Minimized weight gain between hemodialysis contributes to a reduced risk of death.

UNLABELLED: The risk of death is higher in dialysis patients compared to age matched healthy subjects, the main reason being cardiovascular. This prospective study investigated if the extent of ultrafiltration was of importance for the outcome. MATERIAL AND METHODS: 88 hemodialysis patients were included and followed prospectively. The outcome was registered in regard to death, acute myocardial infarction or coronary vascular intervention. The extent of ultrafiltration needed at dialysis was calculated as a mean during the observation period as were other variables. The mean extent of ultrafiltration was compared for patients who had survived without end-points (group 1, n=53) versus those who reached any end-point during the period (group 2, n=35). RESULTS: In total, 40% of the patients reached end-point during the observation period. There was no difference at baseline between the groups in regard to age, prevalence of diabetes mellitus or history of previous cardiovascular disease, KT/V, residual renal function ultrafiltration need, C-reactive protein, s-albumin, cholesterol, LDL-cholesterol, HDL-cholesterol, appetite or wellbeing, while triglyceride was lower in group 2 (p=0.035). The observation period for group 1 was at a mean 24.7 months (SD13.1) and for those in group 2 at a mean 13.8 (+/-11.7 months, p<0.001). Patients representing group 1 at 24 and 30 months had less need of ultrafiltration than those in group 2. Thus, the need of ultrafiltration was about 27% lower at 24 months (for 29 persons in group 1: 3.63+/-1.93 weight% versus 4.97+/-1.70 weight% for 9 patients from group 2, p=0.046) and 46% at 30 months (for 18 from group 1: 3.48+/-1.95 versus 6.45+/-1.55 for 3 from group 2, p=0.030). C-reactive protein did not differ significantly between the groups during the period. CONCLUSION: After a prolonged period of 24 months the extent of ultrafiltration need seems to be important for the outcome of the patients. Thereby those with higher need of ultrafiltration had worse prognosis. It seems important to motivate patients to reduce the extent of fluid intake between dialysis to prolong survival.

Increased immunoreactivity of transforming growth factor-beta in human kidney transplants.

Transforming growth factor-beta (TGF-beta) has been known to be involved in the pathogenesis of various kidney diseases. TGF-beta is also a potent immunosuppressor that has been shown to be induced after allogeneic transplantation. We have studied the distribution of immunoreactive TGF-beta proteins in different compartments of 21 allogeneic transplanted kidneys that had been rejected through acute (eight interstitial or six vascular) and chronic (seven vascular) processes. This distribution was compared with that in seven non-rejected transplanted and five non-transplanted kidneys with intact morphology. There were no obvious differences between the three groups of rejected grafts and the transplanted non-rejected group for the expression of TGF-beta s. A major difference was seen between transplanted kidneys, which exhibited clearly positive TGF-beta and LTBP1 (latent TGF-beta binding protein) immunoreactivities, and the non-transplanted kidneys. The non-transplanted kidneys showed only very weak or no immunoreactivity for these proteins. The morphologically intact non-rejected grafts showed a significantly increased immunoreactivity compared with the non-transplanted kidneys. When the transplanted kidneys were classified into two groups (i.e. with or without diabetes mellitus) and compared with regard to the expression of all TGF-beta s, no difference was found. Thus, transplantation was the most important predictor for expression of TGF-beta s and LTBP1, and the largest expression increase in the allografts occurred in the interstitium, followed by the glomeruli and blood vessels. Tubuli and lymphocyte aggregates stained only faintly. The results imply that TGF-beta is induced rapidly after kidney transplantation. This induction can suppress immunoreactivation, but concomitantly promotes changes such as arteriosclerosis and fibrosis associated with rejection.

Metabolic factors and outcome of organ transplantation.

Chronic vascular rejection (CVR)--transplant atherosclerosis--is a major problem in organ transplantation and a leading cause of late graft failure. The purpose of the present investigation was to examine the impact of metabolic factors on the outcome of experimental and clinical transplantation. In an experimental model of CVR in rat cardiac allografts it was shown that the development of proliferative vascular lesions, characteristic of CVR, was accelerated 2-4 times by a cholesterol enriched diet. Renal transplant patients with manifest CVR had hyperlipoproteinaemia and atherogenic lipid patterns, the degree of which correlated with the histopathological severity of CVR and was only partially explained by renal dysfunction. The influence of pre-existing lipoprotein abnormalities on graft function was investigated prospectively in renal transplant recipients. It was found that patients with pretransplant hypercholesterolaemia had an increased number of acute rejection episodes, worse graft function and a higher degree of vascular intimal hyperplasia at six months posttransplantation and more graft losses during follow-up. Oxidatively modified LDL may be the link between hypercholesterolaemia and graft failure. Plasminogen activator inhibitor type-1 (PAI-1), a major inhibitor of fibrinolysis and another risk factor for atherothrombosis, which is associated with features of the metabolic risk factor syndrome (Syndrome X) was also followed prospectively. Patients presenting with all features of this syndrome six months after transplantation were at increased risk of losing their graft during a three-year follow-up. Pretransplant hypercholesterolaemia was associated with a more than a two-fold increase in the risk of graft failure during the first two posttransplant years, and elevated PAI-1 levels before transplantation with a five-fold increase during the first three years. A chronic graft damage (CGD) score was constructed for glomerular, vascular and tubulointerstitial changes characteristic of CVR. The CGD score at six months was higher in patients with hypercholesterolaemia or elevated PAI-1 activity before transplantation. An elevated CGD score at six months predicted an eight-fold increase in the risk of renal allograft failure within three years following transplantation. It can be anticipated that intervention directed against lipid abnormalities or other metabolic risk factors may improve the long-term success rate in organ transplantation.

Low-dose atorvastatin in severe chronic kidney disease patients: a randomized, controlled endpoint study.

OBJECTIVE: There have been no endpoint studies with statins for patients with severe renal failure. The purpose of this prospective, open, randomized, controlled study was to investigate whether atorvastatin (10 mg/day) would alter cardiovascular endpoints and the overall mortality rate of patients with chronic kidney disease stage 4 or 5 (creatinine clearance < 30 ml/min). MATERIAL AND METHODS: The study subjects comprised 143 patients who were randomized either to placebo (controls; n=73; mean age 69.5 years) or to treatment with atorvastatin (n=70; mean age 67.9 years). The patients included were either non-dialysis (n=33), haemodialysis (n=97) or peritoneal dialysis (n=13) patients. Analysis focused on the primary endpoints of all-cause mortality, non-lethal acute myocardial infarction, coronary artery bypass graft surgery and percutaneous transluminal coronary angioplasty. Statistical analysis for endpoint data was mainly by intention-to-treat. RESULTS: Primary endpoints occurred in 74% of the subjects. There was no difference in outcome between the control and atorvastatin groups. The 5-year endpoint-free survival rate from study entry was 20%. Atorvastatin was withdrawn in 20% of patients due to unacceptable side-effects. In the atorvastatin group, low-density lipoprotein (LDL) cholesterol was reduced by 35% at 1 month and then sustained. The controls showed a progressive reduction in LDL cholesterol until 36 months. CONCLUSIONS: Although atorvastatin reduced total and LDL cholesterol effectively it was not beneficial regarding the long-term outcomes of cardiovascular endpoints or survival. In contrast to other patient groups, patients with severe chronic kidney disease, especially those on dialysis, seem to derive limited benefit from this lower dose of atorvastatin.

Safety and efficacy of atorvastatin in patients with severe renal dysfunction.

OBJECTIVE: To investigate the efficacy and safety of a daily dose of 10 mg of atorvastatin in patients with chronic kidney disease (CKD) stages 4 and 5 and a glomerular filtration rate of <30 ml/min. MATERIAL AND METHODS: This was an open, prospective, randomized study. A total of 143 patients were included: 73 were controls and 70 were prescribed 10 mg/day of atorvastatin. As efficacy variables, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels were determined at the start of the study and at 1, 3, 6, 12, 18, 24, 30 and 36 months. RESULTS: The follow-up period was a mean of 20+/-14.4 months (range 1-36 months) for those on atorvastatin versus 22+/-12.7 months (range 0.5-36 months) for the controls. Compared with baseline values, patients treated with atorvastatin had significantly lower concentrations of total cholesterol at Month 36 (5.8 vs 4.4 mmol/l; -23%; p<0.001), of LDL cholesterol at Month 36 (3.6 vs 2.2 mmol/l; -35%; p<0.001) and of triglycerides at Months 24 (2.5 vs 1.9 mmol/l) and 36 (2.5 vs 1.8 mmol/l). The controls had significantly reduced levels of total cholesterol at Month 36 (p<0.21) and of LDL cholesterol at Months 30 and 36. Compared with the controls, the atorvastatin group had lower levels of total cholesterol and LDL cholesterol at Months 1-30. Fifteen patients (21%) stopped taking their medication as they could not tolerate the side-effects, the most frequent complaints being gastrointestinal discomfort and headache. CONCLUSION: Although the medication caused no severe adverse events, we recommend caution when using atorvastatin for severe CKD patients until further evidence of its safety and efficacy is verified.

Metabolic abnormalities in renal transplant recipients. Risk factors and predictors of chronic graft dysfunction?

In summary, abnormalities in lipid and carbohydrate metabolism, including features of the metabolic risk factor syndrome, are frequently present in patients both before and after renal transplantation. Risk factors of atherosclerosis may not only contribute to increased cardiovascular morbidity and mortality in this patient population, but can also be assumed to contribute to the development and progression of CVR and chronic graft dysfunction. For preventing both early graft losses and the development of graft damage leading to late graft dysfunction and graft loss, it appears to be essential to identify patients at risk early, prior to transplantation. Intervention aiming to reduce overweight, diet and exercise may be of benefit. The role of omega-3 unsaturated fatty acid supplementation remains controversial. Pharmacological intervention by antioxidants or agents to reduce lipids and/or decrease PAI-1 synthesis may prove to be beneficial. Early identification of patients at risk and intervention in due time may improve the results of renal transplantation.

Hyperlipidaemia in renal transplantation--risk factor for long-term graft outcome.

The role of hyperlipidaemia for the outcome of renal transplantation was evaluated in a prospective study involving 151 patients. Graft losses were associated with more pronounced pre-transplant lipid abnormalities. An increased risk of graft loss during the first two post-transplant years was found in patients with marked pre-transplant hypercholesterolaemia (> or = 6.9 mmol L-1, P = 0.014; relative risk 2.2). Hypercholesterolaemia > or = 6.9 mmol L-1 at 6 months after transplantation, present in 41/115 patients, was associated with a lower GFR (P = 0.007) and more pronounced albuminuria (P = 0.009) at 2 years. In patients with graft dysfunction (serum creatinine > 160 mumol L-1) at 2 years, more pronounced lipid abnormalities before and at 6 months after transplantation were found. Between 6 months and 2 years, total and LDL cholesterol did not change significantly, but HDL cholesterol decreased (P = 0.03). In conclusion, hyperlipidaemia is also a risk factor for the long-term outcome in renal transplantation. Further investigations are needed to determine whether graft losses and late graft failure can be prevented or ameliorated by treating hyperlipidaemia in renal transplantation.

Can histopathological findings in early renal allograft biopsies identify patients at risk for chronic vascular rejection?

In order to assess the prognostic value of renal transplant biopsies for identifying patients at risk for chronic vascular rejection (CVR), 99 biopsies performed at 6 months after renal transplantation were evaluated as part of a prospective study. A chronic graft damage (CGD) score was calculated from the scores of vascular intimal hyperplasia, glomerular mesangial changes, focal lymphocytic infiltration, focal and diffuse interstitial fibrosis, and tubular atrophy, features compatible with CVR. The mean score for the whole patient population was 4.7 +/- 2.9 (range 0-11). There was a strong association between the CGD score at 6 months and the risk of graft loss up to 2 and 3 years following transplantation. Patients with a CGD-score of > or = 6 had a higher graft loss rate at 2 years than those with a score of < 6 (6/35 vs 2/54; p = 0.037). In patients with a functioning graft at 2 years, the CGD-score at 6 months correlated with graft function at 2 years. In addition to higher serum creatinine (p = 0.003) and lower GFR (p = 0.01), patients with a CGD-score of > or = 6 at 6 months also had a higher degree of albuminuria (p = 0.008) at 2 years as compared with patients with a CGD-score of < 6. At 3 years 10/35 patients with a CGD score of > or = 6 and 2/54 patients with a CGD-score of < 6 had lost their grafts (p = 0.002). The relative risk for graft loss associated with a CGD-score of > or = 6 was 7.65.(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of pretransplant lipoprotein abnormalities on the early results of renal transplantation.

Lipoprotein patterns were investigated before and after renal transplantation in a prospective study including 151 patients. Kidney graft losses during the first 6 months were associated with higher total cholesterol (P = 0.03), LDL cholesterol (P = 0.003) and LDL triglyceride levels (P = 0.01) before transplantation. Patients with serum cholesterol > or = 6.9 mmol l-1 before transplantation had more acute rejections (1.7 vs. 0.9), a worse graft function and more vascular intimal hyperplasia and glomerular mesangial changes in transplant biopsies at 6 months. Patients with serum creatinine levels exceeding 160 mumol l-1 at 6 months had more severe lipid disorders already before transplantation. Serum creatinine at 6 months was influenced by the number of acute rejection episodes (P = 0.0001) and the age of the donor (P = 0.009) while the number of acute rejections was found to be related to pretransplant total cholesterol levels (P = 0.0086) and the age of the recipient (P = 0.025). In conclusion, pretransplant lipoprotein disturbances have an impact on the early outcome of renal transplantation. Since there is a progression of hyperlipidaemia following transplantation, this may have an influence also on the cardiovascular morbidity and late graft dysfunction.

The anti-Leu4 (CD3) monoclonal antibody reacts with proximal tubular cells of the human kidney.

A recent observation that certain kidney tubular cells, especially those in the normal kidney, were positively stained with the anti-Leu4 monoclonal antibody (MoAb) led us to investigate systematically the reactivity of three different anti-CD3 MoAb with a panel of normal human kidneys. Using immunohistochemical and immunofluorescence staining techniques, the anti-Leu4 MoAb was found to react with proximal tubular cells in all eight examined kidneys, while no tubular-cell reactivity was observed with the OKT3 or DAKO-T3 MoAb. In each kidney, however, all three antibodies reacted with a similar number of occasionally encountered T cells. The G11 MoAb, which has been reported to react with a calcium receptor-associated molecule, and the anti-Leu4 MoAb showed almost identical patterns of tubular-cell reactivity. The observed co-distribution of Leu4-expressing structures with a putative Ca2+ sensor in the kidney and the fact that binding of anti-Leu4 to T cells induces Ca2+-mediated signal transduction, warrant further studies on a potential role of Leu4-expressing structures in Ca2+ regulation of proximal tubular cells.

Serum total homocysteine concentration does not predict outcome in renal transplant recipients.

Established cardiovascular risk factors such as hypercholesterolemia have been claimed to adversely influence the outcome of renal transplants. The aim of the present study was to assess the effect of another risk factor, hyperhomocysteinemia, on graft outcome. This was relevant for two reasons; hyperhomocysteinemia is by now recognized as an independent risk factor for the development of atherosclerosis and it is highly prevalent in both dialysis patients and renal transplant recipients. The serum concentration of total homocysteine (tHcy) was analyzed in samples collected before transplantation in 81 patients and at 6 months after transplantation in 57 of these patients. Before transplantation, mean tHcy was 33.2 +/- 19.2 mumol/L and the prevalence of hyperhomocysteinemia was 94%. Six months after transplantation, mean tHcy was 27.7 +/- 14.6 mumol/L and the prevalence of hyperhomocysteinemia was 88%. The patients were followed up for 5 yr. Six months and 5 yr after transplantation, serum creatinine concentration and endogenous creatinine clearance were determined. After 6 months, allograft biopsy was evaluated. Neither pre- nor post-transplant tHcy was found to influence patient or graft survival, graft function or histopathology. Thus, tHcy does not seem to predict either short-term or long-term outcome of renal transplantation.