Thiazolidinediones provide better renoprotection than insulin in an obese, hypertensive type II diabetic rat model.

Hyperinsulinemia has been implicated in the development of diabetic nephropathy. In the present study we compared the renoprotective effects of the thiazolidinedione, pioglitazone (PGZ), to that of insulin in a hypertensive, obese, type II diabetic rat model. PGZ aggravated obesity and gave less glycemic control than insulin. However, renoprotection was markedly better with PZG compared to insulin as shown by lower proteinuria, improved renal function, and less histological evidence of diabetic glomerular and tubulointerstitial lesions. PZG and insulin both reduced renal accumulation of pentosidine and oxidative stress to a similar extent. In contrast, PGZ but not insulin suppressed enhanced transforming growth factor-beta (TGF-beta) expression. We further confirmed in cultured rat proximal tubular cells that insulin enhanced TGF-beta mRNA expression and protein production. Our results identify hyperinsulinemia and the attendant increase of TGF-beta expression as potential therapeutic targets in diabetes independent of glycemic control. This confirms prior clinical evidence that PZG provides renoprotection in obese, diabetic patients with nephropathy.

Advanced glycation in uraemic toxicity.

The Maillard reaction involves the non enzymatic combination of carbohydrates such as glucose with protein aminogroups to yield schiff bases and Amadori protein adducts evolving into irreversible advanced glycation end products (AGEs). This phenomenon, part of normal ageing, is accelerated in diabetes, as a result of hyperglycaemia, and in renal failure, as a consequence of the accumulation of reactive carbonyl compounds (RCOs). AGEs and RCOs are implicated in uraemic toxicity both at the biochemical and the clinical level (dialysis amyloidosis, atherosclerosis, alterations of peritoneal membrane permeability). Reduction of plasma AGEs and RCOs is an interesting avenue to reduce uraemic toxicity. Therapeutic strategies involve dialysis technique (haemodialysis membranes, daily haemodialysis, ultrapure dialysate, RCO free peritoneal dialysate) as well as drugs inhibiting AGE formation (aminoguanidine and the less toxic angiotensin converting enzyme inhibitors or angiotensin receptor blockers).

Glyoxalase I deficiency is associated with an unusual level of advanced glycation end products in a hemodialysis patient.

BACKGROUND: Advanced glycation of proteins and their attendant advanced glycation end products (AGEs) contribute to the complications associated with diabetes mellitus or uremia. Regulatory mechanisms of AGE formation in vivo remain an issue of particular interest. We investigated a role of the glyoxalase detoxification system of precursor reactive carbonyl compounds (RCOs) in the in vivo AGE formation. METHODS: Plasma levels of AGEs [pentosidine and Nepsilon-carboxymethyllysine (CML)], their RCO precursors, d-lactate (the final product resulting from the glyoxalase detoxification pathway), as well as of various compounds known to generate AGE precursors and surrogate markers for oxidative stress (antioxidant enzymes and glutathione), were measured in both hemodialysis (HD) patients and normal subjects. The activity and protein expression of glyoxalase I, an enzyme essential for the detoxification of alpha-oxoaldehydes, in red blood cells (RBC) were also examined. RESULTS: In one 69-year-old lady who had been on hemodialysis (HD) for three years and had suffered from recurrent cardiovascular complications despite the absence of significant risk factors, plasma levels of pentosidine (77.3 +/- 2.4 pmol/mg protein) and CML (330.8 +/- 8.2 pmol/mg protein) were markedly elevated as compared to other HD patients (N = 20: 26.6 +/- 11.8 pmol/mg protein for pentosidine and 224.4 +/- 51.7 pmol/mg protein for CML). The plasma level of RCO precursors for pentosidine and CML was also higher in this patient than in other HD patients. Further investigation disclosed a very low activity in RBC of glyoxalase I (1.5 +/- 0.4 mU/106 RBC), as compared to other HD patients (3.9 +/- 0.6 mU/106 RBC) or normal subjects (4.0 +/- 0.6 mU/106 RBC). The glyoxalase I protein level, assessed in RBC by immunoblot analysis with a specific antibody, was markedly lower than that observed in HD patients and normal subjects. The causes of this deficiency remain unknown. Nucleotide sequencing of the products of reverse transcription-polymerase chain reaction from the patient's mononuclear cells revealed no genetic mutation within the coding region of the glyoxalase I gene. Plasma d-lactate level was also in the lower range (0.18 +/- 0.03 mg/dL) of the values measured in the other HD patients (0.27 +/- 0.09 mg/dL) and normal subjects (0.35 +/- 0.12 mg/dL). The plasma levels of various compounds known to generate AGE precursors (glucose, lipids and ascorbic acid) were either normal or low. The surrogate markers for oxidative stress such as antioxidant enzymes (glutathione peroxidases and superoxide dismutase) and glutathione were all within the range observed in the other HD patients. CONCLUSION: The unusually high levels of AGEs in this patient implicate a deficient glyoxalase detoxification of RCO precursors. The present clinical observation implicates, to our knowledge for the first time, the glyoxalase detoxification system and, in particular, glyoxalase in the actual level of AGEs in a uremic patient.

Aristolochic acid nephropathy in a Chinese patient: time to abandon the term "Chinese herbs nephropathy"?

The causal role of aristolochic acid (AA) in the so-called Chinese herbs nephropathy (CHN) has been conclusively demonstrated only in the Belgian epidemic. We report a biopsy-proven hypocellular interstitial fibrosing nephropathy in a Chinese patient who had ingested a Chinese herbal preparation bought in Shanghai. The identification of AA in the preparation and of AA-DNA adducts in the kidney tissue unequivocally demonstrates, for the first time, the causal role of AA outside the Belgian epidemic. Because the ingested preparation is very popular in China as an over-the-counter product, our observation raises the possibility that many such cases due to AA might be currently unrecognized in China. AA should be banned from herbal preparations worldwide. All cases of the so-called CHN, in which the causal role of AA has been thoroughly documented, should be further identified as aristolochic acid nephropathy (AAN). The term phytotherapy-associated interstitial nephritis (PAIN) might refer to the other cases associated with phytotherapy without identification, as yet, of the causal agent.

Chronic aristolochic acid toxicity in rabbits: a model of Chinese herbs nephropathy?

BACKGROUND: Chinese herbs nephropathy (CHN) is a new type of subacute interstitial nephritis that is attributed to aristolochic acid (AA), which inadvertently has been included in slimming pills. The contribution of other simultaneously prescribed drugs remains disputed. In the present study, the effects of a chronic intake of AA given as a single drug was evaluated through renal histology and function in rabbits. METHODS: Female New Zealand White rabbits were injected intraperitoneally with either 0.1 mg AA/kg or with saline 5 days a week for 17 to 21 months. Body weight, renal function, and urinary excretion of glucose and low molecular weight proteins were monitored prior to sacrifice at the end of the study period. RESULTS: All animals given AA developed renal hypocellular interstitial fibrosis, which was classified into three patterns. Fibrosis was confined to medullary rays (MRs) in pattern I (N = 3), extended to the outer cortical labyrinth (OCL) in pattern II (N = 2), and eventually to the inner cortical labyrinth (ICL) in pattern III (N = 6). Fibrosis in MR and OCL was associated with mainly proximal tubular epithelial cell flattening. All treated animals displayed urothelial atypia. Three of them also developed tumors of the urinary tract. No significant pathologic changes were found in control rabbits. AA-treated animals differed from controls by an impaired growth, increased serum creatinine, glucosuria, tubular proteinuria, and anemia. CONCLUSION: The observed pattern of renal histopathological lesions and disorders of the renal function, as well as urothelial atypia and malignancy, are very reminiscent of CHN. Our observations therefore support a causal role of AA alone in the genesis of this new nephropathy.

Pathological aspects of beta(2)-microglobulin amyloidosis.

Histology remains the gold standard to diagnose beta(2)-microglobulin amyloidosis (A beta(2)M). Two diagnostic criteria are required: positive Congo red staining with typical birefringence under polarized light and immunostaining of amyloid deposits with a labeled anti-beta(2)M antibody. A beta(2)M is preferentially located in the joints. Small deposits are also found in various organs, mainly the heart and gastrointestinal tract. Pathologic studies have demonstrated a high prevalence of articular A beta(2)M early in the course of hemodialysis and peritoneal dialysis, antedating clinical manifestations by several years. The stages of beta(2)M amyloid formation have been delineated: beta(2)M amyloid deposits first on the surface of the cartilage, in the absence of macrophages (stage 1), and subsequently involves capsules and synovia (stage 2), with eventual recruitment of macrophages around large beta(2)M amyloid deposits (stage 3). Clinical manifestations are likely associated with the inflammation observed in stage 3. The factors triggering the fibrillar precipitation of beta(2)M remain unknown. Macrophages do not play a role: their presence is the consequence rather than the cause of beta(2)M amyloid deposits. Several substances coprecipitated with beta(2)M amyloid have been incriminated: highly sulfated glycosaminoglycans such as chondroitin or keratan sulfate, antiproteases such as alpha(2)-macroglobulin, and apolipoprotein E. As yet, no definitive conclusion has been reached.

Effect of dwell time on carbonyl stress using icodextrin and amino acid peritoneal dialysis fluids.

BACKGROUND: Deterioration of the peritoneal membrane limits the technical survival of peritoneal dialysis (PD). Advanced glycation of the membrane has been incriminated in this evolution. Advanced glycation end products (AGEs) develop under the influence of glucose and of its degradation products, mainly reactive carbonyl compounds (RCOs) such as glyoxal (GO), methylglyoxal (MGO), and 3-deoxyglucosone (3-DG). The present study was undertaken to evaluate the impact of recently developed glucose-free PD fluids on AGE generation. METHODS: Recently developed glucose-free PD fluids containing either icodextrin or amino acids were investigated. GO, MGO, and 3-DG [high-performance liquid chromatography (HPLC)] and total RCOs (spectrophotometry) were measured in fresh solutions and in effluents after various dwell duration. The AGE formation potential of PD fluids and effluents was assessed by incubation at 37 degrees C, for one week, with bovine serum albumin and by the eventual measurement of pentosidine (HPLC) and Nepsilon-carboxymethyllysine (CML; gas chromatography/mass spectrometry). RESULTS: GO, MGO, and 3-DG (P < 0. 001) as well as total RCOs levels (P < 0.01) were significantly lower in icodextrin and amino acid PD fluid than in commercial, heat-sterilized, 1.36% glucose PD fluid. Pentosidine and CML generation were also significantly lower (P < 0.001) in icodextrin and amino acid PD fluid than in conventional 1.36% glucose PD fluid. The levels of total RCOs, however, increased in icodextrin and amino acid PD fluid effluents with dwell time. AGE formation potential rose accordingly, as demonstrated by a parallel increase in the generation of pentosidine and CML during incubation of PD effluents. CONCLUSION: The present data demonstrate lower RCO contents and AGE formation potential in fresh icodextrin and amino acid PD fluids than in fresh heat-sterilized glucose PD fluids. However, this difference decreases progressively during dwell time, mainly as a result of the influx of total RCOs.

Relevance of oxidative and carbonyl stress to long-term uremic complications.

Oxidative stress is a disturbance of balance between oxidants and antioxidant species. The existence of an increased oxidative stress in chronic renal failure is supported by evidence of increased lipid, carbohydrate, and protein oxidation products in plasma and cell membrane. Recent studies have implicated the oxidative stress in the nonenzymatic biochemistry leading to irreversible protein modifications. Reactive oxygen species may directly alter proteins with the eventual formation of oxidized amino acids. Alternatively, reactive carbonyl compounds formed by the oxidation of carbohydrates and lipids may indirectly lead to advanced glycation or lipoxidation of proteins. Chronic uremia is associated with increased modification of protein caused by reactive carbonyl compounds derived from both carbohydrates and lipids. Increased carbonyl modification of proteins subsequently results in the rise of plasma and tissue contents of advanced glycation end products and advanced lipoxidation end products, in which the deleterious biological effects have been revealed. This article focuses on the irreversible nonenzymatic modification of proteins, which might, at least in part, contribute to the development of complications associated with chronic renal failure and long-term dialysis, such as atherosclerosis and dialysis-related amyloidosis.

Advanced glycation and lipidoxidation of the peritoneal membrane: respective roles of serum and peritoneal fluid reactive carbonyl compounds.

BACKGROUND: Advanced glycation of proteins has been incriminated in the progressive alteration of the peritoneal membrane during chronic peritoneal dialysis (PD). Advanced glycation end products (AGEs) result from a modification of proteins by reactive carbonyl compounds (RCOs). RCOs resulting from glucose breakdown are present in commercial PD fluid. They also accumulate in uremic plasma. The present study was undertaken to evaluate the respective contribution of these two sources of RCOs in the genesis of peritoneal AGEs. METHODS: Three major RCOs formed during heat sterilization of PD fluid, that is, glyoxal, methylglyoxal, and 3-deoxyglucosone, and total RCOs were measured in commercial PD fluid and in PD effluent. The generation of pentosidine, used as a surrogate marker for AGEs, during one-week incubations of PD fluid and effluent samples fortified with bovine serum albumin (BSA) was measured by high-performance liquid chromatography. Peritoneal samples were stained with antibodies specific for two AGEs derived from carbohydrate-dependent RCOs, Nepsilon-(carboxymethyl)lysine (CML) and pentosidine, or for two advanced lipoxidation end products (ALEs) derived from lipid-dependent RCOs, malondialdehyde (MDA)-lysine and 4-hydroxynonenal (HNE)-protein adduct. RESULTS: Glyoxal, methylglyoxal, and 3-deoxyglucosone were identified in commercial PD fluid. Their levels in PD effluents decreased with dwell time probably by diffusion into blood circulation. In contrast, the levels of total RCOs were initially low in commercial PD fluid, increased in PD effluent with dwell time probably by diffusion from circulation into the peritoneal cavity, and after 12 hours, reached values observed in uremic serum. The relevance of the rise in total RCOs for AGE formation is demonstrated by a parallel increase in the generation of pentosidine during incubations of PD effluents. In contrast with RCOs present in glucose-rich PD fluid, RCOs diffusing from uremic circulation originate from both carbohydrates and lipids. Their role in the modification of peritoneal proteins is demonstrated by the immunohistochemical study of peritoneal tissue. Two AGEs and two ALEs increase in parallel in the mesothelial layers and in vascular wall of small arteries in the peritoneum. CONCLUSIONS: Protein modification of the peritoneum is determined not only by RCOs originating in PD fluid, but also by RCOs originating from the uremic circulation. The present data might be relevant to current attempts to improve PD fluid toxicity by lowering its glucose content.

[Morphogenesis of beta 2m (A beta 2m) amyloid deposits in dialysis patients]. / Morphogenèse des dépôts d'amyloïde à beta 2m (A beta 2m) chez le patient en dialyse.

beta 2m related amyloidosis (A beta 2m) is a late complication of renal replacement therapy (RRT), first identified in 1980. It is preferentially located in the joints. Its clinical manifestations and risk factors have been clearly delineated. Still, its true prevalence and the factors determining the fibrillar precipitation of beta 2m remain to be defined. A prospective autopsy study of the joints of dialyzed patients, confirms that A beta 2m prevalence increases with dialysis duration and age of the patients at the onset of RRT. Prevalence is not significantly different according to the modality of RRT, hemo--or peritoneal dialysis. Of great interest is the finding that histologic evidence of A beta 2m preceeds by over five years the onset of clinical symptoms. The detailed study of A beta 2m deposits has allowed their classification into 3 successives stages: stage 1, impregnation of the cartilage; stage 2, extension to capsules and synovia; stage 3, invasion of synovial and capsular deposits by macrophages. In the first 2 stages, in the absence of macrophages, there is no immunohistochemical evidence of advanced glycation of the A beta 2m. We conclude that neither macrophages nor the advanced glycation of beta 2m are prerequisities of A beta 2m formation.

Glucose degradation product methylglyoxal enhances the production of vascular endothelial growth factor in peritoneal cells: role in the functional and morphological alterations of peritoneal membranes in peritoneal dialysis.

Peritoneal membrane permeability deteriorates in peritoneal dialysis (PD) patients. We test whether glucose degradation products (GDPs) in PD fluids, glyoxal, methylglyoxal and 3-deoxyglucosone, stimulate the production of vascular endothelial growth factor (VEGF), a factor known to enhance vascular permeability and angiogenesis. VEGF increased in cultured rat mesothelial and human endothelial cells exposed to methylglyoxal, but not to glyoxal or 3-deoxyglucosone. VEGF also increased in peritoneal tissue of rats given intraperitoneally methylglyoxal. VEGF and carboxymethyllysine (CML) (formed from GDPs) co-localized immunohistochemically in mesothelial layer and vascular walls of the peritoneal membrane of patients given chronic PD. By contrast, in the peritoneum of non-uremic subjects, VEGF was identified only in vascular walls, in the absence of CML. VEGF production induced by GDPs may play a role in the progressive deterioration of the peritoneal membrane.

Influence of hemodialysis membrane type on pentosidine plasma level, a marker of "carbonyl stress".

UNLABELLED: Influence of hemodialysis membrane type on pentosidine plasma level, a marker of "carbonyl stress." BACKGROUND: The accumulation of advanced glycation end products (AGEs) in uremia has been ascribed to the retention of carbonyl precursors of AGEs. Pentosidine plasma level has been identified as a surrogate marker of carbonyl precursors ("carbonyl stress"). The influence of hemodialysis (HD) membrane type and residual diuresis on carbonyl stress has not been studied. METHODS: We measured protein-linked and free plasma pentosidine (a surrogate marker of carbonyl stress) by high-performance liquid chromatography in patients on HD with low-flux cellulose (N = 29), high-flux polysulfone (PS; N = 57), polymethylmethacrylate (PMMA) (N = 25), and AN69 (N = 15). RESULTS: Both protein-linked and free pentosidine were similar on low-flux cellulose, high-flux PMMA, and AN69, but were lower (P < 0.01) on high-flux PS. Pentosidine levels were virtually identical on Fresenius and Asahi PS in Japanese and Belgian patients. By multivariate analysis, only the type of HD membrane and residual diuresis proved to be independent determinants (P < 0.001) of pentosidine levels. During a single HD session, the clearance of free pentosidine was similar with all membranes. In three patients who were switched from AN69 to PS, the protein-linked pentosidine level dropped to the control level after resumption of the AN69 membrane. CONCLUSIONS: Both HD membrane type and residual diuresis are independent determinants of pentosidine plasma level, which is a marker of carbonyl stress.

Urothelial lesions in Chinese-herb nephropathy.

Rapidly progressive renal fibrosis after a slimming regimen including Chinese herbs containing aristolochic acid (AA) has been identified as Chinese-herb nephropathy (CHN). We reported urothelial atypia in three patients with CHN, with the subsequent development in one patient of overt transitional cell carcinoma (TCC). Therefore, it was decided to remove the native kidneys, as well as the ureters, in all patients with CHN. Nineteen kidneys and ureters removed during and/or after renal transplantation from 10 patients were studied to assess critically urothelial lesions and to characterize the cellular expression of p53, a tumor-suppressor gene overexpressed in several types of malignancies. Multifocal high-grade flat TCC in situ (carcinoma in situ; CiS) was observed, mainly in the upper urinary tract, in four patients, a prevalence of 40%. In one of those patients, a superficially invasive flat TCC of the right upper ureter, as well as two additional foci of noninvasive papillary TCC, were found in the right pelvis and left lower ureter, respectively. This patient also presented recurrent noninvasive papillary TCC of the bladder. Furthermore, in all cases, multifocal, overall moderate atypia was found in the medullary collecting ducts, pelvis, and ureter. All CiS and papillary TCC, as well as urothelial atypia, overexpressed p53. These results show that the intake of Chinese herbs containing AA has a dramatic carcinogenic effect. Carcinogenesis is associated with the overexpression of p53, which suggests a role for a p53 gene mutation. The relationship of this mutation with the reported presence of AA DNA adducts in the kidney remains to be explored.

Histological characteristics of sternoclavicular beta 2-microglobulin amyloidosis and clues for its histogenesis.

BACKGROUND: The pathogenesis of beta 2-microglobulin amyloidosis (A beta 2m) has yet to be fully elucidated. METHODS: We describe the distribution and extent of A beta 2m deposition and macrophagic infiltration in cartilage, capsule, and synovium of sternoclavicular joints obtained postmortem from 54 patients after 3 to 244 (median 46) months of dialysis. Twenty-four nonuremic patients served as a control group. The diagnosis of amyloidosis (A) rested on a positive Congo Red staining (typical birefringence) and that of A beta 2m on positive immunostaining of the A deposits with a monoclonal anti-beta 2m antibody. The size of A deposits was measured. RESULTS: A beta 2m was detected in 32 (59%), and non-beta 2m amyloid (Anon beta 2m) was detected in an additional 8 (15%) of the 54 dialyzed patients. A beta 2m deposits were present in the cartilage of all A beta 2m (+) patients (100%). They were localized solely in the cartilage in 27% of the cases, either as a thin patchy layer or as a continuous thicker layer (identified as stage I). A beta 2m was additionally present in the capsule and/or synovium without macrophages in 27% of the cases (identified as stage II). The correlation between the size of cartilaginous deposits and dialysis duration (P = 0.02) as well as with the prevalence (P = 0.03) and size of capsular deposits (P = 0.02) suggests that stage II is a later stage of A deposition. Clusters of macrophages were detected around capsular and synovial amyloid deposits in 46% of the cases (identified as stage III). The longer duration of dialysis in those with stage III as well as the relationship between the size of the A beta 2m deposits and the prevalence of macrophagic infiltration suggests that stage III is the last stage of A beta 2m deposition. Marginal bone erosions were observed in 9 out of 12 patients with stage III deposits. Their size was correlated with that of cartilaginous deposits (P = 0.01). Among the 24 control patients, Anon beta 2m was detected in 12 patients (cartilage 100%, capsule 8%, synovium 30%). CONCLUSIONS: The earliest stage of A beta 2m deposition occurs in the cartilage. A beta 2m subsequently extends to capsule and synovium. These two first stages do not require macrophage infiltration. Macrophages are eventually recruited around larger synovial or capsular deposits in the final stage. Marginal bone erosions develop in this late stage.

Should anaemia in subtypes of CRF patients be managed differently?

In patients with cardiovascular disease, partial correction of anaemia with epoetin improves quality of life and exercise capacity, and reduces left ventricular hypertrophy. The currently recommended haemoglobin in these patients is 11-12 g/dl. The optimal haemoglobin in patients with diabetes mellitus does not differ from that in non-diabetic patients; however, haemoglobin should be increased slowly. There is no difference in the recommended haemoglobin between children and adults. However, epoetin sensitivity is lower in children who, therefore, typically need the same absolute dose of epoetin as adults. Epoetin treatment may delay the progression of chronic renal failure (CRF) in paediatric patients. Elderly patients obtain similar benefits from epoetin as younger adults; moreover, there are no differences in the doses of epoetin required or the optimal haemoglobin. There are very few data available on the effects of epoetin in patients with CRF and chronic obstructive pulmonary disease. At present, a haemoglobin of 11 g/dl seems appropriate. In sickle-cell anaemia patients with CRF, a high haemoglobin could precipitate painful crises; consequently, the recommended haemoglobin is the pre-CRF concentration of 6-9 g/dl. There is no convincing evidence of any effect of previous epoetin treatment on the long-term outcome of renal transplantation. In patients with a failing or failed transplant, the required dose of epoetin may be higher than in pre-transplantation patients. In such cases, transplant nephrectomy might be considered.

Alterations in nonenzymatic biochemistry in uremia: origin and significance of "carbonyl stress" in long-term uremic complications.

Advanced glycation end products (AGEs), formed during Maillard or browning reactions by nonenzymatic glycation and oxidation (glycoxidation) of proteins, have been implicated in the pathogenesis of several diseases, including diabetes and uremia. AGEs, such as pentosidine and carboxymethyllysine, are markedly elevated in both plasma proteins and skin collagen of uremic patients, irrespective of the presence of diabetes. The increased chemical modification of proteins is not limited to AGEs, because increased levels of advanced lipoxidation end products (ALEs), such as malondialdehydelysine, are also detected in plasma proteins in uremia. The accumulation of AGEs and ALEs in uremic plasma proteins is not correlated with increased blood glucose or triglycerides, nor is it determined by a decreased removal of chemically modified proteins by glomerular filtration. It more likely results from increased plasma concentrations of small, reactive carbonyl precursors of AGEs and ALEs, such as glyoxal, methylglyoxal, 3-deoxyglucosone, dehydroascorbate, and malondialdehyde. Thus, uremia may be described as a state of carbonyl overload or "carbonyl stress" resulting from either increased oxidation of carbohydrates and lipids (oxidative stress) or inadequate detoxification or inactivation of reactive carbonyl compounds derived from both carbohydrates and lipids by oxidative and nonoxidative chemistry. Carbonyl stress in uremia may contribute to the long-term complications associated with chronic renal failure and dialysis, such as dialysis-related amyloidosis and accelerated atherosclerosis. The increased levels of AGEs and ALEs in uremic blood and tissue proteins suggest a broad derangement in the nonenzymatic biochemistry of both carbohydrates and lipids.