Jan Wahlberg

Sotrastaurin, a novel small molecule inhibiting protein-kinase C: Randomized phase II study in renal transplant recipients

Sotrastaurin, a selective protein‐kinase‐C inhibitor, blocks early T‐cell activation through a calcineurin‐independent mechanism. In this study, de novo renal transplant recipients with immediate graft function were randomized 1:2 to tacrolimus (control, n = 44) or sotrastaurin (300 mg b.i.d.; n = 81). All patients received basiliximab, mycophenolic acid (MPA) and steroids. The primary endpoint was the composite of treated biopsy‐proven acute rejection (BPAR), graft loss, death or lost to follow‐up at month 3. The main safety assessment was estimated glomerular filtration rate (eGFR); modification of diet in renal disease (MDRD) at month 3. Composite efficacy failure at month 3 was higher for the sotrastaurin versus control regimen (25.7% vs. 4.5%, p = 0.001), driven by higher BPAR rates (23.6% vs. 4.5%, p = 0.003), which led to early study termination. Median (± standard deviation [SD]) eGFR was higher for sotrastaurin versus control at all timepoints from day 7 (month 3: 59.0 ± 22.3 vs. 49.5 ± 17.7 mL/min/1.73 m2, p = 0.006). The most common adverse events were gastrointestinal disorders (control: 63.6%; sotrastaurin: 88.9%) which led to study‐medication discontinuation in two sotrastaurin patients. This study demonstrated a lower degree of efficacy but better renal function with the calcineurin‐inhibitor‐free regimen of sotrastaurin+MPA versus the tacrolimus‐based control. Ongoing studies are evaluating alternative sotrastaurin regimens.

Consistent absorption of cyclosporine from a microemulsion formulation assessed in stable renal transplant recipients over a one-year study period.

To evaluate the pharmacokinetic properties of the new microemulsion formulation of cyclosporine (Sandimmun Neoral), a double-blind, prospective study in stable renal transplant recipients was performed. The patients were randomized on a 4:1 basis either to receive Sandimmun Neoral (n = 45) or continue on regular Sandimmun (n = 12). Before randomization, a steady-state pharmacokinetic profile study was performed in all patients while they were still on regular Sandimmun. Pharmacokinetic assessments were then performed after 8 and 12 weeks and after 1 year. A milligram-to-milligram dose conversion was shown to be adequate to maintain the patients within a predefined target therapeutic window. Changes in pharmacokinetic parameters after conversion to Sandimmun Neoral were consistent with an increased rate and extent of cyclosporine absorption from the Neoral formulation. This was reflected by a shorter time to reach peak concentration and also by a mean increase in peak concentration by 67%, and an overall mean increase in drug exposure (area under the curve) by 34%. These findings were also confirmed 1 year after conversion. Furthermore, significantly reduced intraindividual variability in pharmacokinetic parameters was found, as well as improvements in the correlation between trough concentrations and area under the curve after conversion to Sandimmun Neoral. In conclusion, our results indicate an improved and consistent absorption of cyclosporine from the Neoral formulation, which should make clinical management easier and safer.

Low molecular weight heparin prophylaxis increases the incidence of lymphocele after kidney transplantation

Lymphocele formation after kidney transplantation has become more frequent at our department after the introduction of routine thromboembolic prophylaxis with low molecular weight heparin (LMWH). A consecutive series of 130 kidney transplant recipients were included in a retrospective study. Fifty-eight patients received prophylaxis and 72 did not. Other background data between the two patient groups was comparable. Lymphocele was diagnosed by ultrasound. Lymphocele formation was significantly more common (p<0.01) among patients who received LMWH prophylaxis (43%) than patients who did not (20%). There was no increase in bleeding-related complications in the prophylaxis group. An interesting finding was that, in the prophylaxis group, fewer grafts were lost due to vascular complications or early rejection, leading us to conclude that the use of LMWH increases the incidence of lymphocele formation after kidney transplantation, but may also reduce early graft loss due to thrombosis and vascular rejection.

Pancreatic islet blood flow after syngeneic pancreaticoduodenal transplantation in rats

Inbred male Sprague-Dawley rats were transplanted with syngeneic pancreaticoduodenal grafts. Diabetes was induced in some of the recipient animals by an i.v. injection of streptozotocin one week before transplantation, while the remaining control rats were untreated, and thus had both an intact native and a transplanted pancreas. The left kidney of the recipient was removed and its blood vessels were used for the graft vascular anastomosis. The graft duodenum was sutured end-to-side to the ileum of the recipient. Two weeks after transplantation the rates of blood flow through both the native and transplanted pancreas and duodenum were measured. The blood perfusion of the whole pancreas and the islets was higher in the tx than in the native gland, although no difference was seen with regard to the duodenum. Administration of glucose to control animals had no effect on either native or tx whole pancreatic or intestinal blood flow. However, the islet blood flow through the native pancreas was increased in response to glucose, while that of the tx gland remained unchanged. The combined data show that the blood flow of a tx pancreas is slightly higher than that of the native organ, and that the response of the islet blood perfusion to glucose administration differs between the native and tx pancreas. This suggests that islets in the tx pancreas 14 days after transplantation are not subject to the same blood flow regulatory mechanisms as native islets.

Safety Aspects and Diagnostic Findings of Serial Renal Allograft Biopsies, Obtained by An Automatic Technique with a Midsize Needle

Percutaneous biopsy is an important diagnostic procedure in evaluating the renal allograft with compromised function. Graft losses and haemorrhagic complication are major risks. To minimize these problems we used a midsize TruCut needle, controlled by an automatic firing device (Biopty-Cut), fixed to an ultrasound guidance system. Core biopsies of 1.2 x 20 mm were obtained from 1,421 kidney grafts. On 5 occasions a haemorrhagic complication that required prolonged hospitalization or intervention occurred. No grafts were lost as a consequence of the biopsy procedure. Typical histological morphological parameters found during allograft rejection has earlier been established. Using a protocol with 27 histological parameters this study confirms that recognized criteria for rejection can be relied upon even with this smaller needle. The results showed that the degree of oedema and lymphocytic infiltration of the interstitium and in the arterial wall discriminated best between rejecting grafts and non-rejection grafts.

Assessment of erythropoiesis following renal transplantation.

Abstract: Ten patients, who received cadaveric kidneys, were followed for 24 wk with serial measurements of serum erythropoietin (S‐Epo), transferrin receptor (S‐TfR) and iron variables. The mean pretransplant creatinine clearance was 8.2 (range 0–22) ml/min and the mean haemoglobin (Hb) level was 99±18.6 (range 66–124) g/l. Nine patients demonstrated a gradual increase in S‐Epo levels, which reached a peak, and was accompanied by a parallel increase in S‐TfR levels with a median lag period of 3 wk between both peaks. Hb correction followed the S‐TfR peak after a second lag period (median 7 wk). Elevated S‐Epo and S‐TfR did not result in correction of anaemia in 1 patient due to impaired graft function. Within 4 months, S‐Epo levels reached the normal range while TfR levels were higher than normal. Follow‐up of iron status demonstrated the development of iron deficiency in 5 patients, which was corrected spontaneously. Improvement in erythropoiesis after renal transplantation seems to occur by means of expansion of the erythroid marrow, as detected by increasing S‐TfR levels, subsequent to a S‐Epo peak. This expansion precedes Hb normalization. A nonuraemic environment is probably a prerequisite for the correction of anaemia but not for the increase in S‐Epo or S‐TfR levels. Iron deficiency may occur after transplantation due to an increase in iron utilization.

RELEVANCE OF ADDITIVE COMPONENTS OF UNIVERSITY OF WISCONSIN COLD-STORAGE SOLUTION: AN EXPERIMENTAL STUDY IN THE RAT

The purpose of this study was to evaluate the value of additive components and colloid included in the University of Wisconsin (UW) solution. Therefore, this solution was compared with a solution consisting of the basic components of the UW solution (potassium lactobionate, raffinose, phosphate buffer and MgSO4). We employed a method of measuring the amount of chromium-51-labeled erythrocyte trapped in the medullary vasculature 20 min after reperfusion of kidney grafts cold-stored for 24-48 h in either the basic UW (bUW) or the original UW (oUW) solution. The amount of trapping has been shown to correlate well with the degree of cold ischemic injury. Both hemodiluted (hct 20-27%) and normal (hct 41-45%) recipients were used. Long-term viability of grafts stored in either bUW or oUW was investigated in survival experiments and the flow rates during in situ flush-out were also measured, as well as weight changes during the storage period. The results showed no significant difference between the two solutions, regardless of ischemia time or whether hemodiluted or normal recipients were used. However, the flow rate and weight measurements showed that flushing was more rapid and kidney swelling less pronounced using oUW. Survival rates in long-term transplantation experiments were similar. It was concluded that the inclusion of a colloid improves the rheological properties of the UW solution and that the additives besides the basic components did not offer any advantage.

Effects of cold ischemia and reperfusion on trapping of erythrocytes in the rat kidney

Abstract. After reperfusion of kidneys subjected to a period of warm ischemia, the medulla displays a vascular congestion of erythrocytes, especially in the inner stripe of the outer zone, a phenomenon referred to as “trapping.” This trapping causes reflow alterations, thus contributing to postperfusion medullary ischemia. The purpose of the present investigation was to study whether trapping also occurs after reperfusion of kidneys following varying periods of cold ischemia and to determine if there is any correlation between the degree of cold ischemic injury and the extent of erythrocyte trapping. Rat kidneys stored at +4°C for 0–30 h were transplanted into recipient animals pretreated with a 51Cr‐labelled erythrocyte suspension. Twenty minutes after reperfusion, the grafts were removed and microdissected into cortex, outer and inner stripes of the outer medullary zone, and inner zone, respectively. The radioactivity of these specimens was measured, and the erythrocyte content for each specimen was calculated. The results show a maximal trapping for cold ischemia time (CIT) of about 12–15 h. A linear correlation between the amount of trapping and CIT could be found in all parts of the kidney (except for the cortex) for CIT 0–15 h. The best correlation was found in the part where the trapping was most prominent, i.e., in the inner stripe. After CIT of 15 h or more, no correlation could be found. It is suggested, as described in models of warm ischemia, that the obstructions of the capillaries by trapped erythrocytes following reperfusion is of pathophysiological significance for the development of post‐transplant acute renal failure. Furthermore, the strong correlation between CIT and the extent of erythrocyte trapping, particularly in the inner stripe, indicates that measurement of erythrocyte trapping after reperfusion could be a sensitive indicator of the degree of cold ischemic damage.

Accelerated atherosclerosis in the transplant recipient: role of hypertension.

An accelerated atherosclerosis may occur in the native arteries of a transplant recipient as well as in arteries of transplanted kidneys or hearts. The dominating cause of patient mortality are cardiovascular diseases, where ischaemic heart disease is predominant. The accelerated form of arteriosclerosis which takes place in transplanted kidneys and hearts, has a complex pathogenesis, which includes both immunological and non-immunological factors. Hypertension is one such factor which has been claimed to be an independent risk factor of chronic renal transplant dysfunction, usually characterised by transplant arteriosclerosis. Whether a more intense treatment of hypertension or a more selective use of antihypertensive drugs would have a beneficial effect upon the progression rate of chronic rejection is still an open question.

Comparison of two Catheters for Peritoneal Access in Patients Undergoing Continuous Ambulatory Peritoneal Dialysis (CAPD)

The results obtained by means of the Tenckhoff and the Toronto Western Hospital-type (TWH) indwelling catheters for peritoneal access in patients undergoing Continuous Ambulatory Peritoneal Dialysis are reported. Fifty-nine Tenckhoff catheters were used for 592 months and 24 TWH-type for 220 months. One-year catheter survival was 71% in the Tenckhoff group and 77% in the TWH group. The difference does not reach statistical significance. Moreover no statistically significant differences as regards complications could be found between the two catheter types. A major disadvantage was noted with the TWH catheter: on two occasions TWH catheters could not be removed without a laparotomy, being firmly adherent to the intestine or omentum. It is concluded that the TWH catheter is not a superior alternative to the Tenckhoff catheter for peritoneal access in patients undergoing Continuous Ambulatory Peritoneal Dialysis.