[show abstract][hide abstract] ABSTRACT: Quality assessment of renal grafts via (31)P magnetic resonance spectroscopy (MRS) has been investigated since 1986. As ATP concentrations decay rapidly during cold ischemia, the ratio of phosphomonoesters (PME) to inorganic phosphate (Pi(O)) within the organ (PME/Pi(O)) is commonly used as a quality marker and is considered to be the most reliable parameter. MRS did not lead to any delay in the transplantation procedure since it was performed during the time necessary for immunological matching (cross-match). Differences in the time period until transplantation call for extrapolation of the measured ratio to the end of cold ischemia before correlating with graft performance after transplantation. Therefore, quantitative determination of PME/Pi(O) kinetics is essential. As a model for metabolite decay in human renal grafts, pig kidneys obtained from a slaughterhouse were monitored for up to 80 h via (31)P MRS at 2 T. By employing chemical shift imaging (CSI) with a spatial resolution of approximately 1 x 1 x 4 cm(3), it was possible to reduce partial volume effects significantly. The improved spectral resolution gained through CSI enabled reliable PME/Pi(O) ratios to be determined only from those voxels containing renal tissue. Spectra were fitted automatically using the magnetic resonance user interface (MRUI), with prior knowledge obtained from unlocalized spectra when necessary. A monoexponential time dependence of PME/Pi(O) for histidine-tryptophane-alpha-ketoglutarate (HTK)-perfused kidneys during cold ischemia was observed, and the determined value of the decay constant alpha was 0.0099 +/- 0.0012 h(-1). In University of Wisconsin solution (UW)-perfused kidneys, an alpha of 0.0183 +/- 0.0053 h(-1) was determined. Determination of the decay constant enables a usable extrapolation of PME/Pi(O) for quality assessment of UW perfusion and a reliable extrapolation for HTK-perfused human renal grafts.
NMR in Biomedicine 12/2007; 20(7):652-7. · 3.45 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mycophenolate mofetil (MMF) based immunosuppression after renal transplantation has proven to be safe and beneficial for children and adolescents. However, long-term analysis, in particular of pediatric patients, is scarce.
Data of 140 patients receiving MMF versus azathioprine (AZA) in combination with cyclosporine A (CsA) and prednisone without induction were analyzed with a main focus on survival and renal function in long-term follow-up.
After 5 years of follow-up, 44 MMF and 20 AZA patients were still on study. Graft survival of intent to treat (ITT) groups was 90.7% for MMF and 68.5% for AZA patients (P<0.001). Cumulative rejection free survival was 51.2% in MMF versus 37.0% in AZA patients (P<0.05). In association with early acute rejections (ARE), projected half-life was 14.4/4.5 years in patients with and 18.7/14.5 years without rejection in the MMF/AZA group, respectively.
MMF based protocols improved long-term graft survival without an increase in side effects. Early ARE were associated with worse half-life of the graft, although more stressed in the AZA group. Thus, to improve quality of life in children for very long-term outcome, ARE should be further decreased and renal function should be better preserved.
[show abstract][hide abstract] ABSTRACT: The objective of this study was to determine outcome after living-donor kidney transplantation in a single-center institution in Germany.
From 1976 to May 2005, a total of 298 living-donor kidney transplants were performed at the University of Freiburg. Most recipients (78.8%) were placed on cyclosporine, mycophenolate mofetil, and corticosteroids maintenance immunosuppression. Cox proportional hazard model was applied to analyze predictors for patient and graft survival. Mean follow-up was 5.3 years.
According to Kaplan-Meier calculation, 1-, 5-, and 10-year patient survival was 98.6, 92.7, and 86.8%, respectively. Kidney function rate was 95.5, 82.8, and 67.9%, respectively. A 5-year graft function rate continued to increase from 79.5% in patients transplanted before 1996 to 83.6% in patients transplanted thereafter. In a Cox regression model recipient age above 50 years, duration of dialysis above 2 years and preexisting type 1 diabetes mellitus were associated with a decreased patient survival. Graft survival was mostly influenced by the type of immunosuppression and preexisting hypertension of the recipient.
Our results demonstrate that living-donor kidney transplantation is a highly effective therapy for patients with end stage renal failure. Updates in immunosuppression, recipient selection, and operative technique may have contributed to the improved graft survival over the past three decades.
Langenbeck s Archives of Surgery 02/2007; 392(1):23-33. · 1.89 Impact Factor
[show abstract][hide abstract] ABSTRACT: Mycophenolate mofetil (MMF) was introduced in pediatric renal transplantation almost 10 years ago. In several pediatric studies, MMF has been associated with improved graft survival and improved renal function with standard immunosuppression of steroids and calcineurin inhibitors (CNI). Both drugs are associated with significant negative effects including influence on growth, blood pressure, glucose metabolism, and also cosmetic side effects. Reduction of CNI was possible with MMF without increased rejection, improving blood pressure and renal function. Information is accumulating that steroid-sparing protocols including CNI are also associated with clinical improvement. Recent reports are positive in the pediatric population using the combination of induction with interleukin-2-receptor antagonists and mTOR inhibitors to spare steroids and CNI. Therefore MMF remains a mainstay of immunosuppressive protocols in the pediatric renal transplantation.
[show abstract][hide abstract] ABSTRACT: We sought to determine the impact of kidney transplantation with simultaneous unilateral nephrectomy on perioperative morbidity and patient and graft survival.
From January 1990 to May 2004, 75 kidney transplantations with simultaneous unilateral nephrectomy (group NE+) were performed at the University of Freiburg. Of these, 49 had polycystic kidney disease. Patients of group NE+ were matched with 75 kidney transplants without nephrectomy (group NE-). Immunosuppressive maintenance therapy in both groups was based on cyclosporine A, mycophenolate mofetil or azathioprine, and prednisone. Mean follow up was 4.1 yrs (range 0.3-11.7 yrs).
Patient survival rate at 1 and 5 yrs was 95% and 84% versus 95% and 93% in group NE+ and NE-, resp. (P=0.56). Accordingly, kidney function rate was 85% and 74% in group NE+ versus 89% and 79% in group NE- (P=0.89). Perioperative (90 days) mortality rate in group NE+ was 1.3% and 2.7% in group NE- (P=0.56). Perioperative surgical complications were similar in both groups.
Kidney transplantation with concomitant unilateral nephrectomy has no negative impact on patient or graft survival and is associated with a reasonable morbidity rate.
[show abstract][hide abstract] ABSTRACT: For years ABO-incompatible kidney transplantations were preferentially performed in Japanese centers. In order to overcome the increased risk of humoral rejections, patients were treated with multiple sessions of plasmapheresis, intensified immunosuppressive therapy and splenectomy before transplantation. Despite good long-term results regarding patient and organ survival rates, increased morbidity during the early post-transplant period prevented a broad application of this method. Recently, a new protocol including the anti-CD20-antibody (Ab) rituximab and blood group-specific immunoadsorption instead of splenectomy and plasmapheresis was published with excellent short-term results.
From April 2004 to September 2005, 11 patients were prepared for ABO-incompatible transplantation. All patients received 375 mg/m2 rituximab intravenous 3 to 4 weeks before transplantation. Immunosuppressive therapy consisted of tacrolimus, mycophenolate mofetil and prednisone and was started at least 7 days before transplantation. Intravenous immunoglobulins (0.5 g/kg) were administered the day before transplantation. Immunoglobulin G (IgG)-anti-A or -B Ab titers before starting immunoadsorption treatment ranged between 1 : 4 and 1 : 1024. Immunoadsorption treatment was started in parallel with immunosuppressive medication and was continued until the anti-A or anti -B Ab titers (IgG and IgM) were lowered to the aimed pre-transplant threshold of <1 : 8. During the early postoperative period, additional immunoadsorption treatments were performed, if the titers increased again above 1 : 8 (days 0 to 7) or 1 : 16 (days 8 to 14), respectively.
Transplantation could be conducted in eight of 11 patients (two females, six males, mean recipient age 52+/-11 yr). The mean follow-up was 7.0 months (range 4 to 17). The blood group constellation was A1 to 0 in four cases, A2 to 0 in two cases, B to A in one case, and A1 to B in another case, respectively. On average, each patient received seven immunoadsorption treatments. All transplants showed primary function and no humoral rejections occurred. Three of our 11 patients showed rapid increases of isoagglutinin titers after each immunoadsorption treatment and thus could not be transplanted. One patient died 4 months after transplantation with a functioning graft due to sepsis secondary to pseudomembranous enterocolitis. The mean creatinine value of the remaining seven patients now is 1.6 mg/dl.
The use of antigen-specific immunoadsorption and an immunosuppressive regimen consisting of a conventional triple immunosuppressive therapy has shown excellent short-term results. The immunoadsorption treatment using antigen-specific columns is highly effective and even patients with high isoagglutinin titers can be transplanted. This protocol is an option for end-stage renal disease patients who have no blood group-compatible donor.
[show abstract][hide abstract] ABSTRACT: The human cytomegalovirus (CMV) is a major cause of morbidity and mortality in transplant patients. In this study, we compared the diagnostic value of pp65 antigen test, qualitative nested polymerase chain reaction (PCR), and quantitative Taqman PCR in predicting the clinical outcome of CMV infection.
A total of 169 samples derived from 59 organ-transplant recipients (kidney n= 46, liver n= 11, kidney and pancreas n= 2) were analyzed. Peripheral blood leukocytes (PBL) were isolated using dextran gradient centrifugation, and 2 x 10 cells were analyzed for pp65 antigen by immunofluorescence. A crude DNA extract obtained from the same number of cells was used for qualitative nested PCR and quantitative Taqman PCR analysis. RESULTS.: The correlation coefficient of pp65 antigen test and Taqman PCR was R= 0.699 (P = 0.001). With cut-off values for pp65 antigen test set at greater than 10 positive nuclei per 2 x 10 PBL, sensitivity was 91%, and positive predictive value (PPV) was 70%. When the corresponding cut-off value for Taqman PCR was applied (>125000 genome copies per 2 x 10 PBL), a sensitivity of 83% and a PPV of 68% were found. Both assays allowed for the monitoring of successful antiviral therapy. Although qualitative nested PCR was highly sensitive (95%), it was less useful in predicting CMV disease (PPV 47%) and in therapy control.
Our data show that pp65 antigen test and Taqman PCR are almost equivalent in the monitoring of CMV infection and disease when identical cell numbers are used for both assays.
[show abstract][hide abstract] ABSTRACT: Phosphorus-31 (P) magnetic resonance spectroscopy (MRS) has been evaluated in several studies for pretransplant assessment of renal viability. As an indicator of graft quality, the ratio of phosphomonoesters (PME) to an organ's inorganic phosphate (Pio) is the parameter of choice. However, exact calculation of the PME/Pio ratio is disturbed by interference from the signal of phosphorus contained in the preservation solution (Pip). In this article, the authors present an improvement attained by using volume selective P-MRS using chemical shift imaging (CSI) enabling reduction in the disturbing influence of Pip.
Sixteen renal grafts were investigated using a 2.0-T whole-body scanner and a cross-coil setting with an active decoupled receiver coil. P-CSI was used to measure two-dimensional spectra of a 4-cm slice of the graft in a 12 x 12 matrix. Peaks of each spectrum were fitted with magnetic resonance user interface-MatLab software using VarPro and the mean PME/Pio ratio was calculated.
Significant correlation between the PME/ Pio ratio and clinical kidney function was found. In comparison to former trials using PME/Pio ratios calculated from non-volume-selective spectra, the correlation outcome improved significantly. Furthermore, overlay of CSI-spectra matrix and corresponding slice image of the kidney illustrates the origin of different signals in the spectra.
The authors' work demonstrates that the PME/Pio ratio calculated from CSI spectra is a reliable indicator of viability of renal grafts. Early knowledge of graft quality may allow therapy to be adapted to the conditions of the organ, for example, by initial withholding of nephrotoxic calcineurin-inhibitors in kidneys with high risk of delayed graft function.
[show abstract][hide abstract] ABSTRACT: In the liver, efficacy of cryosurgical ablation of tumors located near the retrohepatic vena cava is impaired by the heat-sink effect. This could be overcome by total vascular exclusion (TVE) of the liver. In this study, the effect of TVE on cryosurgical ablation of liver tissue close to the retrohepatic vena cava was investigated with regard to the extent of the cryolesion and complications arising from necrosis of the caval wall.
Of a total of 28 pigs, 14 underwent cryotherapy with TVE compared to 14 without TVE, both involving the vena cava. 7 animals in each group were subjected to one freeze cycle and 7 in each group to two freeze cycles. Temperatures in the cryolesion were monitored and cryolesions were documented sonographically. Laboratory parameters were determined pre- and postoperatively. Follow-up was 14 days. Morphology, extent of the cryolesion, damage to the vena cava and complications were assessed after autopsy.
With TVE, freezing rates were increased and cryolesions were significantly larger than without TVE. Transmural necroses of the vena cava with complete necrosis of the intima occurred significantly more frequently after TVE. Macro- and microscopically, the damage to the caval wall was considerably more marked after cryotherapy under TVE but in all cases the continuity of the vessel wall remained intact. There were no ruptures, thrombosis, or strictures of the vena cava.
The combination of cryotherapy and TVE increases the effectiveness of cryoablation in the liver involving the retrohepatic vena cava without any severe vascular complications occurring in the pig.
Journal of Surgical Research 02/2004; 116(1):32-41. · 2.02 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: The human cytomegalovirus (CMV) is a major cause of morbidity and mortality in transplant patients. In this study, we compared the diagnostic value of pp65 antigen test, qualitative nested polymerase chain reaction (PCR), and quantitative Taqman PCR in predicting the clinical outcome of CMV infection. METHODS: A total of 169 samples derived from 59 organ-transplant recipients (kidney n= 46, liver n= 11, kidney and pancreas n= 2) were analyzed. Peripheral blood leukocytes (PBL) were isolated using dextran gradient centrifugation, and 2 x 10 cells were analyzed for pp65 antigen by immunofluorescence. A crude DNA extract obtained from the same number of cells was used for qualitative nested PCR and quantitative Taqman PCR analysis. RESULTS.: The correlation coefficient of pp65 antigen test and Taqman PCR was R= 0.699 (P = 0.001). With cut-off values for pp65 antigen test set at greater than 10 positive nuclei per 2 x 10 PBL, sensitivity was 91%, and positive predictive value (PPV) was 70%. When the corresponding cut-off value for Taqman PCR was applied (>125000 genome copies per 2 x 10 PBL), a sensitivity of 83% and a PPV of 68% were found. Both assays allowed for the monitoring of successful antiviral therapy. Although qualitative nested PCR was highly sensitive (95%), it was less useful in predicting CMV disease (PPV 47%) and in therapy control. CONCLUSION: Our data show that pp65 antigen test and Taqman PCR are almost equivalent in the monitoring of CMV infection and disease when identical cell numbers are used for both assays.
[show abstract][hide abstract] ABSTRACT: Mycophenolate mofetil (MMF)-based immunosuppression has reduced the acute rejection rate in adults and in children in the early posttransplantation period. Three-year posttransplantation results have been reported for adults but not for children thus far. In the present open-labeled study, patients 18 years old and younger were evaluated prospectively for up to 3 years after renal transplantation (RTX).
Eighty-six patients receiving MMF in combination with cyclosporine and prednisone without induction were evaluated for patient survival, transplant survival, renal function, arterial blood pressure, adverse events, and opportunistic infections. These patients were compared with a historic control group (n=54) receiving azathioprine (AZA) instead of MMF.
Patient survival after 3 years was 98.8% in the MMF group and 94.4% in the AZA group (NS). Intent-to-treat analysis of graft survival demonstrated superiority for MMF (98% vs. 80%; P<0.001). Cumulative acute rejection episodes occurred in 47% of patients in the MMF group versus 61% in the AZA group (P<0.05). Renal function was not significantly different, neither after 3 years nor in the long-term calculation. Antihypertensive medication was administered to 73% to 84% of patients, similar in both groups. Opportunistic infections were recorded only for MMF. Infection rates were comparable to those reported in adults.
These results suggest that MMF is safe and beneficial as a longer term maintenance immunosuppressive drug in children and adolescents.
[show abstract][hide abstract] ABSTRACT: Liver tumors located near the retrohepatic vena cava are often considered nonresectable. For these patients cryoablation could be a therapeutic option. In this study the safety and efficacy of hepatic cryosurgery involving the retrohepatic vena cava were investigated. Cryolesions involving the vena cava were created in 26 pigs. Follow-up was 24 h and 14 days. The extent of the cryolesion, damage to the vena cava and complications were assessed after autopsy. The cyronecrosis extended into the wall of the vena cava in 81% of the animals. All animals had an uneventful recovery without any complications such as ruptures of the vessel, thrombosis or pulmonary embolism. Microscopically elastic and collagenous fibers of the cava wall remained intact. The continuity of the vessel wall was conserved. In conclusion, the safety and efficacy of cryosurgical treatment involving the retrohepatic vena cava were shown in a pig model.
European Surgical Research - EUR SURG RES. 01/2003; 35(2):67-74.
[show abstract][hide abstract] ABSTRACT: En bloc kidneys from pediatric donors are regarded as questionable with respect to the safety and quality of the transplant outcome. Therefore, we retrospectively studied graft outcome and graft function of our 56 en bloc kidneys transplanted in paraaortal position between 1992 and 1999.
Graft outcome of en bloc kidneys (group A) was compared with graft outcome of single cadaveric adult donor kidneys (group B). Matched pairs were generated regarding HLA-missmatch, cold ischemic time, recipient age, body mass index, and systolic arterial blood pressure.
Allograft survival rates of pediatric en bloc kidneys at 1, 3, and 5 years were significantly lower (group A: 78, 70, 70% vs. group B: 92, 92, 81%, P<0.05). Lower survival rate was caused by a higher number of graft losses in the early postoperative period (group A: 21% vs. group B: 4%, P<0.01) due to vascular complications. Main risk factor for graft loss was donor age of less than 12 months. Five years after transplantation serum creatinine of pediatric en bloc kidneys was significantly better than of adult kidneys (0.9+/-0.06 vs. 1.8+/-0.2 mg/dl, P<0.001).
En bloc kidneys show a high percentage of graft survival with excellent long-term graft function. However, the early postoperative period carries a higher risk of graft loss in very young donors due to vascular complications. In the face of donor shortage en bloc kidneys from pediatric donors can successfully be transplanted in a paraaortal position.
[show abstract][hide abstract] ABSTRACT: The aim of this study was to evaluate pp65 antigen-guided antiviral therapy in preventing human cytomegalovirus (HCMV) infection in solid organ transplant recipients.
Ten kidney and two liver transplant recipients with asymptomatic HCMV infection were randomized either for i.v. ganciclovir or placebo treatment in a prospective, double-blind study. All patients were positive by HCMV pp65 antigen test at levels >5 positive cells/2 x 10(5) investigated cells.
No cases of HCMV end-organ disease occurred. In contrast to patients on placebo (5/7), none of the patients on ganciclovir (0/5) developed HCMV-associated symptoms (P=0.01). However, because of the small number of patients, all three high-risk patients (donor seropositive, recipient seronegative) were randomized to placebo and all three developed symptoms.
Preemptive antiviral therapy guided by the pp65 antigen test seems to have a beneficial effect on preventing HCMV-associated symptoms in kidney and liver transplant recipients.
[show abstract][hide abstract] ABSTRACT: Germline mutations of the VHL gene cause von Hippel-Lindau syndrome (VHL). In southern Germany, a specific mutation in this gene, c.505 T>C, is one of the most frequent alterations owing to a founder effect.
This study was conducted to evaluate morbidity, specific clinical risk profile, and mortality among a series of VHL c.505 T/C mutation carriers. A total of 125 eligible subjects carrying VHL c.505 T/C underwent ophthalmoscopy and gadolinium enhanced magnetic resonance imaging of the brain, the spinal cord, and the abdomen. Age related penetrance, morbidity, and mortality were assessed.
Frequently observed lesions were phaeochromocytoma (47%), retinal angiomas (36%), haemangioblastoma of the spine (36%), and haemangioblastoma of the brain (16%). Four patients developed renal cell carcinoma. VHL was symptomatic in 47% of subjects; 30% were asymptomatic despite the presence of at least one VHL related tumour and 23% of the carriers had no detectable VHL lesion. Of the 19 patients who had died (15%), 10 died of symptomatic VHL lesions. Overall penetrance by cumulative incidence functions is estimated at 48% by 35 years and 88% by 70 years. In contrast to the only existing published report based on patients with presumably unselected VHL germline mutations, the mortality rate for c.505 T/C mutation carriers is comparable to that of the general population of Germany.
Our results are an important example that a specific genotype, at least in the case of VHL c.505 T/C, can favourably impact on mortality despite a high age related penetrance. Our study also indirectly provides objective data which might be useful to the life and health insurance industry; it would appear that c.505 T>C mutation positive subjects have similar disease specific mortality to that of the general population owing to a combination of phenotype and timely detection of mutation carrier status followed by aggressive clinical screening and, if necessary, treatment.
Journal of Medical Genetics 09/2001; 38(8):508-14. · 5.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: Severe osteoporosis frequently is observed after organ transplantation. In kidney transplantation, it adds to pre-existing renal bone disease and strategies to prevent osteoporosis are not established. Eighty kidney recipients were included in a randomized controlled prospective intervention trial. Treated patients (n = 40) received an injection of ibandronate, a bisphosphonate, immediately before and at 3, 6, and 9 mo after transplantation. The primary outcome measured was the change in bone mineral density. Secondary measures included graft outcome, spinal deformities, fracture rate, body height, and hormonal and metabolic data. Loss of spongy and cortical bone after transplantation was prevented by ibandronate. Changes of bone mineral density (ibandronate versus controls) were as follows: lumbar spine, -0.9 +/- 6.1% versus -6.5 +/- 5.4% (P < 0.0001); femoral neck, +0.5 +/- 5.2% versus -7.7 +/- 6.5% (P < 0.0001); and midfemoral shaft, +2.7 +/- 12.2% versus -4.0 +/- 10.9% (P = 0.024). Fewer spinal deformities developed with ibandronate (7 patients with 7 deformities versus 12 patients with 23 deformities; P = 0.047). Loss of body height was 0.5 +/- 1.0 cm versus 1.1 +/- 1.0 cm in control subjects (P = 0.040). Two bone fractures occurred in each group. There were fewer acute rejection episodes with ibandronate (11 versus 22; P = 0.009). Graft function after 1 yr was comparable. Bone loss, spinal deformation, and loss of body height during the first year after kidney transplantation are prevented by injection of ibandronate at intervals of 3 mo. The smaller number of rejection episodes of the ibandronate-treated group should be confirmed and its mechanism should be explored in additional studies.
Journal of the American Society of Nephrology 07/2001; 12(7):1530-7. · 8.99 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background. Acute rejection episodes (ARE) of kidney transplants are considered as risk factor in the development of chronic rejection. In adult renal transplantation (RTx), ARE have been significantly reduced by mycophenolate mofetil (MMF) in combination with cyclosporin (CyA) and steroids (Pred). Reports of pediatric RTx on a maintenance immuno-suppression with MMF are restricted to patients (P) after antibody induction therapy.
Methods. The efficacy and safety of MMF combined with CyA and Pred in pediatric RTx without induction therapy were evaluated in an open-labeled multicenter study.
Results. From 10/1996 to 6/1999, 65 pediatric P (MMF group) were followed for at least 6 months, 58 of 65 for 12 months. These P were compared with 54 retrospectively analyzed pediatric P who were transplanted between 1990 and 1996 and had received CyA, Pred, and azathioprine for immunosuppression (historic AZA group). Within the first 6 months after RTx, 18 of 65 (MMF group) and 32 of 54 (historic AZA group) P showed clinical signs of acute rejection (P <0.01). Thereafter only one further P in the MMF group developed a first ARE. Graft loss due to rejection occurred in one MMF- and seven AZA-treated P (P <0.05). The creatinine-clearance 3 and 6 months after RTx was higher in the MMF group. Major adverse events (MMF group) included infections of the urinary and the upper respiratory tract, diarrhea, and leukopenia. Cytomegalovirus-infection occurred in 13 P and 2 P developed cytomegalovirus disease. One P developed PTLD 10 months after RTx and recovered after the reduction of immunosuppression.
Conclusions. The combination of MMF, CyA, and Pred reduced ARE in pediatric RTx without incurring major side effects.