Antiproteinuric efficacy of fosinopril after renal transplantation is determined by the extent of vascular and tubulointerstitial damage.

BACKGROUND: Angiotensin converting enzyme (ACE) inhibitors have been successfully used for treatment of proteinuria after renal transplantation (RTx). Factors possibly responsible for the great inter-patient variance of the antiproteinuric effect (APE) have not yet been investigated in renal-transplanted patients. METHODS: 28 patients after RTx with a persistent proteinuria of more than 1.25 g/d were treated prospectively with does of fosinopril (10-15 mg/d) which were not effective on systemic arterial blood pressure. Prior to initiation of fosinopril, renal graft biopsy was performed in all patients and renal graft artery stenosis was excluded by duplex ultrasound. Serum creatinine and proteinuria were measured prior to, as well as 3 and 8 months after initiation of ACE inhibition, mean arterial pressure was controlled via 24-h measurement and repeated spot measurements. Reduction of proteinuria was correlated with renal histology, serum creatinine, creatinine clearance, mean arterial blood pressure, sodium excretion before therapy and the relative changes of these parameters during therapy respectively. RESULTS: Therapy had to be stopped in 8/28 patients due to side effects including rise of serum creatinine (n = 4). Three patients were excluded due to non-compliance. In the remaining patients (n = 17) proteinuria was reduced from 2.94 +/- 1.66 to 1.82 +/- 1.39 and 2.48 +/- 3.05 g/d after 3 and 8 months respectively, in the mean +/- SD. There was a significant inverse correlation between the APE and the extent of benign nephrosclerosis, interstitial fibrosis and tubular atrophy. No correlation of the APE to any of the other parameters could be demonstrated. CONCLUSIONS: Fosinopril can be administered effectively in a subgroup of proteinuric renal transplant recipients. However, because of a high proportion of patients developing side effects, careful monitoring is obligatory. Our results show that the lesser the degree of chronic morphological injury, the greater is the antiproteinuric effect. Thus, the degree of pre-existing histologically proven damage of the graft may serve as an indicator for the antiproteinuric efficacy of ACE inhibitor therapy after RTx.

Alterations of synovial tissue and their potential role in the deposition of beta2-microglobulin-associated amyloid.

BACKGROUND: Beta-2-microglobulin-associated amyloidosis (AB2M) is a frequent complication of long-term dialysis treatment. Uraemic retention of beta2-microglobulin (beta2M) apparently constitutes the basis for AB2M. However, it is unclear why clinical manifestations are largely confined to osteoarticular tissues. It has been speculated that synovial inflammatory changes, induced by uraemia and/or dialysis therapy could predispose this tissue to amyloid deposition. METHODS: We investigated which local synovial alterations preceded or paralleled amyloid deposition. Using immunohistology we evaluated synovial leukocyte infiltration (B and T lymphocytes, monocytes/macrophages), cell proliferation, fibroblast activation (de novo expression of alpha-smooth-muscle actin), the expression of extracellular matrix components (heparan sulphate proteoglycan, collagen types I, III, IV), and advanced glycation end-products (AGEs). RESULTS: Synovial AB2M was detected in 20 of 36 chronic peritoneal and haemodialysis patients and none of eight non-uraemic controls. Notably, non-AB2M synovial amyloid was present in six additional dialysis and three control patients. Cellular infiltration was largely restricted to patients with advanced AB2M deposits. The infiltrates consisted mainly of macrophages and progressed with increasing degrees of AB2M deposition. In advanced cases they exhibited characteristics of a foreign-body reaction. Other infiltrating leukocyte types, altered cell proliferation, or fibroblast activation were absent or uncommon in periarticular tissue of dialysis patients with and without AB2M. Neither dialysis treatment nor the presence of AB2M deposits appreciably altered the qualitative matrix composition in periarticular tissue. AGEs were present in AB2M deposits, the extracellular synovial matrix of dialysis patients (of both, patients with and without AB2M) and, to a lesser degree, in synovia of controls. CONCLUSIONS: These data suggest that, except for AGE formation, alterations of none of the parameters assessed, and in particular no inflammatory tissue alterations, precede periarticular AB2M. Rather synovial tissue, possibly modified by AGEs, seems to have an intrinsic propensity for amyloid deposition and inflammatory changes appear to only arise secondary to amyloid deposition.

Risk of renal cell carcinoma after kidney transplantation.

Between December 1968 and July 1995, 2372 renal transplant recipients were seen regularly in our outpatient clinic. 154 patients (6.5%) of these subsequently developed a malignant tumor. One of the most frequently observed malignancies was a renal cell carcinoma in the native kidneys, found in 12 patients (7.8%; i.e. 0.5% of the total population), two of them with analgesic nephropathy and one with adult polycystic kidney disease. So-called acquired cystic kidney disease of the native kidneys was found in 73% of the patients with renal cell carcinoma. In the patients with renal cell carcinoma the median age at transplantation was 43.9 (39-55) yr. The median time from onset of end-stage renal failure and from transplantation to the appearance of the tumor amounted to 117.3 (43-206) and 75.8 (5-164) months, respectively. Despite nephrectomy, four patients died of the cancer (6-57 months). As a consequence we suggest a regular sonographic screening of the native kidneys twice a year in all renal transplant patients. As in dialysis patients, the main risk factors for the development of renal cell carcinoma seem to be so-called acquired cystic disease of the native kidneys and the underlying renal disease, such as analgesic nephropathy, and obviously not the immunosuppressive regimen after transplantation.

Clinical experience with a new recombinant hepatitis-B vaccine in previous non-responders with chronic renal insufficiency.

Patients with renal insufficiency have an increased risk of hepatitis B infection and a high probability to develop a chronic course of this disease. After hepatitis B vaccination they are known to show a low rate of seroconversion. In the present study we assessed the efficacy of a new recombinant pre-S1 and pre-S2 containing hepatitis B vaccine in 17 non-responders (anti-HBs titer 0) and 4 low-responders (anti-HBs titer < or = 5 IU/ml) with chronic renal insufficiency (16 on chronic hemodialysis therapy and 5 without hemodialysis treatment). Seroconversion rate was 65% after the third and 71% after the fourth vaccination. Only minor side effects were seen. These results encourage to use the new vaccine in a larger number of patients with renal insufficiency.

Beta-2-microglobulin-associated amyloidosis.

beta2-Microglobulin-associated amyloidosis has emerged as a major complication of long-term renal replacement therapy. The syndrome is confined to those patients on nontransplant modes of therapy. It does not occur in patients with a functioning renal transplant or, if already present, it does not progress any further in such patients. In the population of ESRD patients on dialysis, beta2-microglobulin-associated amyloidosis affects most patients treated for more than 15 years and is a cause of significant morbidity and in rare cases even mortality. The present review, which is based on the presentation of a typical case, discusses the current knowledge on the pathogenesis, clinical manifestations, diagnosis, prevention and therapy of beta2-microglobulin-associated amyloidosis.

Advanced glycation end-products in the peritoneal fluid and in the peritoneal membrane of continuous ambulant peritoneal dialysis patients.

In patients on continuous ambulant peritoneal dialysis (CAPD) treatment, the peritoneal membrane is continuously exposed to the high glucose concentration contained in the dialysate. This may lead to the local generation of advanced glycation end-products (AGEs). To test this hypothesis we evaluated the plasma and dialysate AGE concentrations in five CAPD patients. The dialysate was measured after a 1 h and after a 12 h dwell time. Additionally, in two patients an immunohistochemical investigation of the peritoneal membrane for AGE was performed. For the determination of AGE an ELISA using a polyclonal antibody against AGE bovine serum albumin was used; the immunohistochemical staining was performed using the streptavidin-biotin complex method. We found only low concentrations of AGE in the dialysate after a 1 h dwell time; after 12 h, however, the dialysate AGE was even greater than the plasma concentration. In both peritoneal specimens we found positive staining for AGE in the interstitium of the mesothelial layer. The dialysate AGE contained a high proportion of high-molecular-weight AGE proteins and low-molecular-weight AGE was found to be in the same concentration range as the total serum AGE. We conclude that there is local generation of AGE in the peritoneal membrane and a 'washing out' of AGE from the peritoneal membrane during longer dwell times. We speculate that the accumulation of AGE might lead to some of the functional and morphological alterations observed after long-term CAPD.

Beta 2-microglobulin amyloidosis: why and how to look for it.

Thirty years after the introduction of chronic dialysis into clinical practice, amyloidosis based on the precursor molecule beta 2-microglobulin (beta 2m-A) has emerged as an important complication of end-stage renal disease in patients on renal replacement therapies other than transplantation. For the individual patient, diagnosis of beta 2m-A is important to exclude other treatable causes of the symptoms, initiate symptomatic treatment, prevent possible life-threatening complications, and assign a high priority for transplantation. For the ESRD population as a whole, early specific diagnosis should help to assess the influence of various therapeutic modes on the development and course of beta 2m-A and to guide further the optimization of renal replacement therapy. Besides, sophisticated diagnostic techniques may yield valuable information on underlying pathogenetic mechanisms of beta 2m-A. Morphology, including immunohistochemistry, as the most definitive and specific diagnostic proof must rely on invasive procedures to obtain the appropriate material from clinically affected sites. Clinical assessment and imaging techniques such as x-ray and joint sonography suffer from non-specificity. Scintigraphic imaging of beta 2m-A after injection of radiolabelled beta 2-microglobulin is a non-invasive, specific, and highly sensitive way of diagnosis. Further refinement and more widespread use of this method can be expected to enhance the understanding of beta 2m-A pathogenesis and promote therapeutic and preventive efforts against this complication.

Prevention of glomerular hypertrophy and glomerulosclerosis in Milan normotensive rats by low-protein diet, but not by low-dose captopril treatment.

Milan normotensive rats, which spontaneously develop marked proteinuria (PU) and glomerulosclerosis (GS), were either kept on a normal-protein diet, a normal-protein diet with additional low-dose captopril (CAP), which did not affect blood pressure, or on a low-protein diet. After 8 months PU (79 +/- 25 mg/day) GS (3 +/- 2%) and total glomerular volume (TGV; 27.9 +/- 2.9 mm3/kidney) were significantly lower (p < 0.05) in the low-protein diet group than in both the normal-protein group (PU 583 +/- 210 mg/day, GS 12 +/- 5%, TGV 34.6 +/- 8 mm3/kidney) and the low-CAP group (PU 611 +/- 224 mg/day, GS 16 +/- 6%, TGV 41.8 +/- 8.6 mm3/kidney). In conclusion, the development of glomerular hypertrophy and GS in Milan normotensive rats was reduced by the low-protein diet, but not by low-CAP treatment.

Pathogenetic and diagnostic aspects of dialysis-related amyloidosis.

Dialysis-related amyloidosis (DRA) is a major cause of morbidity in end-stage renal disease patients. While retention of the precursor protein beta 2-microglobulin (beta 2-m) forms the essential basis for DRA, pathogenetic concepts include: qualitative and quantitative alterations in beta 2-m metabolism; local and systemic inflammatory changes, partly related to different treatment modes; general predisposing factors such as age at the onset of dialysis treatment. Clinical and radiological signs, as well as synovial thickening on sonography, suggest the presence of DRA, but histomorphological demonstration of beta 2m-amyloid is required for definitive proof. Scintigraphic imaging of DRA represents an additional, sensitive non-invasive diagnostic tool. Successful kidney transplantation stops the progression of DRA.

Significance of portal venous drainage after whole-organ pancreas transplantation for endocrine graft function and prevention of diabetic nephropathy.

The significance of portal venous drainage after whole-pancreas transplantation both for metabolic control and development of diabetic nephropathy was investigated. Streptozotocin-diabetic inbred LEW rats received a duct-ligated pancreas graft with either systemic or portal venous drainage and were followed for up to one year. Normal and untreated diabetic rats (n=18 in each group) served as controls. Irrespective of the route of venous drainage pancreas transplants normalized the diabetic polyuria, polyphagia, and polydipsia. Growth rates and general health did not differ from normal rats. Pancreas transplantation with portal venous drainage furthermore normalized nonfasting blood glucose and peripheral insulin levels, and intravenous glucose tolerance. Pancreas transplantation with systemic venous drainage, however, was associated with peripheral hyperinsulinemia, slightly elevated nonfasting blood glucose levels, and supranormal K-values in intravenous glucose tolerance tests. Though portal venous drainage was associated with better metabolic control than systemic venous drainage, both techniques of pancreas transplantation proved equally effective to prevent the development of diabetic glomerular membrane thickening determined 6 and 12 months posttransplant.