Which parameters affect cytosolic free calcium in polymorphonuclear leukocytes of haemodialysis patients?

BACKGROUND: Cytosolic free calcium ([Ca(2+)](i)) is an important second messenger during stimulation in a wide variety of cells, including polymorphonuclear leukocytes (PMNs). Its mobilization in PMNs is altered in various diseases such as atherosclerosis and ageing. In chronic haemodialysis (HD) patients, both atherosclerosis and accelerated ageing are well known. Therefore [Ca(2+)](i) in resting PMNs of HD patients was determined along with certain parameters which might affect it, such as recombinant human erythropoietin (rHuEpo) treatment, calcium-phosphate balance, and biocompatibility of dialysis membranes. METHODS: PMNs were separated by density centrifugation and [Ca(2+)](i) was determined by spectrofluorimetry using Quin 2/AM fluorescent dye. Laboratory parameters were determined by standard methods in clinical chemistry. RESULTS: It was found that [Ca(2+)](i) in resting PMNs of HD patients not undergoing rHuEpo therapy was higher than that of controls. After 12-weeks of rHuEpo therapy, [Ca(2+)](i) decreased to near normal level. The role of erythropoiesis in normalization of [Ca(2+)](i) in resting PMNs was supported by PMN [Ca(2+)](i) which was elevated in patients who had low haemoglobin (<100 g/l) or haematocrit (<0.30) values. In some patients, including those receiving rHuEpo treatment, [Ca(2+)](i) remained high, suggesting a role for other parameters in increasing [Ca(2+)](i). One possible parameter might be the disturbed calcium-phosphate metabolism of chronic renal failure, because we found a strong correlation between [Ca(2+)](i) and plasma iPTH levels in HD patients (r=0.743, P<0.001). [Ca(2+)](i) was also elevated in PMNs of those patients who had either low plasma calcium or high plasma phosphate levels. PMN [Ca(2+)](i) of HD patients correlated positively with the duration of HD (r=0.671, P<0.001). However, there was no correlation between [Ca(2+)](i) and patient age. The dialysis procedure itself also transiently increased PMN [Ca(2+)](i) HD patients, independently of the type of dialysis membrane. CONCLUSION: PMN [Ca(2+)](i) is modulated by various parameters in HD patients, including the degree of anaemia, disturbances of calcium metabolism, and duration of dialysis treatment. The elevated [Ca(2+)](i) of resting PMNs might contribute to altered functions in these cells.

[Analgesics-induced chronic renal failure in patients on dialysis therapy in Hungary]. / Analgetikum-nephropathia elófordulása krónikus veseelégtelenség miatt dializált betegekben Magyarországon.

In recent years elaboration of the diagnosis of analgesic-nephropathy (ANP) with the help of imaging techniques significantly increased the possibility of diagnosing the disease. Therefore, evaluating the prevalence of ANP has become more accurate in our country as well. The prevalence of ANP has been investigated in patients who have newly been taken into the dialysis program due to renal disease of unknown aetiology in 22 dialysis centers between December 1994-December 1997. The diagnosis of ANP has been based on revealing chronic drug abuse in the history and positive results of renal imaging (decrease in length of both kidneys combined with either bumpy contours and/or papillary calcification). Among 284 patients dialysed with unknown diagnosis 42 (14.8% of all cases) proved to have ANP. All patients except 2 took analgesic mixtures containing phenacetin/paracetamol, phenason derivatives, acetilsalysilic acid, caffeine and/or codeine. According to their investigations, ANP is a common disease resulting in end-stage renal failure in Hungary as well.

[Results and complications of parathyroidectomy in secondary hyperparathyroidism]. / Szekunder hyperparathyreosis miatt végzett parathyroidectomiák eredményessége és szövódményei.

Retrospective study was performed to measure the results of parathyroidectomy in patients with secondary hyperparathyroidism. From 1987 to 2000, 48 patients underwent surgery for secondary hyperparathyroidism. There were 30 of 48 patients on haemodialysis treatment, and 11 patients were in pre-dialysis stage. Parathyroidectomy was performed after successful kidney transplantation in 4 cases. Indication of the surgery was extremely elevated serum level of parathyroid hormone (at least 10 fold elevation), which was resistant for the conservative medical therapy. Subtotal parathyroidectomy (3 1/2) was performed in 30 patients. Five patients underwent total parathyroidectomy and autotransplantation. Only 2 or 3 parathyroid glands have been removed in 13 patients. Haematoma occurred in 3 cases after parathyroidectomy. Recurrent nerve injury or septic complication did not occur. Two patients died in the early postoperative period due to cardiac failure. Tetania was noted in 2 patients after surgery. Permanent postoperative hypocalcaemia (over 6 months) occurred in 3 cases. Persistent hyperparathyroidism was diagnosed in 5 patients. In these patients 2 parathyroid glands were removed during the primary operation. Recurrent hyperparathyroidism was detected in 2 patients. Subtotal parathyroidectomy was carried out in these cases previously. At the reoperation for persistent and recurrent hyperparathyroidism, total parathyroidectomy and autotransplantation was performed. Serum alkaline phosphatase level and serum parathyroid hormone value decreased after surgery, except those patients with persistent hyperparathyroidism. Bone pain decreased in 96% of the cases and pruritus decreased in 92% of the patients after parathyroidectomy. Soft tissue calcification showed improvement in 45% of cases. In conclusion, the subtotal parathyroidectomy or total parathyroidectomy with autotransplantation cause a rapid decrease of PTH level and the improvement of the clinical symptoms in patients with medical treatment resistant secondary hyperparathyroidism. Persistent hyperparathyroidism occurs in those cases when inadequate parathyroidectomy was performed.

[Hypophosphatemic oncogenic osteomalacia]. / Hypophosphataemiával járó onkogén osteomalacia.

The first case of oncogen osteomalacia in Hungary is reported, to draw the attention of the medical profession to it and to present the new data about its pathomechanism. Pathological hip fracture caused by hypophosphataemic osteomalacia due to isolated renal phosphate wasting was found in a previously healthy 19 years old sportsman. In spite of daily 1.5 micrograms calcitriol treatment and phosphate supplementation, hypophosphataemia persisted for 13 years and he needed regular indometacin medication for his bone pain. During that time an 1.5 cm gingival tumour was found and radically removed. The serum phosphate level returned to normal in a few hours after the operation (preoperative 0.51, after 2, 4 and 8 hours 0.61, 0.68 and 0.79 mmol/l respectively), and remained normal without calcitriol. The histological examination showed epulis with fibroblast and vascular cell proliferation, which has never been previously reported in connection with oncogenic osteomalacia. The pain resolved after 3 months and the bone density became normal in one year. Oncogenic osteomalacia must be considered in every case presenting with atypical hypophosphataemic osteomalacia. Careful dental examination is needed also in the course of search for the underlying tumour. Every tumour-like growth, even the common epulis, has to be operated radically and serum phosphate monitored in the postoperative period in all such cases.

Serum paraoxonase activity changes in uremic and kidney-transplanted patients.

Serum paraoxonase (PON) is a high-density lipoprotein (HDL)-associated hydrolase, which inhibits low-density lipoprotein oxidation. Uremic and kidney-transplanted patients have an increased risk of atherosclerosis, to which an increased lipoprotein oxidation may contribute. The aim of our study was to determine whether the PON activity or phenotype is altered in uremic and kidney-transplanted patients, and to compare the values with those of healthy controls. 117 uremic patients on long-term hemodialysis treatment, 115 renal-transplanted patients, and 110 healthy controls were involved in the study. The PON activity was significantly reduced in the uremic patients compared to controls (PON 101.36+/-30. 12 vs. control 188.05+/-58.96 U/ml; p < 0.001), while in kidney-transplanted patients the values were almost identical to those of controls (PON 161.5+/-35.39 U/ml). The different immunosuppressive drug combinations did not influence PON activity. To assess whether the altered PON activity was due to a decrease HDL level, we standardized the enzyme activity for the HDL concentration (PON/HDL ratio). We found that the standardized enzyme activity was lower in the uremic (102.7+/-54.8) and kidney-transplanted patients (144.5+/-32.7) when compared to controls (194.5+/-94.5; p < 0.001). The phenotypic distribution of PON in uremic, renal transplant and control patients are as follows: AA 66.67, 56.48 and 66.67%; AB 31. 62, 33.3 and 26.67%; BB 1.71, 10.19 and 6.67%. We conclude that the decreased PON/HDL and PON/apoA-1 ratios may lead to a reduction in the antioxidant capacity of HDL, which might contribute to the accelerated development of atherosclerosis in uremic and kidney-transplanted patients.

QT dispersion in patients with end-stage renal failure and during hemodialysis.

Interlead variability of the QT interval in surface electrocardiogram (ECG), i.e., QT dispersion, reflects regional differences in ventricular recovery time, and it has been linked to the occurrence of malignant arrhythmias in different cardiac diseases. The purpose of the study was to assess the effect of hemodialysis on QT and corrected QT (QTc) interval and dispersion in chronic hemodialyzed patients. Data of 34 nondiabetic patients (male/female = 21/13; mean age, 54 +/- 15 yr) on chronic hemodialysis were studied. Polysulfone capillaries and bicarbonate dialysate containing (in mEq/L) 135 Na+, 2.0 K+, 1.5 Ca2+, and 1.0 Mg2+ were used. Simultaneous 12-lead ECG were recorded before and after hemodialysis in a standard setting. The QT intervals for each lead were measured manually on enlarged (x3) ECG by one observer using calipers. Each QT interval was corrected for patient heart rate: QTc = QT/square root of RR (in milliseconds [ms]). The average cycle intervals were 853 +/- 152 ms predialysis and 830 +/- 173 ms postdialysis; the difference was not significant. The maximal QT interval changed significantly from 449 +/- 43 to 469 +/- 41 ms (P < 0.01). The corrected maximal QT interval increased significantly from 482 +/- 42 to 519 +/- 33 ms (P < 0.01). The QT dispersion changed from 56 +/- 15 to 85 +/- 12 ms (P < 0.001) and the corrected QT interval dispersion from 62 +/- 18 to 95 +/- 17 ms (P < 0.001). During hemodialysis, the serum potassium and phosphate levels decreased from 5.5 +/- 0.8 to 3.9 +/- 0.5 (mM) and from 2.3 +/- 0.5 to 1.6 +/- 0.4 (mM), respectively, whereas calcium increased from 2.2 +/- 0.23 to 2.5 +/- 0.22 (mM). It is concluded that hemodialysis increases the QT and QTc interval and QT and QTc dispersion in patients with end-stage renal failure. Thus, it may be stated that the nonhomogeneity of regional ventricular repolarization increases during hemodialysis. Measurement of QT and QTc dispersion is a simple bedside method that can be used for analyzing ventricular repolarization during hemodialysis.

[Effect of hemodialysis on QT dispersion in chronic uremia]. / A hemodialízis hatása a QT diszperzióra krónikus uraemiás betegekben.

Interlead variability of the QT interval in surface 12-lead ECG (i.e. QT dispersion) reflects regional differences in ventricular recovery time and it has been linked to the occurrence of malignant arrhythmias in different cardiac diseases. The purpose of the study was to assess the effect of hemodialysis on QT dispersion in chronic hemodialyzed patients. The data of 34 patients (Male/Female = 21/13, mean age 54 +/- 15 years) on chronic hemodialysis were studied. Simultaneous 12 lead ECGs were recorded pre- and post-hemodialysis in a standard setting. The QT intervals for each lead were measured manually by one observer. Each QT interval was corrected for patient's heart rate: QTc = QT/square route of RR (sec). The maximal QT interval changed from 449 +/- 43 to 469 +/- 41 ms (p < 0.01). The maximal QTc interval increased from 482 +/- 42 to 519 +/- 33 ms (p < 0.01). The QT dispersion changed rom 56 +/- 15 to 85 +/- 12 ms (p < 0.001), and the QTc interval from 62 +/- 18 to 95 +/- 17 ms (p < 0.001). During hemodialysis the serum potassium and phosphate decreased from 5.5 +/- 0.8 to 3.9 +/- 0.5 (p < 0.001), and from 2.3 +/- 0.5 to 1.6 +/- 0.4, respectively, whereas calcium level increased from 2.2 +/- 0.23 to 2.5 +/- 0.22 (p < 0.001). It can be concluded that the hemodialysis increased the inhomogeneity of regional ventricular repolarization. Measurement of QT and QTc dispersion by a cheap and simple bedside method could predict the increased myocardial inhomogeneity in dialyzed patients.

The serum paraoxonase activity in patients with chronic renal failure and hyperlipidemia.

Human serum paraoxonase is physically associated with an apolipoprotein (Apo-A1) and clusterin-containing high-density lipoprotein (HDL) and prevents low-density lipoprotein from lipid peroxidation. The aim of our study was to determine whether paraoxonase activity or phenotype is altered in patients with chronic renal failure and in hyperlipidemic subjects without renal insufficiency and to compare the values with those of healthy controls. We investigated the serum paraoxonase activity and polymorphism in 119 hemodialyzed uremic patients, 107 patients with primary hyperlipoproteinemia, and in 110 healthy control subjects. The serum paraoxonase activity was significantly decreased both in hyperlipidemic (p < 0.01) and uremic patients (p < 0.001) as compared with controls. On comparison, the serum paraoxonase activity was significantly lower (p < 0.001) in uremic than in hyperlipoproteinemic patients. The HDL and Apo-A1 levels were as follows: uremic < hyperlipidemic < control. To assess whether the observed reduction in paraoxonase activity was due to HDL and Apo-A1 level decreases, we standardized the enzyme activity for HDL and Apo-A1 concentrations. We found that the standardized paraoxonase activity (paraoxonase/HDL ratio) was also lower in the uremic patients (103.3 +/- 69.5) as compared with hyperlipidemic patients (137.64 +/- 81.0) and controls (194.45 +/- 94.45). The standardized values for Apo-A1 showed a similar tendency: paraoxonase/Apo-A1 ratio in uremic patients 89.64 +/- 47.8, in hyperlipidemic patients 128.12 +/- 69.83, and in controls 161.40 +/- 47.35. The phenotypic distribution of paraoxonase (AA, AB, BB) did not change significantly in the patient groups. These results suggest that HDL concentration and phenotypic distribution of paraoxonase may not be the only determining factors, but that other as yet undetermined factors could be involved in the enzyme activity changes.

[Use of erythropoietin in pregnancy: review of the literature in connection with 2 cases]. / Erythropoietin alkalmazása terhességben: irodalmi áttekintés két eset kapcsán.

Recently a growing number of case reports has been published about successful pregnancy outcome of dialysed women on recombinant human erythropoietin therapy. During pregnancy the maternal demand for erythropoietin may undergo changes, with consideration of recombinant human erythropoietin therapy in the early stage of renal insufficiency, as is shown by our two reported cases. The use of recombinant human erythropoietin seems to be safe for the foetus: it does not cross the placental barrier, and therefore lacks any direct foetal effect. The treatment of anaemia with recombinant human erythropoietin carries benefits for both the mother and foetus. One of the most important preconditions for successful recombinant human erythropoietin therapy is adequate iron supplementation. Due to the increased risk of pregnancy induced hypertension or preeclampsia, there is a need for slow and gradual correction of anaemia, and an individually tailored target hematocrit. A close follow up of he patient by the obstetrical-nephrological team is essential, with the intensive monitoring of the fetuses. In some cases with normal renal function the stimulation of erythropoiesis with recombinant human erythropoietin may also be needed during the pregnancy.

[Interferon therapy in cryoglobulinemic membranoproliferative glomerulonephritis associated with hepatitis C virus infection]. / Interferon kezelés hepatitis-C vírusfertózéssel társult cryoglobulinaemiás membranoproliferatív glomerulonephritisben.

The authors report the case of a 38 year old man with horseshoe kidney who developed a severe nephroso-nephritis syndrome, caused by cryoglobulinemic membranoproliferative glomerulo-nephritis. A combination of steroid and cyclophosphamide treatment resulted in partial improvement, but was discontinued after 12 weeks due to adverse reactions, with a consequent early relapse. The 4 week course of cyclosporine monotherapy proved ineffective and signs of cryoglobulinemia appeared. The elevation of transaminase, manifested during the immunosuppressive therapy demonstrated the presence of underlying chronic C hepatitis. In the light of the liver biopsy result, interferon treatment was commenced at a dose of 3 million unit thrice weekly. After 4 months of interferon treatment the persistent nephrotic range proteinuria decreased to below 0.5 g/day. Four months later clinical signs of cryoglobulinemia disappeared, and after the 10th month of interferon treatment no cryoglobulin could be detected in the patient's sera. After one year, the interferon treatment was discontinued following a negative PCR result for HCV. However, one month later the proteinuria increased and the quantitative hepatitis C virus nucleic acid test in sera became positive again. Our case demonstrates that interferon therapy may be effective in the treatment of cryoglobulinemic glomerulonephritis responding poorly to the immunosuppressive therapy, though larger doses or longer periods of treatment may be required to prevent relapses.

[Amyloidosis associated with dialysis]. / Dialízishez társult amyloidosis.

Recently dialysis related amyloidosis has become a major complication in patients treated with long-term dialysis therapy. The serum level of the amyloid precursor beta 2-microglobulin is significantly elevated in uraemia, mostly due to the retention. The bioincompatibility of dialysis membranes and the endotoxin content of the dialysate may contribute to the synthesis and tissue deposition of beta 2-microglobulin, but the details of pathogenesis are not yet cleared. At first periarticular and perineural structures are involved in the deposition of amyloid. The carpal tunnel syndrome is of great differential diagnostic value, it appears frequently together with the beginning of the joint pain. The main target of arthropathy are the large and medium-sized joints symmetrically. Deposition of the amyloid to the subchondral bone cysts might lead to pathological fractures, mainly in the hips and destructive spondylarthrophathy might involve severe neurologic complications. Visceral organs (gastrointestinal and urogeniteal tract, heart etc.) are involved rarely and later. Ultrasonography and isotope methods in addition to the conventional radiologic examinations are also used to differentiate the joint complaints nowadays. The definitive diagnosis is based on immunohistology. The alteration of dialysis strategy first of all the usage of high permeable, biocompatibile membranes and pure dialysis water has a role in the prevention of disease and decreasing its progression. In the case of developed lesions timely surgical-orthopedic interventions are required in addition to drug therapy. Todays' renal transplantation is a successful treatment, but the consequences of amyloid depositions already formed can't be left out of considerations even after transplantation.

[Pseudoporphyria]. / Pseudoporphyria.

A 46-year-old patient with chronic renal failure receiving maintenance haemodialysis for 3 years had a few months history of blister formation and skin fragility involving the face, arms and dorsa of the hands. In this case clinically mimicking porphyria cutanea tarda (PCT) no demonstrable abnormality in the porphyrin metabolism excretion was detected.

Lipid abnormalities in uraemic patients on chronic haemodialysis.

Patients kept on haemodialysis because of chronic renal insufficiency were investigated for lipid profiles. The cholesterol level did not differ as compared to the age-matched control, while the triglyceride level was elevated. The correlation was found between the lipid parameters, period spent in dialysis programme and level of serum creatinine and urea. In renal failures of different origin the lipid levels are in relationship with the underlying disorders.

[Recombinant human erythropoietin in the therapy of anemia in hemodialyzed patients]. / Haemodializált betegek anaemiájának kezelése rekombináns human erythropoietinnel.

The authors reported on a three month long EPREX (human recombinant erythropoietin) therapy of 5 hemodialysis patients for the treatment of their anemia. The drug was administered in bolus form 2 or 3 times a week after dialysis in a dose of 50 to 150 IU/bodyweight increased gradually in every (or every second) week. Hgb ad Htk values were determined once a week while erythrocyte, leukocyte, thrombocyte and reticulocyte count once a month. Serum iron, TIBC, serum ferritin, BUN, serum creatinine, urea, serum ions, liver function assays, serum lipids and amylase were also established. Hgb, Htk levels and reticulocyte count have significantly increased in the 4th week of treatment already, severe anemia ceased with improved appetite, general condition and physical strength. Serum urea and LDH levels significantly increased while SGOT decreased. No significant change in leukocyte and thrombocyte count, serum Na, K, Ca, P, Cl, BUN, creatinine, total protein level, serum albumin, bilirubin, alkaline phosphatase, GGT, GPT, amylase and blood sugar as well as serum lipid level were observed. No adverse reactions occurred during the treatment. After the three gradually decreased and within 6 weeks they had to be transfused again. In three patients the need for transfusion has significantly grown after the treatment. The authors consider EPREX a highly efficient drug in the treatment of anemia in dialysis patients.

Use of tensiomin (captopril) in the antihypertensive treatment of haemodialysis patients.

The observations of a 16-week Tensiomin therapy of 10 hypertensive patients treated with hemodialysis have been discussed. The patients have been treated for about 5 years with hemodialysis, suffered from anuria and required besides systhematical ultrafiltration a combination antihypertensive therapy. Tensiomin was combined with Minipress, Trasicor, Depressan, Estulic and Corinfar by using three- or four-drug combinations. In the course of the administration of Tensiomin the doses of the other antihypertensive drugs could be decreased by 50% on average, while the blood pressure of the patients was normalized. By controlling the patients on weeks 1, 4, 12 and 16 of therapy toxic side-effects or notable pathological changes of the examined laboratory parameters (WBC, serum total protein, Na, K, Ca, P, bilirubin, blood sugar and SGOT values) were not seen. It has been concluded that Tensiomin is an effective drug in combination therapy applied for normalizing the hypertension of dialysed patients.

[Bone scintigraphy in uremic osteodystrophy]. / Csont scintigráfia végzése uraemiás osteodystrophiában.

99mTc-HEDP bone scan was carried out on 12 long-time haemodialysed patients, suffering from bone pains. X-ray examinations of the bone and laboratory tests (serum calcium, -phosphor, -alkaline phosphatase, -parathormone, -aluminium, -ferritin) were also performed. The scintigrams were evaluated by two semiquantitative scores. Based on diffuse, increased radiopharmacon uptake of the bones and more than five points in the Fogelman score 5 patients most likely had serious and 3 had moderate hyperparathyroidism. In two patients osteomalacy was presumed based on decreased radiopharmacon uptake of the bones, increased uptake of the soft tissues and zero Fogelman score. Mixed or other bone disease was suggested in two other patients. Good correlation was found between the results of bone scans, the parathormone values and the results of histology obtained after parathyreoidectomy of 4 patients and autopsy of two others. This non-invasive examination (ie. bone scan) is helpful in differential diagnosis of uraemic osteodystrophy and its wide use is proposed in domestic nephrological practice.