[(99m)Tc]-sestamibi parathyroid scintigraphy in chronic haemodialysis patients: static and dynamic explorations.

BACKGROUND: The place of parathyroid gland imaging by [(99m)Tc](technetium)-sestamibi scintigraphy in uraemic patients with secondary hyperparathyroidism remains a matter of debate. The purpose of the present study was (i) to assess its value with respect to plasma intact parathyroid hormone (iPTH) levels and to surgical parathyroidectomy (PTx), and (ii) to explore the possibility of suppressing parathyroid [(99m)Tc]-sestamibi uptake by calcitriol. METHODS: In a first cross-sectional, static study 52 chronic haemodialysis (HD) patients with plasma iPTH levels between 14 and 2791 pg/ml (normal, 10-65 pg/ml) had a [(99m)Tc]-sestamibi scan, and 21 of them underwent surgical PTx. In a second longitudinal, dynamic study 14 chronic HD patients with advanced secondary hyperparathyroidism received short-term calcitriol treatment in an attempt to suppress [(99m)Tc]-sestamibi imaging of parathyroid glands. Calcitriol was given intravenously for 2 weeks, 2 microg after each haemodialysis session. Scintigraphy was carried out before and at the end of this inhibition test. RESULTS: [(99m)Tc]-Sestamibi scan led to imaging of one or more (maximum three) parathyroid glands in most, but not all, HD patients with plasma iPTH values >600 pg/ml. Based on surgical findings, overall sensitivity of [(99m)Tc]-sestamibi scan in correctly locating parathyroid glands was only 50%, whereas specificity was 100%. In contrast, its sensitivity was 100% in locating single glands in the subgroup of five patients with recurrent hyperparathyroidism. The calcitriol inhibition test showed suppression of [(99m)Tc]-sestamibi uptake by at least one parathyroid gland in eight patients (57%), with complete suppression in five of them (36%). Basal plasma iPTH or decrease of plasma iPTH in response to calcitriol was not predictive of suppressible [(99m)Tc]-sestamibi uptake in the individual case, although mean iPTH was markedly higher in patients with non-suppressible parathyroid glands. CONCLUSION: Because of its relatively low sensitivity the [(99m)Tc]-sestamibi scan is of limited help in the exploration of uraemic patients with severe secondary hyperparathyroidism before a first surgical PTx. However, it is very useful in locating the remaining parathyroid gland(s) in case of reoperation. The novel calcitriol inhibition test of [(99m)Tc]-sestamibi uptake could help to better distinguish parathyroid glands with non-suppressible, autonomous activity from glands whose activity might be amenable to long-term suppression.

Effective correction of hyperhomocysteinemia in hemodialysis patients by intravenous folinic acid and pyridoxine therapy.

UNLABELLED: Effective correction of hyperhomocysteinemia in hemodialysis patients by intravenous folinic acid and pyridoxine therapy. BACKGROUND: Folic acid supplementation is only partially efficacious in correcting moderate elevation of plasma total homocysteine (tHcy) concentrations observed in hemodialysis (HD) patients. Experimental and clinical data have suggested that this partial efficacy may be due to impairment of folic acid metabolism to 5-methyltetrahydrofolate (MTHF) and of MTHF transmembrane transport as well. To bypass these difficulties, we assessed the efficacy of intravenous (i.v.) folinic acid, a ready precursor of MTHF, on reducing plasma tHcy concentrations in HD patients. METHODS: In a cohort of 37 patients on intermittent HD treatment, plasma tHcy concentrations were determined before and during i.v. supplementation of folinic acid (50 mg once per week), together with i.v. pyridoxine (250 mg 3 times per week), to prevent vitamin deficiency, particularly in those treated by recombinant erythropoietin. RESULTS: Folinic acid and pyridoxine i.v. supplementation was given for 11.2 +/- 2.45 months (range 7.5 to 17 months). The mean plasma tHcy levels decreased significantly from 37. 3 +/- 5.8 microM at baseline to 12.3 +/- 5.4 microM on folinic acid treatment (P < 0.001). Moreover, 29 of the 37 patients (78%) had normal plasma tHcy levels at the end of follow-up (that is, <14.1 microM, mean 9.8 microM, range 6.2 to 13 microM). No adverse effects attributable to folinic acid treatment were observed during this time. CONCLUSIONS: Intravenous folinic acid therapy (50 mg) once per week associated with pyridoxine supplementation appears to be an effective and safe strategy to normalize plasma tHcy levels in the majority of chronic HD patients.

Incidence of atherosclerotic arterial occlusive accidents in predialysis and dialysis patients: a multicentric study in the Ile de France district.

BACKGROUND: An abnormally high mortality from atherosclerotic cardiovascular (CV) accidents has long been reported in patients on maintenance haemodialysis (HD). However, incidence of atherosclerotic CV accidents had not been so far assessed in predialysis patients. In order to evaluate the respective influence of uraemia and the dialysis procedure, we compared incidence of atherosclerotic accidents before and after initiation of HD in a large population of patients. STUDY DESIGN: A total of 748 patients (411 male) were included in a retrospective study based on anamnestic data of patients living on maintenance haemodialysis in March 1993 in nine dialysis units of the Paris area. Incidence of first myocardial infarction (MI) or cerebral infarction (CI) was calculated by reference to the number of years of exposure to the risk both before and after initiation of HD in the various age groups. RESULTS: Overall, 103 first atherosclerotic accidents were recorded, including 10 CI (7 in males) and 93 MI (68 in males). Of the latter, 39 occurred before and 54 after start of HD, at a mean (+/-SD) age of 62.4+/-9.9 and 63.7+/-11.1 years respectively. The annual incidence of MI in males was 8.0, 19.5 and 28.3/1000 patient-years, before and 18.8, 21.6 and 29.9 patient-years after start of HD in the age groups 45-54.9, 55-64.9 and > or = 65 years respectively, compared to figures of 3.4, 7.5 and 10.4/1000 subject-years in the corresponding age groups in the general French population. CONCLUSION: Incidence of atherosclerotic CV accidents is nearly three times higher in uraemic patients than in the general population in the same age range in both genders. The fact that incidence and age at onset of first MI was similar in predialysis and in dialysed patients suggests that the uraemic state per se is a main determinant of such accelerated atherosclerosis.

[Benefits of early nephrological management in chronic renal failure]. / Bénéfices d'une prise en charge néphrologique précoce de l'insuffisance rénale chronique.

OBJECTIVES: We evaluated whether early nephrological referral of patients with chronic renal failure (CRF) resulted in improved condition of patients at initiation of maintenance dialysis and in better outcome on dialysis. PATIENTS AND METHODS: We prospectively recorded clinical status, laboratory parameters, length of hospital stay and outcome of 900 CRF patients who started maintenance dialysis at Necker hospital between January 1989 and December 1996. We compared patients who benefited regular nephrological follow-up, and patients who were referred in emergency conditions at the ultimate stage of CRF. RESULTS: Among the 900 patients, 731 (81.2%) had regular nephrological follow-up, including 632 (70.2%, group IA) with optimal preparation to dialysis and 99 (11%, group IB) whose clinical course was complicated due to heavy comorbidity, whereas 169 (18.8%, group II) had no previous nephrological management. Over the 8-year observation period, the proportion of the latter group did not decrease. Late referred patients had higher blood pressure level, more frequent fluid overload, higher serum levels of urea, creatinine, uric acid and phosphate, and lower levels of bicarbonate, calcium, albumin and creatinine clearance that did well-prepared patients. Mean (+/- SD) hospital stay was 29.7 +/- 15.8 days in the former compared to only 4.8 +/- 3.3 days (p < 0.001) in the latter. Early deaths within 3 months of dialysis initiation were more frequent (7.1 vs 1.6%, p < 0.05) and less patients subsequently were able to be treated out-center (20.1 vs 40.7%, p < 0.05) in group II than in group IA. The overcost induced by late referral may be estimated at 0.25 million French francs per patient. CONCLUSION: An unjustified late nephrological referral of CRF patients still is observed in nearly 20% of cases. Such late referral is detrimental to both patients in terms of altered quality of life and long hospital stay, and to the collectivity due to heavy overcost. Closer cooperation between family physicians and nephrologists is needed to provide optimal management and allow timely preparation to maintenance dialysis of CRF patients.

[Benefits of early nephrological management of chronic renal failure]. / Bénéfices d'une prise en charge néphrologique précoce de l'insuffisance rénale chronique.

OBJECTIVES: We evaluated whether early nephrological referral of patients with chronic renal failure (CRF) resulted in improved condition of patients at initiation of maintenance dialysis and in better outcome on dialysis. PATIENTS AND METHODS: We prospectively recorded clinical status, laboratory parameters, length of hospital stay and outcome of 900 CRF patients who started maintenance dialysis at Necker hospital between January 1989 and December 1996. We compared patients who benefited regular nephrological follow-up, and patients who were referred in emergency conditions at the ultimate stage of CRF. RESULTS: Among the 900 patients, 731 (81.2%) had regular nephrological follow-up, including 632 (70.2%, group IA) with optimal preparation to dialysis and 99 (11%, group IB) whose clinical course was complicated due to heavy comorbidity, whereas 169 (18.8%, group II) had no previous nephrological management. Over the 8-year observation period, the proportion of the latter group did not decrease. Late referred patients had higher blood pressure level, more frequent fluid overload, higher serum levels of urea, creatinine, uric acid and phosphate, and lower levels of bicarbonate, calcium, albumin and creatinine clearance that did well-prepared patients. Mean (+/- SD) hospital stay was 29.7 +/- 15.8 days in the former compared to only 4.8 +/- 3.3 days (p < 0.001) in the latter. Early deaths within 3 months of dialysis initiation were more frequent (7.1 vs 1.6% p < 0.05) and less patients subsequently were able to be treated out-center (20.1 vs 40.7%, p < 0.05) in group II than in group IA. The overcost induced by late referral may be estimated at 0.25 million French francs per patient. CONCLUSION: An unjustified late nephrological referral of CRF patients still is observed in nearly 20% of cases. Such late referral is detrimental to both patients in terms of altered quality of life and long hospital stay, and to the collectivity due to heavy overcost. Closer cooperation between family physicians and nephrologists is needed to provide optimal management and allow timely preparation to maintenance dialysis of CRF patients.

Advanced oxidation protein products as a novel marker of oxidative stress in uremia.

Evidence suggests an imbalance between antioxidant and oxidant-generating systems resulting in oxidative stress in uremic patients. As plasma proteins are critical targets for oxidants, we developed a novel spectrophotometric assay which allows to detect advanced oxidation protein products (AOPP) in uremic plasma. By size-exclusion chromatography AOPP are retrieved in two distinct peaks at 600 and below 80 kDa in uremic plasma, while no such peaks are found in control plasma. Further biochemical characterization revealed that AOPP are carried by oxidized plasma proteins, especially albumin and do not have oxidant properties. AOPP increased in a dose-dependent manner following in vitro exposure of plasma or purified human serum albumin (HSA) to hypochlorous acid. Advanced glycation end products of human serum albumin (AGE-HSA) also increased AOPP levels. In vivo, plasma level of AOPP was the highest in patients on hemodialysis, followed by those on peritoneal dialysis and by undialyzed patients with advanced chronic renal failure. AOPP levels correlated with plasma concentrations of dityrosine and AGE-pentosidine, as indices of oxidant-mediated protein damage, but not with thiobarbituric reactive substances as lipid peroxidation markers. A close correlation was also found between AOPP and neopterin levels, suggesting that AOPP could be part in the monocyte-mediated inflammatory disorders associated with uremia. In conclusion, we propose the measurement of AOPP as a reliable marker to estimate the degree of oxidant-mediated protein damage in uremic patients and to predict the potential efficacy of therapeutic strategies aimed at reducing such an oxidative stress.

Potential effect of metabolic acidosis on beta 2-microglobulin generation: in vivo and in vitro studies.

Beta 2-microglobulin (beta 2M) is responsible for dialysis-associated amyloidosis. Level of beta 2M in plasma increase during chronic renal failure; however, retention does not appear to be the sole mechanism responsible. The effect of metabolic acidosis on beta 2M production was examined. Thirty-six patients with stable chronic renal insufficiency, 12 uremic patients before their first dialysis, 8 hemodialysis patients who were assigned to acetate or bicarbonate dialysate and then crossed over to the alternative regimen, and 6 normal subjects given NH4Cl to initiate metabolic acidosis were studied. In vitro studies in the human myeloid cell line U 937 were also performed. beta 2M protein was measured with ELISA, beta 2M mRNA was measured with reverse transcription polymerase chain reaction, and the U 937 cells were studied at two pH levels with FACScan flow cytometry. The cells were exposed in vitro up to 60 min in a buffered incubation medium to either pH 5.10 or pH 7.34. An inverse correlation was found between beta 2M and bicarbonate concentrations in plasma in the stable chronic renal failure patients (r = -0.54; P < 0.05) and in the uremic patients before their first dialysis (r = -0.72; P < 0.05). In hemodialysis patients, blood pH and plasma bicarbonate values were lower (P < 0.05) and beta 2M concentrations in plasma were higher (P < 0.05) with acetate than with bicarbonate dialysate. In normal men, NH4Cl resulted in an increase (P < 0.05) in beta 2M mRNA expression in lymphocytes by an average factor of 1.5 (range, 1.1 to 1.8). In U 937 cells, the cell surface expression of beta 2M and HLA Class I heavy chain assembled with beta 2M decreased at low pH compared with normal pH. Concomitantly, an increase in beta 2M release into the supernatant was observed, possibly as the result of beta 2M dissociation from cell surface HLA Class I complex. The results suggest that metabolic acidosis may enhance cellular beta 2M generation and release.

Glutathione antioxidant system as a marker of oxidative stress in chronic renal failure.

A profound imbalance between oxidants and antioxidants has been suggested in uremic patients on maintenance hemodialysis. However, the respective influence of uremia and dialysis procedure has not been evaluated. Circulating levels of copper-zinc superoxide dismutase (CuZn SOD), glutathione peroxidase (GSH-Px), and reductase (GSSG-Rd), total GSH and GSSG were determined in a large cohort of 233 uremic patients including 185 undialyzed patients with mild to severe chronic renal failure, and 48 patients treated by peritoneal dialysis or hemodialysis. Compared to controls, erythrocyte GSH-Px and GSSG-Rd activities were significantly increased at the mild stage of chronic uremia (p < .001), whereas erythrocyte CuZn SOD activity was unchanged, total level of GSH and plasma GSH-Px activity were significantly decreased, and GSSG level and GSSG-Rd activity were unchanged. Positive Spearman rank correlations were observed between creatinine clearance and plasma levels of GSH-Px (r = .65, p < .001), selenium (r = .47, p < .001), and GSH (r = .41, p < .001). Alterations in antioxidant systems gradually increased with the degree of renal failure, further rose in patients on peritoneal dialysis and culminated in hemodialysis patients in whom an almost complete abolishment of GSH-Px activity was observed. In conclusion, such disturbances in antioxidant systems that occur from the early stage of chronic uremia and are exacerbated by dialysis provide additional evidence for a resulting oxidative stress that could contribute to the development of accelerated atherosclerosis and other long-term complications in uremic patients.

Dialysis arthropathy: outcome after renal transplantation.

PURPOSE: Patients treated by long-term maintenance hemodialysis frequently develop a form of chronic arthropathy that is strongly associated with beta 2-microglobulin amyloid deposition and related, at least in part, to beta 2-microglobulin retention. Successful renal transplantation is followed by a rapid fall in serum beta 2-microglobulin levels and might allow dissolution of amyloid deposits. The purpose of this work was to investigate the effects of renal transplantation on dialysis arthropathy. PATIENTS AND METHODS: Fourteen renal transplant recipients were selected on the basis of previous hemodialysis treatment for at least 10 years (mean 16) and a history of chronic joint pain prior to transplantation. They all received 10 to 17.5 mg/d of prednisone. Posttransplant rheumatologic manifestations were studied prospectively and compared to pretransplant rheumatologic manifestations recorded in medical charts and reported during patient interviews. Pretransplant and posttransplant articular roentgenograms were separately analyzed by three observers who were blinded to timing of the films. Beta 2-microglobulin amyloid was identified by Congo red staining and immunohistology. RESULTS: After a mean posttransplant interval of 54 months (range 12 to 121), the articular condition was improved in 10 patients, unchanged in 1, and worsened in 3, according to patients' assessments. The number of painful joints decreased significantly (P < 0.05) as compared to the pretransplant period. However, the number and size of subchondral bone erosions remained unchanged, destructive arthropathies generally worsened, and articular beta 2-microglobulin amyloid deposits were identified in 2 patients, 2 and 10 years after renal transplantation, respectively. CONCLUSION: Renal transplantation appeared to arrest progression of beta 2-microglobulin amyloid in dialysis patients, but it neither led to dissolution of deposits nor prevented progression of destructive arthropathies. Most articular symptoms were improved, probably as a result of corticosteroid therapy.

Balance between IL-1 beta, TNF-alpha, and their specific inhibitors in chronic renal failure and maintenance dialysis. Relationships with activation markers of T cells, B cells, and monocytes.

Patients with end-stage renal disease present an immunodeficiency that paradoxically coexists with activation of most immunocompetent cells, and the roles of chronic uremia and maintenance dialysis are poorly understood. We determined circulating levels of IL-1 beta and IL-1Ra, TNF-alpha and its soluble receptors (TNF-sR55 and TNF-sR75), and activation markers of T cells (soluble CD25), B cells (soluble CD23), and monocytes (neopterin) in a large cohort of undialyzed patients at various stages of chronic renal failure and in dialyzed patients on maintenance hemodialysis or chronic peritoneal dialysis. The progression of uremia was associated with a gradual increase in soluble CD25, CD23, and especially neopterin levels. Although IL-1 beta could not be detected, IL-1Ra levels were significantly increased from the earliest stage of renal failure. Plasma levels of TNF-alpha, TNF-sR55, and TNF-sR75 progressed with the severity of renal failure and correlated with soluble CD25, CD23, and neopterin levels, whereas IL-1Ra levels correlated exclusively with TNF-sR55 levels. Compared with undialyzed patients, levels of IL-1 beta were higher in patients on maintenance hemodialysis, whereas those of IL-1Ra were lower and decreased further at the end of dialysis sessions. In contrast, both TNF-sR55 and TNF-sR75 levels were significantly higher than in undialyzed patients and increased further at the end of dialysis sessions in the absence of an increase of TNF-alpha. Such an imbalance between cytokines and their inhibitors may play a pivotal role in the multifaceted process of immune dysfunction.

Plasma kinetics of 125I-labelled amyloid P component in beta 2M amyloidosis: a possible approach to quantitate disease activity.

Dialysis amyloidosis is one of the most incapacitating complications of long-term dialysis treatment. Quantitative assessment of amyloid deposition using radiolabelled tracers has been recently proposed but convincing evidence of its validity in uraemic patients remains to be provided. We studied the plasma kinetics of i.v. administered 125I-labelled serum amyloid P component (125I-SAP) in 20 chronic haemodialysis patients compared with those of nine healthy volunteers and three non-dialysed patients with systemic amyloidosis. Plasma clearance of the tracer was abnormal in 17 of 20 dialysis patients in whom plasma radioactivity declined in a bi-exponential mode, in contrast to the single-exponential slope observed in all healthy controls. 125I-SAP plasma half-life of the second component, probably reflecting metabolic clearance, was significantly prolonged in these dialysis patients compared with the healthy controls (35.3 versus 24.6 h, P < 0.001). Among the long-term haemodialysis patients the calculated extravascular distribution of 125I-SAP was significantly greater in those with severe arthropathy than in asymptomatic patients. These findings demonstrate for the first time that SAP clearance is disturbed in haemodialysis patients due to both failing renal elimination and retention in extravascular sites. The extravascular diffusion is greatly enhanced in patients with clinical evidence of amyloidosis. Therefore the study of plasma 125I-SAP kinetics promises to be a valuable tool to quantitate the extent of amyloidosis.

Dialysis-associated amyloidosis.

Dialysis-related arthropathy represents a major complication of uremic patients treated by hemodialysis or other renal replacement therapies. Nearly 10 years ago, this syndrome was shown to be associated with a new type of amyloid, mainly composed of beta-2 microglobulin (beta 2-M). Retention of the beta 2-M protein due to chronic renal failure, although unquestionably a prerequisite for the occurrence of beta 2-M amyloidosis, appears not to be the unique pathogenetic factor involved in this complication. A role has also been attributed to an enhanced local or systemic generation of inflammatory mediators, an increased production of beta 2-M, and an altered metabolism of the molecule including partial proteolysis and glycation. It is possible that factors related to renal replacement therapy such as dialysis membrane biocompatibility also play a role. However, the clarification of the precise underlying mechanism(s) awaits further study. Because dialysis technology has progressed considerably during the last decade, a significant beta 2-M removal can be achieved at present using high-flux dialyzers. Moreover, a marked reduction in bioincompatibility during the dialysis procedure as manifested by activation of complement and stimulation of mononuclear blood cells can now be attained. Future studies will tell whether technical progress in dialysis technique results in a decrease in the incidence of symptomatic dialysis-associated amyloidosis.