Dialysis‐related Amyloidosis: Is It Gone or Should It Be?

The prevalence and severity of dialysis‐related amyloidosis (DRA) appear to have decreased significantly over the last two decades, although recent, large‐scale epidemiological studies show that DRA continues to occur. Recent experimental findings have documented a direct cellular toxicity of β2microglobulin (β2m) fibrils but the mechanisms of β2m fibrillogenesis remain incompletely understood. Although a high plasma concentration of β2m is still considered as a prerequisite for developing DRA, other factors have been clearly incriminated such as older age at dialysis onset and longer dialysis vintage, or suspected effects such as proinflammatory effects of bioincompatible dialysis techniques. Improved dialysis technology has definitely played a role in delaying the onset of the disease, although the respective contributions of high‐flux biocompatible membranes, use of convective mode, and ultrapure dialysate remain imperfectly defined. Importantly, DRA still does exist and no current dialytic modality seems able to fully prevent it. Awaiting further progress in the understanding of DRA pathogenesis, the use of biocompatible high‐flux membranes and ultrapure dialysate is strongly recommended in order to minimize or delay its onset. Convective regimens may provide an additional benefit.     

Nontransplant therapy for dialysis-related amyloidosis

There is no specific treatment for dialysis-related amyloidosis (DRA). Available therapy is directed at removal of large quantities of beta(2)-microglobulin (beta(2)M) and palliation of symptoms. Plasma concentrations of beta(2)M in end-stage renal disease (ESRD) depend on the degree of residual renal function, the type of blood purification therapy, and properties of the dialysis filtration membrane. Retention of beta(2)M appears to be a necessary, although not sufficient, condition for DRA. While preserving residual renal function is important, dialysis modality largely determines beta(2)M removal. Convective dialysis treatments (hemofiltration and hemodiafiltration) remove beta(2)M more efficiently than diffusive treatments (conventional dialysis). In addition, column adsorption of beta(2)M can extensively remove the molecule, as can nocturnal hemodialysis. Hemodialysis membrane properties that are particularly important with regard to beta(2)M removal include permeability, adsorptive capacity, and biocompatibility. As such, beta(2)M removal with highly permeable biocompatible membranes such as polysulfone and polyacrylonitrile is relatively large. Several studies have suggested that use of such membranes can significantly delay DRA development and may be useful in ameliorating DRA-associated symptoms. Non-dialysis-related therapy for DRA is palliative and includes both medical and surgical therapies. Medical therapy includes low-dose corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs). Surgical therapy consists of relief of carpal tunnel syndrome, or palliation of shoulder pain, destroyed weight-bearing joints, or spinal cord compression. DRA is a serious complication of long-term dialysis. It is important for nephrologists to recognize the condition and attempt to slow its progression.     

The beta-2 microglobulin urine-to-serum ratio: an early marker of renal dysfunction in primary hyperparathyroidism

Human beta-2 microglobulin (beta-2 M) is released into body fluids as a result of cell turnover, excreted by the kidney, and catabolized in the proximal tubule. Urinary excretion rates constitute a sensitive index of renal tubular function. The beta-2 M urine-to-serum ratio was measured in 25 patients with primary hyperparathyroidism (15 preoperative and 10 treated conservatively) in addition to 20 age- and sex-matched control subjects. The ratio was found to be significantly higher in both the operative and the conservatively managed groups compared to controls (p less than 0.05, Mann-Whitney U test). After surgical excision of a single parathyroid adenoma in the 15 operative cases, the beta-2 M urine-to-serum ratio fell to normal limits. These preliminary findings indicate that the urine-to-serum beta-2 M ratio may be of value in detecting change in renal function in asymptomatic patients with hyperparathyroidism. Further studies are indicated to establish whether these subtle changes are associated with long-term morbidity.     

In vitro removal of beta-2-microglobulin from uremic blood with an immunoadsorption wall

Dialysis-related amyloidosis (DRA), caused by the accumulation of beta-2-microglobulin (β-2M), remains a major concern in long-term renal replacement therapies. For years, we have developed an immunoadsorption wall (iWall) for the removal of β-2M. In this study, we employed a new approach taking advantage of the melting of a buffer ice rod to improve the conditions associated with the manufacturing of an iWall and tested its performance with uremic serum and blood. The preliminary results reveal that the present iWalls thus prepared not only possess the superior properties of affinity and specificity but also show structural stability and acceptable hemocompatibility. We believe that this breakthrough might provide a promising path to successful treatment of DRA as well as establish a useful platform for studying removal of certain pathological toxins accumulated in the blood.     

The renal handling of amylase in normal man.

The renal glomerular and tubular transport rate of amylase was studied by measuring the urinary excretion of this protein before and during inhibition of tubular protein reabsorption by lysine. The excretion of amylase was compared with the excretion of albumin, beta-2 microglobulin and free light chains of immunoglobulins. This investigation showed that amylase is reabsorbed by the tubular cells, but only to a very modest degree compared with the reabsorption of the other three proteins. In the case of amylase only about 45% of the filtered molecules are reabsorbed, whereas more than 90% of the filtered amount of the other molecules is reabsorbed by the tubular cells. The excretion of amylase rose after lysine injection only by a factor 1.8, whereas excretion rose by a factor 28 for albumin, 1,500 for beta-2 microglobulin, 16 for kappa chains and 8 for lambda chains. Minimal values for tubular reabsorption were found to be 5.5 +/- (SD) 4.3 U/min for amylase, 174.0 +/- 35.7 micrograms/min for albumin, 90.5 +/- 14.4 micrograms/min for beta-2-microglobulin, 70.4 +/- 17.4 micrograms/min for kappa chains and 24.2 +/- 9.2 micrograms/min for lambda chains.     

Dialysis-related amyloidosis: Pathogenetic aspects and therapeutic considerations

Summary: Beyond renal transplantation and the provision of symptomatic relief, approaches to treat dialysis-related amyloidosis (DRA), an important long-term complication in patients on regular dialysis, must be based on the knowledge of the underlying pathogenetic process. Retention of beta₂-microglobulin (β₂m) is the prerequisite; biochemical alterations of β₃₂m increasing its amyloidogenicity, and local predisposing tissue factors together with age appear to be relevant. A growing body of evidence points toward the importance of pro-inflammatory effects of dialysis (blood-membrane interactions, pyrogen-related priming of cytokine producing mononuclear cells) in the development of DRA. Advanced glycation endproduct formation (AGE-β₂m) may represent a central element in the pathogenesis of DRA. For non-transplant therapy of DRA, the main goals must be the optimization of β₂m removal (high-flux haemodialysis, haemofiltration, especially pre-dilution haemofiltration) and reduction of pro-inflammatory effects of dialysis (use of non-complement activating biocompatible membranes, pyrogen free dialysate). At least patients at high risk for DRA should be treated according to these guidelines.     

14例亲属活体供肾动脉变异的血管重建

目的 探讨亲属活体供肾动脉变异的血管重建方法.方法 在104例亲属活体供肾移植中,有14例供肾动脉变异.供肾动脉变异的分类和血管重建方法分别为:(1)单支动脉较早分支型2例,取肾时分支受损,分别用受者髂内动脉及其分支、腹壁下动脉离体重建受损动脉.(2)双支动脉型10例,4例用受者髂内动脉及其分支离体重建血管,3例用受者腹壁下动脉与较细分支于体内吻合,1例较短肾动脉与较长肾动脉端侧吻合,1例较细副.肾动脉与主肾动脉端侧吻合,1例双支分别与髂外动脉端侧吻合.(3)3支动脉型2例,1例用受者髂内动脉及分支离体重建血管,1例结扎细小分支后,将较细的副肾动脉与主肾动脉端侧吻合.14例血管重建后,分别将供肾动脉较粗支和/或髂内动脉主干端与受者髂外动脉端侧吻合.结果 术后各支动脉血流通畅,移植.肾血液供应丰富、均匀.12例肾功能早期恢复正常,其中1例术后第14天发生急性排斥反应.1例术后即发生急性排斥反应;1例血肌酐下降缓慢.随访至2008年7月,除1例动脉粥样硬化较重的受者(三支动脉)下极动脉栓塞,血肌酐升高并稳定在170μmol/L外,其余患者动脉血流通畅,血液供应丰富、均匀.结论 供肾动脉变异时,利用所得供肾动脉的自身条件重建血管,或用受者髂内动脉及分支或腹壁下动脉重建血管,可获得较好的移植肾功能.受者动脉粥样硬化较重,同时有较细肾动脉支做重建吻合时,应注意该支动脉发生栓塞的可能.     

Alterations in the biochemical markers of renal function after sevoflurane anaesthesia

AIM: This study has been carried out to see whether renal function is acutely altered in patients undergoing sevoflurane anaesthesia. For this purpose, the urinary levels of markers of renal tubular function, namely leucine amino peptidase (LAP), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH) and beta-2 microglobulin (beta-2M), and urinary albumin as a predictor of renal glomerular function were measured before and after sevoflurane anaesthesia. METHODS: This study was comprised of 20 patients (11 males and nine females) aged 18-55, who underwent various elective surgical procedures under general anaesthesia. Urine samples of all patients were collected before and 1, 2 and 8 h after the anaesthesia. The levels of LAP, GGT, beta-2M, and albumin were then expressed as factored by urinary creatinine. In all patients, the anaesthesia was maintained with sevoflurane (2% end-tidal) at a high flow-rate (6 L/min). RESULTS: Urinary beta-2M and LAP levels after anaesthesia were unchanged (P > 0.05). While urinary GGT and ALP levels were found elevated in the first hour, LDH levels were higher in the second hour (P < 0.05). They returned to normal levels in the later periods after the anaesthesia. Urinary albumin excretion (UAE) was significantly elevated in the second hour after the anaesthesia (P < 0.001). Although UAE was decreased in the eighth hour after the anaesthesia, it still remained higher than the pre-anaesthesia level (P < 0.001). CONCLUSIONS: These results suggest that a 2% end-tidal concentration of sevoflurane at a high flow-rate (6 L/min) acutely alters renal glomerular function but does not have a significant acute effect on biochemical markers of renal tubular damage.     

Hemodialysis-associated amyloidosis of bone of beta-2 microglobulin origin

Summary A case of hemodialysis-associated amyloidosis in a patient who had been on hemodialysis for 10 years is described. Bone lesions were found in the humeral heads, carpal bones, and femoral heads and necks. Specimens obtained from the pathologically fractured left femoral neck revealed amyloid deposits histologically. Immunoperoxidase staining for beta-2 microglobulin was positive in the amyloid at the light-microscopic level. We reconfirmed that bone lesions associated with long-term hemodialysis are manifestations of amyloidosis of beta-2 microglobulin origin. Hemodialysis-associated amyloidosis should be considered in the treatment of long-term hemodialysis patients.     

Ontogeny of renal beta adrenoceptors in the sheep

The renal vasodilatory response to beta-2 adrenoceptor stimulation is greater in fetal than adult sheep. Since this phenomenon could not be explained by differences in cAMP-mediated events, we examined the ontogeny of renal beta adrenoceptor subtypes by radioligand binding using the beta adrenergic antagonist¹²⁵I-pindolol. The specific binding of¹²⁵I-pindolol was saturable, reversible, and stereoselective. Competition studies using the selective beta-1 and beta-2 adrenergic antagonists (ICI 89406 and ICI 118551, respectively) revealed two beta adrenoceptor subtypes in adult kidneys but only the beta-2 subtype in fetal kidneys. Preincubation of renal cortical membranes with either the beta-1 or the beta-2 adrenergic antagonist prior to competition studies in adult kidneys decreased specific binding and resulted in the detection of only one beta adrenoceptor subtype. Preincubation of fetal kidneys with the beta-1 adrenergic antagonist did not affect binding characteristics; preincubation of fetal kidneys with the beta-2 adrenergic antagonist markedly decreased specific binding from 64±2% (n=4) to 29±2% (n=3) (P<0.05). Analysis of Rosenthal plots revealed similar beta adrenoceptor densities and affinities between fetal and adult kidneys. Since the beta-2 adrenoceptor subtype is mainly found in the fetal kidney, while both adrenoceptor subtypes are found in adult kidneys, the density of renal beta-2 adrenoceptors is greater in fetal than adult kidneys. It is possible that the greater renal vasodilatory effect of beta-2 adrenergic agonist in fetal kidneys is due to increased density of beta-2 adrenoceptors.     

Complications of axial arthropathies

Involvement of the cervical spine by rheumatoid arthritis may have severe consequences secondary to subluxation, erosive changes, and soft-tissue inflammation. Unfortunately, the severity of radiographic findings may not directly correlate with the occurrence of cervical myelopathy. MRI has emerged as a noninvasive method of assessing the condition of the spinal cord and thecal sac as well as more precisely defining the nature of inflammatory soft-tissue changes that may result in bony erosion and cord compression. Ankylosing spondylitis is an arthropathy that classically involves the axial skeleton. Complications include acute fracture and pseudarthroses of the spine. Rarely, the development of a cauda equina syndrome has been reported. In addition to classic erosive arthropathies affecting the axial skeleton, ossification of the posterior longitudinal ligament may be associated with the development of severe myelopathy. A recently described type of amyloidosis characterized by beta-2 microglobulin deposition has been reported in patients on long-term hemodialysis. Bony erosion is seen in the spine in these patients. A causal relationship between beta-2 microglobulin and hemodialysis spondylarthropathy has yet to be definitely established.     

Beta-2 microglobulin amyloidosis presenting as bilateral ovarian masses: a case report and review of the literature.

We report a case of systemic beta-2 microglobulin amyloidosis (B2M) in which the initial clinical presentation was that of bilateral ovarian masses. A 56-year-old woman who had been on renal dialysis for 12 years because of familial glomerulonephritis underwent a total hysterectomy and bilateral salpingo-oophorectomy for suspected ovarian malignancy. Pathologic findings included extensive amyloid infiltration of both ovaries, fallopian tubes, and focal perivascular deposition in the myometrium. The diagnosis of amyloidosis was confirmed with Congo red stain, B2M immunohistochemistry, and electron microscopy. Systemic amyloidosis in renal dialysis patients commonly presents as bone and/or joint disease, although visceral involvement has been reported. This is the first report in the English language literature to describe amyloidosis presenting as bilateral ovarian masses.     

Renal tubular function in children with beta-thalassemia minor

Background: beta-thalassemia minor is a common heterozygous haemoglobinopathy that is characterized by both microcytosis and hypochromia. It requires no treatment. It has been postulated that low-grade haemolysis, tubular iron deposition and toxins derived from erythrocytes might cause renal tubular damage in adult patients with beta-thalassemia minor. Our aim was to investigate the renal tubular functions in children with beta-thalassemia minor and to determine its possible harmful effects. Methods: The study was conducted on 32 children (14 female and 18 male) at the age of 5.8 +/- 3.1 years (range 2-14 years) with beta-thalassemia minor. The patients were classified as anaemic (haemoglobin (Hb) 11 g/dL) (Group 2, n = 18). A control group was formed with 18 healthy children whose ages and sexes match those in other groups (Group 3, n = 18). Fractional excretion of sodium (FE(Na), %), fractional excretion of magnesium (FE(Mg), %), fractional excretion of uric acid (FE(UA), %) and tubular phosphorus reabsorption (TPR,%) were calculated with standard formulas. Urinary calcium excretion (mg/kg per 24 h), zinc (Zn) (microg/dL), glucosuria (mg/dL), beta-2 microglobulin (mg/dL) and N-acetyl-beta-D-glycosaminidase (NAG, U/mmol creatinine) levels were measured through biochemical methods. Results: There was no statistically significant difference among the three groups in terms of the results of FE(Na) (%), FE(Mg) (%), FE(UA) (%), TPR (%), calciuria (mg/kg per 24 h), NAG, urine Zn, proteinuria, glucosuria or urine beta- 2 microglobulin levels (P > 0.05). Conclusion: On the contrary of children with beta-thalassemia major, renal tubular dysfunction has not been determined in children with beta-thalassemia minor in the present study.     

Renal function in children with β-thalassemia major and thalassemia intermedia

In beta-thalassemia, profound anemia and severe hemosiderosis cause functional and physiological abnormalities in various organ systems. In recent years, there have been few published studies demonstrating proteinuria, aminoaciduria, low urine osmolality, and excess secretion of the tubular damage markers, such as urinary N-acetyl-D-glucosaminidase (U(NAG)) and beta2 microglobulin, in patients with thalassemia. The object of this study was to analyze renal tubular and glomerular function in pediatric patients with beta-thalassemia and to correlate the renal findings to iron overload. Thirty-seven patients with beta-thalassemia major and 11 with thalassemia intermedia were studied. Twelve children without iron metabolism disorders or renal diseases served as a control group. No difference in blood urea nitrogen (BUN), serum creatinine, creatinine clearance, electrolytes, fractional excretion of sodium and potassium, and tubular phosphorus reabsorption was found. Serum uric acid was equal in the two groups, but its urine excretion was significantly higher in the thalassemic group. U(NAG) and U(NAG) to creatinine ratio (U(NAG/CR)) were elevated in all patients with thalassemia compared with the control group (p < 0.001) and were directly correlated to the amount of transfused iron but not to actual ferritin level. We found that renal tubular function is impaired in children with beta- thalassemia major and intermedia. It is not known whether these functional abnormalities would have any long-term effects on the patients. Further studies are needed, and means of preventing these disturbances should be sought.     

Renal protein metabolism in obstructive uropathy.

Measurements of serum beta 2 microglobulin and creatinine concentrations were determined in 18 patients with lower urinary tract obstruction. Nine patients were azotemic on admission to the hospital. In 3 of these patients who had normal pre-treatment serum levels of beta 2 microglobulin, the correction of obstruction was followed by return of normal renal function. The remaining 6 patients with elevated serum beta 2 microglobulin concentrations on hospitalization, showed no significant improvement in renal function parameters in the post-obstructive period. These data suggest that determination of serum beta 2 microglobulin concentrations is helpful in predicting the return of renal function in azotemic patients with obstructive uropathy.     

The elephant in uremia: oxidant stress as a unifying concept of cardiovascular disease in uremia

Cardiovascular disease is the leading cause of mortality in uremic patients. In large cross-sectional studies of dialysis patients, traditional cardiovascular risk factors such as hypertension and hypercholesterolemia have been found to have low predictive power, while markers of inflammation and malnutrition are highly correlated with cardiovascular mortality. However, the pathophysiology of the disease process that links uremia, inflammation, and malnutrition with increased cardiovascular complications is not well understood. We hereby propose the hypothesis that increased oxidative stress and its sequalae is a major contributor to increased atherosclerosis and cardiovascular morbidity and mortality found in uremia. This hypothesis is based on studies that conclusively demonstrate an increased oxidative burden in uremic patients, before and particularly after renal replacement therapies, as evidenced by higher concentrations of multiple biomarkers of oxidative stress. This hypothesis also provides a framework to explain the link that activated phagocytes provide between oxidative stress and inflammation (from infectious and non-infections causes) and the synergistic role that malnutrition (as reflected by low concentrations of albumin and/or antioxidants) contributes to the increased burden of cardiovascular disease in uremia. We further propose that retained uremic solutes such as beta-2 microglobulin, advanced glycosylated end products (AGE), cysteine, and homocysteine, which are substrates for oxidative injury, further contribute to the pro-atherogenic milieu of uremia. Dialytic therapy, which acts to reduce the concentration of oxidized substrates, improves the redox balance. However, processes related to dialytic therapy, such as the prolonged use of catheters for vascular access and the use of bioincompatible dialysis membranes, can contribute to a pro-inflammatory and pro-oxidative state and thus to a pro-atherogenic state. Anti-oxidative therapeutic strategies for patients with uremia are in their very early stages; nonetheless, early studies demonstrate the potential for significant efficacy in reducing cardiovascular complications.     

Increased levels of serum matrix metalloproteinase-3 in haemodialysis patients with dialysis-related amyloidosis

Background: It is recognized that matrix metalloproteinase‐3 (MMP‐3) is abundantly expressed in active rheumatoid synovium, and that serum level of MMP‐3 is a useful marker for diagnosis of rheumatoid arthritis and for evaluation of prognosis in joint destruction. Little is known about serum MMP‐3 levels in haemodialysis (HD) patients, and thus, the association between serum MMP‐3 and dialysis‐related amyloidosis (DRA) has yet to be elucidated. Methods: Serum levels of MMP‐3 were measured by enzyme immunoassay in 150 HD patients, 90 without DRA and 60 with DRA, before HD. Simple regression analysis was performed to investigate the relationship between serum level of MMP‐3 and clinical parameters, including age, HD duration, C‐reactive protein and β2 microglobulin (BMG). Results: Serum levels of MMP‐3 were significantly higher in HD patients with DRA than in HD patients without DRA (258.2 ± 118.1 vs 201.5 ± 98.4 pg/mL, P = 0.0017), and both levels were significantly higher than those of healthy subjects (45.6 ± 13.4 pg/mL, P < 0.0001). Serum MMP‐3 levels significantly correlated with serum levels of BMG (r = 0.197, P = 0.0164) and HD duration (r = 0.168, P = 0.0427). Moreover, serum MMP‐3 levels significantly correlated with serum BMG levels in HD patients without DRA (r = 0.341, P = 0.0012), but not in HD patients with DRA. Conclusion: Our results suggest that matrix metalloproteinase activity increases in HD patients, which may be associated with BMG and DRA.     

Dialysis-related amyloidosis: history and clinical manifestations

Dialysis-related amyloidosis (DRA) or beta(2)-microglobulin amyloidosis (A beta(2)M) is a unique type of amyloidosis that has been described in individuals with both long-standing chronic renal disease and end-stage renal disease (ESRD). It has been associated with serious complications that significantly add to the morbidity of long-term dialysis patients. The deposition of beta(2)M in amyloid fibrils in various joint and osteoarticular surfaces leads to the clinical complaints and findings typical of this disorder. However, a visceral form with systemic organ involvement has also been described. Despite advances in the understanding of this disorder and in the delivery of dialysis, the ability to alter the incidence of DRA and its course remains uncertain.     

Serum levels of alpha-1 microglobulin and beta-2 microglobulin in bone marrow transplant recipients treated with cyclosporin A

Abstract. The levels of alpha-1 microglobulin (α₁m) and beta-2 microglobulin (β₂m) in serum were estimated in 77 bone marrow transplant recipients. In comparison to pretransplant levels, the highest levels of α₁m and β₂m were found during impairment of renal function, i. e., during cyclosporin-induced nephrotoxicity and during treatment with other nephrotoxic drugs ( P < 0.001). The α₁m levels were less elevated during infections and acute graft-versus-host disease ( P < 0.01), while β₂m levels were markedly elevated during the same conditions ( P < 0.001). The linear correlations between serum creatinine and α₁m and creatinine and β₂m were r = 0.7 and 0.8, respectively ( P < 0.001). The overall correlation between α₁m and β₂m was 0.4 ( P < 0.001). It is concluded that α₁m might be a complement to serum creatinine levels in monitoring renal function after bone marrow transplantation.