Effect of interleukin-1beta on transforming growth factor-beta and bone morphogenetic protein-2 expression in human periodontal ligament and alveolar bone cells in culture: modulation by avocado and soybean unsaponifiables.

BACKGROUND: In periodontal disease, interleukin-1beta (IL-1beta) is responsible for the matrix breakdown through excessive production of degrading enzymes by periodontal ligament fibroblasts and osteoblasts. Transforming growth factor-beta (TGF-beta) plays an important role in tissue regeneration as one of the factors capable of counteracting IL-1beta effects. In this study, we investigated the in vitro effect of avocado and soya unsaponifiables (ASU) on the expression of TGF-beta1, TGF-beta2, and bone morphogenetic protein-2 (BMP-2) by human periodontal ligament (HPL) and human alveolar bone (HAB) cells in the presence of IL-1beta. METHODS: HPL and HAB cells were incubated for 48 hours with ASU (10 microg/ml) in the presence or absence of IL-1beta (10 ng/ml). The steady-state levels of TGF-beta1, TGF-beta2, and BMP-2 mRNAs were determined by Northern blot or reverse transcription-polymerase chain reaction (RT-PCR). The amounts of TGF-beta1 and TGF-beta2 proteins were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The data indicated that IL-1beta strongly decreases the expression of TGF-beta1 and TGF-beta2 by HPL cells. ASU were capable of opposing the cytokine effect. In HAB cells, TGF-beta1 and BMP-2 mRNA levels were downregulated by the cytokine. ASU were found to reverse the IL-1beta-inhibiting effect. In contrast, the cytokine stimulated the production of TGF-beta2 in alveolar bone cells, with no significant effect of ASU. CONCLUSIONS: The results indicate that the IL-1beta-driven erosive effect in periodontitis could be enhanced by a decreased expression of members of the TGF-beta family. The ASU stimulation of TGF-beta1, TGF-beta2, and BMP-2 expression may explain their promoting effects in the treatment of periodontal disorders, at least partly. These findings support the hypothesis that ASU could exert a preventive action on the deleterious effects exerted by IL-1beta in periodontal diseases.

Congestive heart failure in dialysis patients.

To determine the prevalence of congestive heart failure in dialysis patients and the disorders with which it is associated, 85% of 153 nondiabetic patients who were undergoing maintenance dialysis had echocardiography and gated cardiac scan. Ten percent (n = 15) had congestive heart failure, 53% (n = 8) of whom had dilated cardiomyopathy, and 47% (n = 7) had hypertrophic hyperkinetic cardiomyopathy. Ischemic heart disease was an additional independent risk factor for congestive heart failure. Significantly more of those patients with dilated cardiomyopathy were smokers and none were hypertensive, whereas all those patients with hypertrophic cardiomyopathy were hypertensive. The prevalence of hypertrophic hyperkinetic disease was 11%, of dilated cardiomyopathy 18%, and of symptomatic ischemic heart disease 18%. We concluded that congestive heart failure in dialysis patients is associated not only with dilated cardiomyopathy but also with hypertrophic cardiomyopathy, a disease that requires echocardiography for diagnosis and that has different risk factors and management.

Hydroxychloroquine treatment of hypercalcemia in a patient with sarcoidosis undergoing hemodialysis.

Hypercalcemia developed in a patient undergoing long-term hemodialysis, and she was found to have noncaseating granulomas on lymph node biopsy. Hydroxychloroquine was administered as therapy for the hypercalcemia. Over 24 weeks of treatment with the drug, concentrations of calcium and 1,25-dihydroxyvitamin D returned to normal. The results demonstrate the capacity of hydroxychloroquine to inhibit the conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D, and emphasize the efficacy of hydroxychloroquine as an alternate to corticosteroids in the treatment of hypercalcemia of granulomatous disease. Hydroxychloroquine may be preferred when existing skeletal disease, or a predisposition to osteopenia, provides relative contraindications to corticosteroid therapy.

Impact of renal transplantation on uremic cardiomyopathy.

In chronic uremia, cardiomyopathy manifests itself as systolic dysfunction, concentric left ventricular (LV) hypertrophy, or LV dilatation. To determine the impact of renal transplantation on uremic cardiomyopathy, all dialysis patients participating in a long-term cohort study who received a successful renal transplant were followed with echocardiography. The transplanted group comprised 102 of 433 (24%) endstage renal disease (ESRD) patients. They were significantly younger and, on starting ESRD therapy, had significantly less ischemic heart disease and cardiac failure than the overall ESRD cohort. During followup, ischemic heart disease developed in only 1 patient and none experienced cardiac failure. In the 12% (n = 12) of patients with systolic dysfunction before renal transplant, fractional shortening normalized in all patients, increasing from 21.5 +/- 4.6% to 33.5 +/- 5.6% after transplantation. In the 41% (n = 41) with concentric LV hypertrophy before transplantation, the LV mass index improved from 158 +/- 39 g/m2 to 132 +/- 39 g/m2. LV dilatation was present in 32% (n = 32) of patients before transplantation. After transplantation, LV volume fell from 116 +/- 3.1 ml/m2 to 89 +/- 21 ml/m2, and LV mass index in this group fell from 166 +/- 55 g/m2 to 135 +/- 37 g/m2. It was not possible to associate risk factors characteristic of the uremic state with the improvement in cardiac structure and function, although the fall in LV mass was significantly associated with fall in blood pressure. We conclude that correction of the uremic state by renal transplantation leads to normalization of LV contractility in systolic dysfunction, regression of hypertrophy in concentric LV hypertrophy, and improvement of cavity volume in LV dilatation. The degree of improvement suggests that dialysis patients with uremic cardiomyopathy would benefit from renal transplantation.

The Kidney Disease Questionnaire: a test for measuring patient knowledge about end-stage renal disease.

Two studies report on the development of the Kidney Disease Questionnaire (KDQ) as a test for measuring patient knowledge about end-stage renal disease and its treatment. The KDQ is available in a 26-item version or as two parallel 13-item tests. Psychometric evaluations indicate that all versions show high levels of reliability. Initial validity tests are also promising. The KDQ is able to discriminate individuals well informed about kidney disease and its treatment from those who are not so well informed. It is also sensitive to the effects of an experimental education program and to ESRD-related knowledge that is acquired as a result of starting dialysis. Data and issues related to the administration, readability, demographic correlates, and a French translation of the KDQ are also presented and discussed.

Renal involvement in malignant histiocytosis. An immunoperoxidase marker study.

In two patients who had malignant histiocytosis, renal involvement was present at an early stage of their diseases and consisted clinically of proteinuria and renal failure. The associated renal lesion was characterized by a diffuse and global endocapillary hypercellularity of the glomeruli imputable to atypical cells occluding the capillary loops. Immunoglobulins were absent from this lesion. The atypical cells were positively identified by lysozyme immunoperoxidase study as malignant histiocytes. It is suggested that renal biopsy complemented by marker study could play a role in the diagnosis of malignant histiocytosis.

A tale of two homocysteines--and two hemodialysis units.

Pharmacologic doses of folic acid are commonly used to reduce the hyperhomocysteinemia of end-stage renal disease (ESRD). Vitamin B12 acts at the same metabolic locus as folic acid, but information is lacking about the specific effects of high doses of this vitamin on homocysteine levels in renal failure. We therefore compared the plasma homocysteine concentrations of maintenance hemodialysis patients in two McGill University-affiliated urban tertiary-care medical centers that differed in the use of vitamin B12 and folic acid therapy. Patients in the first hemodialysis unit are routinely prescribed high-dose folic acid (HI-F, 6 mg/d), whereas those in the second unit receive high-dose vitamin B12 in the form of a monthly 1-mg intravenous injection, along with conventional oral folic acid (HI-B12, 1 mg/d). Predialysis homocysteine was 23.4 +/- 6.8 micromol/L (mean +/- SD) in the HI-F unit and 18.2 +/- 6.1 micromol/L in the HI-B12 unit (P < .002). Postdialysis homocysteine was 14.5 +/- 4.1 in the HI-F unit and 10.6 +/- 3.4 micromol/L in the HI-B12 unit (P = .0001). Multiple regression analysis indicated that high-dose parenteral vitamin B12 was associated with a lower homocysteine concentration even after controlling for the potential confounders of sex, serum urea, serum creatinine, urea reduction ratio, and plasma cysteine. Because this was a cross-sectional observational study, we cannot exclude the possibility that unidentified factors, rather than the different vitamin therapies, account for the different homocysteine levels in the two units. Careful prospective studies of the homocysteine-lowering effect of high-dose parenteral vitamin B12 in ESRD should be undertaken.

A prospective study on the impact of the renal biopsy in clinical management.

A three year prospective study involving 80 patients was conducted to assess the impact of renal biopsy on clinical management. Pre-biopsy predicted histologic diagnosis was changed in 35 (44%) of the patients as a result of the biopsy. Prognosis changed in 45 (57%) of the patients. Therapy changed in 25 (31%) of the patients. These results suggest that, overall, renal biopsy had a marked effect on management. However, we identified subgroups of patients who were unlikely to have their management changed as a result of the biopsy: of 16 patients with a pre-biopsy diagnosis of IgA nephropathy, 1 (6%) had treatment changed because of the biopsy; and of the 50 patients without heavy proteinuria (greater than 3 g/24 h), 10 (20%) had treatment changed because of the biopsy. Although our overall results suggest an important role for renal biopsy in clinical management, renal biopsy has the least apparent impact in patients with a pre-biopsy diagnosis of IgA nephropathy or without heavy proteinuria.

Combined hemofiltration and desferrioxamine treatment for aluminum induced osteomalacia.

A 61-year-old male hemodialysis patient developed the syndrome of aluminum intoxication including bone pain, fractures, proximal myopathy, progressive anemia and expressive aphasia. Serum aluminum was 130 micrograms/l and rose to 445 micrograms/l after the administration of 2 grams of desferrioxamine. Bone biopsy of the iliac crest revealed severe osteomalacia, heavy staining for aluminum and a bone aluminum content of 229 mg/kg dry bone. Treatment with combined hemofiltration and desferrioxamine administration led to a marked clinical improvement and a repeat bone biopsy striking healing of the osteomalacia with a bone aluminum content of 11 mg/kg dry bone.

Routine clinical applications of hemodialysis-hemoperfusion in chronic renal failure: case reports.

Five hemodialysis patients were treated with combined hemodialysis-hemoperfusion with their conventional hemodialyzer plus a 70-gram ultrathin collodion coated activated charcoal device for a total of 63 months. Indications for this therapy included pericarditis, peripheral neuropathy, clotting of conventional hemodialyzers and reduction of dialysis time and frequency. The outcome was beneficial in all cases and stable biochemical and hematological parameters were maintained. No increase in heparin requirements was noted and the therapy was thought to be cost-effective.

A randomized double blind trial of dialysate sodiums of 145 mEq/L, 150 mEq/L, and 155 mEq/L.

Most hemodialysis is now carried out with a dialysate sodium concentration of 140-145 mEq/L. Higher dialysate sodium has been used, but controversy exists concerning the increased incidence of high blood pressure (HBP), thirst, and weight gain. A double blind prospective study was carried out in five stable men on chronic hemodialysis. Dialysis was performed in random sequence with a dialysate sodium of 145, 150, or 155 mEq/L for 2 months at a time. Vital signs were monitored before, during, and after dialysis, and the presence of symptoms during and between dialyses was documented. There was a significant increase in interdialytic weight gain with increasing dialysate sodium: 145 mEq/L (2.2 kg), 150 mEq/L (2.6 kg), 155 mEq/L (2.9 kg). There was a small, nonsignificant increment in dry weight of 0.5 kg between a dialysate of 145 mEq/L to 155 mEq/L but no increase in the mean arterial blood pressure. There was no difference in the incidence of interdialytic or intradialytic symptoms, including cramps, nausea, or fatigue, nor any change in serum sodium or other routine laboratory data before dialysis. It is concluded that a high dialysate sodium is not associated with an increased incidence of hypertension, symptoms, or a change in serum sodium but is associated with an increase in interdialytic weight gain.

The natural history of myocardial disease in dialysis patients.

Among dialysis patients, only 23% have a normal echocardiogram, about 10% have recurrent or chronic congestive heart failure, and 17% have asymptomatic ischemic heart disease. The predisposing factors for congestive heart failure are dilated cardiomyopathy, hypertrophic hyperkinetic disease, and ischemic heart disease. Dilated cardiomyopathy, a disorder of systolic function, includes among its risk factors age, hyperparathyroidism, and smoking. Hypertrophic disease results in diastolic dysfunction, and its predictors include age, hypertension, aluminum accumulation, anemia, and, perhaps, hyperparathyroidism. Ischemic heart disease is due to the presence of coronary artery disease and also to nonatherosclerotic disease caused by the reduction in coronary vasodilator reserve and altered myocardial oxygen delivery and use. The clinical outcome of congestive heart failure is comparable to that of nonrenal patients with medically refractory heart failure. Left ventricular hypertrophy is an important independent determinant of survival. A subset have hyperkinetic disease with severe hypertrophy and have a bad survival, as low as 43% have a 2-yr survival after the first admission to hospital with cardiac failure. The prognosis for those with dilated cardiomyopathy is less severe but is worse than those with normal echocardiogram. The survival of patients with symptomatic ischemic heart disease was little different from that of patients without symptoms, suggesting that the underlying cardiomyopathies had an adverse impact on survival independent of ischemic disease. Much research needs to be undertaken on the risk factors, natural history, and therapy of the various types of cardiac disease prevalent in dialysis patients.

Does the maternal kidney contribute to the increased circulating 1,25-dihydroxyvitamin D concentrations during pregnancy?

The observation that during pregnancy the circulating 1,25-dihydroxyvitamin D, 1,25(OH)2D, concentrations are higher than in the nonpregnant state as well as recent evidence showing that, in vitro, the placenta and/or decidua are sites of 1,25(OH)2D synthesis has led to the general belief that the increased circulating 1,25(OH)2D concentrations originate from the placenta and/or decidua during pregnancy. The observation of a patient with end-stage renal disease who became pregnant after 10 years of chronic hemodialysis treatment has revealed that, despite delivery of a viable infant who had a normal development for gestational age and of normal serum 25-hydroxyvitamin D levels, her serum 1,25(OH)2D3 concentrations were only 10-15 pg/ml following 25 weeks of gestation. These 1,25(OH)2D3 concentrations are far lower than those usually encountered in normal women at the end of the 2nd trimester of pregnancy. It is felt that an important contribution of the placenta and/or of the decidua to the synthesis of the hormone should have led to higher 1,25(OH)2D3 concentrations than those observed in this patient. These observations, along with evidence from the literature, prompted us to reappraise the hypothesis on the origin of the circulating maternal 1,25(OH)2D3 during pregnancy and to postulate that the kidney might be more important than previously thought to the synthesis of the hormone during pregnancy.

Impact of left ventricular hypertrophy on survival in end-stage renal disease.

We examined the prognostic significance of left ventricular hypertrophy determined by echocardiography in a cohort beginning renal replacement therapy. No patient had hemodynamically significant valvular disease or echocardiographic signs of obstructive cardiomyopathy. Using the Cox proportional hazards model, left ventricular hypertrophy was significantly associated with survival. The relative risk, based on comparison of upper and lower quintiles of left ventricular mass index, was 3.7 (95% confidence intervals, 1.6 to 8.3) for all-cause mortality and 3.7 (95% confidence intervals, 1.2 to 11.1) for cardiac mortality. The independent risk, adjusted for age, known coronary artery disease, diabetes, level of systolic blood pressure, and treatment (dialysis or transplantation), was 2.9 (95% confidence intervals, 1.3 to 6.9) for all-cause mortality and 2.7 (95% confidence intervals, 0.9 to 8.2) for cardiac mortality. Therefore, left ventricular hypertrophy appears to be an important, independent, determinant of survival in patients receiving therapy for end-stage renal failure.

Risk factors for the development of left ventricular hypertrophy in a prospectively followed cohort of dialysis patients.

The objective of this study was to determine the role of hypertension, age, anemia, and hyperparathyroidism in the pathogenesis of left ventricular hypertrophy (LVH) developing after the initiation of dialysis for ESRD. A cohort of dialysis patients who were being treated for ESRD and whose initial echocardiograms after the start of dialysis therapy do not show LVH were studied. Three hundred and thirty-nine patients have been monitored at three centers since 1985. Serial echocardiograms have been performed with M-mode and two-dimensional echocardiography. Data on blood pressure, height, weight, hemoglobin, number and type of antihypertensive medications, and the presence of functioning vascular access have been collected prospectively. Prospective data on serum calcium, serum phosphorus, alkaline phosphatase, and parathyroid hormone levels and skeletal x-rays have also been collected. By the use of set criteria and blinding to echocardiographic outcome, the presence and severity of hyperparathyroidism were graded by consensus. Fifty-one patients met eligibility criteria for inclusion; of these, 14 developed LVH (cases) and 37 did not (controls). Cases had significantly higher systolic blood pressure (P = 0.009) and were older (P = 0.01) than controls. Systolic blood pressure correlated significantly with final posterior left ventricular wall thickness (r = 0.39; P < 0.01). By the use of multivariate analysis, age and systolic blood pressure were significantly and independently associated with increased left ventricular mass index. The frequency of hyperparathyroidism was low and equal in both groups. There was a trend toward more severe anemia in cases that did not reach statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Semiquantitative reverse transcription-polymerase chain reaction analysis of syndecan-1 and -4 messages in cartilage and cultured chondrocytes from osteoarthritic joints.

OBJECTIVE: To determine the steady-state of messenger RNA (mRNA) levels of syndecan-1 and syndecan-4 in cartilage samples and chondrocytes derived from human osteoarthritic knee joints. METHODS: Steady-state levels of gene-specific mRNA (relative to beta-actin) were measured by semiquantitative polymerase chain reaction (PCR). RESULTS: RT-PCR allowed detection of syndecan-1 (for the first time) and syndecan-4 in both cartilage samples and articular chondrocytes cultured as primary monolayers. The mRNA levels of syndecan-1 were reduced in cartilage tissue from heavily damaged compared to normal-looking areas whereas those of syndecan-4 were significantly increased. In contrast, the expression of syndecan-1 was higher in cultured chondrocytes derived from the fibrillated osteoarthritic cartilage than in cells obtained from intact cartilage, while the syndecan-4 message levels did not differ between the two sites. CONCLUSION: The expression of the cell-surface syndecans 1 and 4 is altered during the osteoarthritic degradative process of the knee joint. The discoordinate syndecan gene expression, which is probably related to the chondrocyte proliferation and clustering, may contribute to the disorganization of the cartilage and the development of OA processes. Isolation and culturing the chondrocytes as monolayers dramatically change the expression of these genes and cannot reflect the in situ condition.

Outcome of congestive heart failure, dilated cardiomyopathy, hypertrophic hyperkinetic disease, and ischemic heart disease in dialysis patients.

Congestive heart failure in dialysis patients is associated with dilated cardiomyopathy, hypertrophic hyperkinetic disease and ischemic heart disease. To determine the natural history of these four diseases, 150 dialysis patients were prospectively followed for 3-5 years. The 2-year cumulative survival rate was 33% in those with recurrent or persistent congestive heart failure vs. 80% in dialysis patients without. Survival was significantly worse in patients with an echocardiographic diagnosis of dilated cardiomyopathy compared to patients with normal echo-cardiogram (2-year survival rate 67 vs. 90%). In hypertrophic hyperkinetic disease the 2-year survival rate was 30% after entry into the study, and 43% after first admission with congestive heart failure. Symptomatic ischemic heart disease did not have an adverse impact on mortality when compared to those without ischemic heart disease. We conclude that congestive heart failure in dialysis patients has a bad prognosis. Its associated disorders include dilated cardiomyopathy and hypertrophic hyperkinetic disease, the latter being associated with a high mortality. As the prognosis for patients with overt ischemic heart disease was not different from patients without, it is likely that the underlying cardiomyopathy directly influenced survival.

The clinical course of left ventricular hypertrophy in dialysis patients.

To determine the clinical and echocardiographic outcome of left ventricular hypertrophy a prospective study was undertaken of 104 nondiabetic dialysis patients without dilated cardiomyopathy, who were followed for 3-5 years. 33% of patients had normal echocardiogram, 41% mild and 27% severe hypertrophy (left ventricular wall thickness greater than or equal to 1.4 cm in diastole). In the first 2 groups 16% progressed to severe hypertrophy, 23% were admitted with congestive heart failure after starting dialysis therapy, and 2-year cumulative survivals were 97 and 85%. In the group with severe hypertrophy 88% already had severe hypertrophy on starting dialysis therapy, it was persistent in 87%, 50% were admitted at least once with congestive heart failure, and the 2-year cumulative survival was 53%. 71% of those who died in the severe group died from cardiac or cerebrovascular causes compared to none of those with normal echocardiogram, which accounted for the significantly worse (p = 0.001) survival. We conclude that severe left ventricular hypertrophy occurs frequently in dialysis patients, is often present at the start of end-stage renal disease therapy, is persistent, may predispose to congestive heart failure, and is associated with a high mortality.

Sporadic aluminum osteomalacia: identification of patients at risk.

Chronic dialysis patients at risk for aluminum osteomalacia in areas of low water-aluminum content are not well identified. We, therefore, studied retrospectively a cohort of 59 patients who underwent bone biopsy at two hospital-based dialysis centers in Montreal (water aluminum content less than 10 micrograms/L). Overall, 25% of patients biopsied had aluminum-related osteomalacia defined by aluminum staining of more than 30% of the trabecular surface and low levels of bone formation as measured by tetracycline labeling. Multiple linear regression analysis showed high predialysis serum creatinine (P less than .05) and the amount of aluminum prescribed per month (P less than .05) as the most important determinants of aluminum staining. We conclude that aluminum-related osteomalacia can be a frequent disease entity in areas of low water-aluminum content. Our findings also suggest predialysis serum creatinine and the amount of aluminum prescribed per month are risk factors for the development of aluminum-related osteomalacia. Though the relationship between serum creatinine and aluminum staining of trabecular bone is unclear, serum creatinine is probably a marker for adequacy of dialysis in these patients.