36-month follow-up of 75 renal allograft recipients treated with steroids, tacrolimus, and azathioprine or mycophenolate mofetil.

OBJECTIVES: The aim of this retrospective study was to assess the incidence of acute rejection episodes (AR), diabetes mellitus (DM), and serum creatinine (SCr) among renal transplant recipients treated with tacrolimus (Tac), steroids (S), and mycophenolate mofetil (MMF) or azathioprine (Aza). METHODS: Seventy-five renal allograft recipients enrolled in the COSTAMP study were followed for a period of 3 years. Patients were randomized to receive either Tac and MMF (n = 41) or Tac and Aza (n = 34) concomitantly with steroids. Follow-up assessments were performed at 3, 6, 12, 24, and 36 months. RESULTS: Patient survival at month 36 was 91.18% in the Tac/Aza/S group and 97.56% in the Tac/MMF/S group. Graft survival at month 36 was 82.35% and 85.37%, respectively. During the study period, 22 cases of biopsy-proven AR were diagnosed in 17 patients (22.6%). After 36 months the total number of AR was 11 in the Aza-treated group (32.4%) and 11 in the MMF-treated group (26.8%). DM was diagnosed de novo in 17 individuals (22.6%). During 36 months, 10 patients from Aza-treated group (29.4%) and seven from MMF-treated group developed DM (17.1%). Serum creatinine values were not significantly different in both arms of the study. Comparison of arterial blood pressure and total cholesterol revealed no significant changes in any of the studied groups. CONCLUSIONS: We conclude that combinations of steroids, tacrolimus, and azathioprine or MMF provide good results with regard to renal function.

Posttransplantation diabetus mellitus under calcineurin inhibitor.

BACKGROUND: The development of postransplantation diabetes mellitus (PTDM) is a serious complication of kidney transplantation. PTDM has a major impact on quality of life decreasing rates of patient and graft survival. It is well known that some currently used immunosuppressants are diabetogenic. Greater diabetogenicity of FK-506 has been reported in multicenter trials. We initiated a study of conversion from tacrolimus (FK-506) to cyclosporine (CsA) among kidney allograft recipients presenting with PTDM to evaluate whether this maneuver would ameliorate a diabetic state. METHODS: This analysis of 20 adult, renal allograft recipients presenting with PTDM assumed the need for insulin therapy or oral hypoglycemics before and after conversion of the immunosuppressive regimen. The criteria for evaluating the outcome were as follows: dose reduction of insulin or oral hypoglycemic agents, adequacy of glucose control, C-peptide levels, and insulin concentration. RESULTS: During the follow-up, we observed an improvement in the control of blood glucose in the converted group. In 13 patients, satisfactory glucose control was obtained without insulin or any other agent. In 3 patients a significant dose reduction of required insulin was possible. In another 2 patients who were insulin-dependent, the switch to oral hypoglycemic treatment was clinically possible after conversion. After conversion we observed significantly lowered fasting blood glucose levels and increased C-peptide levels. CONCLUSIONS: The conversion from a tacrolimus to a CsA-based immunosuppressive regimen resulted in better glucose metabolism. We demonstrated a positive effect of conversion on the diabetic state of patients with PTDM.

Randomised open clinical trial of conversion from mycophenolate mofetil to azathioprine in cadaveric renal transplantation.

Mycophenolate mofetil (MMF) is a powerful immunosuppressive drug with established efficacy and safety. The search for a less expensive immunosuppressive protocol has led to an open randomised clinical trial of conversion from MMF to azathioprine (Aza). A total of 28 renal allograft recipients treated with prednisone, cyclosporine, and MMF was randomised into two groups: converted (early conversion) and control (late conversion). Conversion from MMF to Aza was conducted at the end of the 4th post-transplant month in the converted group and after the 12th month in the control. During the 20-month observation period, biopsy-proven acute rejection occurred more frequently in the converted than in the control group, although the difference was not statistically significant. Early conversion from MMF to Aza increased the risk of subsequent rejection in those patients who underwent at least one episode of acute rejection prior to conversion.

Liver transplantation in the experience of the centre commencing the program.

From 1989 to 1999, 43 orthotopic liver transplantations (OLT) in 40 patients (3 retransplantations) were performed in our Department. The most common indications for OLT were noninflammatory, primary cholestatic liver diseases and postinflammatory liver cirrhosis. Fourty OLT's were done for elective indications, three--on emergency basis, because of fulminant liver failure. The majority of transplantations was performed with classical technique with the excision of retrohepatic vena cava and routine use of the extracorporeal veno-venous bypass. Only in 4 patients the piggyback technique was used and performed without temporary portocaval anastomosis. All 3 patients transplanted for fulminant liver failure died in the perioperative period. Twenty four patients are still alive and well, the longest period of observation exceeding 5 years.

Urine activity of cathepsin B, collagenase and urine excretion of TGF-beta 1 and fibronectin in membranous glomerulonephritis.

In 30% of cases nephrotic syndrome is caused by membranous glomerulonephritis (MG). Protein accumulation in glomeruli leads to progressive loss of kidney function and damage of structure in MG. The role of tissue proteolytic systems and growth factors in this process is not known. The purpose of the study was to estimate urine cathepsin B, collagenase activity and urine excretion of TGF-beta 1 and fibronectin in MG. Cathepsin B activity was greater in the urine of MG patients than in the control group (10.58 +/- 8.73 pmol AMC/mg creatinine per min-1 vs control 7.11 +/- 2.05 pmol AMC/mg creatinine per min-1; P < 0.05). Urine collagenase activity was higher in the group of patients than in the control group (8.59 +/- 4.26 pmol AMC/mg creatinine per min-1 vs control 3.84 +/- 2.09 pmol AMC/mg creatinine per min-1 P < 0.02). Urine excretion of fibronectin (45.60 ng/mg creatinine vs control 10.30 ng/mg creatinine; P < 0.04) and TGF-beta 1 levels in the urine were higher than in controls (283.55 +/- 248.13 pg/ml vs 36.11 +/- 48.01 pg/ml; P < 0.01). Results suggest glomerular overproduction of TGF-beta 1 and urinary leak of proteolytic enzymes (PE). This may result in decreased glomerular PE activity in MG and, with time, may lead to protein accumulation in renal glomeruli and to progressive loss of kidney function and damage of structures as the course of MG progresses. PE urine composition as well as ECM protein and cytokine urine excretion may allow noninvasive glomerulopathy course monitoring in humans in the future.

[The effect of hypolipidemia treatment on the function of kidney transplanted from cadavers]. / Wplyw leczenia hipolipemicznego na czynnosc nerki przeszczepionej ze zwlok.

The high prevalence of hypercholesterolemia (HCh) in kidney transplant recipients probably contributes to the high cardiovascular mortality of these patients. Additionally, HCh is a contributing factor to the progression of renal failure. We conducted a prospective, randomised study with low dose Lovastatin in 42 kidney transplant recipients during 32 weeks, focusing on side effect and kidney function 42 consecutive patients with kidney transplanted in our Institute, with stable renal function (creatinine level < 160 mmol/l) treated with ciclosporine, azathioprine, prednisone were enrolled for the study (regardless of the initial cholesterol level). Every second patient was given Lovastatin 20 mg/night. In the Lovastatin group total cholesterol (TC) and LDL concentration were significantly lower after 6 months of treatment (TC was reduced from 242.5 +/- 12.8 to 220 +/- 15.4 mg/dl, p < 0.05) in Lovastatin group whereas in control group it increased nonsignificantly. Similarly LDL in Lovastatin group decreased from 140.0 +/- 7.0 to 121.3 +/- 10.8 mg/dl, p < 0.02 whereas in control group it increased from 143.6 +/- 5.4 to 169.9 +/- 10.3 mg/dl, p < 0.01. HDL and trigliceride concentrations were unchanged. The Lovastatin treatment did not results in more adverse events than the placebo treatment. Notably, the tendency to increase creatinine level in Lovastatin group was observed from 1.59 +/- 0.17 to 1.74 +/- 0.22 in Lovastatin group versus 1.89 +/- 0.22 to 2.21 +/- 0.35 mg/dl (NS). Low dose Lovastatin treatment seems to be safe and efficient cholesterol-lowering procedure. However we did not observe beneficial effect on kidney graft function.

[The role of proteolytic enzymes in the pathogenesis of primary glomerulonephritis]. / Rola enzymów proteolitycznych w patogenezie pierwotnych klebuszkowych zapalen nerek.

There are many evidences that nonimmunologic factors contribute to pathogenesis of primary glomerulonephritides. Proteolytic enzymes plays important role in glomerular protein turn-over and their altered activities may have influence on glomerular function. The purpose of this paper was to review the role of proteolytic enzymes in initiation and progression of idiopathic glomerular diseases.

[Urinary excretion of extracellular matrix proteins in insulin dependent diabetes mellitus]. / Wydalanie z moczem bialek macierzy zewnatrzkomórkowej w cukrzycy insulinozaleznej.

The purpose of the study was to assess urinary excretion of extracellular matrix proteins and proteolytic enzymes in 12 subjects with IDDM with albuminuria, 12 subjects with IDDM without microalbuminuria and 10 normal healthy subjects. Urinary excretion of FN was significantly higher in subjects with IDDM and albuminuria as compared to patients with IDDM without microalbuminuria and healthy subjects (223.6 +/- 143.2 vs. 103.2 +/- 59.7 vs. 58.3 +/- 12.0 ng/mg creatinine, p < 0.01). Urinary level of type IV collagen was significantly elevated in subjects with IDDM and albuminuria as compared to IDDM without microalbuminuria and healthy subjects of cathepsin B was significantly higher in diabetic patients with albuminuria as compared to patients without microalbuminuria and healthy subjects (0.82 +/- 0.53 vs. 0.25 +/- 0.17 vs. 0.22 +/- 0.05 mlU/mg creatinine, p < 0.01). Urinary activity of plasmin was significantly elevated in diabetic patients with albuminuria as compared to subjects without microalbuminuria and healthy control (0.477 +/- 0.37 vs. 0.194 +/- 0.09 vs. 0.21 +/- 0.02 mlU/mg creatinine, p < 0.01). Our data indicate that increase in the urinary excretion of extracellular matrix proteins may be the useful tool for monitoring glomerular injury.

[Activity of cathepsin B and collagenase in urine and excretion of fibronectin and TGF-beta 1 in urine of patients with membranous glomerulonephritis]. / Aktywnosc katepsyny B i kolagenazy w moczu oraz wydalanie fibronektyny i TGF-beta 1 z moczem u chorych z bloniastym klebuszkowym zapaleniem nerek.

In 30% cases nephrotic syndrome is due to membranous glomerulonephritis (MG). Fifty percent of patients reveal end stage renal disease in 15 years follow-up. The another 50% gain persistent remission. The pathogenesis of disease is not known. Protein accumulation in glomeruli leads to progressive loss of kidney structure and function in MG. Also the role of tissue proteolytic systems and growth factors in this process is not known. We aimed to estimate urine cathepsin B, collagenase activity and urine excretion of TGF-beta 1 and fibronectin in MG. MG patients revealed increased urine cathepsin B activity (10.58 +/- 8.73 pmol AMC/mg creatinine/min. vs. control 7.11 +/- 2.05 pmol AMC/mg creatinine/min. [p < 0.05]), urine collagenase activity (8.59 +/- 4.26 pmol AMC/mg creatinine/min. vs. control 3.84 +/- 2.09 pmol AMC/mg creatinine/min. [p > 0.02]) and increased urine excretion of fibronectin (214 +/- 335 ng/mg creatinine vs. control 12.7 +/- 6.7 ng/mg creatinine [p < 0.05]) and increased urine excretion of TGF-beta 1 (283.55 +/- 248.13 pg/ml vs. control 36.11 +/- 48.01 pg/ml [p < 0.05]). The results indicates on glomerular overproduction of TGF-beta 1 and urinary leak of proteolytic enzymes which may exacerbate glomerular proteolytic activity in MG. This may lead to glomerular protein accumulation and progressive loss of kidney function and structure in MG. Increased urine fibronectin excretion in MG patients seems to confirm the hypothesis.