Anemia and secondary hyperparathyroidism.

Anemia has been recognized recently as a possible complication of primary hyperparathyroidism. If the hyperparathyroid state can induce anemia in patients with normal kidney function, the extremely high levels of circulating parathyroid hormone usually observed in hyperparathyroidism secondary to chronic renal failure may have an unfavorable influence on the anemia of uremic patients. We investigated the influence of subtotal parathyroidectomy on the severity of the anemia of 18 uremic subjects undergoing long-term hemodialysis therapy. Subtotal parathyroidectomy resulted in a significant increase of mean hematocrit value. RBC count, and hemoglobin level. Serial bone biopsies suggested a relationship between the amount of marrow fibrosis and the improvement of anemia after surgery, but the precise mechanism of this phenomenon is still unknown.

Plasma digitalislike activity in essential hypertension or end-stage renal disease.

Plasma extracts from 119 subjects showed a digitalislike activity, as evidenced by the ability of these extracts to inhibit ouabain binding to the Na+-K+ pump. High levels of the digitalislike compound were found in 18 of 54 untreated hypertensive subjects, 7 of 21 normotensive subjects with a family history of hypertension, and 10 of 14 patients with end-stage renal failure. Dialysis significantly reduced the activity of this compound. These results suggest 1) that endogenous digitalislike factor is not directly linked to hypertension but rather is related to sodium balance and 2) that it neither originates nor is activated by renal tissue, as it was present in four of six anephric patients.

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.

Different patterns of uremic polyneuropathy: clinicopathologic study.

Ten patients with a uremic polyneuropathy were investigated. Chronic renal failure was associated with a variety of neuropathies, including an acute axonal neuropathy, a progressive axonal neuropathy with secondary segmental demyelination, and a predominantly demyelinative neuropathy. All patterns were associated with distal degeneration of fibers evidenced by axonal sprouting observed on single-fiber preparations. The etiology of such variations in pathology of uremic neuropathy is still not clearly understood.

The effect of 1alpha(OH)D3 and 1alpha,25(OH)2D3 on the bone in patients with renal osteodystrophy.

Six patients with chronic renal disease and variable degrees of renal osteodystrophy were treated for three weeks with either 1alpha,25-dihydroxyvitamin D3 (1alpha25(OH)D3) or 1alpha,hydroxyvitamin D3 (1alpha(OH)D3) and both the biochemical and osseous responses measured. The most consistent changes seen were an increase in serum calcium concentration to normal, a decrease in immunoreactive parathyroid hormone toward normal, an increase in the extent of the calcification front and a decrease in the extent of fibrous dysplasia in the marrow cavity. Two important parameters which did not change significantly were serum alkaline phosphatase activity and the osteoid volume. These data, in conjunction with that from previous studies, indicate that therapy with 1alpha,25(OH)2D3 or 1alpha(OH)D3 does not heal the osteomalacia of renal osteodystrophy, but that it does suppress the secondary hyperparathyroidism, and ameliorate the osteitis fibrosa seen in patients with chronic renal disease. They raise the likelihood that additional factors, such as metabolites of vitamin D other than 1alpha,25(OH)2D3, play a role in regulating bone formation and/or mineralization.

Measles virus and Guillain-Barré syndrome during long-term hemodialysis.

In a black man, recently receiving long-term hemodialysis, a severe, rapidly progressive polyradiculoneuritis (Guillain-Barre syndrome) developed. Routine virologic study revealed a high antimeasles virus antibody titer (1:1280 by hemagglutination-inhibition) which progressively decreased. There was no clinical evidence of measles. Discussed here is the possible relationship between the Guillain-Barre syndrome and clinically inapparent measles associated with and perhaps modified by the uremic state.

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.

Hemodialysis-associated amyloidosis and beta-2 microglobulin. Clinical and immunohistochemical study.

The beta-2 microglobulin type of amyloidosis was identified in articular and para-articular tissues of 14 patients with non-amyloid nephropathies undergoing long-term hemodialysis. Ten patients had carpal tunnel syndrome, 13 had juxta-articular radiolucent cysts (complicated by spontaneous fractures of the femoral neck in three), and six had destructive arthropathies of the large joints of the limbs. Massive amyloid deposits were found in the synovium, capsule, ligaments, articular cartilage, and/or bone. They were characterized by Congo red-induced green birefringence that was sensitive to potassium permanganate treatment. They reacted with anti-beta-2 microglobulin antiserum, whereas they did not react with antibodies directed against AA protein, prealbumin, or immunoglobulins. These data suggest that the potentially disabling arthropathy of hemodialysis is due to amyloid lesions. The persistently elevated plasma beta-2 microglobulin levels may play a role in the pathogenesis of this recently recognized complication, and if so, this complication should be preventable.

Detrimental effects of late referral in patients with chronic renal failure: a case-control study.

Despite broader indications and easier access to renal replacement therapy during the past decades in Western countries, an unduly high number of patients is still referred to maintenance hemodialysis (HD) at a very advanced stage of chronic renal failure (CRF). To assess whether such late referral induces detrimental effects, we retrospectively compared clinical status and laboratory features in 20 patients who had been referred to us less than one month prior to first HD (late referral, or LR group) and in 20 sex- and age-matched controls who had undergone regular follow-up for at least six months prior to HD (early referral, or ER group). Male to female ratio was 12/8 and age averaged 53.5 years in both groups. Mean (+/- 1 SD) systolic and diastolic blood pressure were higher in LR group than in controls (180 +/- 14/102 +/- 10 vs. 153 +/- 15/86 +/- 7 mm Hg, P < 0.001) and fluid overload with pulmonary edema was present in 13/20 versus 3/20 patients (P < 0.001). Plasma concentrations (mmol/liter) of creatinine (1.12 +/- 0.27 vs 0.97 +/- 0.11, P < 0.01) and phosphate (2.58 +/- 0.47 vs. 1.92 +/- 0.31, P < 0.001) were higher, whereas plasma levels of bicarbonate (14.2 +/- 3.9 vs 22.5 +/- 4.2, P < 0.001) and calcium (1.85 +/- 0.24 vs. 2.27 +/- 0.15, P < 0.001) were lower in LR than in ER group, as were hemoglobin (7.1 +/- 1.1 vs. 9.4 +/- 0.9 g/dl, P < 0.001) and serum albumin levels (35.3 +/- 4.8 vs. 39.7 +/- 3.4, P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The response of heart rate to isoproterenol in hemodialyzed patients before and after parathyroidectomy.

The response of the heart rate to intravenous isoproterenol was studied in seven chronic hemodialysis patients with severe hyperparathyroidism, before and after subtotal parathyroidectomy (PTX). Before PTX, significantly higher doses of isoproterenol were needed to achieve a standardized increase in heart rate when compared with the doses needed following PTX. A similar difference was observed before and after removal of a parathyroid adenoma in an additional nonuremic patient with primary hyperparathyroidism. This decreased cardiac responsiveness to a beta-adrenergic stimulus seemed to be related to the hyperparathyroid state.

Possible persistent endocrine function of a rejected renal allograft.

The case is described of a patient on intermittent hemodialysis who had had a bilateral nephrectomy but had hypertension and a surprisingly mild degree of anemia. Repeated determinations showed high plasma renin activity and plasma erythropoietin activity within the detectable range. These results were thought to be related to a completely calcified renal allograft which had been inserted 8 years before and which had been rejected four years later, but left in situ. The patient had become anuric. It is suggested that chronically rejected renal allografts, even calcified, may maintain some endocrine activity in the absence of any excretory function.

Decrease of tumor-like calcification in uremia despite aggravation of secondary hyperparathyroidism: a case report.

Extraskeletal pseudotumoral calcifications generally develop in uremic patients with a high calcium x phosphorus (Ca x P) product and severe secondary hyperparathyroidism. In the present case report we describe a chronic hemodialysis patient presenting with a massive calcification of the left shoulder region, severe aluminum (Al) intoxication and moderate hyperparathyroidism. Her initial serum Ca x P product was only slightly elevated: 5.01 mmol2/l2. Under deferoxamine treatment during the subsequent 4 months, Al overload decreased. On the other hand, parathyroid overfunction worsened, as reflected by an increase of the serum immunoreactive parathyroid hormone [1-84] level from initially 690 to 1052 pg/ml (normal, 15-60 pg/ml) and an increase of alkaline phosphatase activity, and plasma calcitriol increased from undetectable to a low-normal value. Predialysis serum total Ca levels decreased rapidly from 2.9 to 2.5 mM but serum P concentrations remained elevated: 1.6-2.5 mM. Unexpectedly, the extent of the periarticular calcification diminished considerably during the same time period. The present observation shows that in a subset of uremic patients with Al overload, pseudotumoral calcifications may regress during Al chelation therapy despite progression of hyperparathyroidism. Since Al may predispose collagen to develop dystrophic or metastatic calcification, it is suggested that this process is reversible by correcting Al intoxication.

Aluminium-induced, reversible microcytic anemia in chronic renal failure: clinical and experimental studies.

Ten chronic hemodialysis patients with severe aluminium (Al) intoxication developed a microcytic anemia despite oral iron supplementation. Their microcytosis was reversible after deionization of the dialysis water. Ten age and sex matched hemodialysis patients who were not Al intoxicated but who had a comparable treatment schedule and time on dialysis had no such microcytosis. In order to investigate a possible direct role of Al we intoxicated uremic rats by daily (6/7 days a week) intraperitoneal injections of 30 nmoles/day of aluminium. After 3 months, the Al-intoxicated uremic rats had a significantly lower hematocrit (34.7%), hemoglobin (12.0 g/dl), and MCV (52.5 fl) than the control, vehicle-injected uremic animals (37.4%, 13.1 g/dl and 60.4 fl., respectively). The reticulocyte counts of the intoxicated rats were increased. Serum iron and transferrin iron binding capacity were unchanged. Thus aluminium intoxication of the uremic organism leads to a microcytic anemia possibly by interfering directly with normal hemoglobin synthesis.

Clofibrate treatment of hyperlipidemia in chronic renal failure.

The pharmacokinetics of the hypolipidemic agent, clofibrate have been studied in anuric patients on intermittent hemodialysis. In addition we have tried to determine whether the treatment of hyperlipidemia of chronic renal failure with clofibrate was safe and efficacious. Seven healthy volunteers and five uremic patients received a single dose of 25 mg/kg body weight of clofibrate. Mean peak plasma levels of clofibrate were comparable in both groups and were reached 3.5 hr after drug ingestion in the control subjects and after 6.5 hr in the uremic patients. The mean plasma half-life of clofibrate was 16.7 hr and 68.4 hr in the control subjects and in the patients, respectively (P less than 0.001). Following a short loading period a daily oral maintenance dose of 5 mg/kg body weight was given leading to a plasma clofibrate level of 75-100 microgram/100 ml. Five hyperlipidemic uremic patients received this dose for 3 months. Their plasma clofibrate and creatine kinase levels were constantly monitoried to detect clofibrate myotoxicity which we have observed in uremic patients at plasma levels generally considered safe in patients with normal renal function. Significant decreases in serum total lipid, triglyceride, and cholesterol levels were observed when compared to pretreatment values. In two of the 5 patients serum lipids remained decreased for 10 and 14 months. It is concluded that clofibrate treatment of hyperlipidemia in uremic patients, when carefully monitored, is safe and efficacious.

Tissue distribution of dialysis amyloidosis.

Twenty-three uremic patients on intermittent hemodialysis for eight to eighteen years provided the material for the present pathological study. In all of them, there was evidence for dialysis related amyloidosis based on previous clinical or histological findings or both. The material examined consisted of nine skin biopsies, five abdominal fat aspirates, eight trans-iliac bone biopsies and numerous post-mortem specimens of various visceral organs from eight cases. None of the skin biopsies or fat aspirates showed amyloid deposits. In only one bone biopsy could a small Congo red positive area be recognized that showed characteristic birefringence under polarizing light. Autopsy material findings were negative except for one case: this patient had been dialyzed for 18 years. Very minute amyloid deposits with a positive immunofluorescence staining for beta 2-microglobulin (beta 2-M) were found in the walls of small vessels from her lung, heart, liver and intestine. Thus, in chronic hemodialysis patients the accumulation of beta 2-M amyloid fibrils in tissues other than joints and juxta-articular structures appears to have a low incidence, to occur lately and to be of limited size. Although extra-articular amyloid deposits may progressively occur and extend with increasing survival time on dialysis, tiny deposits such as those observed in only two of our patients will hardly lead to serious complications.

Beta 2-microglobulin amyloidosis: a sternoclavicular joint biopsy study in hemodialysis patients.

The incidence of beta 2-microglobulin deposits appears to increase with time on dialysis. However, the precise prevalence of the disease is not known at present because adequate, noninvasive diagnostic procedures are still lacking. We performed systematic synovial biopsies of the sternoclavicular joint during surgical parathyroidectomy in 22 chronic hemodialysis patients with severe hyperparathyroidism. Nine of the patients proved to have beta 2-microglobulin amyloid deposits as demonstrated by Congo red staining and by immunofluorescence. They had undergone dialysis for longer time periods (12.6 vs 8.5 years, p less than 0.02) and tended to be older than the 13 amyloid-negative patients. They also had a significantly higher body aluminum overload, as demonstrated by a higher increase of plasma aluminum after desferrioxamine infusion. Finally, the presence of Congo-red-positive deposits correlated well with clinical and x-ray findings suggestive of dialysis amyloidosis.

[Arterial hypertension and mortality due to cardiovascular complications in patients on chronic hemodialysis]. / Hypertension artérielle et mortalité par accident cardiovasculaire chez les hémodialysés chroniques.

Cardiovascular accidents are the commonest cause of death in patients on intermittent haemodialysis. Our study concerns 158 adult patients in terminal renal failure who were treated by periodic dialysis; it was carried out at Necker Hospital between January 1967 and December 1970. Between these dates, 35 patients died, 17 of the deaths being due to unequivocal or probable cardiovascular complications. The diagnosis of cerebrovascular accident was made in 13 cases. The mean age of the patients who died was 38 years. Fatal cerebrovascular accidents occurred especially during the first 12 to 24 months of treatment. The incidence of fatal vascular accidents is greatest in patients who were hypertensive at the beginning of periodic dialysis, and who remained so after six months of dialysis. Our study has therefore shown that hypertension in patients on chronic haemodialysis is a major vascular risk factors; other risk factors, especially metabolic ones, may also play a part.

[Amyloidosis in hemodialysis patients]. / L'amylose des hémodialysés.

Amyloidosis in long-term haemodialysis patients mainly involves the osteo-articular system. It is held responsible for carpal tunnel syndrome, chronic arthralgia and various types of arthropathy, chronic synovitis and tenosynovitis, haemarthrosis, subacute polyarthritis and destructive arthropathies of the limbs and spine. Radiologically, amyloidosis may appear as bone cavities, particularly visible in the hips and wrists. Its frequency increases with the duration of haemodialysis. Biochemically, amyloidosis consists of beta 2-microglobulin (beta 2-M). This protein accumulates in uraemic patients under dialysis and seems to play a major role in the pathogenesis of amyloid deposits. The accumulation is due to renal impairment, being maximum in anuric patients. However, the unsatisfactory clearance of beta 2-M by dialysis methods also contributes to its retention: the production and elimination of beta 2-M seems to vary according to the extrarenal clearing technique. These data suggest that improvements in clearing techniques will eventually prevent dialysis amyloidosis.

[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.

[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.