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Biomedical subjects

M Klinger

Publications and source records attributed to M Klinger.

At least 37 records · Page 2Linked to original sources
PubMed2003

Electron paramagnetic resonance study of erythrocyte membrane fluidity in renal transplant recipients.

Renal transplantation (KTx) patients receiving calcineurin inhibitors-cyclosporine (CsA) or tacrolimus (TAC)-are known to be at risk for the development of posttransplant hemolytic uremic syndrome. The syndrome has been reported to occur more often with CsA than TAC treatment. It has also been noted that CsA affects erythrocyte membrane fluidity. The aim of this study was to investigate whether the impairment of erythrocyte membrane fluidity is similar among patients under treatment with different calcineurin inhibitors (CsA or TAC). Venous blood was collected from 29 KTx patients and from nine healthy volunteers. To investigate the fluidity of intact erythrocyte membranes spin label electron paramagnetic resonance spectroscopy was applied. Comparison of values for controls versus CsA-treated patients demonstrated a significant decrease in membrane viscosity in the hydrophobic region of the lipid bilayer among CsA-treated patients, whereas there was no significant difference between control and patients treated with TAC. There was no significant difference in the molecular order close to the polar heads of lipid molecules among all groups. The observed changes in erythrocyte membrane fluidity among CsA-treated patients and the lack of this phenomenon in the TAC group may correlate with more frequent prevalence of hemolytic anemia among CsA than TAC-treated patients.

Cyclosporine↗
PubMed2003

Mycophenolate mofetil severely depresses antibody response to CMV infection in early posttransplant period.

Estimation of anti-CMV-IgG and anti-CMV-IgM is considered a relatively inexpensive screening tool of CMV status. The aim of study was to estimate how the immunosuppressive protocol influence serum anti-CMV IgG and IgM concentration in renal graft recipients and to estimate the adequacy of anti-CMV-IgG concentration and anti-CMV-IgM index as screening parameters of active CMV disease in patients receiving different immunosuppression. The study group consisted of 33 patients with clinical signs of CMV disease who received one of three types of immunosuppression: (1) azathioprine (Aza) + cyclosporine (CyA) + prednisone (Pr), 20 patients; (2) mycophenolate mofetil (MMF) + CyA + Pr, eight patients; tacrolimus (Tac) + MMF, five patients. Patients were enrolled when the pp65-antigen (pp65) of PBL was positive within 1 to 5 months after transplant (75 patients tested). The IgM-i in the Aza + CyA + Pr group was higher than in MMF + CyA + Pr group (2.73 + 1.8 vs 1.08 +/- 1.07, P =.021). The IgM-i in the Aza + CyA + Pr group was higher than in Tac + MMF (2.73 +/- 1.8 vs 0.78 +/- 0.69; P =.014). There was no difference in IgM-i between MMF + CyA + Pr and Tac + MMF. There was no difference in relative increase of IgG-c among all groups but there was a difference in relative increase of IgM-i between Aza + CyA + Pr and MMF + CyA + Pr groups (6.7 +/- 9.4 vs 2.3 +/- 5.9; P =.007) and between Aza + CyA + Pr and MMF + Tac groups (6.7 +/- 9.4 vs 0.6 +/- 0.54; P =.003). Immunosuppressive protocols including MMF exert an inhibitory influence on B-cell response and synthesis of anti-CMV-IgM. It makes the anti-CMV-IgM index an inadequate rough screening diagnostic parameter of active CMV disease.

Antibody Formation↗
PubMed2003

Tacrolimus decreases tubular phosphate wasting in renal allograft recipients.

The aim of the study was to elucidate whether cyclosporine- and tacrolimus-based immunosuppression impairs tubular reabsorption of phosphate after kidney transplantation. Sixty cadaveric allograft recipients were included in the study. Forty patients receiving triple immunosupression with cyclosporine, azathioprine, and prednisone were studied for 1, 6, 12 months (groups A1 and A2, 20 patients) and for 24, 30, and 36 months (groups B1 and B2, 20 patients) after transplantation. Twenty patients who received tacrolimus with steroid withdrawal after 3 months were included in the study (group C). Recipients from groups A2 and B2 were treated additionally with vitamin D and calcium carbonate. Serum iPTH, 25-OHD, 1.25(OH)(2)D concentrations were determined, and TRP (mmol/L) and TmP/GFR (mmol/L) were calculated using Walton-Bijvoet nomogram. Higher values of total calcium serum concentration in group A were detected. Lower inorganic phosphate serum concentrations were detected in groups A and C, in contrast to group B where they remained within normal values. TmP/GFR values were significantly higher in group C in the first and third examination in comparison with patients of group A. Moreover, TRP index values were significantly higher than analogous values of groups A and B. Tacrolimus-treated patients exhibit significantly faster recovery from tubular phosphate reabsorption impairment compared to cyclosporine-treated recipients. No correlation between iPTH, 25-OHD, 1,25(OH)(2)D concentration, and tubular dysfunction parameters was observed. Amelioration of phosphate handling, in spite of hyperparathyroidism intensity, can follow early steroid avoidance.

Adolescent↗
PubMed2003

Influence of hypercholesterolemia and acute graft rejection on chronic nephropathy development in renal transplant recipients.

Graft endothelial lesions resulting from acute rejection may be sustained by concomitant hypercholesterolemia, thus increasing the risk of chronic graft failure. The present study was undertaken to examine the influence of hypercholesterolemia and acute graft rejection (AGR) episodes on graft function and graft loss due to chronic nephropathy. A cohort of 336 patients transplanted between 1993 and 2000 having graft function at 12 months after transplantation were examined. Immunosuppressive therapy consisted of CsA, azathioprine, and corticosteroids in 90% with 10% of patients receiving mycophenolate mofetil in place of azathioprine. During the first year after transplantation, AGR occurred in 134 (39.8%) and hypercholesterolemia (6.2 mmol/L) in 132 (39.2%) of patients. The population was divided into four groups according to AGR occurrence and cholesterol concentrations during the first year after transplantation for analysis of serum creatinine concentrations and graft loss at 5 years of follow-up. Patients with AGR irrespective of cholesterol levels displayed significantly higher creatinine concentrations. Graft loss in these patients increased over twofold compared to the remaining groups. Patients without hypercholesterolemia and AGR showed normal creatinine concentrations and low graft loss rates during 5 years of follow-up.

Cholesterol↗
PubMed2003

Biopsy eosinophilia as a predictor of renal graft dysfunction.

AIM: The aim of this research was to assess the impact of eosinophilia in renal biopsy specimens obtained during an acute rejection (AR) episode on the severity and reversibility of rejection and on long-term graft function. MATERIAL: Among 165 renal graft recipients who underwent transplantation (Tx) in 2001 and 2002 whose biopsy specimens revealed AR, 49 with tissue eosinophilia were compared with control group of 48 without this feature. The average biopsy time was 60.6 and 95.8 days, respectively. Biopsies during delayed graft function were performed in 46.9% of patients with eosinophilia and 29% in the control group. The immunosuppressive regimen was based on tacrolimus or cyclosporine. RESULTS: Tissue eosinophilia was observed in 49 of 165 patients (29.6%): 5 patients had eosinophilia <10/mm(2), 31 patients 10-100/mm(2), 13 patients >100mm(2) (3 patients >300/mm(2)). Severity of AR according to Banff score was statistically lower in the control group (P <.002). Patients with tissue eosinophilia who initially received steroid-free treatment presented with significantly higher (P =.02) biopsy/patients index (2.3 vs 1.81) than the total eosinophilic group. Serum creatinine values at 6 and 12 months after transplantation (Tx) were higher among eosinophilic when compared with the control group (2.41 vs 1.82 mg/dL, P <.002; 2.10 vs 1.98 mg/dL, P =.006, respectively). Chronic rejection within the first year occurred in 25% of patients with tissue eosinophilia, and 8.3% of patients in the control group. One-year graft survival rate among patients with tissue eosinophilia was lower compared with the control group (89.8% and 93.7%, respectively). CONCLUSIONS: Biopsy eosinophilia is a negative predictor that indicates a more severe course of AR and a worse response to treatment with the threat of chronic graft dysfunction.

Biopsy↗
PubMed2003

Gingival overgrowth in kidney transplant recipients treated with cyclosporine and its relationship with chronic graft nephropathy.

Our previous study of a group of renal transplant recipients treated with CsA showed a significantly faster development of chronic graft failure among patients with gingival hyperplasia (GH) compared to unaffected patients. The aim of the present research was to establish the impact of CsA dose and blood levels on the incidence of chronic graft nephropathy and gingival overgrowth as well as to assess risk factors for chronic graft nephropathy. The study included 64 renal graft recipients (32 patients with GH and 32 without GH) transplanted between 1989 and 1994. There were no significant differences between the pretransplant demographic and clinical data of the patients with and without GH. Patients with GH received a significantly higher total yearly dosages of CsA compared those without GH (P <.03). Serum creatinine in the first year posttransplant in patients with GH was 1.9 mg/dL versus 1.6 mg/dL in those without GH. During 9 to 14 years follow-up, end-stage renal failure due to chronic nephropathy occurred in 18 patients (56%) with GH and eight patients (25%) without GH. Ten-year renal graft survival was 35% in GH patients and 69% in patients without GH. Ten-year patient survival was 69% in the GH group and 91% in the group without GH. CsA dosage was a risk factor for GH and for graft loss, which implies a role of CsA toxic effects on the pathological mechanisms of GH and of chronic allograft nephropathy.

Adult↗
PubMed2002

Polarized expression of Tamm-Horsfall protein by renal tubular epithelial cells activates human granulocytes.

In renal bacterial infections granulocytes are of major importance in the primary immune defense against invading pathogens. However, the mechanisms of granulocytic activation in renal interstitial invasion have not been clarified. Renal tubular epithelial cell mechanisms inducing granulocytic activation and bacterial killing may include tubular cell expression of Tamm-Horsfall protein (THP), a urinary protein that is known to enhance cytokine expression in monocytes. We studied the role of THP in granulocytic activation. A strong binding of THP to human granulocytes was demonstrated by fluorescence-activated cell sorter analysis. Urinary THP and supernatants of THP-expressing cultured tubular epithelial cells (MDCK) enhanced interleukin-8 (IL-8) expression by human granulocytes. Renal tubular cells growing polarized on polycarbonate membranes were used to study apical versus basal THP expression. By electron microscopy THP immunoreactivity was exclusively found on the apical surfaces of tubular cells and was absent on the basolateral cell membrane. In the apical cell culture compartment we found significantly more stimulatory activity for granulocytic IL-8 expression. CD62L, a selectin less expressed in activated granulocytes, was decreased in granulocytes incubated with urinary THP and in supernatants of THP-producing renal tubular cells but not in supernatants from THP-negative cells. Again, the effect on CD62L expression was found only in apical culture media and was absent in the basal compartment. In summary our data give evidence that renal tubular cell THP expression may be relevant in kidney diseases since THP is a potent activator of human granulocytes. The regulation of apical versus basal THP expression and release in vivo may be crucial in the induction of the inflammatory response, e.g., in bacterial renal diseases.

Animals↗
PubMed2002

Freedom from rejection and stable kidney function are excellent criteria for steroid withdrawal in tacrolimus-treated kidney transplant recipients.

OBJECTIVES: This prospective, randomized, multicentre study investigated the efficacy and safety of two tacrolimus-based regimens and their potential to withdraw steroids. METHODS: In total 489 patients were randomised to receive either tacrolimus and MMF (n = 243) or tacrolimus and azathioprine (n = 246) concomitantly with steroids in both treatment groups. The initial oral dose of tacrolimus was 0.2 mg/kg/day, MMF dose was 1 g/day, azathioprine was administered at 1-2 mg/day. Steroids were tapered from 20 mg/day to 5 mg/day. From month 3 onwards, steroids were withdrawn in patients who were free from steroid-resistant rejection and who had serum creatinine concentrations < 160 mumol/L. Study duration was 6 months. RESULTS: Patient survival at month 6 was 98.3% (Tac/MMF/S) and 98.4% (Tac/Aza/S), graft survival at 6 month was 95.0% (Tac/MMF/S) and 93.5% (Tac/Aza/S). The 6-month incidences of biopsy-proven acute rejection were 18.9% (Tac/MMF/S) compared with 26.8% (Tac/Aza/S), p = 0.038. The 6-month incidences of steroid-resistant acute rejection were 2.1% (Tac/MMF/S) and 4.9% (Tac/Aza/S), p = ns. At the end of month 3, steroid withdrawal was performed in 60.5% (Tac/MMF/S) and 48.8% (Tac/Aza/S) of patients, p < 0.01. During months 4-6, 2.7% of patients in the Tac/MMF group had a biopsy-confirmed acute rejection compared with 0.8% of patients in the Tac/Aza group. In patients who continued to receive steroids, the incidences of biopsy-proven acute rejections during months 4-6 were 3.5% (Tac/MMF/S) and 7.1% (Tac/Aza/S). At study end, the steroid-free patients had an excellent kidney function, the median serum creatinine concentration was 119.5 mumol/L (Tac/MMF) and 115.1 mumol/L (Tac/Aza); the median serum creatinine of the total study group was 130.5 mumol/L (Tac/MMF/S) and 132.8 mumol/L (Tac/Aza/S). CONCLUSION: Both tacrolimus regimens are efficacious and safe. The combination of Tacrolimus and MMF achieved a lower rejection rate and permitted a higher proportion of steroid-free patients. The overall incidence of acute rejection was low and kidney function was good.

Adult↗
PubMed2001

Suramin and the suramin analogue NF307 discriminate among calmodulin-binding sites.

Calmodulin-binding sites on target proteins show considerable variation in primary sequence; hence compounds that block the access of calmodulin to these binding sites may be more selective than compounds that inactivate calmodulin. Suramin and its analogue NF307 inhibit the interaction of calmodulin with the ryanodine receptor. We have investigated whether inhibition of calmodulin binding to target proteins is a general property of these compounds. Suramin inhibited binding of [(125)I]calmodulin to porcine brain membranes and to sarcoplasmic reticulum from skeletal muscle (IC(50)=4.9+/-1.2 microM and 19.9+/-1.8 microM, respectively) and blocked the cross-linking of [(125)I]calmodulin to some, but not all, target proteins in brain membranes by [(125)I]calmodulin. Four calmodulin-binding proteins were purified [ryanodine receptor-1 (RyR1) from rabbit skeletal muscle, neuronal NO synthase (nNOS) from Sf9 cells, G-protein betagamma dimers (Gbetagamma) from porcine brain and a glutathione S-transferase-fusion protein comprising the C-terminal calmodulin-binding domain of the metabotropic glutamate receptor 7A (GST-CmGluR7A) from bacterial lysates]. Three of the proteins employed (Gbetagamma, GST-CmGluR7A and RyR1) display a comparable affinity for calmodulin (in the range of 50-70 nM). Nevertheless, suramin and NF307 only blocked the binding of Gbetagamma and RyR1 to calmodulin-Sepharose. In contrast, the association of GST-CmGluR7A and nNOS was not impaired, whereas excess calmodulin uniformly displaced all proteins from the matrix. Thus suramin and NF307 are prototypes of a new class of calmodulin antagonists that do not interact directly with calmodulin but with calmodulin-recognition sites. In addition, these compounds discriminate among calmodulin-binding motifs.

Allosteric Regulation↗
PubMed2001

Chlamydia pneumoniae infection in circulating human monocytes is refractory to antibiotic treatment.

BACKGROUND: Recovery of the intracellular bacterium Chlamydia pneumoniae from atherosclerotic plaques has initiated large studies on antimicrobial therapy in coronary artery disease. The basic concept that antibiotic therapy may eliminate and prevent vascular infection was evaluated in vitro and in vivo by examining the antibiotic susceptibility of C pneumoniae in circulating human monocytes, which are thought to transport chlamydiae from the respiratory tract to the vascular wall. METHODS AND RESULTS: Blood monocytes (CD14+) from 2 healthy volunteers were obtained before and after oral treatment with azithromycin or rifampin and then inoculated with a vascular C pneumoniae strain and continuously cultured in the presence of the respective antibiotic. Progress of infection and chlamydial viability was assessed by immunogold-labeling and detection of C pneumoniae-specific mRNA transcripts. Circulating monocytes from patients undergoing treatment with experimental azithromycin for coronary artery disease were examined for C pneumoniae infection by cell culture. Antibiotics did not inhibit chlamydial growth within monocytes. Electron microscopy showed development of chlamydial inclusion bodies. Reverse transcription-polymerase chain reaction demonstrated continuous synthesis of chlamydial mRNA for 10 days without lysis of the monocytes. The in vivo presence of viable pathogen not eliminated by azithromycin was shown by cultural recovery of C pneumoniae from the circulating monocytes of 2 patients with coronary artery disease. CONCLUSIONS: C pneumoniae uses monocytes as a transport system for systemic dissemination and enters a persistent state not covered by an otherwise effective antichlamydial treatment. Prevention of vascular infection by antichlamydial treatment may be problematic: circulating monocytes carrying a pathogen with reduced antimicrobial susceptibility might initiate reinfection or promote atherosclerosis by the release of proinflammatory mediators.

Aged↗
PubMed2001

[Non-complicated Horton's disease: initial treatment with methylprednisolone 500 mg/day bolus for three days followed by 20 mg/day prednisone-equivalent. Evaluation of 15 patients].

PURPOSE: To assess the efficacy and tolerance of three methylprednisolone boluses (500 mg/d) followed by a standard dose of prednisolone, 20 mg/d, as the initial treatment of non-complicated giant-cell arteritis. METHOD: A retrospective study of 15 cases. RESULTS: Six men and nine women with a mean age of 70.9 years were treated and followed for 41.5 months. Initial mean ESR was 83 mm; mean C-reactive protein level was 94.6 mg/L. The boluses were well tolerated, excepted in one patient who developed acute psychosis. After initiating the oral treatment, two patients presented signs of clinical relapse during the first month, and were given higher doses of corticosteroids. At 1 month, 12 patients were asymptomatic, nine of whom had normalized ESR and CRP. Mean ESR was 23; mean CRP was 13 mg/L. At 3 months, the mean prednisone dose delivered was 18.2 mg/d. Mean ESR was 12 mm. The cumulative prednisone dose given during the first year was 5,349 (+/- 2,512) mg. In the 13 patients who necessitated no more than 20 mg/d prednisone, no sequelae of giant-cell arteritis, no fractures nor major treatment intolerance occurred-during the first 2 years of treatment. Treatment was stopped in eight patients after a mean duration of 48.6 months. CONCLUSION: Treatment with pulse methylprednisolone 500 mg/d for 3 days followed by 20 mg/d oral prednisone could be a valuable corticosteroid-sparing strategy in many patients with uncomplicated temporal arteritis.

Aged↗
PubMed2001

[Therapeutic use of potassium citrate].

Therapeutic indications of potassium citrate include: 1. Oxaluric renal stone disease and some cases of uric acid stone disease. Prevention of stone formation in patients with renal polycystic disease. Prevention of stone relapse after ESWL or lithotomy; 2. Distal renal tubular acidosis complicated by hypercalciuria, mainly in children. 3. Renal hypercalciuria and hyperoxaluria. 4. Prevention of renal complications at the time of glaucoma treatment with acetazolamide. 5. Potassium supplementation during treatment of hypertension. Potassium citrate is usually contraindicated in the case of: 1. Urinary tract infection. 2. Struvite renal stone disease. 3. Hyperpotassemia and advanced chronic renal failure. 4. Peptic ulcer or gastritis. 5. Gastrointestinal bleeding. 6. Disorders of coagulation, crural varices. 7. Metabolic alkalosis. Potassium citrate, when used at therapeutic doses, is to be considered as quite safe. The average daily dose even if admitted as a single dose day engages 60-75% of free renal capacity for potassium excretion. Physiologic and therapeutic citrate concentration in urine exceeds much those available for other inhibitors. The therapeutic dose does not induce any significant changes in any biochemical or endocrine parameter of blood except mild transient metabolic alkalosis. The decrease of urine calcium and increase in oxalate calcium phosphate excretion is observed. In hypo-cytriaturic patients the response to therapeutic dose of citrate is smaller. One-year remission of stone disease is observed in 70-75% cases.

Acetazolamide↗