Martina Franz

N-terminal fragments of the proatrial natriuretic peptide in plasma and urine of kidney graft recipients.

Background. Successful kidney transplantation normalizes elevated proatrial natriuretic peptide (proANP) plasma concentrations of renal failure patients in the early posttransplant period. We evaluated plasma and urinary proANP fragments in the late posttransplant period. Methods. Immunoreactive proANP(1-30) and proANP(31-67) were determined in 389 renal transplant (Rtx) recipients in the long-term, follow-up period and in 16 healthy controls. Results. Rtx recipients had significantly higher concentrations of proANP(1-30) and proANP(31-67) in both plasma and urine than healthy controls. Although their graft function was normal, all of these long-term Rtx recipients were taking glucocorticoids, which increase proANP(1-30) and proANP(31-67) in the circulation to the extent found in this investigation. Two-thirds of these recipients were also taking cyclosporine, which also increases atrial peptides. Urinary proANP(31-67) was significantly higher than urinary proANP(1-30); 5.5-fold in Rtx patients and 2-fold in controls. Deterioration of renal graft function was associated with a rise of plasma proANP(1-30) from 0.98±0.66 to 6.28±3.55 nmol/l (P< 0.0001) and plasma proANP(31-67) from 1.81±1.04 to 7.89±3.76 nmol/l (P <0.0001). Urinary excretion of proANP(1-30) increased from 0.27±0.34 to 5.96±5.07 nmol/24 hr (P< 0.0001) and proANP(31-67) from 1.45±0.85 to 12.23±5.12 nmol/24 hr (P< 0.0001). Also proteinuria enhanced plasma and urinary proANP fragments. Conclusions. ProANP(1-30) and proANP(31-67) of Rtx recipients are affected by immunosuppression, hypertension, renal failure, and proteinuria. One would have expected proANP(1-30) and proANP(31-67) not to normalize because of the glucocorticoids that they were receiving.

POSTTRANSPLANT HEMOLYTIC UREMIC SYNDROME IN ADULT RETRANSPLANTED KIDNEY GRAFT RECIPIENTS: ADVANTAGE OF FK506 THERAPY?

BACKGROUND Posttransplant hemolytic uremic syndrome (pHUS) is a rare but severe disorder that confers a poor prognosis on an allograft due to thrombotic microangiopathy. Immunosuppression with cyclosporine (CsA) is implicated as a significant risk factor for the development of pHUS. In early reports, it was hypothesized that immunosuppression with FK506 (tacrolimus) would avoid the development of pHUS. However, this initially supposed beneficial effect remains controversial, because pHUS associated with tacrolimus therapy has been published in some later case reports. This article aims to further evaluate FK506 with respect to the development and resolution of pHUS. METHODS We describe the course of seven adult kidney graft recipients with pHUS, treated with FK506 either as initial immunosuppression for retransplantation or after discontinuation of CsA for resolution of pHUS. Work-up for pHUS was initiated when certain clinical features, such as hemolytic anemia, thrombocytopenia, and deterioration of graft function, were found. The diagnosis was confirmed by histologic examination of a renal allograft biopsy specimen (thrombotic microangiopathy). With the onset of pHUS, additional plasma exchange was performed in all patients. RESULTS Two patients suffered from end-stage renal disease due to primary HUS and had a history of recurrent pHUS in previous renal transplants. In both patients, the attempt to regraft was only made because of the early optimistic reports using FK506. Despite initial FK506 therapy, both recipients developed pHUS again, leading to loss of graft function. Two additional kidney graft recipients with primary renal failure other than HUS also received FK506 as initial immunosuppression. One of them (loss of the first kidney graft due to CsA-induced pHUS) was successfully treated with FK506 for his second renal transplant. The other recipient, a patient in whom de novo pHUS had occurred in the first graft despite initial therapy with FK506, was treated with CsA for his second graft and again developed pHUS. The latter process, however, could be reversed by a switch to steroids and azathioprine. In all three patients regrafted for reasons other than pHUS, development of de novo pHUS was treated by CsA withdrawal and a switch to FK506; this approach was effective in two patients. CONCLUSION Our results demonstrate that three of seven renal allograft recipients benefited from FK506 therapy for prevention or resolution of pHUS. Treatment or prophylaxis with FK506 can be considered advantageous in some patients with de novo pHUS, but FK506 fails to prevent recurrent pHUS in patients with primary HUS.

Recombinant human granulocyte colony-stimulating factor after kidney transplantation: a retrospective analysis to evaluate the benefit or risk of immunostimulation.

BACKGROUND Leukopenia due to immunosuppressive drugs represents a well-known complication in graft recipients, which might put patients at an increased risk for infections. In this study, recombinant human granulocyte colony-stimulating factor (rhG-CSF), a hematopoietic growth factor that selectively stimulates neutrophil colony formation and neutrophil cell differentiation, was tested for safety and efficacy. METHODS We evaluated 30 episodes of leukopenia (<2000/mm3) in 19 kidney graft recipients treated with rhG-CSF. This cohort was compared with an age- and sex-matched historical control group without therapy. Peripheral and differential blood cell counts were analyzed, and the duration of leukopenia was estimated. Furthermore, the occurrence of infections associated with leukopenia was investigated. RESULTS All patients responded to rhG-CSF therapy. Peripheral leukocyte counts increased from 1756+/-582 to a peak of 8723+/-3038/mm3 (P<0.0001). On the average, the peak was reached after 2.7 days (range 1 to 8). Furthermore, the effect was fairly persistent, because in 22 of 30 episodes leukocyte counts were within the normal range after 7 days. The elevation of total leukocytes was mainly due to a specific increase in neutrophil granulocytes from 1143+/-514 to 6895+/-1950/mm3 on the peak day (P<0.0001). Patients in the G-CSF group were leukopenic for a mean of 1.29+/-0.59 days, whereas in the control group leukopenia persisted for at least 7 days. Consequently, the rate of infections was significantly higher (P<0.045) in nontreated patients. CONCLUSION rhG-CSF was safe and effective in leukopenic kidney graft recipients. Leukopenic episodes in treated patients were significantly shorter, and infections occurred at a significantly lower rate. No evidence was found that rhG-CSF therapy might trigger rejection episodes, and no side effects were observed.

Treatment of Hyperlipidemic Kidney Graft Recipients with Lovastatin: Effect on LDL-Cholesterol and Lipoprotein (a)

An increased incidence of hyperlipidemia places kidney graft recipients at increased risk for cardiovascular disease and may contribute to a decline in graft function. A study was undertaken to evaluate the safety and efficacy of lovastatin in these patients. Twelve kidney graft recipients with stable graft function and a cholesterol (chol) level over 250 mg/dl (6.46 mmol/l) were included. The lipid-lowering treatment consisted of 20 mg lovastatin daily, and all patients received immunosuppression with ciclosporin (CS) and prednisolone. Total chol decreased by 27% (300 +/- 56 to 219 +/- 28 mg/dl; 7.76 +/- 1.45 to 5.66 +/- 0.72 mmol/l; p < 0.01), LDL-chol by 35% (220 +/- 38 to 143 +/- 17 mg/dl; 5.69 +/- 0.98 to 3.70 +/- 0.44 mmol/l; p < 0.01) and triglycerides by 33% (207 +/- 127 to 138 +/- 56 mg/dl; 2.36 +/- 1.44 to 1.57 +/- 0.64 mmol/l; p < 0.05). HDL-chol increased by 10% (57 +/- 11 to 63 +/- 13 mg/dl; 1.47 +/- 0.28 to 1.63 +/- 0.34 mmol/l; NS). The ratio of total chol/HDL-chol, a generally accepted risk predictor of atherosclerosis, fell from 5.4 +/- 1.3 to 3.3 +/- 1.2, p < 0.01. Lipoprotein (a) [lp(a)], an independent risk predictor for atherosclerosis, was also evaluated at baseline and after 6 months of lovastatin treatment and showed a decrease of 39% (32.9 +/- 27.6 to 19.9 +/- 22.9 mg/dl; 0.85 +/- 0.71 to 0.51 +/- 0.59 mmol/l; p < 0.05). No adverse side effects were seen at this dosage, and hepatic and renal parameters remained unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence that sensitivity to cyclosporine is influenced by the HLA-DR phenotype of kidney graft recipients

Clinical as well as experimental studies have shown a great interindividual variability in the immunosuppressive efficacy of CsA. Evaluating previous in vitro findings of a correlation between sensitivity of alloresponsiveness to CsA and the HLA-DR phenotype CsA levels were compared in kidney transplant recipients with and without rejections during the early posttransplant period and tested for a possible relationship to the HLA-DR phenotype of the recipient. In patients treated with CsA and prednisolone only, rejection frequency was significantly higher in HLA-DRw6 positive than in DRw6 negative graft recipients (77% vs. 53%, P = 0.045). In the DRw6 positive group incidence of rejection was independent of CsA blood levels, whereas in DRw6 negative patients frequency of rejection episodes decreased as a function of increasing CsA levels. Therefore the relative risk in developing graft rejection continuously increased in HLA-DRw6 positive patients. In HLA-DR2 positive graft recipients, however, a decrease in the relative risk could be observed with increasing CsA levels. Within patients with bioptically verified rejection episodes HLA-DR2 positive recipients had significantly lower CsA levels than DR2 negative patients (P = 0.01). In other HLA-DR phenotypes no association with CsA blood levels could be assessed. Also no statistically significant difference could be found in nonrejecting patients. These clinical findings demonstrate an association of sensitivity to immunosuppressive treatment and the HLA-DR phenotype of the graft recipient. Our results would indicate a very low CsA sensitivity of HLA-DRw6 positive graft recipients and thus might offer an explanation for previous findings about an increase in the incidence of rejection reported on those patients.

Erkrankungen von Niere und Urogenitaltrakt

Das akute Nierenversagen (ANV) ist ein klinisches Syndrom, das durch die abrupte, meist reversible Einschrankung der exkretorischen Nierenfunktion gekennzeichnet ist, die zur Akkumulation von Stoffwechselendprodukten und Storungen des Wasser-, Elektrolyt- und Sauren-Basen-Haushaltes fuhrt. Das ANV geht haufig mit einer Oligurie einher (oligurisches Nierenversagen), kann aber in vielen Fallen mit einer nicht beeintrachtigten Flussigkeitsausscheidung verlaufen (nichtoligurisches ANV).

Determination of Gamma Interferon and Neopterin Serum Levels for Graft Monitoring

Despite many atempts to find reliable methods for immunological graft monitoring most parameters ([1]–[4]) failed to become established for clinical routine. The reason for this failure is mainly due to a lack of specificity i.e. most parameters are elevated not only in case of rejections but also in bacterial or viral infections. In order to find a more sophisticated method we tested a two marker model. Two different parameters were determined for immune monitoring of kidney grafts. Serum neopterin (sNPT) as unspecific marker ([5]–[7]) was used to indicate conditions of “immunological activation” i.e. acute rejections and infection episodes. Serum gamma interferon levels (sGIF), however, which have been found to be significantly elevated in infections only were used for further differentiation.