Mycophenolate mofetil treatment following renal transplantation decreases GTP concentrations in mononuclear leucocytes

2004 ◽  
Vol 107 (1) ◽  
pp. 69-74 ◽  
Author(s):  
Piotr JAGODZINSKI ◽  
Slawomir LIZAKOWSKI ◽  
Ryszard T. SMOLENSKI ◽  
Ewa M. SLOMINSKA ◽  
David GOLDSMITH ◽  
...  
Keyword(s):  
Renal Failure ◽  
Mycophenolate Mofetil ◽  
Renal Transplantation ◽  
Adenine Nucleotide ◽  
Target Cells ◽  
Renal Transplant Recipients ◽  
Guanine Nucleotide ◽  
Inosine Monophosphate Dehydrogenase ◽  
Pyrimidine Nucleotides ◽  
Mononuclear Leucocytes

MMF (mycophenolate mofetil) has been proven to provide an effective immunosuppression by non-competitive selective reversible inhibition of IMPDH (inosine monophosphate dehydrogenase), the enzyme playing a crucial role in GTP biosynthesis. However, the exact metabolic changes induced by inhibition of IMPDH in target cells of the immune system have been the subject of recent debate. The aim of the present study was to evaluate whether MMF treatment produced sustained changes in the guanosine nucleotide pool of MNLs (mononuclear leucocytes) in vivo. Sixty-two renal failure patients were divided into three groups: chronic renal failure patients undergoing haemodialysis (CRF-HD; n=20) and two groups of patients after renal transplantation, the first on AZA (azathioprine; TN-AZA; n=23) and the second treated with MMF (TN-MMF; n=19). In addition, MNLs from 25 healthy subjects were analysed as controls. Anion-exchange HPLC was used to quantify purine and pyrimidine nucleotides in MNLs. We report a significant decrease in GTP and the total MNL guanine nucleotide pool in the TN-MMF group (P<0.05) compared with control, CRF-HD and TN-AZA groups, although no significant differences were found between any of the other groups. Adenine nucleotide concentrations in MNLs were decreased in the TN-AZA group, but not in the TN-MMF group compared with the CRF-HD group and controls. There were no differences in CTP concentrations, but UTP concentrations were decreased in the CRF-HD, TN-AZA and TN-MMF groups compared with controls. MMF caused a significant and sustained decrease in the guanine nucleotide pool in MNLs from renal transplant recipients. This decrease contrasts with the elevation in GTP reported in erythrocytes of MMF-treated patients.

Mycophenolate mofetil, an inhibitor of inosine monophosphate dehydrogenase, causes a paradoxical elevation of GTP in erythrocytes of renal transplant patients

2004 ◽  
Vol 107 (1) ◽  
pp. 63-68 ◽  
Author(s):  
David GOLDSMITH ◽  
Elizabeth A. CARREY ◽  
Stephen EDBURY ◽  
Ryszard T. SMOLENSKI ◽  
Piotr. JAGODZINSKI ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Renal Transplantation ◽  
Renal Transplant ◽  
Plasma Metabolites ◽  
Renal Transplant Recipients ◽  
Inosine Monophosphate Dehydrogenase ◽  
Inosine Monophosphate ◽  
Transplant Patients ◽  
Renal Transplant Patients ◽  
Monophosphate Dehydrogenase

The immunosuppressant MMF (mycophenolate mofetil) has increasingly replaced AZA (azathioprine) in renal transplantation. MMF is a prodrug of MPA (mycophenolic acid), which inhibits lymphocyte IMPDH (inosine monophosphate dehydrogenase), thereby drastically decreasing GTP concentrations essential to lymphocyte proliferation in vitro and in vivo. Erythrocyte GTP concentrations are commonly elevated in severe renal disease, but normalize following successful engraftment. Consequently, elevated GTP in renal transplant recipients might signal impending loss of immunosuppression and graft failure. In the present study, we compared erythrocyte nucleotides and plasma metabolites in two groups of 25 patients after renal transplantation, both receiving prednisolone and cyclosporin A, but one group receiving MMF and the other AZA. No patients had recent allograft biopsy evidence of rejection. Erythrocyte GTP concentrations at MMF commencement were 50.4±23.4 μmol/l. An increase occurred during the first 3 months after transplant when MMF was used de novo, stabilizing at 146.7±62.9 μmol/l after 4 months. This was significantly higher (P=2.5×10−6) than erythrocyte GTP (40.4±15.9 μmol/l) in the AZA group, which was essentially unchanged from values immediately after successful transplantation. The effect of MMF on erythrocyte GTP levels was reversible, since GTP levels fell when MMF therapy was terminated. The results demonstrate paradoxically high GTP concentrations in erythrocytes of renal transplant patients receiving MMF. MPA may stabilize reticulocyte IMPDH, allowing the protein to persist during erythropoiesis. This behaviour is in marked contrast with the decrease in GTP levels seen in white blood cells of patients on chronic MMF therapy.

Renal transplantation and quality of life in Tanzania

2020 ◽  
Vol 31 (1) ◽  
pp. 1-15
Author(s):  
Onesmo A. Kisanga ◽  
Francis F. Furia ◽  
Paschal J. Ruggajo ◽  
Eden E. Maro
Keyword(s):  
Quality Of Life ◽  
Renal Failure ◽  
Kidney Transplantation ◽  
Renal Transplantation ◽  
Renal Transplant Recipients ◽  
End Stage Renal Failure ◽  
Laboratory Test Results ◽  
The Government ◽  
End Stage

Background: Renal replacement therapy (RRT), which includes dialysis and kidney transplantation, is the treatment of choice for patients with end stage renal failure (ESRF). Most sub-Saharan African countries have not developed renal transplantation services and are relying on referring patients to overseas countries. This study was carried out to describe renal transplantation experience in Tanzania.Methods: Forty-four renal transplant recipients were recruited in this study. Standardized questionnaire and Swahili version of standard form – 36 (SF-36) were used to collect socio-demographic information, clinical data, laboratory test results and health related quality of life information.Results: Ages of transplant recipient ranged from 21 to 66 years with mean age of 45.9 ± 10.5 years. The leading causes of end stage renal failure among participants was hypertension 58.8% (25/44) followed by glomerulonephritis 15.9% (7/44). Twentyeight (63.6%) of transplantations were paid by the government. Most of the donors (97.7%) were living out of which 26 (59.1%) were siblings and 11 (25%) were second-degree relatives (cousins and nephews). Most common complication noted following transplantation was diabetes mellitus 9 (20.5%) and 3 (6.8%) had chronic rejection. Mental health was the domain with highest mean score (75.6 ± 14.3) and role physical had the least mean score (44 ± 45.6).Conclusions:  Hypertension was the leading cause of ESRF in this study. Most of the donors were siblings and the costs of transplantation were largely covered by the government. There is a need for concerted effort to establish local kidney transplantation services in Tanzania. Keywords: Renal transplantation, quality of life in transplantation, Tanzania.

scholarly journals Ensemble cryo-EM structures demonstrate human IMPDH2 filament assembly tunes allosteric regulation

2019 ◽  
Author(s):  
Matthew C. Johnson ◽  
Justin M. Kollman
Keyword(s):  
T Cell Activation ◽  
Cellular Proliferation ◽  
Feedback Inhibition ◽  
Adenine Nucleotide ◽  
Allosteric Regulation ◽  
Regulatory Control ◽  
Guanine Nucleotide ◽  
Inosine Monophosphate Dehydrogenase ◽  
Filament Assembly ◽  
Nucleotide Pools

SummaryInosine monophosphate dehydrogenase (IMPDH) mediates the first committed step in guanine nucleotide biosynthesis and plays important roles in cellular proliferation and the immune response. The enzyme is heavily regulated to maintain balance between guanine and adenine nucleotide pools. IMPDH reversibly polymerizes in cells and tissues in response to changes in metabolic demand, providing an additional layer of regulatory control associated with increased flux through the guanine synthesis pathway. Here, we report a series of human IMPDH2 cryo-EM structures in active and inactive conformations, and show that the filament resists inhibition by guanine nucleotides. The structures define the mechanism of filament assembly, and reveal how assembly interactions tune the response to guanine inhibition. Filament-dependent allosteric regulation of IMPDH2 makes the enzyme less sensitive to feedback inhibition, explaining why assembly occurs under physiological conditions, like stem cell proliferation and T-cell activation, that require expansion of guanine nucleotide pools.

Overview of blood purification in uremia

1980 ◽  
Vol 3 (4) ◽  
pp. 203-208
Author(s):  
B.T. Burton
Keyword(s):  
Renal Failure ◽  
Peritoneal Dialysis ◽  
Renal Transplantation ◽  
Rejection Rate ◽  
Blood Purification ◽  
Maintenance Hemodialysis ◽  
Dialysis Patients ◽  
Transplant Patients ◽  
Maintenance Dialysis ◽  
Transplanted Kidneys

Today, management of irreversible renal failure is based primarily on maintenance hemodialysis and renal transplantation with a growing minority of patients treated by peritoneal dialysis. With regard to renal transplantation — the early promise of renal transplantation in the mid 1960's has given way to the realities of the late 1970's. There have been no major changes in the rejection rate of transplanted kidneys in recent years though today's mortality of transplant patients is considerably reduced over what it used to be. Moreover, universally the lack of availability of a sufficient number of organs for transplantation poses a formidable problem. It is all too apparent that current methods of blood purification in uremia are far from optimal. Even though the mortality in maintenance dialysis is relatively low, hemodialysis is characterized by a variety of complications and most maintenance dialysis patients are not optimally rehabilitated.

A Case of Living-Donor Renal Transplantation for Chronic Renal Failure Caused by Secondary Amyloidosis

2011 ◽  
Vol 43 (6) ◽  
pp. 2418-2420 ◽  
Author(s):  
K. Sakai ◽  
M. Okamoto ◽  
K. Koshino ◽  
T. Suzuki ◽  
S. Nobori ◽  
...  
Keyword(s):  
Renal Failure ◽  
Renal Transplantation ◽  
Chronic Renal Failure ◽  
Living Donor ◽  
Secondary Amyloidosis
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