Echocardiographic findings in kidney transplant patients with autosomal dominant polycystic kidney disease.

OBJECTIVE: Autosomal dominant polycystic kidney disease (ADPKD) is a systemic disorder with a tendency for aneurysm formation which may also affect the heart. ADPKD kidney transplant patients were studied by echocardiography. MATERIAL AND METHODS: The case-control study consisted of 21 kidney transplant recipients and a group of 21 transplant patients with other diagnoses. They were in a stable phase a median of 3 years (range 1-10) after transplantation. M-mode and two-dimensional echocardiography were performed. RESULTS: Age, haemoglobin and renal function were not different between the groups but ADPKD patients had significantly lower systolic blood pressure (p=0.004). There were no abnormalities in the aortic or mitral valve in either group. The diameter of the left ventricular outflow tract, the bulb or the ascending aorta did not differ between the groups. The diameters of the left ventricle or atrium were also similar. The left ventricular mass index was 132+/-36 in ADPKD patients versus 163+/-63 g/m(2) in the controls (p=0.11). The left ventricular ejection fraction was 69+/-9.0 versus 70+/-8.9%. Early and atrial filling waves were equal. CONCLUSION: Valvular anomalies were infrequent. Aneurysm formation in the aorta and signs of dilated cardiomyopathy were not increased in patients with ADPKD.

Impact of parathyroid hormone on bone density in long-term renal transplant patients with good graft function.

BACKGROUND: It remains unknown whether low-grade hyperparathyroidism persisting beyond the first year postrenal transplantation has any impact on bone density. METHODS: Parathyroid hormone (PTH), glomerular filtration rate (GFR), and bone density (by dual-energy x-ray absorptiometry [DXA]) were monitored in the follow-up of our transplant patients. Of 260 long-term renal transplant patients, 41 fulfilled the following criteria: Two DXA measurements performed at least five years apart (median 6.8 years, range 5-9); GFR>or=35 ml/min per 1.73 m body surface area (median 50, range 35-76); no bisphosphonate treatment or parathyroidectomy in the study period. RESULTS: In all, 40% had mean PTH values above the normal limit 6.9 pmol/L (65 pg/ml), and the range was 0.9-17 pmol/L. In the first DXA, 8 of 41 patients had osteoporosis and 17 more had osteopenia. Hip bone density Z-score was -0.60 SD, range (-2.6 to +2.3). The absolute median value (g/cm) remained unchanged until the second DXA, but among patients there was a variation which ranged from -2.3% to +1.7% per year. In a simple linear regression analysis, these changes were significantly correlated to mean PTH (r=0.16, P=0.010). Median lumbar spine bone density was also reduced in the first DXA and was not different at follow-up, but with this variable individual changes did not correlate to mean PTH. CONCLUSION: Bone density is often reduced and PTH remains elevated in long-term renal transplant patients with good transplant function. Slight to moderate elevation of PTH is associated with reduction in hip bone mineral density.

Glomerular C3c deposition and intravascular macrophage accumulation in early humoral renal allograft rejection signifies a poor short-term outcome.

C4d deposition in the walls of peritubular capillaries is considered the key phenomenon in the histopathological diagnosis of humoral, i.e. antibody-mediated, allograft rejection. We have earlier proposed that deposition of C3c in glomerular capillaries and simultaneous intravascular accumulation of macrophages in allografts with immediate or early humoral rejection indicates a potentially serious condition with very poor prognosis. The clinical outcome of 45 cadaveric grafts with this phenomenon among 1960 renal allografts transplanted at our centre during 1984-1999, and the recipients of the contralateral kidneys, was retrospectively evaluated. Graft failure occurred in 44/45 grafts within 3 weeks, with graft loss in 33/45 (77%) within 4 months and 37/45 (82%) within 1 year. From the contralateral kidneys, 5/33 (15%) were lost within 1 year. In a recent series of early biopsies, we recognised that of 13 cases showing C4d positivity in peritubular capillaries but lacking C3c in glomeruli, 10/13 (77%) were still functioning after 4 months. The mean number of CD68(+) macrophages per glomerular profile, i.e. the glomerular macrophage index, shows a significant difference between C4d(+)C3c(-) and C4d(+)C3c(+) cases (p<0.001). Our results indicate the existence of a clinically important subgroup of early humoral rejection with particular morphological features.

Cardiovascular risk and renal transplantation: post hoc analyses of the Assessment of Lescol in Renal Transplantation (ALERT) Study.

BACKGROUND: Renal transplantation is associated with an increased risk for premature cardiovascular disease. We analyzed the data in the placebo arm of Assessment of Lescol in Renal Transplantation (ALERT) to improve our understanding of the relationship between cardiovascular risk factors and outcomes in this unique population. METHODS: We performed Cox survival analysis for myocardial infarction, cardiac death, and noncardiac death in 1,052 patients recruited to the placebo arm of ALERT. These subjects were aged 30 to 75 years, had stable graft function at least 6 months after transplantation, had a serum total cholesterol level between 155 and 348 mg/dL (4 and 9 mmol/L), and were receiving cyclosporine-based immunosuppression. RESULTS: The results confirm previous studies. In multivariate analysis, preexisting coronary heart disease (hazard ratio [HR], 3.69; P < 0.001), total cholesterol level (HR, 1.55 per 50 mg/dL; P = 0.0045), and prior acute rejection (HR, 2.36; P = 0.0023) were independent risk factors. Conversely, independent risk factors for cardiac death were age (HR, 1.58 per decade; P = 0.0033), diabetes (HR, 3.35; P = 0.0002), ST-T changes on the ECG (HR, 3.17; P = 0.0004), and serum creatinine level (HR, 2.65 per milligram per deciliter; P < 0.0001). CONCLUSION: This analysis confirms that renal transplant recipients share risk factors for myocardial infarction and cardiac death with the general population. However, the pattern of risk factors and their relationship with outcomes is atypical, highlighting the unique nature of cardiovascular risk in transplant recipients.

Beneficial effect of early initiation of lipid-lowering therapy following renal transplantation.

BACKGROUND: Renal transplant recipients have a significantly reduced life expectancy, largely due to premature cardiovascular disease. The aim of the current analysis was to investigate the importance of time of initiation of therapy after transplantation, on the benefits of statin therapy. METHODS: 2102 renal transplant recipients with total cholesterol levels of 4.0-9.0 mmol/l were randomly assigned to treatment with fluvastatin (n = 1050) or placebo (n = 1052) and followed for a mean time of 5.1 years. The end-points were major cardiac events. The average median time from transplantation to randomization was 4.5 years (range: 0.5-29 years). RESULTS: In patients starting treatment with fluvastatin <4.5 years after renal transplantation, the incidence of cardiac events was 4.6% over 5.1 years vs 9.2% in those on placebo (P = 0.007). Fluvastatin significantly reduced the risk of cardiac death and non-fatal myocardial infarction by 56% [risk ratio (RR): 0.44; 95% confidence interval (95% CI): 0.26-0.74; P = 0.002]. In a more detailed analysis patients were grouped into 2-year intervals (since the last transplantation). The frequency of cardiac death and non-fatal myocardial infarction was reduced by 3.2%, 5.1%, 9.6% and 8.2% with fluvastatin treatment as compared to 6%, 10.4%, 13.4% and 9.6% with placebo when treatment was initiated at 0-2, 2-4, 4-6 and >6 years, respectively. The risk reduction for patients initiating therapy with fluvastatin at years 0-2 (compared with >6 years) following transplantation was 59% (RR: 0.41; 95% CI: 0.18-0.92; P = 0.0328). This is also reflected in total time on renal replacement therapy: in patients in the first quartile (<47 months) fluvastatin use was associated with a risk reduction of 64% compared with 19% for patients in the fourth quartile (>120 months) (P = 0.033). CONCLUSIONS: Our data support an early introduction of fluvastatin therapy in a population of transplant recipients at high risk of premature coronary heart disease.

Risk factors for reaching renal endpoints in the assessment of Lescol in renal transplantation (ALERT) trial.

BACKGROUND: The aim of the study was to identity risk factors for long-term renal transplant function and development of chronic allograft nephropathy (CAN) in renal transplant recipients included in the Assessment of Lescol in Renal Transplantation (ALERT) trial. METHODS: The ALERT trial was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40 and 80 mg/day, in renal transplant recipients who were randomized to receive fluvastatin (Lescol) (n = 1,050) or placebo (n = 1,052) over 5 to 6 years of follow-up. Renal endpoints including graft loss or doubling of serum creatinine or death were analyzed by univariate and multivariate regression analysis in the placebo group. RESULTS: There were 137 graft losses (13.5%) in the placebo group, mainly caused by CAN (82%). Univariate risk factors for graft loss or doubling of serum creatinine were as follows: serum creatinine, proteinuria, hypertension, pulse pressure, time since transplantation, donor age, human leukocyte antigen-DR mismatches, treatment for rejection, low high-density lipoprotein cholesterol, and smoking. Multivariate analysis revealed independent risk factors for graft loss as follows: serum creatinine (relative risk [RR], 3.12 per 100-microM increase), proteinuria (RR, 1.64 per 1-g/24 hr increase), and pulse pressure (RR, 1.12 per 10 mm Hg), whereas age was a protective factor. With patient death in the composite endpoint, diabetes mellitus, smoking, age, and number of transplantations were also risk factors. CONCLUSIONS: Independent risk factors for graft loss or doubling of serum creatinine or patient death are mainly related to renal transplant function, proteinuria, and blood pressure, which emphasizes the importance of renoprotective treatment regimens in this population.

Effect of fluvastatin on renal end points in the Assessment of Lescol in Renal Transplant (ALERT) trial.

BACKGROUND: Hyperlipidemia is a risk factor for long-term renal transplant dysfunction, but no prospective clinical trials have investigated the effects of statin treatment on graft function in renal transplant recipients. The aim of the present study was to evaluate the effect of fluvastatin on long-term renal transplant function and development of chronic allograft nephropathy in the ALERT (Assessment of Lescol in Renal Transplantation) study. METHODS: ALERT was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40 mg and 80 mg daily, in renal transplant recipients. Patients were randomized to receive either fluvastatin (N= 1050) or placebo (N= 1052) and followed for five to six years. Renal end points included graft loss or doubling of serum creatinine or death; glomerular filtration rate (GFR) was also measured during follow-up in a subset of patients (N= 439). RESULTS: There were 283 patients (13.5%) with graft loss, mainly due to chronic rejection (82%), yielding an annual rate of 2.4%. Fluvastatin treatment significantly lowered mean low-density lipoprotein (LDL)-cholesterol levels by 32% (95% CI -33 to -30) compared with placebo, but had no significant effect on the incidence of renal graft loss or doubling of serum creatinine, or decline in GFR throughout follow-up in the whole study population. Neither was any treatment effect by fluvastatin found in any of the subgroups analyzed. CONCLUSION: Fluvastatin treatment significantly improves lipid values in renal transplant recipients but has no effect on graft loss or doubling of serum creatinine.

Written information for potential living kidney donors.

To meet the constantly growing demand for organs for transplantation the use of living related and unrelated donors continues to increase. Transplant units with a living-donor programme often provide written information to their potential kidney donors. We saw a need to assess the contents of these brochures. Written information for potential live kidney donors was requested from different Transplant units throughout the world. We obtained and analysed 16 different brochures from 14 countries. The general approach ranged from persuasive to almost deterring. Sixteen main themes were identified in the information material. Eight of those were considered paramount, namely voluntarism, medical suitability, short-term donor risks, long-term donor risks, risk of graft loss, outcome with and without a living donor, postoperative course, and financial conditions. Five brochures covered all these crucial matters. When mentioned, examples and interpretations of donor risks were very dissimilar. Furthermore, the conditions for donation were obviously very different in the various countries. This review points at essential issues to be included in the written information for living kidney donors. All transplant units with a living-donor programme should provide such information, thus enabling the potential donor to make a thorough decision.

Macrovascular disease after simultaneous pancreas and kidney transplantation.

The objective of this study was to evaluate the outcome of simultaneous pancreas and kidney transplantation (SPK) with focus on cardiovascular mortality and morbidity in relation to graft function. From January 1985 through 1999, 87 SPK were performed in the unit. Sixty recipients were males, median age at diabetes onset 13 yr (1-40) and age at transplantation 39 yr (29-54). No case was lost to follow-up. Morbidity and mortality during median 8 yr of follow-up (range 1-15 yr) were recorded. Major macrovascular disease (MVD) was defined as myocardial infarction or sudden death (AMI), stroke or peripheral gangrene requiring amputation of leg, foot or fingers. At the evaluation, 26 of 87 patients (30%) had died, 19 after loss of the pancreas graft and 20 after loss of the kidney. MVD was the dominant cause of death. Non-lethal MVD had previously been recorded in 62%. Of the 61 patients alive, 22 had lost their pancreas graft and 12 the concomitant kidney. MVD had occurred in 32%. Whereas 89% of the concomitant kidneys functioned when the pancreas graft did so, only 37% of the kidneys functioned if the pancreas had been lost, p < 0.0001. The mortality rate was significantly higher among patients who lost both grafts (16/26) than in those who lost only the pancreas graft (3/15), p = 0.01. Progressive MVD is a major clinical problem for SPK transplant patients, particularly if the kidney fails.

fluvastatin prevents cardiac death and myocardial infarction in renal transplant recipients: post-hoc subgroup analyses of the ALERT Study.

Renal transplant recipients have a greatly increased risk of premature cardiovascular disease. The ALERT study was a multicenter, randomized, double-blind, placebo-controlled trial of fluvastatin (40-80 mg/day) in 2102 renal transplant recipients followed for 5-6 years. The main study used a composite cardiac end-point including myocardial infarction, cardiac death and cardiac interventions. Although reduced by fluvastatin, this primary end-point failed to achieve statistical significance thus precluding analysis of predefined subgroups. Therefore, in the present survival analysis, we used an alternative primary end-point of cardiac death or definite nonfatal myocardial infarction (as used in other cardiac outcome trials) which was significantly reduced by Fluvastatin therapy and permits subgroup analysis. Fluvastatin reduced LDL-cholesterol by 1 mmol/L compared with placebo, and the incidence of cardiac death or definite myocardial infarction was reduced from 104 to 70 events (RR 0.65; 95% CI 0.48, 0.88; p = 0.005). Fluvastatin use was associated with reduction in cardiac death or nonfatal myocardial infarction, which achieved statistical significance in many subgroups. The subgroups included patients at lower cardiovascular risk, who were younger, nondiabetic, nonsmokers and without pre-existing CVD. These data support the early introduction of statins following renal transplantation.

Motives for becoming a living kidney donor.

BACKGROUND: Recruitment of living donors represents a medical and moral responsibility. Their motives are often complex. Categories of motives and factors causing concern were identified from a previous in-depth interview study and from the literature. The aim of the present study was to evaluate these motives. METHODS: A questionnaire was sent to 207 potential kidney donors undergoing evaluation for donation in Norway and Sweden. They were asked to mark on a visual analogue scale, 0-10, the importance given to each of nine motives and five factors of concern. Questions were also asked about who took the initiative and the source of information. RESULTS: The response rate was 74%; 154 questionnaires were returned. The strongest motives to become a donor were a wish to help (median 9.3), self-benefit from the recipient's improved health (median 9.2) and identification with the recipient (median 9.1). In contrast, a sense of guilt regarding past relationships (median 0.9), pressure from others (median 0.8), a religious motive (median 0.8) and increased self-esteem (median 0.7) were rare or weak incentives for donation. There were large individual variations in the mix, particularly regarding moral duty (5.6, range 0.1-10.0). Most potential donors (64%) had taken the initiative for the assessment themselves, but in 22% it was the recipient's physician. Physicians were the dominant source of information. The potential donors expressed much more concern for the recipient than for themselves. CONCLUSIONS: Living kidney donor assessment includes an exploration of the individuals' mixed feelings. An analysis of the motive enables individualized treatment and support for non-donors.

Becoming a living kidney donor.

Earlier investigations of attitudes of living kidney donors have been performed in retrospect. We saw a need to investigate in depth those motives and feelings that are relevant in potential kidney donors. With a phenomenologic approach, interviews were performed with 12 potential donors. Seven categories of motives were identified: a desire to help, increased self-esteem from doing good deeds, identification with the recipient, self-benefit from the relative's improved health, mere logic, external pressure, and a feeling of moral duty. In the individual, these categories interacted to create a perception of donation being the only option.

Impact of cadaveric renal donor morbidity on long-term graft function.

The significance of donor age, cause of death, and morbidity for the outcome of renal cadaveric transplantation was evaluated in 534 cases from 1994 through 2001. Half of the kidneys (49.4%) were from donors without identified risk, the others were age 50-64 or > or =65 years, had died of cerebrovascular lesion (CVL), or had known cardiovascular disease, or hypertension. Only death from CVL influenced cumulative graft survival (P=0.04), the actual survival at 6 months being 87% vs 95% with other donors (P=0.004). Clearance of 51Cr EDTA (glomerular filtration rate, GFR) after 1 year was a more sensitive marker of graft quality and was significantly reduced with each tested risk factor. For instance, the median GFR (range) in the three donor age groups was 52 (9-125), 37 (13-83), and 29 (15-60) ml/min, respectively (P<0.0001). Combinations of risk factors significantly increased their impact on GFR. However, the overall results with such suboptimal donors should rather encourage a widening of the donor acceptance criteria.

Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo-controlled trial.

BACKGROUND: Renal transplant recipients are at increased risk of premature cardiovascular disease. Although statins reduce cardiovascular risk in the general population, their efficacy and safety in renal transplant recipients have not been established. We investigated the effects of fluvastatin on cardiac and renal endpoints in this population. METHODS: We did a multicentre, randomised, double-blind, placebo-controlled trial in 2102 renal transplant recipients with total cholesterol 4.0-9.0 mmol/L. We randomly assigned patients fluvastatin (n=1050) or placebo (n=1052) and follow up was for 5-6 years. The primary endpoint was the occurrence of a major adverse cardiac event, defined as cardiac death, non-fatal myocardial infarction (MI), or coronary intervention procedure. Secondary endpoints were individual cardiac events, combined cardiac death or non-fatal MI, cerebrovascular events, non-cardiovascular death, all-cause mortality, and graft loss or doubling of serum creatinine. Analysis was by intention to treat. FINDINGS: After a mean follow-up of 5.1 years, fluvastatin lowered LDL cholesterol concentrations by 32%. Risk reduction with fluvastatin for the primary endpoint (risk ratio 0.83 [95% CI 0.64-1.06], p=0.139) was not significant, although there were fewer cardiac deaths or non-fatal MI (70 vs 104, 0.65 [0.48-0.88] p=0.005) in the fluvastatin group than in the placebo group. Coronary intervention procedures and other secondary endpoints did not differ significantly between groups. INTERPRETATION: Although cardiac deaths and non-fatal MI seemed to be reduced, fluvastatin did not generally reduce rates of coronary intervention procedures or mortality. Overall effects of fluvastatin were similar to those of statins in other populations.

Remaining experiences of living kidney donors more than 3 yr after early recipient graft loss.

Living kidney donor programs, based on willingness among family members and close relatives to donate, have made it possible to perform a satisfactory number of kidney transplantations. Early graft loss in the recipient may occur and it is not known if such an event will result mainly in acute, rather transient, emotional reactions or if long-lasting reactions may be evoked in the living kidney donor. The aim of the present study was to assess and describe the remaining experiences of donors (n = 10) more than 3 yr after early recipient graft loss or death of the recipient. A phenomenographic, interview-based research approach was used. Five different fields or domains were identified: (i) the decision to donate; (ii) the information provided; (iii) care received at the time of donation; (iv) responses at graft failure; and (v) concerns remaining at the time of the interview. All donors expressed that they had volunteered to donate and that no stress had been put on them. The information given prior to and in connection with the donation procedure was deemed insufficient but all donors were satisfied with the medical care provided in connection with the nephrectomy and in the immediate post-operative period. Graft failure was immediately accepted on the intellectual level by nine of 10 donors but still evoked emotional reactions and responses included a wish that continuing contact with the transplant staff had been provided. The present interview-based study shows that it is of importance that the donor is thoroughly informed about all donor as well as recipient-related factors including the potential risk of recipient graft failure. In case of graft failure, or the death of the recipient, the transplant unit staff members should offer contact for discussions of medical matters as well as for psychosocial support. In individual cases it may be necessary to maintain such a supportive contact channel for a prolonged period of time.