher relationship satisfaction than patients whose partner did not participate in the study. DISCUSSION: It is encouraging that of the large number of variables tested, only 2 were associated with the participation of partners. Nevertheless, well-functioning couples appear to be overrepresented in our study, calling for specific effort to include marital distressed couples in research focusing on dyadic adaptation to illness.

Interstitial pneumonitis caused by everolimus: a case-cohort study in renal transplant recipients.

The use of inhibitors of the mammalian target of rapamycin (mTORi) in renal transplantation is associated with many side effects, the potentially most severe being interstitial pneumonitis. Several papers have reported on sirolimus-induced pneumonitis, but less is published on everolimus-induced pneumonitis (EIP). Data on risk factors for contracting EIP are even more scarce. In the present case-cohort study in renal transplant recipients (RTR), we aimed to assess the incidence and risk factors of EIP after renal transplantation. This study is a retrospective substudy of a multicenter randomized controlled trial. All patients included in the original trial and treated with prednisolone/everolimus were included in this substudy. RTR who developed EIP were identified as cases. RTR without pulmonary symptoms served as controls. Thirteen of 102 patients (12.7%) developed EIP. We did not find any predisposing factors, especially no correlation with everolimus concentration. On pulmonary CT scan, EIP presented with an organizing pneumonia-like pattern, a nonspecific interstitial pneumonitis-like pattern, or both. Median time (range) to the development of EIP after start of everolimus was 162 (38-407) days. In conclusion, EIP is common in RTR, presenting with an organizing pneumonia, a nonspecific interstitial pneumonitis-like pattern, or both. No predisposing factors could be identified (Trial registration number: NTR567 (www.trialregister.nl), ISRCTN69188731).

Cyclosporine versus everolimus: effects on the glomerulus.

Inhibitors of the mammalian target of rapamycin (mTOR) have been associated with proteinuria. We studied the development of proteinuria in renal transplant recipients (RTR) treated with the mTOR inhibitor everolimus in comparison with a calcineurin inhibitor. We related the presence of proteinuria to histopathological glomerular findings in two-yr protocol biopsies. In a single-center study, nested in a multicenter randomized controlled trial, we determined eGFR, proteinuria, and renal biopsy data (light- and electron microscopy) of RTR receiving prednisolone/everolimus (P/EVL) (n = 16) in comparison with patients treated with prednisolone/cyclosporine A (P/CsA) (n = 7). All patients had been on the above-described maintenance immunosuppression for 18 months. Renal function at two yr after transplantation did not differ between patients receiving P/EVL or P/CsA (eGFR 45.5 vs. 45.7 mL/min/1.73 m(2)). Proteinuria was slightly increased in P/EVL vs. P/CsA group (0.29 vs. 0.14 g/24 h, p = 0.06). There were no differences in light- or electron microscopic findings. We could not demonstrate increased podocyte effacement or changes in glomerular basement membrane (GBM) thickness in P/EVL-treated patients. In conclusion, long-term treatment with everolimus leaves the GBM and podocytes unaffected.

Effects of preexistent hypertension on blood pressure and residual renal function after donor nephrectomy.

BACKGROUND: Living kidney donor selection has become more liberal with acceptation of hypertensive donors. Here, we evaluate short-term and 1- and 5-year renal outcome of living kidney donors with preexistent hypertension. METHODS: We compared outcome of hypertensive donors by gender, age, and body mass index with matched control donors. Hypertension was defined as predonation antihypertensive drug use. All donors had glomerular filtration rate (I-iothalamate) and effective renal plasma flow (I-hippuran) measured 4 months before and 2 months after donation. A subset of donors had serum creatinine measured 1 year after donation or a renal function measurement 5 years after donation. RESULTS: Included were 47 hypertensive donors and 94 control donors (both 53% male; mean age, 57±7 years; and body mass index, 28±4 kg/m). Pre- and early postdonation, systolic blood pressure, and mean arterial pressure were significantly higher in hypertensive donors. Control donors showed a rise in diastolic blood pressure after donation, and thus the predonation difference was lost postdonation. Both at 1 year (29 hypertensive donors, 58 controls) and 5 years after donation (13 hypertensive donors and 26 controls) blood pressure was similar. Renal function was similar at all time points. DISCUSSION: In summary, hypertensive living kidney donors have similar outcome in terms of blood pressure and renal function as control donors, early and 1 and 5 years after donation.

Tubular epithelial syndecan-1 maintains renal function in murine ischemia/reperfusion and human transplantation.

Syndecan-1, a heparan sulfate proteoglycan, has an important role in wound healing by binding several growth factors and cytokines. As these processes are also crucial in damage and repair after renal transplantation, we examined syndecan-1 expression in human control kidney tissue, renal allograft protocol biopsies, renal allograft biopsies taken at indication, and non-transplant interstitial fibrosis. Syndecan-1 expression was increased in tubular epithelial cells in renal allograft biopsies compared with control. Increased epithelial syndecan-1 in allografts correlated with low proteinuria and serum creatinine, less interstitial inflammation, less tubular atrophy, and prolonged allograft survival. Knockdown of syndecan-1 in human tubular epithelial cells in vitro reduced cell proliferation. Selective binding of growth factors suggests that syndecan-1 may promote epithelial restoration. Bilateral renal ischemia/reperfusion in syndecan-1-deficient mice resulted in increased initial renal failure and tubular injury compared with wild-type mice. Macrophage and myofibroblast numbers, tubular damage, and plasma urea levels were increased, and tubular proliferation reduced in the kidneys of syndecan-1 deficient compared with wild-type mice 14 days following injury. Hence syndecan-1 promotes tubular survival and repair in murine ischemia/reperfusion injury and correlates with functional improvement in human renal allograft transplantation.

Alcohol consumption, new onset of diabetes after transplantation, and all-cause mortality in renal transplant recipients.

BACKGROUND: Renal transplant recipients (RTR) are often advised to refrain from alcohol because of possible interaction with their immunosuppressive medication. Although moderate alcohol consumption is associated with reduced risk of diabetes and mortality in the general population, this is unknown for RTR. Therefore, we investigated the association of alcohol consumption with new onset of diabetes after transplantation (NODAT), mortality, and graft failure in RTR. METHOD: RTR were investigated between 2001 and 2003. Alcohol consumption was assessed by self-report. Mortality and graft failure was recorded until May 2009. RESULTS: Six hundred RTR were studied (age 51 ± 12 years, 55% men). Of these RTR, 48% were abstainers, 38% had light alcohol intake, 13% had moderate intake, and 1% were heavy consumers. Moderate alcohol consumption was associated with a lower risk of developing NODAT over the follow-up period than was abstention (OR = 0.36 [0.2-0.6], P = <0.001). During follow-up for 7.0 years [6.2-7.5 years], 133 recipients died. In Cox regression analyses, moderate alcohol consumption was associated with lower mortality period than was abstention (hazard ratio = 0.40 [0.2-0.8], P = 0.009). Adjustment for confounders, including age and smoking, did not materially change this association. No association was found between alcohol consumption and graft failure. CONCLUSIONS: Moderate alcohol consumption is associated with low prevalence of NODAT and reduced risk for mortality in RTR, in line with findings in the general population. These findings refute the common advice to refrain from alcohol in RTR.

Smoking is a risk factor for graft failure and mortality after renal transplantation.

BACKGROUND: Smoking in renal transplant recipients (RTR) is an acknowledged cardiovascular risk factor. It is, however, unclear whether smoking also increases the risk of graft failure (GF). METHOD: In this study, we prospectively assessed the association of current smoking versus past and never smoking with GF and mortality in 604 RTR (age 51.5 ± 12.1 years, 55% male). RESULTS: At inclusion, 133 (22%) were current smokers, 255 (42%) were past smokers and 216 (36%) never smoked. During follow-up of 5.3 (4.7-5.7) years, 41 (7%) RTR experienced GF and 95 RTR (16%) died. Current smoking RTR had higher risk for GF compared to never smoking RTR (hazard ratio, HR = 3.3, 95% CI 1.5-7.1, p = 0.002). Past smoking RTR had similar risk of GF as never smoking RTR (HR = 1.1, 95% CI 0.5-2.6, p = 0.7). Current smoking RTR and past smoking RTR were at higher risk for death than never smoking RTR (HR = 2.1, 95% CI 1.1-3.8, p = 0.016, and HR = 2.4, 95% CI 1.4-4.0, p = 0.001, respectively). CONCLUSION: Smoking after renal transplantation is associated with risk for GF and mortality. Since past smoking is a risk factor for mortality but not for GF, smoking cessation may be beneficial to RTR in delaying GF in long term.

Albuminuria, proteinuria, and novel urine biomarkers as predictors of long-term allograft outcomes in kidney transplant recipients.

BACKGROUND: Proteinuria is an established marker of decreased kidney function after kidney transplant. It recently has been suggested that albuminuria might be a more reliable marker. Although albuminuria often is regarded as a marker of glomerular damage, because chronic renal allograft damage is believed to be predominantly an interstitial process, albuminuria in this case might reflect tubular damage. Accordingly, we investigated the value of albuminuria, proteinuria, and tubular damage markers (KIM-1 [kidney injury molecule 1], NAG [N-acetyl-ß-d-glucosaminidase], NGAL [neutrophil gelatinase-associated lipocalin], and H-FABP [heart fatty acid binding protein]) in predicting graft outcome in kidney transplant recipients. STUDY DESIGN: Prospective observational cohort study. SETTING & PARTICIPANTS: 606 patients visiting our outpatient kidney transplant clinic in 2001-2003 were included and used in the analysis for death-censored graft failure. Median follow-up was 4.7 (25th-75th percentile, 3.8-5.2) years. 577 patients had follow-up longer than 1 year and were included in the analysis for estimated glomerular filtration rate (eGFR) decrease. Median follow-up was 3.2 (25th-75th percentile, 2.7-3.7) years. PREDICTORS: Urine protein, albumin, and tubular damage markers in 24-hour urine samples. OUTCOMES: Death-censored graft failure and decrease in eGFR. RESULTS: There were 42 patients with graft failure; mean eGFR change was -0.46 ± 3.7 (standard deviation) mL/min/1.73 m(2)/y. The area under the receiver operating characteristic curve for death-censored graft failure showed that albuminuria (0.78; 95% CI, 0.59-0.76) was significantly higher than proteinuria (0.67; 95% CI, 0.59-0.76; P = 0.001), NGAL (0.63; 95% CI, 0.52-0.74; P = 0.02), and H-FABP (0.62; 95% CI, 0.53-0.73; P = 0.005) and not significantly different from KIM-1 (0.74; 95% CI, 0.66-0.82) and NAG (0.75; 95% CI, 0.67-0.83). Results were similar for the eGFR decrease outcome. LIMITATIONS: Single-center observational study. CONCLUSIONS: Measuring albuminuria may provide superior predictions for long-term renal outcomes after kidney transplant than total proteinuria. Additional assessment of urinary excretion of tubular damage markers may have limited value.

Low physical activity and risk of cardiovascular and all-cause mortality in renal transplant recipients.

BACKGROUND AND OBJECTIVES: Low physical activity (PA) is a risk factor for mortality in the general population. This is largely unexplored in renal transplant recipients (RTRs). We studied whether PA is associated with cardiovascular and all-cause mortality in a prospective cohort of RTR. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Between 2001 and 2003, 540 RTRs were studied (age, 51 ± 12 years; 54% male). PA was assessed using validated questionnaires (Tecumseh Occupational Activity Questionnaire and the Minnesota Leisure Time Physical Activity Questionnaire). Cardiovascular and all-cause mortality were recorded until August 2007. RESULTS: Independent of age, PA was inversely associated with metabolic syndrome, history of cardiovascular disease, fasting insulin, and triglyceride concentration, and positively associated with kidney function and 24-hour urinary creatinine excretion (i.e., muscle mass). During follow-up for 5.3 years (range, 4.7 to 5.7 years), 81 RTRs died, with 37 cardiovascular deaths. Cardiovascular mortality was 11.7, 7.2, and 1.7%, respectively, according to gender-stratified tertiles of PA (P=0.001). All-cause mortality was 24.4, 15.0, and 5.6% according to these tertiles (P<0.001). In Cox regression analyses, adjustment for potential confounders including history of cardiovascular disease, muscle mass, and traditional risk factors for cardiovascular disease did not materially change these associations. CONCLUSIONS: Low PA is strongly associated with increased risk for cardiovascular and all-cause mortality in RTRs. Intervention studies are necessary to investigate whether PA improves long-term survival after renal transplantation.

Renal function equations before and after living kidney donation: a within-individual comparison of performance at different levels of renal function.

BACKGROUND AND OBJECTIVES: The Modification of Diet in Renal Disease (MDRD) study equation and the Cockcroft-Gault (CG) equation perform poorly in the (near-) normal range of GFR. Whether this is due to the level of GFR as such or to differences in individual characteristics between healthy individuals and patient with chronic kidney disease (CKD) is unknown. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We evaluated the performance of MDRD, CG per BSA (CG/(BSA)) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations compared with measured GFR (mGFR; I-iothalamate) at 4 months before and 2 months after donation in 253 consecutive living kidney donors. RESULTS: mGFR declined from 103 ± 15 to 66 ± 11 ml/min per 1.73 m(2) after donation. All equations underestimated mGFR at both time points. Arithmetic performance analysis showed improved performance after donation of all equations, with significant reduction of bias after donation. Expressed as percentage difference, mGFR-estimated GFR (eGFR) bias was reduced after donation only for CG/(BSA). Finally, in 295 unselected individuals who were screened for donation, mGFR was below the cutoff for donation of 80 ml/min per 1.73 m(2) in 19 individual but in 166, 98, and 74 for MDRD, CDK-EPI, and CG/(BSA), respectively. CONCLUSIONS: A higher level of GFR as such is associated with larger absolute underestimation of true GFR by eGFR. For donor screening purposes, eGFR should be interpreted with great caution; when in doubt, true GFR should be performed to prevent unjustified decline of prospective kidney donors.

Influence of C-reactive protein and urinary protein excretion on prediction of graft failure and mortality by serum albumin in renal transplant recipients.

BACKGROUND: Hypoalbuminemia is an established predictor of poor outcome in renal transplant recipients (RTR). It is considered to reflect inflammation, poor nutritional status, or proteinuria. We explored the roles of high-sensitivity C-reactive protein (hsCRP) and urinary protein excretion in prediction of graft failure and mortality by serum albumin in RTR. METHODS: We included 605 RTR at a median (interquartile range) time of 6.0 years (2.5-11.5 years) after transplantation for baseline measurements. RESULTS: At baseline, urinary protein excretion (beta=-0.242, P<0.0001), hsCRP concentration (beta=-0.207, P<0.0001), recipient age (beta=-0.115, P=0.004), living kidney donor (beta=0.100, P=0.01), and a history of myocardial infarction (beta=-0.084, P=0.03) were independently related to serum albumin. Prospectively, 94 RTR died and 42 had graft failure during 5.3 years (4.7-5.7 years) of follow-up. After adjustment for potential confounders, including hsCRP and urinary protein excretion in Cox-regression analyses, low serum albumin was significantly associated with graft failure (hazard ratio=0.34 [95% confidence interval=0.15-0.76] per g/dL, P=0.008) and mortality (hazard ratio=0.43 [95% confidence interval=0.24-0.78] per g/dL, P=0.005), with significant modification of the effect of serum albumin on graft failure by urinary protein excretion (P=0.003). CONCLUSION: Low serum albumin concentrations predict graft failure and mortality in RTR independent of hsCRP and urinary protein excretion. The effect of serum albumin on graft failure is strongly modified by urinary protein excretion. These results suggest that chronic low-grade inflammation is not an important mechanism underlying inverse associations of serum albumin with graft failure and mortality. They also suggest that proteinuria is involved in the association of low serum albumin with graft failure.

Gastrointestinal symptoms in kidney transplant recipients: what about silent sufferers?

CONTEXT: Transplantation improves health-related quality of life in patients with end-stage renal disease. However, primarily because of adverse effects of medication, among other gastrointestinal symptoms, health-related quality of life is not completely restored to normal. Although many patients have various gastrointestinal symptoms only a small proportion may be reported spontaneously. OBJECTIVE: To evaluate the prevalence of gastrointestinal symptoms in kidney transplant recipients, also the difference between spontaneously reported symptoms and symptoms elicited by specific questioning was assessed. The burden of these symptoms in daily life also was analyzed. DESIGN: A single-center, sequential, mixed method study to assess the difference between spontaneous patient reports of gastrointestinal symptoms and active screening by a questionnaire in kidney transplant patients. PATIENTS: In February 2008, patients received a questionnaire on gastrointestinal symptoms; notes in medical records were consulted for patients scoring less than 100. In June 2008, those patients received a second, extended questionnaire aimed to assess the burden of gastrointestinal symptoms in daily life. RESULTS: Ninety-two of 513 patients eventually proved to have gastrointestinal symptoms. Completed questionnaires were compared with notes in the patients' files of the past year. A total of 51 of these 92 patients appeared to have not mentioned their gastrointestinal symptoms during the outpatient clinic visits. Of these 51 patients, 37 reported a significant impact of gastrointestinal symptoms on daily life. CONCLUSIONS: The silent sufferer exists. Specific questioning helps to improve communication concerning bothersome gastrointestinal symptoms. To assess the burden of these symptoms, a validated questionnaire should be developed.

Plasma procalcitonin is an independent predictor of graft failure late after renal transplantation.

BACKGROUND: Chronic low-grade inflammation is involved in chronic transplant dysfunction after renal transplantation. Procalcitonin (PCT), known to reflect microbial inflammation, may also reflect ongoing noninfectious chronic low-grade inflammation in organ parenchyma, including transplanted kidneys. We aimed to compare predictive performance of plasma PCT for development of graft failure in renal transplant recipients (RTR) with that of high-sensitivity C-reactive protein (hsCRP), an established marker of systemic chronic low-grade inflammation. METHODS: We included 575 RTR with functioning grafts for more than or equal to 1 year at a median (interquartile range) time of 6.1 (2.9-11.7) years posttransplant. PCT was determined using an ultrasensitive immunoluminometric assay and hsCRP using high-sensitivity enzyme-linked immunosorbent assay. RESULTS: Median (interquartile range) plasma PCT and hsCRP concentrations were 0.023 (0.017-0.036) ng/mL and 2.1 (0.8-4.9) mg/L, respectively. After a median (interquartile range) of 5.2 (4.5-5.7) years of follow-up, incidence of graft failure was 0.5%, 2.6%, and 18.5% according to increasing PCT tertiles (P<0.001 by log-rank test). Area under the curve of receiver operating characteristic analysis of PCT for prediction of graft failure was significantly higher than that of hsCRP (0.84 vs. 0.56, P<0.001). After adjustment for potential confounders, PCT remained an independent predictor of graft failure (hazard ratio=2.3 [95% confidence interval 1.4-3.7] per doubling PCT, P=0.0004), whereas this was not the case for hsCRP. CONCLUSION: We identified plasma PCT as a strong and an independent predictor of graft failure in RTR. These data suggest that PCT in RTR reflects ongoing inflammation in parenchyma of transplanted kidneys. Further studies are required to investigate whether PCT could be of use as an early biomarker for chronic transplant dysfunction.

Pre-kidney-transplant blood transfusions do not improve transplantation outcome: a Dutch national study.

BACKGROUND: Female renal transplant candidates are prone to be sensitized by prior pregnancies, and undetected historical sensitization might decrease transplantation outcome. Hypothesis of our study was that pre-transplant blood transfusions (PTFs) can elucidate historical sensitization and that the avoidance of the associated antigens can improve transplantation outcome. METHODS: Data from all female non-immunized renal transplant candidates who received a random PTF (rPTF) (n = 620), matched PTF (mPTF) (one HLA-A and B and one HLA-DR match) (n = 86) or donor-specific blood transfusion (DST) (n = 100) between 1996 and 2006 were collected. Complement-dependent cytoxicity was used to detect anti-HLA antibodies. Sensitization and transplantation outcomes after a PTF were analyzed. Non-immunized female renal transplant recipients who did not receive a PTF were used as the control group. RESULTS: In 165 patients, anti-HLA antibodies (IgG) were detected after the PTF. Both historical and primary sensitizations were found. A DST induced donor-specific anti-HLA antibodies in 25% of the DST recipients. Our policy did not improve transplantation outcome in recipients of a kidney from a deceased donor (n = 368) or in recipients of a living donor [DST (n = 49) and mPTF (n = 66)]. CONCLUSIONS: A PTF did elucidate historical sensitization but induce primary sensitization as well. No beneficial effect of PTFs on transplantation outcome was found, and PTFs with the intention to detect historical sensitization are therefore not suggested.

N-terminal pro-B-type natriuretic peptide and mortality in renal transplant recipients versus the general population.

BACKGROUND: Mortality rates are higher in renal transplant recipients (RTR) than in the general population (GP). It is unknown what risk factors account for this difference. METHODS: We prospectively followed a cohort of 606 RTR for 3026 person-years, during which 95 died. A GP cohort of 3234 subjects was followed for 24,940 person-years, during which 130 died. RESULTS: All investigated risk factors, except ethnicity, body mass index, and total cholesterol, differed significantly between cohorts, with an adverse risk profile in the RTR. The age-adjusted and gender-adjusted hazard ratio for mortality in RTR was 6.2 (95% confidence interval [CI] 4.6-8.3) compared with GP, which was reduced to 2.4 (95% CI 1.6-3.6), 4.3 (95% CI 3.0-6.1), and 5.0 (95% CI 3.5-7.3) after additional adjustment for differences in N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatinine clearance, and need for antihypertensive medication, respectively (all P<0.001), whereas adjustment for variables more related to atherosclerosis, including history of cardiovascular disease, diabetes, and high-density lipoprotein cholesterol, did not affect the difference in mortality between RTR and GP. Associations of NT-proBNP, creatinine clearance, and the use of antihypertensive medication with mortality were significantly steeper in RTR than in GP. Risk for mortality was similar for RTR and GP with low NT-proBNP (<100 pg/mL). CONCLUSIONS: Elevated NT-proBNP, low creatinine clearance, and need for antihypertensive medication are stronger risk factors for mortality in RTR than in GP. The increased mortality seen in the RTR population may well be related to cardiac failure rather than "accelerated atherosclerosis."

Machine perfusion or cold storage in deceased-donor kidney transplantation.

BACKGROUND: Static cold storage is generally used to preserve kidney allografts from deceased donors. Hypothermic machine perfusion may improve outcomes after transplantation, but few sufficiently powered prospective studies have addressed this possibility. METHODS: In this international randomized, controlled trial, we randomly assigned one kidney from 336 consecutive deceased donors to machine perfusion and the other to cold storage. All 672 recipients were followed for 1 year. The primary end point was delayed graft function (requiring dialysis in the first week after transplantation). Secondary end points were the duration of delayed graft function, delayed graft function defined by the rate of the decrease in the serum creatinine level, primary nonfunction, the serum creatinine level and clearance, acute rejection, toxicity of the calcineurin inhibitor, the length of hospital stay, and allograft and patient survival. RESULTS: Machine perfusion significantly reduced the risk of delayed graft function. Delayed graft function developed in 70 patients in the machine-perfusion group versus 89 in the cold-storage group (adjusted odds ratio, 0.57; P=0.01). Machine perfusion also significantly improved the rate of the decrease in the serum creatinine level and reduced the duration of delayed graft function. Machine perfusion was associated with lower serum creatinine levels during the first 2 weeks after transplantation and a reduced risk of graft failure (hazard ratio, 0.52; P=0.03). One-year allograft survival was superior in the machine-perfusion group (94% vs. 90%, P=0.04). No significant differences were observed for the other secondary end points. No serious adverse events were directly attributable to machine perfusion. CONCLUSIONS: Hypothermic machine perfusion was associated with a reduced risk of delayed graft function and improved graft survival in the first year after transplantation. (Current Controlled Trials number, ISRCTN83876362.)

Determinants of insulin resistance in renal transplant recipients.

BACKGROUND: Insulin resistance is considered to play an important role in the development of cardiovascular disease, which limits long-term renal transplant survival. Renal transplant recipients are more insulin-resistant compared with healthy controls. It is not known to date which factors relate to this excess insulin resistance. Therefore, we investigated which factors are related to insulin resistance long-term after renal transplantation. METHODS: All renal transplant recipients at our outpatient clinic with a functioning graft for more than one year were invited to participate. We excluded diabetic recipients. Recipient, donor, and transplant characteristics were collected as putative determinants. We used fasting insulin, homeostasis model assessment index, and McAuley's index as valid estimates of insulin resistance. Linear regression models were created to investigate independent determinants of all indexes. RESULTS: A total of 483 recipients (57% male, 50+/-12 years) were analyzed at a median (interquartile range) time of 6.0 (2.6-11.6) years posttransplant. The most consistent determinants across all three indices were body mass index (P<0.001), waist-to-hip ratio (P<0.001), and prednisolone dose (P<0.05). Independent associations were present for total cholesterol (P<0.001), high-density lipoprotein cholesterol (P<0.001), creatinine clearance (P<0.05), recipient age (P<0.001), and gender (P< or =0.002). No independent associations were present for transplant-related factors such as acute rejection treatment or cytomegalovirus seropositivity. CONCLUSIONS: Our results indicate that obesity, distribution of obesity, and prednisolone treatment are the predominant determinants of insulin resistance long term after transplantation. Insulin resistance after renal transplantation could be managed favorably by weight and prednisolone dose reduction, which may reduce cardiovascular disease.

Elevated levels of C-reactive protein independently predict accelerated deterioration of graft function in renal transplant recipients.

BACKGROUND: Chronic transplant dysfunction is characterized by a gradual decline in renal function with slowly rising serum creatinine. The underlying mechanism is thought to include inflammation and atherosclerosis. C-reactive protein (CRP) is a well-established marker of both inflammation and atherosclerosis. In this prospective study, we investigated whether CRP could be of use as a clinical marker for early identification of renal transplant recipients at increased risk of deterioration of graft function. METHODS: In this prospective study, all participating patients (n = 606) visited the out-patient clinic at least once a year, and serum creatinine was assessed at every visit. Subjects with a follow-up of <1 year (n = 31) were excluded from analysis. RESULTS: A total of 575 patients participated at a median (interquartile range) time of 5.9 (2.6-11.3) years post-transplantation. Median time of follow-up was 3.0 (2.4-3.4) years. Changes in serum creatinine during follow-up were -0.45 (-4.83-4.76) micromol/l/year in 172 subjects with CRP <1.0 mg/l, 1.04 (-3.36-6.12) micromol/l/year in 184 subjects with CRP 1.0-3.0 mg/l and 2.34 (-3.33-9.07) micromol/l/year in 219 subjects with CRP >3.0 mg/l (P < 0.05 for comparison of the three groups). Proteinuria (P = 0.003), CMV IgG titre (P = 0.01), donor age (P = 0.01), CRP concentration (P = 0.02), recipient age (P = 0.02) and recipient gender (P = 0.047) were independently associated with change in serum creatinine during follow-up in a multivariate analysis. CONCLUSIONS: Elevated levels of CRP independently predict accelerated deterioration of graft function in renal transplant recipients >1 year post-transplantation. Further prospective studies are required to investigate whether early intervention can prevent deterioration of graft function in subjects with elevated levels of CRP.

Risk factors for chronic transplant dysfunction and cardiovascular disease are related to accumulation of advanced glycation end-products in renal transplant recipients.

BACKGROUND: Accumulation of advanced glycation end-products (AGEs) has been implicated in the pathogenesis of chronic transplant dysfunction and cardiovascular disease in renal transplant recipients. We aimed to investigate which factors are associated with tissue AGE accumulation in renal transplant recipients. METHODS: The AGE accumulation was assessed using a validated skin-autofluorescence reader (AFR) in 285 consecutive renal transplant recipients (57% male, aged 50+/-12 years) visiting the outpatient clinic at a median (interquartile range) time of 73 (32-143) months after transplantation. Furthermore, various transplant- and recipient-related factors of interest were collected. RESULTS: Average skin-autofluorescence of lower arm and leg was 2.7+/-0.8 a.u. Skin-autofluorescence was positively determined by recipient age, systolic blood pressure, smoking, high-sensitivity C-reactive protein, duration of pre-transplant dialysis, and negatively by plasma vitamin C levels, creatinine clearance at baseline, and change in creatinine clearance since one year after transplantation in linear multivariate regression analysis. Together, these factors explained 41% of the variance of skin-autofluorescence. CONCLUSIONS: Skin-autofluorescence was associated with several risk factors for cardiovascular disease and chronic renal transplant dysfunction. These results are in line with the hypothesis that AGEs play a role in the pathogenesis of these conditions in renal transplant recipients. Prospective studies are required to investigate whether the AFR can be used as a simple, non-invasive tool to identify and monitor patients at risk for chronic renal transplant dysfunction and cardiovascular disease.