Efficacy of hyperphosphatemia control in the progression of chronic renal failure and the prevalence of cardiovascular calcification.

BACKGROUND AND AIMS: Chronic kidney disease mineral- and bone disorder (CKD-MBD) has been studied more often in dialysis than in predialysis CKD patients. The association between efficacy of hyperphosphatemia control and chronic renal failure (CRF) progression, prevalence of bone disease and cardiovascular calcification was the objective of the present investigation. MATERIAL AND METHODS: 42 patients with CKD in Stage 5, regularly monitored for 5 years, were divided into Group 1 of 20 patients with normal serum phosphate (sPO4) levels and Group 2 of 22 patients with hyperphosphatemia registered at the majority of checks. Serum urea, creatinine, calcium (sCa) and sPO4 levels were regularly determined in the retrospective 5-year period. At the end of this period iPTH, bone alkaline phosphatase-BAP and inflammation markers (CRP, fetuin-A) were measured, valvular and arterial calcifications were detected by B mode echocardiogram and soft-tissue native radiograms of the pelvis and the wrist. RESULTS: Progression of CRF (1/sCr over time) was faster in Group 2 than in Group 1 (b = -0.0577 vs. -0.0288, p = 0.003) during the study period. Average BAP and iPTH values were similar in both groups and 23/42 patients had PTH > 300 pg/ml. Arterial and valvular calcifications were found in 5/23 patients from Group 1 and 14/22 patients from Group 2 (p = 0.011). Linear regression analysis revealed sPO4 as a predictor for total calcification number, inflammatory diseases as a predictor for valvular calcifications, while sPO4 and iPTH were predictors for arterial calcifications. CONCLUSIONS: More than half the patients with Stage 5 CKD not yet on dialysis exhibited elevated PTH. Faster CRF progression and frequent arterial and valvular calcifications were seen in patients with poor phosphate control and sPO4 was selected as an independent predictor of total calcification score.

Relation between serum urea and mortality of hemodialysis patients.

BACKGROUND: It is well known that serum urea concentration is not a good predictor of mortality in hemodialysis patients. On the other hand, urea kinetic modeling has been very successfully used to measure dialysis dose by the Kt/V index, which was found to be a good predictor of mortality. Could there be a relation between urea and mortality, but in some more complex way? METHODS: This is a post-hoc analysis of a single center observation study that included 242 patients and an 11-year observation period. Mortality rates between the quartiles of serum urea levels were examined by a 2 x 4 table with the chi(2) test. Both univariate and multivariate survival analyses were performed with standard and segmented extended Cox regression. RESULTS: The relation between mean urea in the baseline period and mortality showed an irregular U-shaped curve. The lowest mortality was observed in the third quartile (28 to 31 mmol/L). The relation between mean urea in the whole observation period and mortality was a J-shaped curve. The lowest mortality was in the second quartile (25-27 mmol/L). Urea was not a predictor of mortality in the whole cohort, but low-urea (binary) and high-urea (binary) were independent predictors of mortality in the corresponding models using standard or extended Cox regression. CONCLUSION: This study revealed a complex relationship between urea and mortality in hemodialysis patients. Patients with low or high urea levels exhibited higher mortality than those with medium levels, while both low and high levels of urea were independent predictors of all-cause mortality.

Benefits of screening for Chronic Kidney Disease.

The number of patients on renal replacement therapy has doubled every decade since 1980, and prevalence of chronic kidney disease (CKD) in the early stages is also markedly increased. In addition, CKD is a significant risk factor for cardiovascular morbidity and mortality. The only effective approach to this problem is prevention and early detection of CKD. In recent years, screening studies have been carried out in several countries. The findings have defined the scope of the problem and indicated which population groups are at risk of developing CKD. The most numerous are patients with hypertension and diabetes. Also, these studies have indicated that screening should include measurement of serum creatinine for eGFR as well as urine albumin. Early detection of CKD allows proper management that could slow down CKD progression, prevent cardiovascular and other comorbidities and enable timely initiation of dialysis. Screening for CKD could be best managed by partnership between primary care physicians and nephrologists. It is necessary to educate primary care physicians about CKD, its risk factors and associated co-morbidities. Although multiple benefits of screening for CKD are doubtless, the results obtained by screening should be interpreted with caution, bearing in mind that screening detects only markers of kidney disease but not the disease itself.

[Treatment of anemia in patients with chronic renal insufficiency with recombinant human erythropoietin]. / Lecenje anemije kod bolesnika s hronicnom insuficijencijom bubrega rekombinovanim ljudskim eritropoetinom.

The discovery of recombinant human erythropoietin has enabled treatment of anaemia in patients whose anaemia was primarily caused by the lack of erythropoietin. This agent was most widely used in the treatment of anaemia in chronic renal failure patients. Non-regulated hypertension is considered to be the only absolute contraindication for recombinant human erythropoietin application, but thrombocytosis, predisposition to thromboses of arterio-venous fistulae, and convulsions are regarded as relative contraindications. Recombinant human erythropoietin may be administered intravenously, but the subcutaneous route is considered more rational. The treatment is initiated by low doses with gradual dose increase, what enables gradual anaemia correction and prevents the appearance of adverse effects. Haemoglobin level of around 100 g/l is considered the target haemoglobin level. The majority of patients respond well to treatment by human recombinant erythropoietin and the absence of anaemia improvement may be the result of iron deficiency, occult haemorrhages, chronic infection, inadequate dialysis, secondary hyperparathyroidism, aluminium intoxication. Anaemia improvement during the treatment with recombinant erythropoietin leads to the improvement of function of most organs and the quality of life in general as well as avoidance of blood transfusions and their adverse effects. The most frequent adverse effect of recombinant erythropoietin is the development of iron deficiency or hypertension aggravation.

[The effect of recombinant human erythropoietin on erythrocyte lines in patients with anemia and chronic renal insufficiency]. / Uticaj rekombinantnog humanog eritropoietina na eritrocitnu lozu bolesnika sa anemijom i hronicnom bubreznom insuficijencijom.

Blood counts, bone marrow cytology and iron status in 13 patients with severe renal anemia assessed prior to and after recombinant human erythropoietin treatment. The mean increase of PCV after 8 weeks of treatment was 50%. Simultaneously, we observed a fourfold increase of the reticulocyte count. This increment correlated with a twofold increase of the percentage of bone marrow erythroblasts. We also observed an increment of the relative number of erythropoietin-dependent early erythroblasts. The tager PCV of 0.30 was achieved in 4 of 5 predialysis patients, but was not achieved in 8 hemodialysis patients because they had an "absolute" bone marrow erythroblastopenia. In conclusion, conventional hematologic examination revealed that application of recombinant human erythropoietin leads to improvement of erythrocytopoiesis in different stages of chronic renal failure.

[Treatment of secondary hyperparathyroidism with vitamin D metabolites]. / Primena metabolita vitamina D u lecenju sekundarnog hiperparatireoidizma.

The aim of this double blind, comparative, randomized study was to eveluate the efficacy of treatment with 1-alpha-OHD3 plus 24,25(OH)2D3 in patients with secondary hyperparathyroidism.A group of 46 patients, 26 females and 20 males, aged 19-67, on chronic haemodialysis, was examined. During the first three months of therapy 0.25 mcg/day 1-alpha-OHD3 was given, and next three months 23 patients were treated with combination of 0.25 mcg/day 1-alpha-OHD3 plus 10 mcg/day 24,25(OH)2D3, and 20 patients recieved 1-alpha-OHD3 plus placebo. Plasma levels of calcium, phosphorus and alkaline phosphatease were measured every two weeks, but PTH and vitamin D metabolites before and eash three months of treatment. At the beginning of investigation all patients had high PTH levels, 25 had high levels of alkaline phosphatase and decreased or unmeasurable concentrations of vitamin D metabolites. Three months later 1,25(OH)2D3 was normal and at the end of the study 24,25(OH)2D3 reached normal value in the group with 24,25(OH)2D3 therapy. During the therapy changes of calcium and phosphorus levels were not significant in both groups, but they were statistically significant only in the group treated with both metabolites. Thus, the study is a good proof of efficacy and usefullnes of 1-alfa-OHD3 plus 24,25 (OH)2D3 regimen recommended.

[Spontaneous proliferative response in patients with chronic renal allograft insufficiency due to chronic rejection]. / Spontana proliferacija limfocita kod bolesnika s hronicnim odbacivanjem i smanjenom funcijom transplantisanog bubrega.

Proliferative response of peripheral blood lymphocytes in patients with chronic renal allograft insufficiency was due to aetiological deterioration factors. The highest values of sponntaneous lymphocyte blastogenesis were found in chronic rejection of renal allografts, but on the similar level detected during acute renal rejection attacks. Significant raise of proliferative response was absent in cyclosporine nephropathy, as well as in patients with excellent renal allograft function, maintained on proliferative healthy control levels.

[Distribution of renal diseases at the Ambulatory Nephrologic Clinical Center in Serbia]. / Struktura oboljenja bubrega u nefroloskim ambulantama klinickog centra Srbije.

At the nephrologic offices of the Clinical Centre of Serbia Polyclinic 2,451 patients (975 males and 1,476 females) were examined over a period of four years (1987-1990). Out of these 647 (26.40%) were suffering from chronic renal failure. Hypertension as the principal diseases was diagnosed in 432 patients (17.62%), being somewhat more frequent in women. Two hundred patients were suffering from glomerulonephritis. Pyelonephritis was diagnosed in nearly the same number of patients (199). Out of the 129 patients suffering from urinary tract infections 112 (86.82%) were women. Women appeared in large numbers in other diagnostic groups as well. Quite a number of patients (14.08%) reported only once for functional examination of the kidneys. It may be concluded that among the examined patients the most numerous were those with chronic renal failure, while many were suffering from chronic nephropathy which points to the comparatively late diagnosing of nephrological disorders.

[Plasma glucose, serum insulin and C-peptide in patients with various stages of chronic renal failure]. / Glikemija, insulinemija i ce-peptidemija kod bolesnika s razlicitim stepenom bubrezne insuficijencije.

Plasma glucose, serum insulin and C-peptide were measured in patients with various stages of chronic renal failure (CRF). In this study we observed 50 patients: 26 women and 24 men, between the ages of 17 and 73. Following various stages of CRF our patients were devided into IV groups, with 10 patients in each. V-th group was control group with 10 healthy persons. Plasma glucose, serum insulin and C-peptide were measured in the fasting state and following the 2 hours oral glucose tolerance test (OGTT). In the fasting state, plasma glucose and serum insulin levels were normal in all groups. With deterioration of the renal function plasma glucose and serum insulin increased slower during OGTT but their levels also decreased slower. Fasting levels of C-peptide increased continually with deterioration of renal function in all patients and values were significantly higher than in control group.

[Causes of anemia after kidney transplantation]. / Uzroci anemije posle transplantacije bubrega.

In this paper possible causes of anemia in patients after kidney transplantation were investigated. Anemia developed in 29 patients 14 to 22 months after kidney transplantation. At the time when these patients became anemic fourteen had normal graft function while the others 15 suffered chronic graft failure due to chronic rejection in 11 patients combined with cyclosporine nephrotoxicity in other four patients. Anemia in patients with normal graft function was caused by iron (in 8), folic acid deficiency (in 16) and vitamin B12 deficiency (in 2 patients). In this patients group anemia improved after substitution therapy. Therapy with rHuEpo was necessary in patients with chronic graft failure, indicating that erythropoietin deficiency was the main cause of their anemia. However, chronic graft failure progression, expressed by 1/sCr/time was not accelerated by anemia improvement. It could be concluded that examination of etiologic factors of posttransplant anemia is prerequisite for the most adequate treatment whose effects depend on graft function.

[Arterial hypertension in patients with primary glomerulonephritis]. / Arterijska hipertenzija kod bolesnika s primarnim glomerulonefritisom.

Arterial hypertension is a state of blood pressure permanently higher than 160/90 mm Hg (21.3/12.6 kPa). The renal cause of hypertension occurs in about 10% of all cases. The aim of this article was to establish the frequency, the level, and the connection of the hypertension in different types of primary glomerulonephritis. In this study 90 patients with primary glomerulonephritis were observed. Hypertension was present in 45 patients (50%) and different frequency were noticed in different types of glomerulonephritis. The smallest frequency was recorded in the group with minimal changes and IgA nephritis. In the group with mesangioproliferative glomerulonephritis 52% of patients had hypertension and in the group with focal segmental sclerosis 78%. The most frequent hypertension was observed in the group with rapidly progressive glomerulonephritis. Renal failure was more frequent in patients with hypertension. Different frequencies of hypertension was established in different types of glomerulonephritis. It was not severe and was well controlled by remedies. In most cases it suggest a severe glomerular lesions and fast progression of the disease.

[Lupus nephritis: clinico-morphologic correlation]. / Lupusni nefritis: klinicko-morfoloska korelacija.

The aim of the study was to determine the correlation between some clinical parameters and histopathologic findings in patients with lupus nephropathy. Eighteen patients (17 female and one male) with the diagnosis of lupus nephritis were examined at the Nephrological Clinical of the Faculty of Medicine. Three to eight months passed between diagnosing systemic lupus erithematosus and kidney biopsy. At the time of biopsy the average age of patients was 33.3 +/- 2.9 years (18-52 years). In more than half of the 18 cases the disease was evidenced as nephrotic syndrome, but most of them had renal failure and increased blood pressure. In patients with diffuse proliferative glomerulonephritis proteinuria was significantly higher than in other histopathologic groups. Serum nitrogen was considerably higher while creatinine clearance was much lower in patients with diffuse proliferative glomerulonephritis than in other histopathologic groups. Circulating immune complexes were increased, and the complement (C3 and C4) concentration was slower in patients with lupus nephropathy, but the significant difference was present only when diffuse glomerulonephritis was compared to other histopathologic groups.

[Lupus nephritis--clinical and morfological correlation]. / Lupus-nefritis (klinicko-morfoloska korelacija).

During the last five years at our Department renal biopsy was carried out in 41 patients with systemic lupus erythematosus. On the basis of the pathologic findings glomerular changes were classified as follows: minimal in 5 patients; mesangial proliferative glomerulonephritis in 11; focal and segmental proliferative glomerulonephritis in 5; diffuse proliferative glomerulonephritis in 15; membranous glomerulonephritis in 3, and diffuse sclerosing glomerulo-nephritis in 2 cases. Morphological changes of renal biopsy did not correlate with the degree of deterioration of glomerular function. Twenty seven patients were regularly followed-up. Most of them had diffuse proliferative glomerulonephritis (11) and mesangial proliferative glomerulonephritis (7). This is a larger number than in other authors' series. The clinical manifestation of lupus nephritis was: nephrotic syndrome (19 patients); minimal urinary abnormalities (6); rapidly progressive renal failure (1), and acute nephrotic syndrome (1). The majority of patients had high blood pressure (23). Their immunosuppressive therapy was ordered according to renal histologic lesions and severity of extrarenal manifestations. Clinical remission was achieved in 22 patients, but 2 died due to extrarenal complications.

[Significance of laboratory tests for differential diagnosis of acute renal allograft rejection and acute cyclosporine nephrotoxicity]. / Znacaj laboratorijskih testova za diferencijalnu dijagnostiku akutnog odbacivanja transplantisanog bubrega i akutne ciklosporinske nefrotoksicnosti.

The most frequent causes of renal allograft function deterioration in early postransplantation period are aucte rejection (AR) and acute cyclosporine nephotoxicity (CyA NT). In order to contribute to noninvasive diagnostics in differential diagnosis of these two disorders, glomerular and tubular function in 40 patients during 2-3 weeks after renal transplantation, were followed-up. The results showed that ischaemia, during any act of transplantation provoked functional and structural disorders of renal allografts. During acute rejection serum creatinine level was increased diuresis, sodium and beta-2 microglobulin levels were decreased, whyle there was no significant change in the urinary enzymes ativity. In acute CyA NT there was significantly greater fractional excretion of sodium and beta-2 mikroblobulin, as well as activity of N-acetly-beta-d glukosaminidase and alkaline phosphatase in urine in comparison to other examined groups.

[Renal tubular function in patients with nephrolithiasis]. / Ispitivanje funkcije tubula bubrega kod bolesnika s nefrolitijazom.

The aim of the study was to establish the frequency of tubular dysfunction in 59 patients with nephrolithiasis, of whom 52 had unilateral and 7 bilateral calculosis. Before the study urinary infection was cured in all patients. Renal function was normal in all subjects. Hypercalcaemia was present in 8 patients, and hypercalciuria in 17 subjects. Phosphate clearance (CPO4) was increased in 40 patients, and had the same number of patients, decreased tubular reabsorbtion of phosphate (TRP). In 31 patients increased CPO4 and decreased percent of TRP was present. Renal threshold phosphate concentration was decreased in 17 patients. High fraction excretion of sodium was observed in 37 patients, while urine sodium level was higher than normal only in 4 patients. Decreased ability of renal acidification of urine was found in 5 patients, and decreased renal concentration ability in 10 subjects. The most common finding in the observed patients was the phosphate excretion defect usually accompanied with defect of calcium excretion, and defect of urine acidification.

[The influence of parathyroidectomy on phagocytic capability of polymorphonuclear cells in patients on hemodialysis]. / Uticaj paratireodectomije na oksidacionu sposobnost polimorfonuklearnih leukocita u toku fagocitoze kod bolesnika s hronicnom insuficijencijom bubrega lecenih hemodijalizom.

Having in mind the fact, that in patients with secondary hyperparathyroidism induced by chronic renal failure, phagocytic capability of leukocytes is supressed, we attempted to investihate the role of parathormone in it. The study included 6 hemodialysed and 5 healthy volunteers. The degree of phagocyosis was determined according to the HBT test on polymorphonuclear leukocytes (PMNL), before, and 7 and 60 days following the subtotal parathyroodectomy. In all patients, value of NBT test was highly significantly decreased. Following the surgical procedure the increase was significant, however it remained significantly lower when compared to the controls. We have concluded that inhibitory role of parathormone in PMNL phagocytosis was significant, however, in such patients the inhibition was contributed by other factors, as well.

Therapy of rapidly progressive glomerulonephritis with immunosuppressive agents.

Rapidly progressive glomerulonephritis is a kidney disease leading to sudden and definitive damages of the renal parenchyma and progressive impairment of its function until the complete failure. Histological findings of the changes are characterized with dominant glomerular lesions with crescentic formations. Early and intensive immunosuppressive therapy with pulse doses of steroids (Solumedrol 1.5 to 2.5 g), followed by Prednisolone 1 mg/kg every other day and cytostatic drugs (cyclophosphamide 1-2 mg-kg/every other day) discontinues the processes of specific and non-specific inflammation in the kidney and could enable regeneration of the kidney tissues with favorable outcome of the disease. Immunosuppressive therapy should be gradually lowered after two months, and applied for at least three to six months.

[Immunosuppressive factors in the blood in patients during the development of various kidney diseases]. / Imunospresivni cinioci u serumu bolesnika tokom evolucije razlicitih bubreznih oboljenja.

Sera of patients suffering from Balkan nephropathy, pyelonephritis and glomerulonephritis inhibit lectin-induced T-cell proliferation in vitro. Immunosuppressive factors were registered in the patients' sera during the early stage of the existing disease, and their activity was not in correlation with the degree of renal insufficiency. Serum inhibitors revealed their activity during the early phase of T-cell activation and had no effect on T-cell proliferation and DNK synthesis. Inhibitor activity was registered even if sera were not present in cell culture continuously but only 6 hours of preincubation; then their action was irretrievable.

[Captopril and enalapril in the treatment of renal hypertension]. / Kaptopril i enalapril u lecenju renalne hipertenzije.

Captopril and Enalapril, angiotensin converting enzyme inhibitors, were used in the treatment of grave renal hypertension. The treatment concerned 40 randomly selected patients with the average creatinine clearance of 55.7 ml/min. The patients were divided in two groups: the first groups was ril. The good regulation of blood pressure was achieved only in combination with furosemide and protreated with captopril and the second with enalappranolol. Furosemide was given to all patients, and propranolol to all treated with captopril and to 12 subjects treated with enalapril. The angiotensin converting enzyme increased plasma renine activity and decreased aldosterone concentration in the serum. No change in renal function was noted. Proteinuria was decreased. Side-effects were manifest in two patients only treated with captopril. In conclusion it can be said that angiotensin converting enzyme inhibitors are efficient in the treatment of renal hypertension.

[Progression of chronic renal insufficiency in chronic rejection: the role of chronic transplantation glomerulopathy]. / Progresija hronicne insuficijencije bubrega kod hronicnog odbacivanja: ucesce hronicne transplantacione glomerulopatije.

Chronic rejection of kidney transplant is a chronic and progressive decline of kidney transplant function related to certain morphologic changes, such as obliterate vasculopathy, interstitial fibrosis, tubular atrophy, and transplant glomerulopathy [1]. The purpose of this study was to investigate the involvement of chronic transplant glomerulopathy in the progression of chronic renal failure. METHOD, PATIENTS: Of 16 transplant patients with histologic diagnosis of chronic kidney transplant rejection in biopsy specimens, 8 patients had chronic transplant glomerulopathy (ChR-1), and in the other 8 patients glomeruli were relatively preserved (ChR-2). Transplant biopsies were performed between the seventh and the 15th month in ChR-1, and between the ninth and the 34th month in ChR-2 group. Morphologic vasculopathy cv2 changes, tubular atrophy ct1 and ct2 in the half of each group, and interstitial fibrosis ci2, were graded according to the BANFF criteria [2]. During the follow up the patients received similar doses of prednisone, as well as of azathioprine and cyclosporine A. IMMUNOHISTOCHEMICAL INVESTIGATION: The expression of MHC I antigen, MHC II antigens, CD3, CD25, CD54 (ICAM-1) was analyzed by indirect immunoperoxidase technique of staining on the frozen sections, (DAKOPATTS). The immunoreactivity score was 0 to 3. BIOCHEMICAL INVESTIGATION: The renal function was expressed as reciprocal serum creatinine values (1/mumol/L) reflecting the mean monthly levels, over the period between the third and the 22nd month following the transplantation. In each patient a decline in kidney functioning was determined in two ways: 1. by the slope of the curve representing the function of regression of the reciprocal serum creatinine over time, started from the third month after the transplantation, 2. by the rate of regression (percent) of the reciprocal serum creatinine values at the sixth, the ninth, the 18th and the 22nd month, compared to the attained serum creatinine level at the third posttransplantation month. RESULTS AND DISCUSSION: Glomeruli with present chronic transplant glomerulopathy (patients of the ChR-1 group) had moderate expression of MHC I antigen [1-2], week expression of ICAM-1 (CD54), whereas DR antigens were almost absent. In cortical tubuli the expression of MHC I antigen was very low. The relatively preserved glomeruli in patients without chronic transplant glomerulopathy (ChR-2 group) showed high expression of MHC I antigen [2], moderate expression of ICAM-1, and low (up to 1) DR expression. The CD25 molecules were not detected in any analyzed glomeruli (62 in total), except a positive cellular crescent formation, seen in 3 patients with chronic transplant glomerulopathy. The regression slopes of reciprocal serum creatinine values according to months, over the third and the 22nd month were similar in both groups of patients, and the speculating mean graft survival time was 44 months, in both groups. However, 4 of 8 patients of the ChR-1 group, and only 1 of 8 patients of the ChR-2 group returned to the haemodialyses because of the graft functioning loss. Besides, the mean percentual rate of the decline in renal functioning, as the rate of decrease of serum reciprocal creatinine values in the chosen growing periods in time after the third month were higher in group ChR-1 with present chronic transplant glomerulopathy in biopsy specimens. The difference was of statistical significance at the end of the 18th month, t = 4.10, p less than 0.01. In this period proteinuria exceeding 3 grams a day was discovered in 6 patients of ChR-1 group, and in 4 patients in ChR-2 group. Our results suggest that the early appearance of chronic transplant glomerulopathy induces a slightly higher loss of function of the kidney transplant with chronic rejection, despite of the absence of the immune activation in the glomeruli with the present chronic transplant glomerulopathy. (ABSTRACT TRUNCATED)