Comorbidities and survival of patients with type 1 diabetes on renal replacement therapy.

AIMS/HYPOTHESIS: Comorbidities are frequent among type 1 diabetes patients on renal replacement therapy, yet the effect of comorbidities on survival is unknown. Our aim was to estimate this effect. METHODS: An incident cohort of all patients with type 1 diabetes entering chronic renal replacement therapy (n = 656) in Finland between 2000 and 2008 was followed until death or the end of follow-up on 31 December 2008. All data were obtained from the Finnish Registry for Kidney Diseases, which collects information on comorbidities at the start of renal replacement therapy. The main outcome measure was relative risk of death according to comorbidities. RESULTS: At start of renal replacement therapy, 22% of the patients with type 1 diabetes had coronary artery disease, 19% peripheral vascular disease, 11% cerebrovascular disease, 33% left ventricular hypertrophy and 7% heart failure. All these comorbidities were significant predictors of death in univariate analyses (RR 1.6-4.9). The 5 year survival probability of patients without comorbidities was 74%, while it was 56% and 37%, respectively, for those with one or more than one comorbidity. When the comorbidities were studied in a multivariate model, adjusting for age and sex, peripheral vascular disease (RR 1.9), left ventricular hypertrophy (RR 1.7) and heart failure (RR 2.5) remained independent risk factors for death. Calculations indicated that one-third of deaths in the study population could be attributed to comorbidities. CONCLUSIONS/INTERPRETATION: Among patients with type 1 diabetes entering renal replacement therapy, comorbidities are common and strong predictors of death. Therefore, it is essential to identify and adequately treat comorbidities.

Risk factors for end-stage renal disease in a community-based population: 26-year follow-up of 25,821 men and women in eastern Finland.

BACKGROUND AND OBJECTIVE: There are very few European cohort studies assessing the risk factors of end-stage renal disease (ESRD) in a community-based population. This study investigated the predictors of ESRD in Finland. DESIGN: Prospective cohort study. SETTING: Eastern Finland. SUBJECTS: A random sample of 25,821 men and women aged 25-64 years from the national population register participating in three independent cross-sectional population surveys in 1972, 1977 and 1982. Only the subjects without diagnosis of ESRD or chronic kidney disease based on the national register data were included in the study. MAIN OUTCOME MEASURE: Initiation of renal replacement therapy (dialysis or kidney transplantation) identified from the Finnish Registry for Kidney Diseases through December 31, 2006. RESULTS: A total of 94 cases with ESRD were identified during a mean follow-up period of 26.5 years. In a multivariate proportional subdistribution hazard regression analysis, taking into account death as a competing risk event, diabetes (hazard ratio [HR] 4.76, 95% confidence interval [CI] 2.32-9.79), hypertension (HR 2.21, 95% CI 1.19-4.12), obesity defined as body mass index > or =30 kg m(-2) (HR 2.02, 95 %CI 1.10-3.71) and male gender (HR 1.68, 95% CI 1.19-4.12) were independent risk factors for ESRD. CONCLUSION: The findings of the present study confirm that modifiable risk factors play a major role in the development of ESRD in the North-European population. People with diabetes, hypertension or obesity should be considered as the target groups when planning preventive measures to control the future epidemic of ESRD.

Is Cystatin C more sensitive than creatinine in detecting early chronic allograft nephropathy?

BACKGROUND: Cystatin C (CyC) has been suggested as a more accurate indicator of renal function than creatinine (Crea). CyC performance against graft histopathology has not been investigated. AIM: To compare CyC and Crea-based methods as predictors of chronic allograft damage index (CADI). MATERIAL AND METHODS: 105 protocol biopsies obtained at 6 months post-transplantation were classified with Banff'97 and CADI. CyC and Crea were measured concomitantly. Histology was correlated to CyC, Crea, their reciprocals, CyC-estimated GFR (Larsson), Cockroft and Gault (C&G) and abbreviated MDRD using Kendall's Tau. The area under ROC curve (ROC-auc),sensitivity/specificity, positive and negative predictive values were calculated at CADI cut-off of 2. RESULTS: Mild histological changes were best revealed by Crea, although with modest sensitivity/ specificity. A Crea threshold of 111 micromol/l distinguished 74% of the patients with CADI > 2 and excluded this condition in 66%. For Crea, ROC-auc was 0.72 (p < 0.001). Crea and 1/Crea correlated best to CADI, chronic allograft nephropathy, chronic inflammation, tubular atrophy, vascular changes and glomerulopathy. Neither C&G nor MDRD improved Crea performance alone. CyC and Larsson formula performed the same (ROC-auc 0.67). A CyC threshold of 1.12 mg/l distinguished 69% of the patients with CADI > 2 and excluded it in 60%. Significant Tau correlation was found between CyC, 1/CyC and Larsson with CADI, chronic inflammation, tubular atrophy and chronic vascular changes. CONCLUSIONS: CyC, 1/CyC and Larsson-estimated GFR did not offer significant advantages over Crea in predicting mild histological allograft changes. Protocol biopsy provides information that cannot be sensitively predicted by biochemical measurements used in clinical practice.

Long-term cardiac outcomes in renal transplant recipients receiving fluvastatin: the ALERT extension study.

Renal transplant recipients (RTR) have an increased risk of premature cardiovascular disease. The ALERT study is the first trial to evaluate the effect of statin therapy on cardiac outcomes following renal transplantation. Patients initially randomized to fluvastatin or placebo in the 5-6 year ALERT study were offered open-label fluvastatin XL 80 mg/day in a 2-year extension to the original study. The primary endpoint was time to first major adverse cardiac event (MACE). Of 1787 patients who completed ALERT, 1652 (92%) were followed in the extension. Mean total follow-up was 6.7 years. Mean LDL-cholesterol was 98 mg/dL (2.5 mmol/L) at last follow-up compared to a pre-study level of 159 mg/dL (4.1 mmol/L). Patients randomized to fluvastatin had a reduced risk of MACE (hazards ratio [HR] 0.79, 95% CI 0.63-0.99, p = 0.036), and a 29% reduction in cardiac death or definite non-fatal MI (HR 0.71, 95% CI 0.55-0.93, p = 0.014). Total mortality and graft loss did not differ significantly between groups. Fluvastatin produces a safe and effective reduction in LDL-cholesterol associated with reduced risk of MACE in RTR. The lipid-lowering and cardiovascular benefits of fluvastatin are comparable to those of statins in other patient groups, and support use of fluvastatin in RTR.

Quantitative PCR in the diagnosis of CMV infection and in the monitoring of viral load during the antiviral treatment in renal transplant patients.

Cytomegalovirus (CMV) infection is a significant problem in transplantation. In this study, a quantitative PCR test was compared with the CMVpp65 antigenemia assay not only in the diagnosis CMV infections but especially in the monitoring of viral loads during ganciclovir treatment of CMV disease in individual renal transplant patients. Altogether 342 blood specimens were obtained from 116 patients. Blood specimens were used for Cobas Amplicor Monitor plasma PCR and for the pp65 assay. Also shell vial culture was performed. The patients with a positive pp65 finding were monitored for CMV weekly during ganciclovir treatment and/or until the antigenemia subsided. CMV was detected in 31/116 (27%) patients, of whom 14 (12%) developed CMV disease and were treated with ganciclovir. CMV was found by shell vial culture in 13/14 cases, but by PCR and pp65 test in all 14 patients. CMV was detected in 156 (45%) samples; by PCR in 121/156 (range 344-103,000 copies/ml) and by pp65 test in 138/156 (range 1-1,000 positive cells/50,000 leukocytes) and by culture in 59/156 (38%) only. The peak viral loads were significantly (P<0.0001) higher in CMV disease than in untreated infections (19,650 vs. 379 copies/ml, and 100 vs. 5pp65 positive cells). In the monitoring of individual patients, the time-related CMV-DNAemia and pp65 antigenemia correlated well during the treatment of CMV disease. In conclusion, Cobas Amplicor Monitor plasma PCR and CMVpp65 antigen assays can be equally used in the diagnosis CMV infection and in the monitoring of viral load during antiviral treatment.

Comparison of two quantitative CMV PCR tests, Cobas Amplicor CMV Monitor and TaqMan assay, and pp65-antigenemia assay in the determination of viral loads from peripheral blood of organ transplant patients.

BACKGROUND: Quantitative PCR assays have become the most common methods in the determination of viral load during cytomegalovirus (CMV) infection of transplant patients. However, usually these tests are still quite time-consuming and labor-intensive which diminishes their utility of these tests in routine diagnostic laboratories. OBJECTIVES: The objective of this study was to develop a quantitative CMV PCR test which is time-saving and easy to perform for the detection and monitoring of CMV infection of transplant patients. STUDY DESIGN: The quantitative real time CMV PCR assay using TaqMan chemistry and an automated sample preparation system, MagNA Pure LC, was developed. The designed quantitative CMV test was compared to commercial quantitative PCR test, Cobas Amplicor Monitor, in the determination of CMV DNA loads in plasma samples of liver and kidney transplant patients. The results were also correlated with the CMV pp65-antigenemia test. The clinical material of 270 blood specimens of transplant patients were tested using these two PCR methods and pp65-antigenemia test in parallel. Plasma samples were used for PCR assays and leucocytes for the antigenemia test. RESULTS: The TaqMan assay described was easy to perform, it was rapid (3-4 h) and hands-on time needed for performing the test was short. The detection limit of the assay was 250 copies/ml (cps/ml) plasma and the linear range up to 25,000,000 cps/ml. TaqMan assay was the most sensitive test detecting 92% of the CMV positive findings. Cobas Monitor detected 80% and pp65 test 88% of the positive findings. The correlations between TaqMan and antigenemia assays, and between Cobas Amplicor and antigenemia were statistically significant and high, R = 0.84 (P < 0.0001) and R = 0.80 (P < 0.0001), respectively. Also correlation between two PCR tests was statistically significant (R = 0.64, P < 0.0001). Of the 27 patient studied, 19 demonstrated CMV antigenemia and DNAemia in their blood during the post transplant monitoring. Thirteen of these patients developed a symptomatic CMV infection and were treated with ganciclovir. The peak viral loads of symptomatic patients were statistically higher by all three methods than those of asymptomatic patients. CONCLUSIONS: The developed real time TaqMan assay was rapid and easily performed and could be the best alternative for the diagnosis of CMV infection and monitoring of liver and kidney transplant patients.

Elevated serum C-reactive protein associates with deterioration of renal function in transplant recipients.

AIM: Since t he elevated concentration of serum C-reactive protein (CRP) is a sensitive indicator of underlying inflammation, we investigated the association between serum CRP during the initial 6 post-transplantation months and histopathological changes in the 6-month protocol biopsies in 79 patients. We stained the biopsies for CRP and C3 to elucidate a possible role of CRP in renal injuries. RESULTS: Forty patients showed no or minimal (Grade 0-1) tubular atrophy or interstitial fibrosis and 39 patients mild to moderate (Grade > or = 2) chronic histopathological changes. The latter group had had higher concentration of CRP during the first 6 post-transplant months. Because the histopathological changes predict poor long-term prognosis, we followed--from 6th month onwards--40 patients who had no or minimal histopathologic changes, and analyzed the association between CRP elevation and development of chronic allograft dysfunction. During this follow-up period (mean 51, range 14-72 months), 23 of 40 patients retained normal CRP level (Group A, mean CRP 1.12 mg/l), and 17 patients had elevated CRP concentrations (Group B, mean CRP 4.16 mg/l); 24-hour creatinine clearance improved or remained the same in all Group A patients, whereas it decreased in 7 of 17 (41%) of Group B patients (p < 0.001). In Group B patients, the annual change of creatinine clearance correlated inversely with the mean CRP concentration (r = -0.682, p < 0.01). CONCLUSION: Our results show that histological changes in 6-month biopsies were more prominent in patients with more transplantation-associated complications, infections and frequently higher CRP levels during the initial 6 post-transplant months than in those with lower CRP levels. During post-biopsy follow-up, we found low-grade systemic inflammation--measured as elevated CRP--to associate with impairment of graft function in patients with no or minimal histological findings in 6-month biopsies, and permanently low CRP to rule out chronic allograft dysfunction.

Glucose metabolism in relatives of type 1 diabetic patients with albuminuria.

OBJECTIVE: Diabetic nephropathy in type 1 diabetes is associated with familial aggregation of diabetes. In order to explore the mechanisms behind this association, we assessed glucose metabolism in glucose-intolerant relatives of type 1 diabetic patients with (ALB+) or without (ALB-) elevated urinary albumin excretion rate (UAER). METHODS: Glucose tolerance and insulin secretion were assessed using an oral glucose tolerance test (OGTT) and insulin sensitivity was measured with the short insulin tolerance test (ITT). RESULTS: One hundred and fourteen parents and siblings of 43 type 1 diabetic patients with ALB+ (UAER > or = 20 microg/min) were identified and 93 parents and siblings of 39 patients with ALB- (UAER < 20 microg/min). From this pool, a further selection was made of those (25 and 13 relatives of patients with ALB+ and ALB-, respectively) with mild abnormalities of glucose metabolism (fasting plasma glucose < 7.8 mmol/L; 2 h plasma glucose > or = 7.8 mmol/L in the OGTT). No difference in insulin sensitivity was discernible between the two groups of relatives (KITT 3.3 +/- 1.0 vs. 3.2 +/- 1.0%/min, p=NS). Although there were no significant differences in the incremental areas under glucose or insulin curves (AUC) between relatives of ALB+ and ALB- in the OGTT, the insulin secretory response to the rise in plasma glucose was impaired in relatives of patients with ALB+ (insulin AUC/glucose AUC: 7.1 [1.1-30.8] vs. 9.8 [3.6-52.2], p=0.039). CONCLUSIONS: Glucose-intolerant relatives of patients with elevated UAER seem to be characterized by impaired insulin secretion. Genetic or environmental factors related to impaired insulin secretion may be important in the development of diabetic nephropathy.

Factors associated with progression of IgA nephropathy are related to renal function--a model for estimating risk of progression in mild disease.

BACKGROUND: A number of factors are linked to the outcome of IgA nephropathy (IgAN). However, it has been difficult to compare results of studies since patient populations have varied greatly. There were 3 aims in the study reported here, namely to compare factors associated with renal outcome in IgAN patients with different levels of renal function on diagnosis; to determine factors which were independently associated with progression of renal disease in initially mild IgAN; and to create a model for the estimation of the risk of progression in individual IgAN patients with normal renal function on diagnosis. METHODS: Two hundred and fifty-nine IgAN patients who had been followed on average for 9.1 (SD 4.5) after diagnosis were divided into 2 groups on the basis of renal function on diagnosis. In group 1 (98 patients), Ccr (creatinine clearance, estimated by the Cockcroft-Gault formula) was < 85 ml/min, in group 2 (161 patients) > or = 85 ml/min. Univariate analyses were used to find significant differences between progressors and non-progressors in both groups. Logistic regression analysis was used to determine factors independently associated with progression in group 2. RESULTS: Several factors were found to be associated with outcome in both groups, such as hypertension, level of Ccr, serum cholesterol, proteinuria, and also histopathological changes. Factors associated with progression in patients with initially decreased renal function (group 1), were predictable, such as male sex, absence of episodes of macroscopic hematuria, serum urate level and degree of tubular atrophy. Surprisingly, in patients with initially normal renal function (group 2), numbers of urinary erythrocytes were associated with outcome. The factors independently associated with progression in this group were number of urinary erythrocytes, existence of hypertension and in histopathology arteriolosclerosis and the level of glomerular score. A model for estimating risk of progression on the basis of various combinations of factors found to be independently associated with outcome is presented. CONCLUSIONS: We concluded that association between variable and outcome in IgAN depends partly on renal function at the time of assessment of the factor. Since there are factors which are independently associated with the outcome of early and apparently mild disease, early diagnosis of IgAN is desirable: outcome in mild IgAN can be predicted reliably on the basis of factors found to be independently associated with outcome.

Henoch-Schoenlein nephritis in adults-clinical features and outcomes in Finnish patients.

BACKGROUND: Henoch-Schoenlein purpura (HSP) is a small vessel vasculitis that often involves the kidneys. It affects many more children than adults. Few studies on HSP nephritis (HSN) in adult patients have been reported. One aim of the study described here was to determine clinical features in adults diagnosed at a single center as suffering from HSN. Other aims were to record outcomes of the disease and factors associated with its progression. METHODS: Between 1980 and 1995, 42 adults attending our clinic were diagnosed consecutively, by means of renal biopsy, as suffering from HSN. Data on 38 patients with a follow-up period of at least a year were subsequently analyzed to determine whether any clinical, laboratory or histopathological variable was associated with the progression of HSN. RESULTS: The mean age of the patients on biopsy was 42.0 years (SD 16.5). Eighteen of the 38 patients were male. Eleven of the 38 patients had isolated hematuria as an indication for renal biopsy and 25 had Ccr > or = 85 ml/min on diagnosis. Eight patients exhibited progression of HSN, 3 to end-stage renal failure (ESRF), during a mean follow-up time of 6.1 years (SD 4.3). Renal survival 10 years after renal biopsy was 91%. No histopathological findings were associated with poor outcome. The only factor statistically significantly related to the progression of HSN was a level of proteinuria greater than 1.0 g/24 h (p < 0.05). Hypertension and level of renal function were not significant prognostic factors either, except in a subgroup of 25 patients with initially normal renal function on diagnosis (p < 0.05 in both). In this subgroup, lower serum albumin levels were also found to be predictive for the progression of HSN. CONCLUSIONS: HSN is rare in adults and outcomes are unpredictable. However, any adult with purpura and persistent urinary abnormalities should undergo renal biopsy to determine a diagnosis: all patients suffering from HSN should be carefully monitored to determine whether the condition progresses. Attention should be paid especially to the degree of proteinuria, and also to hypertension in early stages of the disease.

Starting a home hemodialysis program: single center experiences.

OBJECTIVES: Home hemodialysis (HHD) has been used only in a minority of patients over past years although it may offer significant advantages over the other renal replacement therapies. This study describes the systems for and the initial results of starting a HHD program. MATERIAL AND METHODS: A program for HHD was instituted at a university hospital having more than 20 years of experience in training patients for self-care hemodialysis. A working group designed the patient and partner education program, installations, water quality assurance, logistics, and control systems. RESULTS: Between May 1998 and May 2001, 37 patients with a mean age of 48.3 +/- 12.5 (24-71) years were trained for HHD (1.0 patient/month) the mean training time being 2.0 +/- 0.6 (1-3) months. Four patients had no helper at home. The dialysis schedules (timing, frequency, duration) were individualized at home 41% of the patients having more frequent and/or longer treatments (including long-slow night and daily short HHD). The weekly dialysis time increased from 13.9 +/- 1.5 (CI 13.4-14.4) initially to 15.5 +/- 3.7 (CI 14.2-16.7) h (p = 0.008) at the end of follow-up. Significantly (p < 0.05) increased serum creatinine concentration was observed during the follow-up suggesting for an increased muscle mass. Initially 32% and at the end of follow-up 60% of the patients required no antihypertensive drugs (p < 0.05). Seventeen of the 21 drop-outs were caused by renal transplantation and the most common causes necessitating hospital back-up were related to vascular access. CONCLUSIONS: In conclusion the HHD program started in a unit having experience on and commitment for training self-care hemodialysis enabled individualization of the dialysis schedules resulting in the institution of long-slow (night) and alternate day as well as daily HHD therapies. It improved the control of hypertension renal transplantation being the single most common cause of drop-out.

Comparison of plasma polymerase chain reaction and pp65-antigenemia assay in the quantification of cytomegalovirus in liver and kidney transplant patients.

BACKGROUND: Cytomegalovirus (CMV) is a significant problem in transplantation. The antiviral treatment is based on the clinical symptoms and the rapid laboratory diagnosis. Although polymerase chain reaction (PCR) methods have already been widely used, the clinical correlation of the findings is not clear. OBJECTIVE: The objective of this study was to investigate the usefulness of a quantitative plasma PCR test and compare it with the pp65-antigenemia test in the detection of clinically significant CMV infections in liver and kidney transplant patients. STUDY DESIGN: The clinical material consisted of 253 consecutive blood samples was tested using a quantitative polymerase chain reaction test, Cobas Amplicor CMV Monitor (Roche) and pp65 antigenemia assay. Plasma was used for PCR and leucocytes were used for the antigenemia test. RESULTS: CMV was detected in 89 out of 253 blood samples by one or both methods. PCR detected 78 (range 274-165000 copies/ml) and pp65 antigenemia test 79 (range 1-1500 positive cells/50000) of the positive findings. The sensitivity and specificity of PCR test was 86 and 94%, respectively. The PCR detected all clinically significant CMV infections (>10 positive cells in pp65 test) and infections which required antiviral treatment. In addition, the correlation between the two tests was almost linear. CONCLUSIONS: The quantitative PCR appears to be a suitable alternative to diagnose and monitor CMV infections in transplant patients.

Renal replacement therapy in Europe: the results of a collaborative effort by the ERA-EDTA registry and six national or regional registries.

BACKGROUND: In June 2000 a new ERA-EDTA Registry Office was opened in Amsterdam. This Registry will only collect core data on renal replacement therapy (RRT) through national and regional registries. This paper reports the technical and epidemiological results of a pilot study combining the data from six registries. METHODS: Data from the national renal registries of Austria, Finland, French-Belgium, The Netherlands, Norway, and Scotland were combined. Patients starting RRT between 1980 and 1999 (n=57371) were included in the analyses. Cox proportional hazards regression was used to predict survival. RESULTS: The use of different coding systems for ESRD treatment by the registries made it difficult to merge the data. Incidence and prevalence of RRT showed a continuous increase with a marked variation in rates between countries. The 2-, 5- and 10-year patient survival was 67, 35 and 11% in dialysis patients and 90, 81 and 64% after a first renal allograft. Multivariate analysis showed a slightly better survival on dialysis in the 1990-1994 (RR 0.94, 95% CI 0.90-0.98) and the 1995-1999 cohort (RR 0.88, 95% CI 0.84-0.92) compared to the 1980-1984 cohort. In contrast, there was a much greater improvement in transplant-patient survival, resulting in a 56% reduction in the risk of death within the 1995-1999 cohort (RR 0.44, 95% CI 0.39-0.50) compared to the 1980-1984 cohort. CONCLUSIONS: This study provides support for the feasibility of a "new style" ERA-EDTA registry and the collection of data is now being extended to other countries. The improvement in patient survival over the last two decades has been much greater in transplant recipients than in dialysis patients.

Human tear fluid PDGF-BB, TNF-alpha and TGF-beta1 vs corneal haze and regeneration of corneal epithelium and subbasal nerve plexus after PRK.

The aim was to determine the association of tear fluid cytokine levels and post-PRK corneal haze evaluated by in vivo confocal microscopy. In addition, the possible association between subbasal neural regeneration and haze formation, or epithelial regeneration were investigated. Twenty eyes of 20 patients (16 women and four men, age 30.7 +/- 7.5 years, range 21-48 years) underwent a myopic PRK. The spherical equivalent (SE) of the intended correction was -4.7 +/- 1.5 D (range -2.75 to -9.00 D). ELISA-methods were used to assess tear fluid concentrations of TGF-beta1, PDGF-BB and TNF-alpha pre-operatively, and post-operatively on day 2 and at 3 months. Tear fluid flow in the collection capillary was recorded, and rates of cytokine release (= tear fluid flow-corrected concentrations) were calculated. In vivo confocal microscopy was performed at 3 months to evaluate the corneal morphology and to determine numerical haze estimate. There was wide interindividual variation between pre-operative and post-operative concentrations and rates of release of TGF-beta1, PDGF-BB and TNF-alpha. Subepithelial haze was observed in all corneas and the mean haze estimate was 506 +/- 401 U (100-1410 U). However, no association was found between tear fluid cytokine levels and post-PRK haze. Regenerating subbasal nerve plexus was found in 18 out of 20 corneas; in two corneas it was absent or could not be visualized due to subepithelial haze. The density of the subbasal nerve fiber bundles had a positive correlation with the epithelial thickness (Pearson correlation, r = 0.56, P = 0.011), but not with the haze estimate or the thickness of the haze area. At 3 months post-PRK, haze could be observed in all patients. The results suggest that tear fluid cytokine analysis, as measured, may not be suitable for screening the potential candidates for haze formation. We did not find any correlation between haze and regeneration of subbasal nerve plexus, but we demonstrated that the regeneration of subbasal nerve plexus might have significant influence on regulation of epithelial healing.

Soluble intercellular adhesion molecule-1 (sICAM-1) after kidney transplantation: the origin and role of urinary sICAM-1?

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1) binds to leukocyte adhesion receptors LFA-1 and MAC-1, and mediates leukocyte adhesion to target structures. During acute rejection there is increased expression of ICAM-1 in vascular and tubulointestial cells, and consequently accumulation of inflammatory leukocytes. Soluble ICAM-1 (sICAM-1) is released from ICAM-1 expressing cells and excreted into the surrounding fluid. Increased serum sICAM-1 levels are found in patients with acute rejections of various allografts, and high urinary levels in steroid resistant acute kidney allograft rejection. METHODS: Urinary excretion of sICAM-1 was measured by EIA in 136 kidney allograft recipients during the first 1-6 post transplant weeks: 30 patients developed acute rejection, and 106 patients had stable graft function. The molecular weight, binding to hyaluronan, and the origin of urinary sICAM-1 were studied. RESULTS: We show that urinary sICAM-1 circulates as a monomer with a molecular weight between 50 and 100 kD. It binds to immobilized, but not to circulating hyaluronan. About one week after transplantation the mean sICAM-1/creatinine ratio (306 ng/mmol) in transplanted patients was higher than in the healthy controls (167 ng/mmol, P<0.01), and remained basically unchanged during the follow-up in patients with stable graft function, whereas it increased in patients developing rejection, being about 2.5-fold above the initial level a few days before rejection (P<0.01). Urinary sICAM-1 did not correlate with the urinary albumin, whereas in patients developing rejection it correlated with urinary IL-2R (r=0.5146, P<0.001), a marker of lymphocyte activation. In the urinary sediment of rejecting patients ICAM-1 was demonstrated in the tubular epithelial cells, and in the macrophages. CONCLUSIONS: Increased urinary excretion of sICAM-1 was demonstrated in kidney transplanted patients a few days before acute rejection. It seems to originate from activated macrophages and/or from the tubular epithelial cells. The fact that urinary sICAM-1 is not bound to hyaluronan or to leukocytes suggests that it is not able to compete with membrane-bound ICAM-1 for these bindings, but may do so for the binding of activated macrophages.

Effects of fluvastatin on cardiac events in renal transplant patients: ALERT (Assessment of Lescol in Renal Transplantation) study design and baseline data.

BACKGROUND: Recent clinical trials of primary and secondary prevention of cardiovascular disease have demonstrated that lowering plasma cholesterol with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors ('statins') reduces morbidity and mortality from coronary heart disease in diverse patient populations. STUDY AIMS: The aim of the present ALERT (Assessment of Lescol in Renal Transplantation) study is to determine whether renal transplant recipients would also benefit from statin therapy. ALERT is a multicentre, randomized, double-blind, placebo-controlled trial to assess the effect of fluvastatin in renal transplant recipients with mild-to-moderate hypercholesterolaemia. The primary objective is to investigate the effects of fluvastatin on major adverse cardiac events (MACE). In addition, the effects on cardiovascular and all-cause mortality, as well as renal function, will be addressed. STUDY POPULATION: The study population contains patients with functioning renal allografts of more than 6 months' duration, recruited from 75 centres in Northern Europe and Canada. Patients of both sexes, aged 30-75 years, with a total cholesterol level of 4.0-9.0 mmol/l (155-348 mg/dl) were included, except for those with a history of myocardial infarction, where the upper limit for inclusion was 7.0 mmol/l (270 mg/dl). STUDY DESIGN: A total of 2100 patients were recruited by the end of October 1997 and will be followed for up to 6 years. This report presents the design features of the study (recruitment, follow-up, sample size, data analysis and study organization), along with baseline results. ALERT is the first large-scale prospective, randomized, double-blind study to address the prevention of cardiovascular mortality in renal transplant patients receiving an HMGCoA reductase inhibitor.

Expression of the cytomegalovirus genome in kidney allografts during active and latent infection.

Cytomegalovirus (CMV) infection is suggested to be a risk factor for chronic rejection. Here we investigated whether CMV can persist in renal allografts, and in which structures the viral genome is found during an acute infection and a latent period after an active infection. CMV infection was diagnosed in 72/157 patients by CMV antigenemia tests and by viral cultures. CMV antigens were demonstrated in 38 available biopsies by immunohistochemistry, and CMV genome by DNA hybridization in situ. Standard histology was also performed. CMV antigens were detected in 7/15 biopsies obtained during acute infection, in three with acute rejection, and chronic changes in the other biopsies. CMV genome was located in inflammatory cells, in tubuli and in the capillary endothelium. During a latent period without a positive finding in blood or urine, CMV antigens were still found in 6/31 biopsies. CMV DNA was found in inflammatory cells, tubular and glomerular structures and in the endothelium of the arterioles. During the latent period with persistent CMV in the graft, in most cases (10/12) mild to moderate chronic changes were recorded.

Changes of urinary alpha1-microglobulin in the assessment of prognosis in renal transplant recipients.

BACKGROUND: After transplantation, even if the graft starts functioning immediately, there are morphological and functional changes in tubular structures. In addition, acute allograft rejection causes damage in the tubular epithelium, tubular basement membrane, and intertubular connective tissue. It also affects the functional capacity of proximal tubular cells resulting in impaired reabsorption and thus increased urinary excretion of low molecular weight proteins. METHODS: We present a double-antibody radioimmunoassay for determination of the concentration of alpha1-microglobulin (alpha1 M) in urine. It was used to measure urinary excretion of alpha1 M approximately once a week during the first 1-6 posttransplant weeks in 136 consecutive patients: 30 patients developing acute rejection (75 24-hr urine samples) and 106 patients with stable graft function (223 24-hr urine samples). The results are expressed as alpha1 M/creatinine ratios. RESULTS: Approximately 8 days after transplantation the mean (+/-SD) urinary alpha1 M/creatinine ratio of all patients was 17.0+/-14.8 mg/mmol, being about the same both in patients with uncomplicated posttransplantation course (16.3+/-14.0 mg/mmol) and in those who later developed rejection (19.3+/-15.1 mg/mmol), but about 60-fold higher than in healthy controls (0.27+/-0.15 mg/mmol). At that time, when all patients were included there was a correlation (r=0.3465, P<0.001) between alpha1 M/creatinine ratio and duration of cold ischemia. Thereafter, during the second week alpha1 M/creatinine ratio decreased in 89% of patients with stable graft function, but only in 14% of patients who later developed rejection (P<0.001). On the contrary, a significant increase (P<0.01) of alpha1 M/creatinine ratio was observed 4 to 1 day before rejection in all 15 patients, who had urines collected at that time. At the end of the follow-up period, alpha1 M/creatinine ratio in patients with rejection was 3-fold compared with the nonrejecting patients, and 100-fold compared with the healthy controls. CONCLUSION: These results show that cadaveric transplantation results in impaired low molecular weight protein reabsorption, the degree of dysfunction relating to the duration of cold ischemia, and suggest that during the posttransplant weeks decreasing alpha1 M/creatinine ratio in consecutively collected urine samples indicates improved tubular function and in most cases rules out development of acute rejection.