Prospective age-matching in elderly kidney transplant recipients--a 5-year analysis of the Eurotransplant Senior Program.

Renal transplantation faces challenges: the organ shortage resulting in extended waiting times and an aging population resulting in death with a functioning graft. The Eurotransplant Senior Program (ESP) allocates kidneys within a narrow geographic area from donors aged >/=65 years to recipients >/=65 years regardless of HLA. This analysis investigates the impact of the ESP on waiting time, graft and patient survival. The ESP group (n = 1406, old to old) was compared to two groups allocated via the Eurotransplant Kidney Allocation System (ETKAS) with either similar donor age (old to any [O/A], donor age >/=65, n = 446) or recipient age (any to old, [A/O], recipient age 60-64, n = 1687). All patients were transplanted between 1999 and 2004. Since initiation of the ESP (1999), availability of elderly donors doubled and waiting time for ESP patients decreased. Local allocation led to shorter cold ischemia time (11.9 vs. >17.0 h, p < 0.001) and less delayed graft function (DGF, ESP 29.7% vs. O/A 36.2%, p = 0.047) but 5-10% higher rejection rates. Graft and patient survival were not negatively affected by the ESP allocation when compared to the standard allocation. The ESP age matching of elderly donors and recipients is an effective allocation system for organs from elderly donors.

Left atrial spontaneous echo contrast in mitral valve disease: an indicator for an increased thromboembolic risk.

The incidence of left atrial spontaneous echo contrast was evaluated in 52 patients with isolated or predominant mitral valve stenosis (Group 1) and 70 other patients who had undergone mitral valve replacement (Group 2). All patients were studied by conventional transthoracic and transesophageal two-dimensional echocardiography. Spontaneous echo contrast could be visualized within the left atrium in 35 Group 1 patients (67.3%) (including 7 patients with sinus rhythm) and 26 Group 2 patients (37.1%) (all with atrial fibrillation). Patients with spontaneous echo contrast had a significantly larger left atrial diameter and a greater incidence of both left atrial thrombi and a history of arterial embolic episodes than did patients without spontaneous echo contrast. Association between spontaneous echo contrast and left atrial thrombi and a history of arterial embolization (considered individually or in combination) showed a high sensitivity and negative predictive value. It is concluded that spontaneous echo contrast is a helpful finding for identification of an increased thromboembolic risk in patients with mitral stenosis and after mitral valve replacement.

Prospective, multicenter, randomized trial to compare incidence of new-onset diabetes mellitus and glucose metabolism in patients receiving cyclosporine microemulsion versus tacrolimus after de novo kidney transplantation.

New-onset diabetes mellitus (NODM) is associated with increased risk of graft failure and death in renal transplant recipients. Some clinical studies have indicated that NODM risk is higher with tacrolimus than cyclosporine, but no comparative trial has used American Diabetic Association (ADA)/World Health Organization (WHO) criteria for diagnosis of diabetes mellitus. The Diabetes Incidence After Renal Transplantation, Neoral C2 Monitoring Versus Tacrolimus (DIRECT) study is a 6-month open-label, multicenter trial comparing the impact of tacrolimus and Neoral (cyclosporine microemulsion) on glucose metabolism in 700 de novo kidney transplant recipients, based on ADA/WHO criteria. Patients are randomized to tacrolimus (C0 monitoring) or Neoral (C2 monitoring), stratified by baseline diabetic status and ethnicity. All patients receive basiliximab, corticosteroids, and mycophenolate mofetil or enteric-coated mycophenolate acid (myfortic). Pooled interim 3-month results from a subset of 115 patients receiving either tacrolimus or Neoral showed that the primary efficacy end-point (biopsy-proven acute rejection [BPAR], graft loss or death) occurred in 11 patients (10%). There were four graft losses and only one death, which occurred after graft loss. Eight patients experienced BPAR (7.3%). Among 99 patients who were nondiabetic at baseline, 14 developed NODM by month 3, 17 developed impaired fasting glucose or impaired glucose tolerance, and another 5 patients received hypoglycemic treatment for at least 14 consecutive days or at the month 3 visit, resulting in a 36% incidence of impaired glucose metabolism. At 3 months, median GFR (Nankivell) was 63.7 mL/min; median serum creatinine was 137 micromol/L. Full complete results are expected in December 2005.

Pneumatic external counterpulsation: a new noninvasive method to improve organ perfusion.

Pneumatic external counterpulsation, which is operated by applying electrocardiographic-triggered diastolic pressure via air-filled cuffs to the vascular limbs of lower limbs, is a relatively new therapeutic option for patients with angina pectoris and cerebrovascular diseases like transient ischemic attacks or sudden deafness. In this study, an augmentation in flow volume in the carotid, renal, and hepatic arteries from 20% to 25% and in the coronary arteries from 20% to 40%, as well as an increase in stroke volume by 12% was demonstrated; this shows the therapeutic results in patients with diseases caused by disturbed organ perfusion.

In vitro production of interleukin-1 from blood mononuclear cells of patients on chronic hemodialysis therapy.

A monocyte defect is thought to be involved in the impaired immune response in patients on regular hemodialysis therapy. As an indicator of cell function, we studied in vitro IL-1 beta production of mononuclear cells from hemodialysis patients in comparison to normal controls. Mononuclear cells were stimulated with endotoxin or Staphylococcus epidermidis in parallel with control incubations in tissue culture medium alone. Spontaneous as well as stimulated total IL-1 beta production (cell-associated plus extracellular) did not differ significantly in cells obtained from patients compared to those from normal controls. However, the relative amounts of IL-1 beta released into the cell supernatants were significantly reduced in mononuclear cells from hemodialysis patients when stimulated with endotoxin but not with Staphylococcus epidermidis. These data indicate a stimulus-dependent defect in the mechanism of IL-1 beta release. As IL-1 is necessary for T-cell activation this alteration in mononuclear cell function may play a role in the impaired cellular immunity observed in patients on chronic hemodialysis therapy.

Atherosclerosis and vascular calcification in chronic renal failure.

Cardiovascular complications are a major clinical problem in patients with chronic kidney disease and end-stage renal failure; cardiac death accounts for approximately 40-50% of all deaths in these patients. Death from cardiovascular causes is up to 20 times more common in uremic patients than in the general population with the risk being even higher than in patients with diabetes mellitus. A high rate of myocardial infarction and excessive cardiac mortality have repeatedly been documented in patients with kidney disease and renal failure. Not only is the prevalence of myocardial infarction high, but also the case fatality rate is significantly higher in uremic patients with and without diabetes, respectively, compared to nonuremic patients. This is of particular interest since the prevalence of coronary atheroma in uremic patients was shown to be approximately 30% by autopsy and coronary angiography studies. Thus, coronary factors, i.e. atherosclerosis, and non-coronary factors may play an important role in the genesis of cardiac complications in the renal patient. In addition, renal failure recently has also be identified as a predictor of mortality in different stages of peripheral vascular disease. In particular, marked differences in the pathogenesis, morphology and course of atherosclerosis and arteriosclerosis under the conditions of renal failure have been documented. Among others increased plaque formation and particularly higher proportion and intensity of vascular calcification have been found in clinical and autopsy studies. In addition to the so-called classical or traditional risk factors, an important role for nonclassical risk factors such as microinflammation, hyperphosphatemia and oxidative stress has been documented in patients with renal failure and is discussed in detail.

[Erythropoietin and hypertension]. / Erythropoietin und Hypertonie.

Recombinant human erythropoietin (rhEpo) has been demonstrated in several studies to be effective in correcting the anemia of regular dialysis patients. This was accompanied by a significant improvement of the physical work capacity shown by exercise testing. The main side effect of rhEpo treatment has been the development or aggravation of hypertension in approximately 30% of the treated patients. In 2% hypertensive encephalopathy and convulsions occurred. Data obtained by measurements of regional blood flow indicate the peripheral resistance did increase probably due to rise of blood viscosity and reversal of preexisting hypoxic vasodilatation. To avoid hypertensive complications anemia should be corrected slowly over a period of 12-16 weeks. Target hematocrit should not exceed 30-35 vol. %. Blood pressure and volume status should be monitored closely.

Hemodynamics in hemodialysis patients treated with recombinant human erythropoietin.

The available data from experimental and clinical studies suggest that in the development of hypertension following correction of renal anemia under rhEPO three mechanisms are operative: (1) an increase in whole blood viscosity; (2) possible also a reduction of hypoxic vasodilatation, and (3) at least in some patients an inadequate reduction of cardiac output. To avoid cardiovascular complications under rhEPO therapy, the following should be considered: Patients that were hypertensive before the start of renal replacement therapy, even if they were normotensive in the anemic state - because of morphological alterations of their peripheral vascular bed-may run a higher risk for developing hypertension under rhEPO. As patients with undetected volume contraction may be more endangered by cardiovascular complications, the hematocrit should be monitored before and after dialysis, especially in patients with high weight gain and in children. Patients who are hypertensive under rhEPO therapy should be treated by antihypertensive drugs as appropriate. Drugs of the first choice are beta-blockers and vasodilating agents. Volume removal should not be the sole measure for blood pressure control and should be applied carefully. To avoid hypertensive and rheological complications, the target hematocrit should not exceed 30 vol%.

Evaluation of endocarditis and its complications by biplane and multiplane transesophageal echocardiography.

Echocardiography is currently the method of choice for the diagnosis of endocarditis-associated vegetations or complications such as abscess formation. Thereby, the transesophageal approach (TEE) is clearly superior to precardial echocardiography and, at present, biplane TEE can be considered as the standard TEE technique. Compared with the monoplane technique, biplane TEE provides additional qualitative and quantitative information concerning the presence and amount of valvular destruction. Multiplane TEE facilitates (and abbreviates) the examination procedure, and may be helpful for easier detection of small initial abnormalities, those developing on native valves with preexisting lesions, or on prosthetic valves. It allows more accurate measurements and three-dimensional reconstruction of vegetations and abscess areas and provides more anatomical details of the disease. However, it remains to be shown by future studies if multiplane TEE will identify endocarditis-associated lesions more frequently than the biplane technique doses.

Hypertension as a possible complication of recombinant human erythropoietin therapy.

The analysis of the hemodynamics accompanying correction of renal anemia by rhEPO shows that--although they behave qualitatively as in nonuremic anemic patients--cardiac output and peripheral resistance may change inadequately and thereby cause a rise of blood pressure. The underlying mechanisms are not yet fully understood but to a great part may be related to preexisting pathology due to a history of longlasting hypertension. In some patients the development of hypertension may only represent a temporary phenomenon of hemodynamic dysregulation. To avoid cardiovascular complications the following should be considered: Patients with a history of hypertension, even if they are normotensive in the anemic state, are at a higher risk of developing hypertension during therapy with rhEPO. Hypertensive complications may be rare events when anemia is corrected slowly. In case of the development or aggravation of hypertension a reduction of the target hematocrit is indicated.

[Destructive non-infectious spondylopathy during hemodialysis]. / Destruierende nicht-infektiöse Spondylopathie bei Hämodialyse.

Improvement of long-term treatment with hemodialysis requires an optimized radiological differential diagnosis of bone changes associated with long-term hemodialysis. 85 patients with chronic renal failure on maintenance hemodialysis were examined. In a conventional radiographic skeletal survey of the whole spine, 22 patients (26%) had involved intervertebral discs. The site of predilection was the cervical spine followed by the lumbar spine; oligosegmental involvement was seen in nine patients. Eighteen patients with destructive non-infectious spondyloarthropahy had juxtaarticular cystic bony changes associated with the hip, shoulder and wrist. Bone biopsy in eight patients revealed amyloid as content of these cysts. The interrelation between the duration of preterminal and terminal renal failure on one hand and destructive bone changes in the spine and cysts on the other hand seems to point to destructive spondyloarthropathy as an important complication of renal insufficiency and dialysis.

Improved physical performance after treatment of renal anemia with recombinant human erythropoietin.

The physical performance of 12 anemic patients on renal dialysis was investigated following treatment of renal anemia with recombinant human erythropoietin (rhEPO; 40-120 U/kg, 3 times a week). Exercise intensity at a heart rate of 130 beats/min (PWC130) on a bicycle ergometer was assessed before rhEPO treatment, after reaching the target hematocrit (73 +/- 18 days), and in the maintenance phase (211 +/- 53 days). Hemoglobin concentrations measured at these time points were 7.3 +/- 1.2, 11.9 +/- 1.5, and 12.1 +/- 1.4 g/dl, respectively. PWC130 rose from 77 +/- 27 to 104 +/- 37 and 104 +/- 51 W, respectively. Aerobic threshold (i.e. blood lactic acid concentration of 2 mmol/l) shifted to higher workloads indicating improved muscle oxygen supply.

Adverse cardiovascular effects of partial correction of renal anemia by recombinant human erythropoietin.

The analysis of the hemodynamic parameters involved in the regulation of blood pressure during correction of anemia shows - although peripheral resistance and cardiac output behave qualitatively as in the nonuremic patient - that the extent of change may be inadequate resulting in an increased blood pressure. The underlying mechanisms are not yet fully understood but to a greater part may be related to preexisting pathology due to a history of long-lasting hypertension. To avoid cardiovascular complications under rhEPO therapy the following should be considered: patients with a history of hypertension, even if they are normotensive in the anemic state, are at a higher risk for developing hypertension under rhEPO. Hypertensive complications may be rare events when anemia is corrected slowly. Further studies will demonstrate whether in addition to the benefit of a very low maintenance dose of rhEPO subcutaneous administration will also contribute to the reduction of the incidence of hypertension.

Two years experience of daily self-administered subcutaneous erythropoietin.

Recombinant human erythropoietin (EPO) has been used for 4 years in end-stage renal disease patients, administered intravenously 3 times a week. A study was undertaken to determine the optimal way of administration comparing 3 times weekly intravenous EPO to self-administered daily subcutaneous EPO (SADSCEPO). In a first group of 4 patients, we demonstrated that the change from 3 times weekly intravenous EPO to SADSCEPO permitted a dose reduction of 70%. In a second group of 20 patients who started the EPO therapy with the daily subcutaneous route at a median dose of 12 U/kg/day, the hematocrit increased from 20 to 30% in 4 months and remained over 30% in spite of a median dose reduction to 9 U/kg/day. The patients' acceptance of SADSCEPO was good. The mechanism allowing such a dose reduction is unknown. However, the significant reduction in median dosage requirement with the subcutaneous route should allow a greater number of patients to be treated more cost-effectively.

Effect of treatment with recombinant human erythropoietin on peripheral hemodynamics and oxygenation.

Slow progressive improvement of renal anemia from 21 up to 33% hematocrit by rhEPO treatment results in an increase of tissue oxygenation as indicated by a rise of the transcutaneous oxygen pressure. In normotensive patients this was accompanied by an increase in MAP (delta 6 mm Hg) within the normal range and a significant fall of the regional blood flow. These hemodynamic changes are caused by increases of the regional and presumably also of the total peripheral vascular resistance. Most likely the increase in total peripheral vascular resistance represents an autoregulatory event triggered by the rising tissue oxygenation. From the present data it is difficult to estimate to what extent the observed rise in hematocrit affects peripheral vascular resistance also via an increase of blood viscosity.

Renal infarction with fatal bleeding--an unusual complication of Candida albicans endocarditis.

A patient with mitral valve endocarditis due to Candida albicans infection is presented. Because of persistent fever and one episode of transient right-sided hemiparesis, the patient underwent mitral valve replacement. Two weeks after successful valve replacement, the patient suddenly developed acute abdominal pain and died before a surgical intervention could be initiated. Autopsy examination revealed a renal infarction in the lower part of the right kidney with a large rupture of the capsule and retroperitoneal bleeding. A myocotic aneurysm could not be detected. The clinical significance of renal infarction in infective endocarditis is discussed.

Long-term effects of treatment with recombinant human erythropoietin on haemodynamics and tissue oxygenation in patients with renal anaemia.

Regional peripheral vascular resistance, transcutaneous oxygen pressure and blood pressure were studied in seven normotensive, chronically haemodialysed patients with renal anaemia before and after 3 and 12 months of rHuEpo therapy. Haematocrit increased from 21% to 33% within 3 months of commencing therapy, and remained stable throughout the following observation time. Though regional blood flow of the calf was markedly reduced after 3 and 12 months of rHuEpo compared to pretreatment values, transcutaneous oxygen pressure was significantly increased after 3 months and remained constantly elevated after 12 months. Mean arterial blood pressure increased significantly by 7.3 mmHg after 3 months of rHuEpo treatment but did not reach hypertensive values and was no longer different from pretreatment values 12 months after the start of rHuEpo. Results of peripheral haemodynamic studies were compared to those obtained by measurement of central haemodynamics in four further normotensive anaemic patients. In these patients cardiac output decreased, total peripheral vascular resistance increased and blood pressure increased slightly (by 5.5 mmHg) when a haematocrit of 37% was reached after 8 weeks of rHuEpo therapy. These effects were partly reversed when the maintenance haematocrit decreased to 32% (after 16 weeks of rHuEpo). In summary rHuEpo treatment induced a long-term increase of the total and regional peripheral resistance, an increase of blood pressure within the normal range, and a decrease in cardiac output. Despite these changes tissue oxygenation improved.

Subcutaneous amyloid-tumor of beta-2-microglobulin origin in a long-term hemodialysis patient.

beta 2-Microglobulin (beta 2M)-derived amyloidosis has become a major concern in long-term hemodialysis patients. Clinical symptomatology is largely restricted to the articular and periarticular sites and in rare cases systemic manifestations have been described. We present a long-term hemodialysis patient, who after 16 years of hemodialysis with regenerated cellulosic membranes not only had a bilateral carpal tunnel syndrome, cystic bone translucencies and humeroscapular periarthritis but also developed two subcutaneous tumors in both gluteal regions, causing discomfort when sitting. Histology, immunohistology and electron microscopy of the tumor from the right side showed that it consisted of beta 2M-derived amyloid with concurrent scattered amyloid infiltration of the overlying skin. This report therefore adds a new clinical manifestation to the symptomatology of this type of amyloid.

Specific imaging of dialysis-related amyloid deposits using 131I-beta-2-microglobulin.

Dialysis-related amyloidosis (DRA), characterized by its association with beta 2-microglobulin (beta 2m), has become a major concern in long-term hemodialysis patients. Hitherto the diagnosis was based on histological examinations of tissue obtained by biopsy or during surgery. In this preliminary study a new noninvasive diagnostic method was developed using the affinity of beta 2m for its derived fibrils. 3 patients on long-term hemodialysis for 10-16 years with biopsy-proven DRA and 1 patient on chronic hemodialysis for only 6 months were examined after intravenous injection of 131I-labelled beta 2m. Specific local accumulation of radioactivity was noted in the DRA patients after 48 h, persisting for further 96 h and corresponding to clinically or radiologically evident sites of amyloid deposition and to several other hitherto unsuspected sites. Examination of an excised amyloid tumor subsequent to in vivo labelling confirmed a highly specific accumulation of radioactivity in the amyloid tissue but not in control tissue. In the patient on chronic hemodialysis for only 6 months, no specific local accumulation was detected even after 1 week. These findings provide in vivo evidence in man that a specific uptake of circulating amyloid precursor molecules into deposits occurs and that this uptake may be used to radiolabel even small tissue infiltrates of amyloid. This method therefore may not only allow an objective, noninvasive detection of DRA but may also be used to obtain new pathophysiologic insights into amyloid formation in man, as well as permitting the evaluation of preventive therapeutic strategies in prospective studies on new patients.