Polyomavirus BK replication in de novo kidney transplant patients receiving tacrolimus or cyclosporine: a prospective, randomized, multicenter study.

Polyomavirus BK (BKV)-associated nephropathy causes premature kidney transplant (KT) failure. BKV viruria and viremia are biomarkers of disease progression, but associated risk factors are controversial. A total of 682 KT patients receiving basiliximab, mycophenolic acid (MPA), corticosteroids were randomized 1:1 to cyclosporine (CsA) or tacrolimus (Tac). Risk factors were analyzed in 629 (92.2%) patients having at least 2 BKV measurements until month 12 posttransplant. Univariate analysis associated CsA-MPA with lower rates of viremia than Tac-MPA at month 6 (10.6% vs. 16.3%, p = 0.048) and 12 (4.8% vs. 12.1%, p = 0.004) and lower plasma BKV loads at month 12 (3.9 vs. 5.1 log(10) copies/mL; p = 0.028). In multivariate models, CsA-MPA remained associated with less viremia than Tac-MPA at month 6 (OR 0.60; 95% CI 0.36-0.99) and month 12 (OR 0.33; 95% CI 0.16-0.68). Viremia at month 6 was also independently associated with higher steroid exposure until month 3 (OR 1.19 per 1 g), and with male gender (OR 2.49) and recipient age (OR 1.14 per 10 years) at month 12. The data suggest a dynamic risk factor evolution of BKV viremia consisting of higher corticosteroids until month 3, Tac-MPA compared to CsA-MPA at month 6 and Tac-MPA, older age, male gender at month 12 posttransplant.

A Pneumocystis jirovecii pneumonia outbreak in a single kidney-transplant center: role of cytomegalovirus co-infection.

Pneumocystis jirovecii pneumonia (PCP) and cytomegalovirus (CMV) infection represent possible complications of medical immunosuppression. Between 2005 and 2010, non-human immunodeficiency virus (HIV) PCP patients admitted to a nephrology unit were analyzed for outcome, CMV comorbidity, and patient-to-patient contacts prior to PCP. In contrast to 2002-2004 (no cases) and 2008-2010 (10 cases), a PCP outbreak of 29 kidney-transplant recipients and one patient with anti-glomerular basement membrane disease occurred between 2005 and 2007. None of the patients were on PCP chemoprophylaxis. In four PCP patients, the genotyping data of bronchoalveolar lavage specimen showed an identical Pneumocystis strain. PCP cases had a higher incidence of CMV infection (12 of 30 PCP patients) and CMV disease (four patients) when compared to matched PCP-free controls (p < 0.05). Cotrimoxazole and, if applicable, ganciclovir were started 2.0 ± 4.0 days following admission, and immunosuppressive medication was reduced. In-hospital mortality was 10% and the three-year mortality was 20%. CMV co-infection did not affect mortality. CMV co-infection more frequently occurred during a cluster outbreak of non-HIV PCP in comparison to PCP-free controls. Here, CMV awareness and specific therapy of both CMV infection and PCP led to a comparatively favorable patient outcome. The role of patient isolation should be further investigated in incident non-HIV PCP.

Switch to a sirolimus-based immunosuppression in long-term renal transplant recipients: reduced rate of (pre-)malignancies and nonmelanoma skin cancer in a prospective, randomized, assessor-blinded, controlled clinical trial.

Renal transplant recipients (RTR) have a 50-200-fold higher risk for nonmelanoma-skin cancer (NMSC) causing high rates of morbidity and sometimes mortality. Cohort-studies gave evidence that a sirolimus-based immunosuppression may inhibit skin tumor growth. This single-center, prospective, assessor-blinded, randomized trial investigated if switching to sirolimus treatment inhibits the progression of premalignancies and moreover how many new NMSC occur compared to continuation of the original immunosuppressive therapy. Forty-four RTR (mean age 59.9 years, mean duration of immunosuppression 229.5 months) with skin lesions were randomized to sirolimus or continuation of their original immunosuppression. Blinded dermatological assessment at month 6 and 12 by the same dermatologist evaluated the clinical change compared to baseline. Biopsy was performed in suspected malignancy. Already the 6-month-assessment showed significant superiority of sirolimus-therapy: a stop of progression, even regression of preexisting premalignancies (p < 0.0005). This effect was increased at month 12 (p < 0.0001). Nine patients developed histologically confirmed NMSC: one in the sirolimus group, eight in the control group, p = 0.0176. Sirolimus-based immunosuppression in RTR, even when established many years after transplantation, can delay the development of premalignancies, induce regression of preexisting lesions and decelerate the incidence of new NMSC.

Residual kidney function after donor nephrectomy. Assessment by 99mTc-MAG3-clearance.

AIM: We evaluated the long-term residual renal function after donor nephrectomy using 99mTc-mercaptoacetyltriglycin (MAG3)-clearance. DONORS, METHODS: Altogether 49 kidney donors were examined using 99mTc-MAG3-clearance after nephrectomy for donation to a relative (m:f = 11:38; age 55+/-27 years). The donors were examined 16+/-8 years postoperatively (1.5-26 years). 42 donors (86%) showed normal creatinine values, whereas the other seven (14%) exhibited slightly elevated levels. 20 donors were examined pre- and postoperatively and compared intraindividually. The kidney function was compared to the age adapted normal values of healthy persons with two kidneys (67-133% of age related mean). RESULTS: After nephrectomy all donors showed a normal perfusion, good secretion, merely physiological intrarenal transit and a normal elimination from the kidneys. The 99mTc-MAG3-clearance was 69+/-15% of the normal mean value of healthy carriers of two kidneys regardless of the gender. 20 donors with a preoperative examination showed a significantly reduced total renal function from 84+/-15% of the mean normal value preoperatively to 60+/-15% postoperatively (p <0.0005). 15 donors of this group exhibited a significant functional increase of the residual kidney from 40% initially to 60% after nephrectomy (p = 0.003). No correlation was found between the initial-99mTc-MAG3-clearance measured prior to nephrectomy and the clearance levels after nephrectomy. Also, no correlation between the preoperative 99mTc-MAG3-clearance and the postoperative serum creatinine values could be observed. Altogether, 22% of the donors (11/49) developed arterial hypertension 10+/-8 years after donation (1-23 years). This corresponds to the normal age prevalence of hypertension in the carriers of two kidneys. Three donors suffered from arterial hypertension prior to the operation. CONCLUSION: Kidney donors with normal or slightly elevated creatinine values postoperatively show a 99mTc-MAG3-clearance value of 69% of the mean value of healthy carriers of two kidneys. This may serve as a reference value for healthy carriers of one kidney. In our study we demonstrated a good compensation of the contralateral kidney via renal scintigraphy by means of 99mTc-MAG3-clearance.

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.

Cyclosporine C2 levels in de novo renal allograft recipients: a German multicenter prospective observational study.

This ongoing multicenter prospective observational study was undertaken in de novo renal allograft recipients managed with cyclosporine (CsA) trough (C0) and 2-hour postdose (C2) level monitoring at defined times so as to assess the risk for an acute rejection episode or allograft dysfunction. The renal transplant recipients (n = 159) were enrolled at 11 German centers. The 6-month posttransplant data from 138 patients were evaluable for this interim analysis. Mean C2 levels (ng/mL), which were measured by liquid chromatography-tandem mass spectrometry at a central laboratory, were: days 3 to 5: 873.1 +/- 391.9; days 7 to 10: 939.1 +/- 422.8; days 14 to 28: 1116.3 +/- 497.6; 3 months: 905.0 +/- 316.8; and after 6 months: 787.0 +/- 276.5. To identify patients at higher risk for acute rejection or allograft dysfunction, we calculated the relative CsA absorption capacity (C2 [ng/mL]/morning dose [mg/kg]; CsA-Abs), yielding mean values on days 3 to 5: 284.4 +/- 115.1; days 7 to 10: 306.7 +/- 134.8; days 14 to 28: 382.5 +/- 164.7; month 3: 501.5 +/- 168.8; month 6: 512.7 +/- 176.5. Three groups were distinguished by CsA-Abs at days 7 to 10: low absorbers (CsA-Abs < 200), normal absorbers (CsA-Abs 200 to 350), and high absorbers (CsA-Abs > 350). A between-group comparison of absorption level at 6 months posttransplant revealed the incidences of biopsy-proven acute rejection and Cockcroft-Gault formula-based mean glomerular filtration rates of 23.8% and 54.7 +/- 19.0 mL/min, 22.6% and 59.5 +/- 20.7 mL/min, and 17.6% and 67.7 +/- 23.5, respectively. In conclusion, mean C2 levels >1000 ng/mL are attained within 2 to 4 weeks, with CsA-Abs increasing continuously over the first 6 posttransplant months. High CsA absorbers show a propensity toward good allograft function and lower acute rejection rates at 6 months after renal transplantation.

Effect of angiotensin II infusion with and without angiotensin II type 1 receptor blockade on nitric oxide metabolism and endothelin in human beings: a placebo-controlled study in healthy volunteers.

BACKGROUND: Angiotensin II has been shown to induce the synthesis of endothelium-derived relaxing factor nitric oxide (NO) and endothelin in vitro. In human beings, to our knowledge, no data on NO release in response to angiotensin II and on the influence of angiotensin II type 1 receptor blockade have been published. METHODS: In a placebo-controlled study in nine healthy volunteers, angiotensin II was administered intravenously for 6 hours with and without pretreatment with valsartan, a specific angiotensin II type 1 receptor antagonist. NO (NO2 + NO3) and endothelin plasma concentrations, clearance values for inulin and paraaminohippuric acid and NO (NO2 + NO3) excretion in urine were determined. RESULTS: During angiotensin II infusion NO plasma concentrations remained unaltered compared with placebo after 3 hours: 6.66 +/- 5.49 versus 5.56 +/- 3.09 micromol/L (P = ns) but increased after 6 hours: 18.36 +/- 20.02 versus 7.13 +/- 3.87 micromol/L (P < .04). The same was noted after pretreatment with valsartan: 7.61 +/- 5.69 versus 5.56 +/- 3.09 micromol/L (P= ns) after 3 hours, and 21.70 +/- 11.51 versus 7.13 +/- 3.87 micromol/L (P = .02) after 6 hours. In urine fractional NO excretion decreased after angiotensin II infusion: 0.87 +/- 0.72 versus 0.95 +/- 0.71 (P = .5) during the first 3 hours, and 0.44 +/- 0.39 versus 0.78 +/- 0.43 (P = .01) during the following 3 hours. After valsartan pretreatment the decrease in fractional urinary NO excretion began earlier: 0.40 +/- 0.15 versus 0.95 +/- 0.71 (P = .04) during the first 3 hours, and 0.17 +/- 0.11 versus 0.78 +/- 0.43 (P = .01) during the following 3 hours. Endothelin plasma concentrations showed no difference after angiotensin II infusion with or without valsartan. CONCLUSIONS: Our observations demonstrate for the first time that angiotensin II increases NO plasma concentrations in human beings and that this response is not mediated by angiotensin II type 1 receptor. In spite of increased NO plasma levels, urinary NO excretion decreased. Endothelin plasma levels remained unchanged during angiotensin II infusion.

Lipoprotein (a) stimulates mitogen activated protein kinase in human mesangial cells.

Evidence suggests an important role of elevated serum lipoproteins in the progression of renal glomerulosclerosis. We report here that lipoprotein (a) (Lp(a)) increased phosphorylation and activity of mitogen activated protein kinase (MAPK) in human mesangial cells. When protein kinase C (PKC) was depleted by long-term incubation with the phorbol 12-O-myristate 13-acetate the effect of Lp(a) on MAPK activation was completely inhibited. Forskolin, a stimulator of the adenylyl cyclase, and dibutyryl-cAMP reduced the effect of Lp(a) on MAPK phosphorylation and activation. We conclude that Lp(a) stimulates the MAPK cascade via activation of PKC and that activation of protein kinase A counteracts Lp(a) induced MAPK activation in human mesangial cells.

Typing of the HLA-DRB3 gene by temperature gradient gel electrophoresis. Prediction of the resolution of four allelic fragments by computational simulation of DNA melting.

Four alleles are currently recognised at the HLA-DRB3 locus (DRB3*0101, DRB3*0201, DRB3*0202 and DRB3*0301). We studied whether 271 bp fragments of the polymorphic second exon, which were prepared using the polymerase chain reaction, could be typed using temperature gradient gel electrophoresis. Thermal stability curves for the allelic DNA molecules were calculated by computer simulation and the results were validated experimentally. The DRB3*0201 and DRB3*0202 derived homoduplexes were predicted to have identical thermal stability. Thus, only three denaturation and relative mobility curves were obtained for the four homoduplex fragments DRB3*0101, DRB3*0201, DRB3*0202 and DRB3*0301. Computational analysis predicted that DRB3*0201 and DRB3*0202 could be distinguished by electrophoresis of artificially generated heteroduplexes. When verified experimentally, the results of the theoretical analyses were confirmed. We conclude, that computational simulation of the melting behaviour of DNA molecules permits the resolution of allelic sequences to be predicted by temperature gradient gel electrophoresis. We also demonstrate that temperature gradient gel electrophoresis is a powerful tool for the assessment of HLA genotypes. It may have wide application in transplantation immunology and in the study of disease associations of allelic variation at the HLA loci.

Anemia in renal transplant recipients caused by concomitant therapy with azathioprine and angiotensin-converting enzyme inhibitors.

Immunosuppression of recipients of renal transplants with azathioprine has been associated with two major side effects: hepatotoxicity and myelotoxicity, mainly in the form of leukopenia. Reports of isolated anemia in these patients have been rare. We now observed the development of severe anemia in 9 out of 11 renal transplant recipients whose immunosuppressive regimen was converted from cyclosporine plus prednisone to azathioprine plus prednisone. A significant (P = 0.001) drop in hematocrit (from 34 +/- 4% to 27 +/- 3%, mean +/- SD) and hemoglobin (from 11.6 +/- 1.3 g/dl to 9.5 +/- 1.0 g/dl) was found. Since a common variable of all these patients was their use of an angiotensin-converting enzyme (ACE) inhibitor as antihypertensive medication, we speculated that the combination of azathioprine and ACE blocker might be the reason for the anemia. We then compared 2 groups of 10 patients each who had been on azathioprine as their regular immunosuppressive agent and who did or did not take an ACE inhibitor. Hematocrit and hemoglobin were significantly (P = 0.01) lower in the group of patients taking ACE inhibitors (33 +/- 6% versus 41 +/- 5% and 11.5 +/- 2.0 g/dl versus 14.0 +/- 1.6 g/dl, respectively). Haptoglobin levels were also significantly (P = 0.05) lower in the ACE inhibitor group (116 +/- 65 mg/dl versus 210 +/- 114 mg/dl). Erythropoietin concentration in the serum and the reticulocyte index were slightly, but not significantly, higher in the ACE inhibitor group but the values were probably too low for their degree of anemia. Comparing hematological parameters of the patients in the ACE inhibitor group before and after beginning of the antihypertensive treatment confirmed a significant reduction of hematocrit and hemoglobin following therapy with an ACE inhibitor. Hematocrit fell from 41 +/- 7% to 36 +/- 6% and hemoglobin from 14.0 +/- 2.3 g/dl to 11.3 +/- 1.5 g/dl (P < 0.05 for both). We conclude that the combination of these two drugs should probably be avoided.

An unusual case of Aspergillus endocarditis in a kidney transplant recipient.

The incidence of aspergillosis in kidney transplant recipients is low and most commonly occurs in the early posttransplantation period. We report an unusual case of a 52-year-old female patient with Aspergillus endocarditis as a late complication after kidney transplantation, presumably spread from a necrosis in the gut, associated with previous cytomegalovirus colitis. As complications, the patient experienced septic embolization into the coronary and pulmonary arteries, and an infarction of the right parietal cortex and insula. The patient died as a result of global heart failure after a 10-day course of antimycotic therapy with amphotericin B plus 5-flucytosine during surgical valve replacement.

Multiple adenomas and hepatocellular carcinoma in a renal transplant patient with glycogen storage disease type 1a (von Gierke disease).

We report on a 42-year-old female patient with glycogen storage disease type 1a (von Gierke disease, GSD 1a) who developed hepatic adenomas and finally a hepatocellular carcinoma 10 years after renal transplantation. The tumor was resected; however, the patient died 6 months later as a result of fulminant carcinoma recurrence. In patients who have GSD 1a with terminal renal failure, combined liver and kidney transplantation may be considered at an early stage of the disease.

Soluble interleukin-2-receptor levels as a marker of coronary microvascular dysfunction after heart transplantation.

BACKGROUND: Immunologic mechanisms operating in a milieu of nonimmunologic risk factors constitute the principal stimuli that result in progressive cardiac allograft vasculopathy. Interleukin-2 has a central role in the development of cell-mediated immunity and is a key factor in the induction of a complex network of cytokines. On exposure to cytokines, endothelial cells can undergo profound alterations of vasomotor function. In this study we characterized the relationship between coronary microvascular function and soluble interleukin-2 receptor (sIL-2R) levels after human heart transplantation. METHODS: We studied 15 heart transplant recipients after an average follow-up time of 39+/-22 months. We measured coronary artery blood flow in an endothelium-dependent manner with acetylcholine (50 microg) and in an endothelium-independent manner with dipyridamole (0.56 mg/kg) by intracoronary Doppler catheter. Blood samples from the superior vena cava were drawn 3 to 12 months after transplantation (early value) and at time of the coronary artery flow measurement (present value). Coronary artery flow reserve was correlated to sIL-2R levels, which were determined by use of an enzyme-linked immunoabsorbent assay. RESULTS: We found a significant inverse correlation between impaired endothelium-mediated (p = 0.03) but not endothelium-independent relaxation of the coronary microvasculature and elevated sIL-2R levels. In heart transplant recipients without acute rejection or an infection episode, an sIL-2R-level of more than 800 U/ml was defined as a cutpoint, indicating disturbed endothelium-dependent microvascular function. Additionally, there was a conspicuous trend toward an inverse correlation between early elevated sIL-2R-levels and endothelium-dependent microvascular dysfunction (p = 0.06). CONCLUSIONS: The results of this study demonstrate the utility of sIL-2R, an index of immunologic activity, to be used as a marker and predictor of impaired endothelial microvascular function in heart transplant recipients. These observations support the hypothesis that after heart transplantation endothelial dysfunction in the microcirculation is an immunologic phenomenon.

Hypertension is associated with hyperlipidemia, coronary heart disease and chronic graft failure in kidney transplant recipients.

BACKGROUND: Hypertension is a common concomitant condition in renal transplant recipients. There is accumulating evidence that this disorder is an important risk factor for chronic renal graft failure and other cardiovascular complications in these patients. SUBJECTS AND METHODS: The current retrospective study in 330 patients treated with cyclosporin or azathioprin covered 5 years and aimed to further characterize the interrelation between hypertension and renal graft failure. Furthermore, the association of hypertension with hyperlipidemia and the prevalence of coronary heart disease was evaluated. RESULTS: Altogether, before transplantation 182 patients were normotensive (no antihypertensive medication except diuretics) and 105 were hypertensive (blood pressure > 160/95 mmHg or patients requiring antihypertensive medication); for the remaining 43 patients no data were available. After transplantation the prevalence of hypertension in the cyclosporin group was 71, 76 and 70% after 1, 3 and 5 years, respectively. The respective numbers for the azathioprin group were 60, 59 and 58%. Hypertension was associated with graft dysfunction both in cyclosporin- and azathioprin-treated patients. Hyperlipidemia (cholesterol, triglycerides) was more severe in hypertensive than in normotensive patients. The prevalence for hypertension was higher in patients with coronary artery disease than in patients without the disease. CONCLUSION: The results further support the view that hypertension may be a risk factor for the development of chronic renal graft failure and coronary artery disease in this population. Furthermore, the association of hypertension with hyperlipidemia hints to an unfavorable accumulation of renal and cardiovascular risk factors in a large number of renal allograft recipients.

Effect of recombinant human erythropoietin on iron balance in maintenance hemodialysis: theoretical considerations, clinical experience and consequences.

Iron deficiency is the main reason for insufficient response to rEPO therapy. Serum ferritin and transferrin saturation give valuable information on storage iron and iron transport. Iron demand for correction of anemia can easily be estimated after HCT (vol%) x average blood volume (dl) = mg iron. Inadequate iron supply of the bone marrow in the presence of sufficient storage iron in the RES develops frequently under rEPO, possibly explaining the improvement of bone marrow response to rEPO by concomitant intravenous iron supply. The reasons of functional iron deficiency are still speculative.

Benign prostatic hyperplasia (BPH) requiring transurethral resection in freshly transplanted renal allograft recipients.

With recent progress in surgery and immunosuppression, more and more older men receive a kidney transplant. Thus, it is likely that the incidence of BPH in male transplant recipients is growing in parallel with age. Nonetheless, no data exist about diagnostic parameters for BPH in freshly transplanted male kidney allograft recipients. We evaluated whether established diagnostic and therapeutic criteria for BPH are valid for the evaluation of renal transplant recipients. BPH was diagnosed in 8 of 11 recipients older than 55 years. In all freshly transplanted renal allograft recipients, lower urinary tract symptoms (LUTS) were detected using an international prostate symptoms score (IPSS). This score was 9.6 +/- 7.1 in patients without BPH, and significantly higher with 21.1 +/- 4.3 in patients with BPH. In receiver-operating characteristics (ROC) curve analysis a cut-off of 15.5 was calculated to distinguish best between BPH and non-BPH giving an accuracy of 90.2%. Acute urinary retention (AUR) was the predominant sign, which occurred in all BPH patients but only in 6.9% in non-BPH patients. Bladder outlet obstruction (BOO) was also common with a reduced uroflow with 9.5 +/- 2.2 ml/sec in non-BPH and 3.0 +/- 1.8 ml/sec in BPH (8/11 BPH-patients developed AUR prior to measurement). By digital rectal examinations, benign prostate enlargement was estimated as minimal in 10 of 11 cases of BPH. In urethrocystoscopy kissing lobes were detected in all cases of BPH. Since medical treatment with alpha-receptor antagonists was not successful, a surgical procedure using a transurethral resection was performed without any complications in all cases. Symptoms did not recur after resection, and BOO improved with increased uroflow measurements with 12.3 +/- 4.8 ml/sec 8 days after resection. We conclude that LUTS and BOO are common in freshly transplanted renal allograft recipients. The sudden onset of outlet obstruction without the potentiality of adaptation of urinary bladder may effect lower urinary tract symptoms and bladder outlet obstruction. We conclude that an elevated IPSS over 15.5 in combination with AUR and typical urethrocystoscopy results are the best methods to diagnose BPH. Conversely, our results indicate that uroflowmetry and digital rectal examination are neither sensitive nor specific. In addition, once BPH has been diagnosed and treatment with receptor antagonists does not relieve urinary tract symptoms, surgical resection should be considered.

HPLC analysis of azathioprine metabolites in red blood cells, plasma and urine in renal transplant recipients.

Anemia has been frequently reported in renal transplant recipients receiving azathioprine for immunosuppression and enalapril for treatment of hypertension. During the course of a prospective trial in such patients we determined azathioprine metabolites in erythrocytes, plasma, and urine as well as erythropoietin and hemoglobin levels in order to evaluate a potential interaction between these 2 drugs, possibly leading to anemia. Two specific high performance liquid chromatography (HPLC) methods for determination of azathioprine metabolites, both employing a mercurial cellulose resin for extraction, are presented. One method using a strong anion exchange column allows detection of 6-thioguanosine di- and triphosphate (thioguanine nucleotides) in red blood cells (RBC) with a sensitivity of 30 pmol/100 microliters RBC. 6-mercaptopurine (MP) and 6-thiouric acid (TUA) in plasma and urine were analyzed simultaneously by reversed-phase HPLC with a sensitivity of 5 ng/ml. The average (median values are given) steady state concentrations of thioguanine nucleotides in erythrocytes came to 267 pmol/100 microliters RBC (range 53-613) with and to 246 pmol/100 microliters RBC (range 39-629) without concomitant enalapril medication. Mean plasma concentrations of MP and TUA 3 hours after drug intake came to 14.8 +/- 9.9 ng/ml and 398 +/- 262 ng/ml, respectively, during enalapril comedication. Withdrawal of enalapril did not influence these metabolite levels coming to 15.3 +/- 9.1 and 451 +/- 253 after stopping enalapril treatment. Thioguanine nucleotides in RBCs were neither related to the dose of azathioprine given (r = -0.113, p > 0.05) nor to hemoglobin levels (r = 0.278, p > 0.05). However, azathioprine dose/kg body weight seemed to be related to hemoglobin concentration, with and without enalapril comedication. We conclude that enalapril therapy does not influence the measured azathioprine metabolites, the reported cases of anemia may rather be due to a pharmacodynamic interaction as shown by the significant increase in erythropoietin after withdrawal of enalapril. The assays described here are suitable to study the metabolism of azathioprine in patients with various diseases.

Renal involvement in HIV-infection. Results from the Frankfurt AIDS Cohort Study (FACS) and a review of the literature.

The current report describes the experience from the Frankfurt AIDS Cohort Study with patients suffering from renal failure. The clinical data of 4993 HIV-infected patients between 1983 and 1998 were analyzed retrospectively. Patients were seen at least twice a year and clinical features, routine laboratory results, including CD4+ cell counts, concomittant diseases, and antiretroviral therapy were documented by standardized methods. The incidence of renal failure during 4 observation periods with different antiretroviral treatment strategies are compared and data are discussed. Within the 16 years of observation 47 patients with impairement of their kidney function were identified. A trend to an increase of RF could be documented (chi superset2 -for trend p = 0.0246). The additional review intends to summarize the diverse reasons leading to renal dysfunction in HIV-infected individuals with special emphasis on glomerular disease and renal complications related to HIV therapy.

[Antiphospholipid antibody syndrome]. / Antiphospholipidantikörpersyndrom.

BACKGROUND: Antiphospholipid antibodies comprise a family of auto-antibodies mainly characterized by the presence of the lupus anticoagulant (LA) and anticardiolipin antibodies (ACA). CLINICAL APPEARANCE: The antiphospholipid antibody syndrome is defined by the appearance of frequent thromboses, repeated fetal losses and thrombocytopenia. Other clinical manifestations associated with APA include migraine, chorea, hemolytic anemia, heart valve disease, Budd-Chiari syndrome, perpetual pancreatitic episodes, intestinal infarctions, malignant hypertension, livedo reticularis, pre-eclampsia, fetal growth retardation or catastrophic antiphospholipid syndrome. LA and ACA occur in a variety of clinical conditions (secondary antiphospholipid antibody syndrome, SAPS), including other autoimmune disorders, infectious diseases, neoplastic disorders, in association with the use of certain drugs or in otherwise healthy individuals (primary antiphospholipid antibody syndrome, PAPS). TREATMENT: Patients with thrombosis associated with APA should receive long-term anticoagulation therapy, whereas treatment of asymptomatic patients seems to be not indicated, because only approximately 10% of patients with APA may develop thrombotic complications. In patients with PAPS there is no evidence that the prophylactic administration of immunosuppressive drugs will prevent thromboembolic events.

Incidence of cytomegalovirus-infection after renal transplantation and first experiences with prophylactic hyperimmunoglobulin.

Incidence and clinical symptomatology of CMV-infection was investigated in 83 patients, who received cadaveric renal transplants in 1982 and 1983. CMV-antibody status was determined using an ELISA-technique, 43 of the 83 patients (52%) were seronegative, and 40 (48%) were seropositive for CMV before transplantation. Seroconversion (i.e. primary CMV-infection) or an increase in titre (i.e. reactivation or reinfection) was found in 18 cases (42% and 45%, respectively) in both groups. 89% of all infections occurred within the first 3 months. Clinical symptomatology was much more severe in the group with primary CMV-infection; all cases with atypical pneumonia (n = 8) and both fatal cases belonged to this group. Preformed CMV-antibodies thus appeared to prevent severe syndromes associated with CMV-infection. Therefore a randomized controlled study was started in 1984 in order to investigate the efficacy of an i.v. applicable CMV-hyperimmunoglobulin passively administered prior to the transplant procedure. The passive immunization was not capable of preventing CMV-infection in every case: 2 (late) seroconversions did occur, but in both cases subclinical infections were diagnosed, whereas in the control group CMV-infections were regularly associated with typical clinical complications (prolonged fever, liver damage, leucopenia etc.). Thus prophylactic CMV-hyperimmunoglobulin seems to be capable of preventing the occurrence of severe CMV-syndromes post transplantation. The study is being continued.