Tests for cell membrane destabilization in assessing activity-progression of chronic glomerulonephritis

AIM: To study the role of cell membrane destabilization (MD) in the serum and urine in assessing activity/progression of primary chronic glomerulonephritis (CGN). MATERIAL AND METHODS: The trial entered 163 patients (mean age 38 +/- 7.3 years) with primary CGN in active phase, 64 patients with CGN in remission and 24 controls. The groups were compared by MD (urine phospholipids--PL, blood and urine ethanolamine--EA), indexes of activity and sclerosis (AI and SI), lipid peroxidation (LPO), etc. RESULTS: In active glomerulonephritis (GN) vs inactive one there were high levels of 24-h proteinuria, AI, PL and EA in the urine, malonic dialdehyde (MDA) and hydroperoxides (HP) in the blood. SI was similar in both groups. In active GN significant correlations were found between urinary SI, systolic and diastolic pressure, elevated levels of beta-lipoproteins and triglycerides; between blood EA and 24-h proteinuria, blood platelets, beta-lipoproteins, triglycerides, MDA, urine EA. CONCLUSION: LPO and MD play an essential role in GN pathogenesis. They reflect activity of inflammation in GN irrespective of the activity type and clinicomorphological form of GN, absence or presence of CRF.     

Streptococcal infection and chronic glomerulonephritis in children]

Microbiological, immunological and immunohistochemical studies were carried out in 78 children with different clinicomorphological forms of chronic glomerulonephritis (GN). According to the data obtained, the role of streptococcal infection (SI) is inconclusive in certain clinicomorphological forms of chronic GN, suggesting different approaches to the treatment of these patients. The etiological role of SI is most probable in mesangioproliferative and mesangiocapillary GN, manifesting by hematuric and mixed forms of chronic GN. Antibacterial therapy is indicated to patients with a rise of the level of ASL-O and with the clinical signs of acute SI or exacerbation of chronic tonsillitis in the same patients, especially during immunosuppressive therapy.     

The first experience of using membranotropic agents in the treatment of the nephrotic syndrome

To treat children suffering from the nephrotic syndrome, use was made of the membrano-stabilizing agents: zaditen that also has an antiallergic action; dimephosphon, a membrano-stabilizer and immunomodulator. The basis for differentiated use of the drugs was formed by the examination data which enabled one to identify the signs of atopy in children with the hormone-dependent nephrotic syndrome, marked signs of the instability of cellular membranes and different immunologic deviations in children with the hormone-resistant variety of the nephrotic syndrome. During zaditen treatment, the majority of the children with the hormone-resistant nephrotic syndrome manifested an appreciable decrease of the process activity; in some cases, including those with hormone dependence, the treatment with prednisolone could be reduced. In part of the children with the hormone-resistant nephrotic syndrome, the treatment with dimephosphone resulted in a decrease of proteinuria, reduced the instability of cellular membranes, and improved the immunologic parameters.     

A comparative evaluation of the efficacy of treatment methods in chronic glomerulonephritis

The results of the treatment of 498 patients with chronic glomerulonephritis (CGN) verified on biopsy were analyzed to reveal that all the types of therapy were less effective in episodes of the nephrotic syndrome and frequent relapses than in rarer exacerbations and the lack of massive proteinuria. Considerable differences in the survival of patients with varying activity of CGN treated in the same way attest to the limited possibilities of the pathogenetic and symptomatic agents as regards their action on the natural disease course. The treatment with glucocorticoids, cytostatics and the combined use of these drugs turned out more successful provided the time of the drugs intake was increased to 1-2 years. Administration of glucocorticoids and the long-term use of cytostatics in cases of the sensitivity to them of mononuclear receptors appeared most effective in all the clinical manifestations of mesangioproliferative, membranous proliferative or membranous glomerulonephritis.     

The role of the kallikrein-kinin and renin-angiotensin-aldosterone systems in the development of hypertension in glomerulonephritis

A total of 74 patients with various clinicomorphological variants of glomerulonephritis (GN) were examined. Only a high activity of the enzyme kinase-1 that destroys kinins and the kallikrein inhibitors alpha 1-antitrypsin, alpha 2-macroglobulin is a contribution of the kallikrein-kinin system made to the general antihypertensive "armoury" of the body, as shown by the study. The correlation between the kallikrein activity and the active renin/total renin ratio predetermines that kallikrein may participate in endogenous plasma renin activation in GN patients. In this case, the vasoconstrictive effect of renin may limit the antihypertensive action of kallikrein and kinins by a feedback mechanism.     

The use of ultrahigh doses of corticosteroids in treating the most severe variants of lupus nephritis

The authors analyze the 10-year experience gained with the use of steroid pulse-therapy for the gravest forms of lupus nephritis--rapid-progressing lupus nephritis and active lupus nephritis associated with the nephrotic syndrome. Ultrahigh doses of prednisolone and methylprednisolone (1000 mg i. v. for 3 days) was monotherapy or as a constituent part of multimodality treatment were given to 30 patients including 27 women and 3 men aged 18 to 48 years. Of these, 12 patients had rapid-progressing lupus nephritis and 18 active lupus nephritis. The short-term treatment results were estimated after 1 to 3 months, whereas the long-term ones after 12 months to 9 years. Analysis of the treatment results allows the following conclusions to be drawn: the use of steroid pulse-therapy was monotherapy is only justified in patients suffering from active lupus nephritis with the nephrotic syndrome without renal failure and only at the disease debut. In rapid-progressing lupus nephritis and long active lupus nephritis with the phenomena of renal failure, the positive effect can only be attained after combination of steroid pulse therapy and high doses of prednisolone per os or long intake of cytostatics per os or in the form of cytostatic pulses.     

Effects of cyclophosphamide on the length of remission in patients suffering from glomerulonephritis with nephrotic syndrome

The authors performed retrospective evaluation of recurrence rate and the length of nephrotic syndrome (NS) remission in 21 patients with chronic glomerulonephritis (GN), who suffered from a first NS attack, cured by corticosteroid (CS) monotherapy; 16 patients had mesangioproliferative GN, 1--mesangiocapillary GN, 1--membranous GN, 3 patients did not undergo biopsy. After obtaining steroid remission of NS, 11 patients (Group I) continued receiving CS in maintaining doses during the next 6 7 +/- 1.0 months; the other 10 patients (Group II) received maintaining doses of CS during the next 5.5 +/- 0.5 months plus cyclophosphamide (CFA) daily or as pulse therapy during 19.7 +/- 3.5 months. There was almost a double increase of mean remission length in Group II vs. Group I (47.6 +/- 9.8 and 25.3 +/- 6.4 months, respectively). There was only one case of a NS relapse in Group II vs. 7 in Group I, which means that the risk of a NS relapse was 7.7 times higher in patients receiving only CS vs. patients on combination of CS and CFA, p = 0. 004. The results of this small retrospective study suggest that administration of CFA as supporting therapy after obtaining steroid remission of NS allows its substantial prolongation in patients with chronic GN.     

Some problems of the therapy of chronic glomerulonephritis

A study of the results of therapy of exacerbations of chronic glomerulonephritides in 416 patients during the entire course of the disease has shown their dependence on the clinical and, to a lesser degree, on morphological peculiarities of disease. With the same anatomy of the process, the efficacy of glucocorticoids, cytostatics and their combinations with anticoagulants and antiaggregants was less in the presence of the nephrotic syndrome and got lower twice or thrice in patients with a tendency to continuous recurrence. The results of the use of all types of therapy in groups of patients identical by their clinical characteristics were worse in membranous glomerulonephritis and did not differ significantly in mesangioproliferative and membranoproliferative glomerulonephritides. The treatment of the latter was less effective than that of mesangioproliferative glomerulonephritis because of higher frequency of an active course and development of the nephrotic syndrome.     

Biological treatment of gastrointestinal diseases

Biological methods are widely used in the treatment of intestinal inflammation (II). The TNFalpha inhibitor infliximab can quickly correct recurrence, provide long-term remission and reduce hormone need in many patients with hormone-resistant and hormone-dependent forms of Crohn's disease (CD) and ulcerative colitis (UC). However, almost half of II patients fail anticytokine therapy. Some clinical trials of biological medicines were stopped because of toxicity and complications. One of promising approaches to II treatment is now transplantation of mesenchymal stromal cells (MSC). The trial with participation of 85 CD and UC patients demonstrates that intravenous injection of allogenic MSC significantly prolongs duration of remission, reduces recurrence risk and is indicated for patients with hormone-resistant, hormone-dependent forms of II. Cell therapy can be also used in combined treatment of other gastrointestinal diseases, hepatic cirrhosis, in particular. A clinical trial is initiated of efficacy of transplantation of bone marrow autologous cells CD133+ for stimulation of regeneration of the liver in its extensive resection and cirrhosis. The future of this method depends on the results of controlled, randomized clinical trials.     

Hyperuricemic variant of latent glomerulonephritis

The authors describe the data of a comparative clinicomorphological analysis made in 40 patients with associated latent nephritis and hyperuricemia and 43 patients suffering from latent nephritis without hyperuricemia. No substantial differences in the disease clinical picture or in the structure of the morphological variants of glomerulonephritis (GN) were found in the above groups of patients. A more detailed morphological study made it possible to reveal a higher incidence of tubulostromal-vascular changes in patients with hyperuricemia. It is assumed that excess uric acid is likely to play an etiological role in the development of latent GN. Emphasis is laid on the necessity of early diagnosis of purine metabolism disorders in patients with latent nephritis whose goal-oriented therapy may improve the characteristics of the uric acid syndrome and renal function.     

An international randomized study with long-term follow-up of single versus combination chemotherapy of multibacillary leprosy.

A total of 307 patients with lepromatous leprosy and borderline lepromatous leprosy were randomized to dapsone monotherapy or to one of two types of drug combinations. A 3-year treatment phase was followed by a 5-year observation phase. The evaluation included 233 patients for whom together there were 1,404 years of observation. A total of 1,956 blinded histopathological specimens were processed centrally. When entering the trial isolates from 13 patients (5.6%) showed dapsone resistance in the mouse footpad test, and these patients were evaluated separately. Dapsone monotherapy (68 patients) had the same frequency of cure as the combination of dapsone and rifampin (77 patients) or the four-drug regimen consisting of dapsone, rifampin, isoniazid, and prothionamide (75 patients). We did not find a significant difference in the clearance of bacteria either between the monotherapy and the two-drug combination or the monotherapy and the four-drug combination. Six months after the initiation of treatment, disease in 15% of the patients who received dapsone monotherapy but none of the patients who received combined treatment were clinically progressive. After another 1 to 9 months of treatment the disease in all patients was stable or regressive. There was no difference in the type or frequency of reactions. Only after the end of the scheduled observation phase three relapses were reported. All three treatment regimens well tolerated. Dapsone monotherapy is highly effective in the treatment of multibacillary leprosy under the conditions of well-controlled treatment. Combination regimens seem only to accelerate the regression of the active disease when they are compared with monotherapy with dapsone. The mouse footpad test does not reflect the clinical resistance and cannot be recommended for use in making therapeutic decisions.     

Clinico-morphological features of acute gastroduodenal erosion and ulcers in an unstable course of myocardial ischemia and role in disturbances of microcirculation,stomach function and their development

AIM: Determination of clinicomorphological characteristics of acute gastroduodenal erosions and ulcers in unstable course of IHD and the role of disorders in microcirculation, hemostasis, gastric function in development of these erosions. MATERIAL AND METHODS: Clinically and endoscopically were examined 124 patients with unstable IHD. By detected gastroduodenal changes the patients were divided into three groups. The study was also made of local and systemic microcirculation, hemostasis, gastric functions. RESULTS: Acute gastroduodenal erosions and ulcers in unstable course of ischemic heart disease manifest with mild abdominal pains and gastric dyspepsia for several days. Disorders in the gastroduodenal zone arise because of focal disturbances of terminal circulation in the mucose according to thromboischemic or thrombohemorrhagic types related to generalized changes of microcirculation and hematasis. High activity of acid-peptic factor, low production of gastromucoproteins and hypomotor dyskinesia of the stomach contribute to development of erosive-ulcerous lesions. CONCLUSION: The above information is useful for early diagnosis of acute gastroduodenal erosions and ulcers in unstable course of IHD and upgrading of therapeutic measures.     

Activation of extracellular signal-regulated kinase in proliferative glomerulonephritis in rats.

Multiple extracellular mitogens are involved in the pathogenesis of proliferative forms of glomerulonephritis (GN). In vitro studies demonstrate the pivotal role of extracellular signal-regulated kinase (ERK) in the regulation of cellular proliferation in response to extracellular mitogens. In this study, we examined whether this kinase, as a convergence point of mitogenic stimuli, is activated in proliferative GN in vivo. Two different proliferative forms of anti-glomerular basal membrane (GBM) GN in rats were induced and whole cortical tissue as well as isolated glomeruli examined using kinase activity assays and Western blot analysis. Administration of rabbit anti-rat GBM serum to rats, preimmunized with rabbit IgG, induced an accelerated crescentic anti-GBM GN. A significant increase in cortical, and more dramatically glomerular ERK activity was detected at 1, 3, and 7 d after induction of GN. Immunization of Wistar-Kyoto rats with bovine GBM also induced a crescentic anti-GBM GN with an increase of renal cortical ERK activity after 4, 6, and 8 wk. ERK is phosphorylated and activated by the MAP kinase/ERK kinase (MEK). We detected a significant increase in the expression of glomerular MEK in the accelerated form of anti-GBM GN, providing a possible mechanism of long-term activation of ERK in this disease model. In contrast to ERK, activation of stress-activated protein kinase was only detectable at early stages of proliferative GN, indicating these related kinases to serve distinct roles in the pathogenesis of GN. Our observations point to ERK as a putative mediator of the proliferative response to immune injury in GN and suggest that upregulation of MEK is involved in the long-term regulation of ERK in vivo.     

Rapidly progressive glomerulonephritis in ANCA-associated vasculitis: a course, treatment efficacy, prognosis

AIM: To study efficacy of ANCA-RPGN treatment with corticosteroids and cyclophosphamide or mycophenolic acid drugs. MATERIAL AND METHODS: We treated 28 patients (17 males and 11 females aged 19-71 years) with morphologically verified ANCA-associated crescentic RPGN (crescentic median 79 (63:88)%. The patients received corticosteroids and cytostatics. RESULTS: The response to the treatment was registered in 22 (78%) patients in 8-16 weeks: a complete remission was achieved in 8 patients, a partial one--in 14 patients. In partial remission renal functions recovered incompletely (median Pcr 200 (180;255) mcmol/l) in persistence of moderate proteinuria (median 0.7 (0.6;1.3)g/day) and absence of microhematuria. Probability of the treatment success depended on severity of glomerulosclerosis and weakly depended on activity of extracapillary reaction. Severe renal failure was not an absolute predictor of treatment failure. CONCLUSION: In the absence of advanced nephrosclerosis early treatment with corticosteroid in combination with cytostatics can produce a positive effect in 70-80% patients with ANCA associated RPGN.     

Repaglinide/troglitazone combination therapy: improved glycemic control in type 2 diabetes

OBJECTIVE: This multicenter open-label clinical trial compared the efficacy and safety of repaglinide/troglitazone combination therapy, repaglinide monotherapy, and troglitazone monotherapy in type 2 diabetes that had been inadequately controlled by sulfonylureas, acarbose, or metformin alone. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes (n = 256) who had inadequate glycemic control (HbA1c > or =7.0%) during previous monotherapy were randomly assigned to receive repaglinide (0.5-4.0 mg at meals), troglitazone (200-600 mg once daily), or a combination of repaglinide (1-4 mg at meals) and troglitazone (200-600 mg once daily). After a 4-6 week washout period, the trial assessed 22 weeks of treatment: 3 weeks (weeks 0-2) of forced titration, 11 weeks of fixed-dose treatment (weeks 3-13), and 8 weeks (weeks 14-21) of titration to maximum dose. Changes in HbA1c and fasting plasma glucose (FPG) values were measured. RESULTS: The combination therapy showed a significant reduction in mean HbA1c values (-1.7%) that was greater than with either type of monotherapy Repaglinide monotherapy resulted in a reduction of HbA1c values that was significantly greater than troglitazone (-0.8 vs. -0.4%) (P < 0.05). Combination therapy was more effective in reducing FPG values (-80 mg/dl) than either repaglinide (-43 mg/dl) or troglitazone (-46 mg/dl) monotherapies. Adverse events were similar in all groups. CONCLUSIONS: Combination therapy with repaglinide and troglitazone leads to better glycemic control than monotherapy with either agent alone. Repaglinide monotherapy was more effective in lowering HbA1c levels than troglitazone monotherapy Repaglinide/troglitazone combination therapy was effective and did not show unexpected adverse events.     

Repeated intravital morphological studies of the kidneys in patients with glomerulonephritis

A clinicomorphological study was conducted over time in 62 patients with different morphological types of glomerulonephritis. An increase in vascular, interstitial and sclerotic changes was noted morphologically in most patients, the worst dynamics was observed in membranoproliferative glomerulonephritis. Disease progression was associated with 2 processes; sclerosis of all elements of the renal tissue or active inflammation.     

One of the possible mechanisms of development and progression of chronic glomerulonephritis

Proceeding from clinical examination of 430 patients with chronic glomerulonephritis (GN) and morphological, histochemical and biochemical studies on kidney biopsy specimens the author has proposed and substantiated a hypothesis, according to which prolonged raised protein reabsorption in cells of the proximal tubules (PT) of the kidney can cause breakage and distortion of the activity of transport systems responsible for the absorption and catabolism of macromolecules. These changes can result in PT cell breakage, escape of lysosomal enzymes into the lumen and basal membrane of PT cells and pericanalicular interstice with further development of cortical interstitial sclerosis. The combination of the above mentioned disturbances would lead to GN progression and development of renal insufficiency.     

Therapy of prostatic cancer with cyproterone acetate

45 patients with recently detected prostatic cancer were treated with cyproterone acetate (CPA) at a dosage of 100 mg/die. 25 patients underwent primary orchiectomy and consecutive treatment with 200 mg CPA/die. In 44.4% of the 45 patients who underwent monotherapy with 100 mg CPA/die progression of cancer was observed 10.8 months after beginning of treatment on average 55.6% of these patients showed a remission or stabilisation. 7 patients died, 4 certainly due to prostatic cancer. In the 25 patients who underwent orchiectomy and treatment with 200 mg CPA/die, 92% showed a remission. One patient of this group died, but not as a result of cancer. Based on the present data it may be concluded that treatment of inoperable prostatic cancer with 100 mg CPA as monotherapy is not indicated in patients with poorly differentiated tumours. Combination therapy--in addition to other possibilities of contrasexual therapy in prostatic cancer--seems to be of high efficacy.     

Amyloidosis in patients with rheumatoid arthritis

Of 467 patients followed-up for 15 yrs, rheumatoid arthritis was complicated by amyloidosis in 47 (10%). The relationship of amyloidosis development with a high or constantly moderate activity and expression of rheumatoid arthritis and its severity was brought to light. The results of biopsies of the mucosa, kidneys and liver, autopsy and clinical findings were analyzed and correlated. An increase in the frequency of amyloidosis development was noted in patients treated with glucocorticoids whereas in patients receiving cytostatics there was not such an increase.     

Fludarabine treatment of chronic lymphoid leukemia

AIM: To try effectiveness of fludarabine monotherapy in verified chronic lymphoid leukemia (CLL) in pretreated patients. MATERIAL AND METHODS: The treatment effectiveness according to the international criteria of complete and partial remission was assessed in 37 patients with progressive, splenic, tumor and bone marrow forms of CLL given 5-day courses of fludarabine in a single daily dose 25 mg. RESULTS: In progressive CLL, the remission was achieved in 45% of the patients (10% complete and 35% partial), in splenic form--62.5% (12.5% complete, 50% partial), in tumor form--50% (100% partial). In bone marrow form no remissions were obtained. CONCLUSION: Fludarabine is effective in therapy of pretreated CLL patients. The treatment should be adjusted to CLL form.