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H H Neumayer

Publications and source records attributed to H H Neumayer.

At least 109 records · Page 6Linked to original sources
PubMed1996

Substitution of conventional cyclosporin with a new microemulsion formulation in renal transplant patients: results after 1 year.

BACKGROUND: A new galenic form of cyclosporin A has been developed, based on microemulsion technology. The bioavailability of the compound is relatively independent of food intake and bile flow. It was the purpose of this prospective clinical trial to study the safety of the microemulsion form of cyclosporin A. METHODS: Three hundred and two renal transplant patients, stratified according to transplant age, were switched from the conventional to the new microemulsion formulation of cyclosporin A. A 1:1 conversion ration was used. Measurements included CsA levels, S-creatinine, liver enzymes, uric acid, and blood pressure. Measurements were performed at baseline and on days 4, 8, 15, 29 and months 3, 6 and 12 after conversion. Dose adjustments were performed to achieve through levels of 80-120 ng/ml. RESULTS: Within the 12-month observation period the cyclosporin dose was reduced by 14.7% (from 204 +/- 60 mg/day at baseline to 174 +/- 51 mg/day after conversion, P < 0.001). Acutely, i.e. by day 8, 1:1 dose conversion resulted in a modest increase of mean drug through levels (from 114 ng/ml at baseline to 120 ng/ml, P < 0.01). This increase was accompanied by an increase in serum creatinine concentration, a decrease in calculated creatinine clearance, and an increase in uric acid values (P < or = 0.05). Liver enzymes remained unchanged while systolic and mean arterial blood pressure decrease (P < 0.05). After 1 month, drug through levels had decreased to baseline (112 ng/ml) and remained there until month 6. They were significantly lower after 12 months (102 +/- 33 ng/ml), P <0.001). Creatinine clearance values increased to above baseline at 6 and 12 months. Within the 1-year period there occurred 24 (= 8%) episodes of biopsy proven rejection and seven episodes of cyclosporin-attributed nephrotoxicity. CONCLUSIONS: The 1:1 conversion from conventional cyclosporin A to the microemulsion formulation s efficacious and safe, but an initial dose reduction of 10% is advised in patients with through levels in the high-normal range.

Administration, Oral↗
PubMed1996

Function and expression of endothelin receptor subtypes in the kidneys of spontaneously hypertensive rats.

OBJECTIVE: The renal endothelin system has been implicated in the development and maintenance of hypertension in spontaneously hypertensive rats (SHR). However, little is known about the function and cellular distribution of endothelin receptor subtypes in the kidneys of SHR. METHODS: We analyzed the expression of endothelin receptor subtypes in the kidneys of 16-week-old SHR using Scatchard analysis, receptor autoradiography, Northern blot analysis and in situ hybridization. Wistar-Kyoto rats (WKY) served as controls. Furthermore, we investigated the effects of the mixed (A/B) endothelin receptor antagonist bosentan and the ETA receptor antagonist BQ 123 on mean arterial blood pressure (MAP), renal blood flow (RBF) and glomerular filtration rate (GFR) in conscious chronically instrumented rats. RESULTS: In SHR, we found by receptor autoradiography an overexpression of the endothelin A receptor (ETA) in the glomeruli (2.2 +/- 0.4-fold; P < 0.05) and smooth muscle cells of intrarenal arteries (1.9 +/- 0.2-fold; P < 0.05) compared to age-matched WKY. In addition, our study revealed a pronounced upregulation of endothelin B receptor (ETB) in the glomeruli of SHR (5.6 +/- 0.8-fold; P < 0.01). Blockade of endothelin receptors in SHR with bosentan (A and B receptor blockade) as well as with BQ 123 (A receptor blockade) led to a significant decrease in MAP (-18.6 +/- 2.1 and -19 +/- 1.3 mmHg, respectively; P < 0.05 in both cases) and a significant increase in RBF (+2.8 +/- 0.5 and +3.1 +/- 0.37 ml/min, respectively; P < 0.05 in both cases). The blockade of both ETA and ETB by bosentan had no further effect on MAP reduction or RBF increase in SHR compared to the ETA blockade by BQ 123. The ETA antagonist BQ 123 had no effect on GFR either in SHR or in WKY, whereas the combined blockade of ETA and ETB by bosentan significantly decreased GFR in SHR by about 50% but not in WKY. CONCLUSIONS: Our data demonstrated a correlation between the overexpression of vascular ETA receptors and the pronounced upregulation of glomerular ETB receptors in the kidneys of SHR and their impact on the regulation of renal blood flow, glomerular filtration rate and blood pressure in these animals.

Animals↗
PubMed1996

Conversion to microemulsion cyclosporine in stable renal transplant patients: results after one year.

We switched 302 renal transplant patients from the conventional to a new microemulsion formulation of cyclosporine, to study the latter's safety and efficacy. We used a simple 1:1 conversion of the patient's total daily dose. We measured trough drug levels as well as serum creatinine, liver enzymes, uric acid, and blood pressure values at baseline and at days 4, 8, 15, 29, and months 3, 6 and 12 after drug substitution. Dose adjustments directed at trough levels 80-120 ng/ml were performed, starting at day 8. Within the 12-month observation period, the cyclosporine dose was reduced by 14.7% (204 +/- 60 mg/day baseline vs 174 +/- 51 mg/day after conversion, p < or = 0.001). By day 8, the 1:1 dosage conversion resulted in a modest mean increase in drug trough levels (114 ng/ml baseline vs 120 ng/ml, p < or = 0.01). This increase was accompanied by an increase in serum creatinine concentration, a decrease in calculated creatinine clearance, and an increase in uric acid values (p < or = 0.05). Liver enzymes remained unchanged while systolic and mean arterial blood pressure decreased (p < or = 0.05). After one month, drug trough levels had decreased to baseline (112 ng/ml) and remained there until month 6. They were significantly lower after 12 months (102 +/- 33 ng/ml, p < or = 0.001). Plasma creatinine values decreased to below baseline by month 6 (p < or = 0.001) and month 12 (p < or = 0.001). Twenty-four (8%) biopsy proven rejection episodes and 7 cases of cyclosporine attributed nephrotoxicity occurred in these 302 patients within these 12 months. We conclude, that a 1:1 conversion from conventional to the microemulsion form of cyclosporine is efficacious and safe. However, we advise an initial 10% decrease in dose reduction in those patients whose trough levels are in the high-normal range.

Adult↗
PubMed1996

Clinical pharmacokinetics of tacrolimus in rescue therapy after renal transplantation.

Tacrolimus, a potent new immunosuppressive drug, was introduced for rescue therapy in 25 renal transplant recipients with ongoing rejection (n = 24) or severe cyclosporine toxicity (n = 1). A highly significant (p < 0.001) rise in serum creatinine from 138 +/- 14 (3 months before conversion) to 295 +/- 26 mumol/l preceded conversion to tacrolimus. Tacrolimus rescue therapy started 73 +/- 9 months after transplantation, the follow-up was 8 +/- 1 months. Outcome, pharmacokinetics, and side-effects were analyzed. Patient survival was 100% on tacrolimus therapy. Graft survival was 88% after 3 months, and 70% after 8 months. Serum creatinine remained stable during the observation period (Crea after 8 months: 271 +/- 26 mumol/l). Starting with an initial dose of 9.6 +/- 0.3 mg/day (0.14 +/- 0.01 mg/kg/day) we could reduce tacrolimus dose to 6.0 +/- 0.9 mg/day (0.09 +/- 0.02 mg/kg/day; p < 0.001) after 1 month. Tacrolimus trough levels were adjusted to a therapeutic window of 5-8 ng/ml. We had to perform 3.4 +/- 0.5 dose adjustments per patient mainly within the first month after conversion (70%). A high variability in interindividual tacrolimus dose was noted. Last cyclosporine dose was a good predictor of required tacrolimus dose after 1 month (r = 0.88; p < 0.001). Overall, 82 adverse events were noted, of which 29 (35%) were associated with high trough levels (> 10 ng/ml). In contrast, 3 patients with trough levels < 4 ng/ml had ongoing rejection. Blood pressure and routine laboratory data remained unchanged. Steroid dose could be tapered from 12 +/- 2 to 5 +/- 0.3 mg/day (p < 0.02). Gingival hyperplasia and hirsutism improved after conversion. We conclude: Tacrolimus conversion for rescue therapy after renal transplantation is efficient and safe with target trough levels between 5 -8 ng/ml. Frequent drug monitoring is necessary, especially within the first month after conversion. Previous cyclosporine dose can be used as a guideline for starting dose.

Adult↗
PubMed1995

Normalization of circadian blood pressure profiles after renal transplantation.

Most patients with secondary hypertension due to renal disease or on maintenance hemodialysis have lost the physiologic fall of blood pressure during sleep. To test the notion that kidney transplantation normalizes the blood pressure profile, we monitored ambulatory blood pressure over 24 hr in 45 patients (29 males and 16 females) after successful renal transplantation. The longer the time after renal transplantation, the more marked was the decrease of blood pressure during sleep (r = 0.38, P < 0.01). This effect of time after renal transplantation on the fall of blood pressure during sleep was independent of the prevailing level of 24-hr ambulatory blood pressure. The prevalence of dippers (defined by a fall in mean blood pressure during sleep of 10% or more of the awake mean) increased from 27% in the early phase (< 7 months) to 73% in the late phase (> or = 1 year) after renal transplantation (P < 0.01). Again, this effect was not attributable to the level of 24-hr ambulatory blood pressure and concomitant antihypertensive or immunosuppressive medication. We conclude that renal transplantation leads to a normalization of the circadian blood pressure profile with a marked decrease of blood pressure during sleep. As a consequence, the lower hemodynamic load imposed on the cardiovascular system may in turn lead to a reduction of cardiovascular morbidity and mortality.

Adult↗
PubMed1995

A multicenter, randomized, double-blind, placebo-controlled, two-year trial to study the effect of nitrendipine on chronic renal transplant function.

The ongoing multicenter, randomized, double-blind, placebo-controlled trial investigates the effect of nitrendipine on kidney function after renal transplantation. Renal transplant recipients (6th-12th postoperative week, serum creatinine < 3 mg/dl) were divided into a normotensive (diastolic blood pressure < 90 mmHg) and a hypertensive group (diastolic blood pressure > or = 90, < 115 mmHg). Normotensive patients are randomly treated for 104 weeks with nitrendipine 2 x 5 mg daily or placebo, hypertensive patients with 2 x 10 mg - 2 x 20 mg nitrendipine daily or placebo and in case of inefficacy with additional antihypertensive drugs. Primary end point of the study is the renal transplant function. The trial was started in June 1990. One hundred and eight patients were included into the normotensive and 138 patients into the hypertensive group. Renal allograft function, cyclosporine trough levels and the donor characteristics were not different between the normotensive and hypertensive groups at entry into the study. After 12 months there was no significant change of renal transplant function in both groups. Cyclosporine trough levels were also similar in the normotensive and hypertensive group after 12 months. As expected, blood pressure decreased significantly after 12 months from 150 +/- 17/95 +/- 11 mmHg to 141 +/- 16/90 +/- 9 mmHg in the hypertensive group (p < 0.01). In contrast, in the normotensive group blood pressure increased significantly from 128 +/- 12/80 +/- 6 mmHg to 135 +/- 15/86 +/- 8 mmHg (p < 0.001). No normotensive but 4 hypertensive patients developed graft failure during the first 12 months of the study.

Adolescent↗
PubMed1995

Clinical experience transferring kidney transplant patients from Sandimmun to Sandimmun Neoral--results after 3 months.

The new galenic formulation of cyclosporine prepared as microemulsion (Sandimmun Neoral, SN) shows a significantly improved correlation between both trough level (Cmin) and dose. Moreover, since the bioavailability is increased by 20 to 30% on average, it may lead to a drug overexposure in so far malabsorbing patients. In order to assess safety and to establish an appropriate procedure to switch patients safely from conventional Sandimmun to SN, we initialized an open, stratified (transplant age) clinical trial enrolling 302 patients of our outpatient clinic. We used a simple 1:1 conversion of the patient's total daily dose. Trough drug levels, as well as serum creatinine, liver enzymes, uric acid, and blood pressure values were measured at baseline, at days 4, 8, 15, 29, and at month 3 after drug substitution. Within the three month observation period, the cyclosporine dose was reduced by 14.2% (204 +/- 60 mg/day baseline vs. 175 +/- 54 mg/day after conversion, p < 0.05). By day 8, the 1:1 dosage conversion resulted in a modest mean increase in drug trough levels (114 ng/ml baseline vs. 120 ng/ml, p < 0.05). This increase was accompanied by a slight increase in mean serum creatinine concentration, a decrease in calculated creatinine clearance, and an increase in mean uric acid values (p < 0.05). Liver enzymes remained unchanged while systolic and mean arterial blood pressure decreased (p < 0.05). Parallel to dosage reduction, drug trough levels had decreased after 1 month to baseline (112 ng/ml) and remained there for the remainder of the study.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological Availability↗
PubMed1994

The diagnostic value of GM-CSF and IL-6 determinations in patients after renal transplantation.

Cytokines are released by graft-infiltrating cells during cellular rejection. We studied the release of GMCSF and IL-6 and their prognostic significance in predicting rejection. Sequential measurements were made in serum and urine samples with an IL-6 specific cell line and a GMCSF ELISA. Biopsy tissue was snap frozen and examined with immunohistochemical methods. The IL-6 values for normal controls (CTR) and stable transplant patients (PTS) were 5-10 pg/ml in serum and 0-2.5 pg/ml in urine. In 51 biopsy-proven rejections (AR), serum IL-6 values at least doubled in 15 (sensitivity 29%, specificity 87%; 19 +/- 7 vs. 7 +/- 2 pg/ml; P = ns). In urine an increase was observed in 29 of 36 AR (sensitivity 80%, specificity 75%; 92 +/- 34 vs. 5 +/- 1 pg/ml; P < 0.05). After treatment, IL-6 decreased in urine in 26/29 PTS to 7 +/- 2 pg/ml (P < 0.05). In three PTS, rejection persisted, as did their elevated IL-6 urine values. In PTS with urinary tract infections, IL-6 increased in the serum of 13/19 and in the urine of 10/12. GMCSF in serum was not influenced by rejection; however, urine values increased in 22/33 AR (sensitivity 67%, specificity 96%; 22 +/- 5 vs. 4.8 +/- 0.3 pg/ml; P < 0.05). These values decreased (5 +/- 0.3; P < 0.05) after treatment. During infection, increased urinary GMCSF levels were observed in 2/9 PTS. Further analysis revealed a better correlation between elevated cytokine levels and rejection episodes in the early posttransplant period. In kidneys with acute rejection, IL-6 was found in the interstitium of all PTS tested. CTR tissue was negative. In PTS GMCSF was found in arterioles and in infiltrate; however, control tissue also showed some staining. Cytokine labeling in tissue could not be correlated with serum or urine values. We concluded: (1) serum IL-6 and GMCSF are of no value in rejection; (2) in urine, they reflect rejection, especially in the early posttransplant period; however, infection confounds the results; (3) IL-6 staining in tissue may be helpful, but requires more study.

Biopsy↗
PubMed1994

Kidneys from pediatric donors: risk versus benefit.

We encountered four adult patients who received renal transplants from young children < 36 months of age, each of whom developed severe hypertension, heavy proteinuria, and progressive renal failure. Biopsies disclosed glomerular sclerosis with crescents in three patients and mesangial expansion in one. We thus analyzed our experience with 74 adults who received grafts from donors < or = 10 years of age and compared the results to those of 804 patients who were transplanted with kidneys from donors > 10 years of age. A Kaplan-Meier analysis revealed that graft survival was significantly worse in patients receiving grafts from younger, compared to older donors. This difference was apparent in patients treated either with or without cyclosporine. A subanalysis comparing patients with donor grafts aged < or = 5 or 6-10 years revealed a further adverse age-related effect. Renal artery thrombosis and recurrent or de novo biopsy-proven glomerulonephritis were more common in patients receiving grafts from younger donors, while graft failure from rejection actually appeared less common. We conclude that severe hypertension and resultant glomerular hyperperfusion promoted glomerulosclerosis and crescent formation in our patients. Our results have caused us to pursue a more conservative approach towards transplanting grafts from donors aged < or = 10 years into adult recipients.

Adult↗
PubMed1994

Serum circulating ICAM-1 levels are not useful to indicate active vasculitis or early renal allograft rejection.

During inflammation, activated vascular endothelial cells and other cell types express various adhesion molecules which facilitate binding of circulating leukocytes. Serum concentration of circulating adhesion molecule ICAM-1 (c-ICAM-1) is supposed to reflect the degree of this activation. In order to evaluate the usefulness of c-ICAM-1 serum levels for assessment of disease activity in various vasculitic disorders, we examined 23 patients with systemic lupus erythematosus (SLE, n = 9). Wegener's granulomatosis (WG, n = 6), Goodpasture syndrome (GP, n = 6) and microscopic polyarteritis (MP, n = 2). Disease activity was defined by clinical criteria and by conventional laboratory data. Circulating ICAM-1 concentrations were measured during periods of active clinical vasculitis and on clinical remission. In a second part of the study, we examined whether or not c-ICAM-1 might be helpful in diagnosing acute allograft rejection early after kidney transplantation. After cadaveric kidney transplantation thirteen patients were included. Serum probes were gathered firstly after transplantation, secondly at time of histologically proven allograft rejection and finally after successful anti-rejection therapy and restored transplant function. c-ICAM-1 levels in healthy volunteers (n = 10) were 270 +/- 47 ng/ml (mean +/- SD). Patients with active vasculitis had mean serum levels of 509 +/- 71 ng/ml (SLE), 594 +/- 118 ng/ml (WG), 472 +/- 126 ng/ml (GP) and 498 ng/ml (MP) (mean +/- SD). In clinical remission, mean serum concentrations were found to be 500 +/- 99 ng/ml (SLE), 597 +/- 84 ng/ml (WG), 782 +/- 163 ng/ml (GP) and 594 ng/ml (MP) (mean +/- SD).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

[Kidney transplantation in patients with anomalies of the lower urinary tract].

In the transplant centre in Erlangen-Nuremberg, 1242 patients underwent renal transplantation between 1966 and 1993. In 4.5% of cases (56 patients) the renal end stage disease had been caused by severe abnormalities or functional disturbance of the lower urinary tract. Despite long-standing defunctionalization, urinary diversions and multiple operative procedures, it was possible to use the original bladder for ureterocystoneostomy in all patients. Only 1 patient needed an enterocystoplasty after transplantation. Altogether 72 transplantations have been performed in 56 patients ranging from 10.2 to 62.7 years of age. At follow up, 40 patients (71%) had a functioning graft with a mean serum creatinine level of 1.5 mg%. The 5-year transplant survival rate is 57.3%. Our results suggest that carefully planned renal transplantation in urological patients has results comparable to those obtained in other, non-risk, kidney transplant recipients. The methods of bladder reconstruction and augmentation, intermittent self-catheterization as well as anticholinergics and continuous antibiotic prophylaxis combine to make the ileal or colonic conduits needed earlier unnecessary.

Adolescent↗
PubMed1993

[Acute cytomegalovirus gastritis after kidney transplantation. Its diagnosis by the polymerase chain reaction, antigenemia assay and immunohistochemistry].

To diagnose possible cytomegalovirus (CMV) infection in a 64-year-old man after renal transplantation, polymerase chain reaction (PCR), pp65 antigenaemia assay (pAA) and virus isolation in cell culture were routinely performed on a weekly basis. The PCR obtained virus DNA in peripheral blood lymphocytes for the first time in the fifth week. Two weeks later the patient complained of feeling unwell with abdominal pain and vomiting on eating. Two days later he developed a fever up to 38 degrees C and nocturnal sweats. Gastroscopy revealed marked antral gastritis which histologically showed typical cytomegalic "owl-eye" cells. The pAA was clearly positive and the cell culture started in the fifth week now showed a cytopathogenic effect. CMV gastritic having been diagnosed treatment consisted of 175 mg ganciclovir intravenously twice daily for 10 days. He became symptom-free after two days. The only side effects were thrombocytopenia down to 67,000/microliters and a rise in transaminase activities, changes which regressed later. To ensure early diagnosis and treatment of any CMV infection, specific virus diagnostic tests should be routinely undertaken after transplantation of organs from CMV-positive persons into CMV-negative patients.

Acute Disease↗
PubMed1993

Prevalence and long-term outcome of glomerulonephritis in renal allografts.

We report long-term results over 10 years in patients developing glomerulonephritis after renal transplantation. The prevalence rate of glomerulonephritis was 6.2% in 785 renal transplants involving 697 patients with end-stage renal disease. This rate was 14% in patients undergoing biopsy of their grafts because of malfunction. The rate was 15% in patients diagnosed as having glomerulonephritis of any cause prior to transplantation. Membranous, focal sclerosing, and IgA glomerulonephritis were the most common histologic diagnoses. Documented histologic recurrence occurred in only 1% of patients with poor, biopsy-proven glomerulonephritis of their native kidneys. Patients with focal sclerosing glomerulonephritis had the greatest risk from recurrence. De novo glomerulonephritis was most likely to be membranous in character. The graft survival rate of patients with glomerulonephritis was not distinguishable from that of patients showing rejection; both were 45% at 60 months and 33% versus 11%, respectively, at 120 months (P = NS); the graft survival rate in patients without rejection was 76% at 120 months. Thus, glomerulonephritis is responsible for approximately 14% of renal graft malfunction. Glomerulonephritis has a prognosis similar to chronic rejection. Finally, glomerulonephritis as specific histologic recurrence is unusual. Patients with glomerulonephritis should not be discouraged from undergoing transplantation because of putative risks related to recurrence.

Adolescent↗