[The course and prognosis of mesangioproliferative glomerulonephritis]. / Techenie i prognoz mezangioproliferativnogo nefrita.

AIM: A retrospective analysis of a clinical course of mesangioproliferative glomerulonephritis (MPGN) in patients with glomerular deposition of IgA (IgA nephropathy--IgA-N), with glomerular deposition of other Ig to determine prognostic factors of MpGN progression including IgA-N and to examine the patients' sensitivity to immunodepressive therapy. MATERIAL AND METHODS: 2000 patients with primary MPGN followed up from 1980 to 1999 from the disease onset to development of chronic renal failure (creatinine > 2.5 mg%). Factors affecting kidney survival were studied using the Cox regression model, factors predicting sensitivity to immunodepressive therapy--using multiple logistic regression. RESULTS: IgA-N differed by the course and prognosis from other forms of MPGN. In IgA-N urinary syndrome and macrohematuria were encountered more frequently, in other forms of MPGN more frequent was nephrotic syndrome. Prognosis of patients with IgA-N was worse than in MPGN patients without IgA deposition: 10-year "renal survival" (creatinine < 2.5 mg%) was 64 and 97% (p < 0.05), respectively. Prognosis-deteriorating factors for MPGN patients were the following: male sex, nephritis onset in 40-year-olds and older subjects, acute nephritic syndrome (creatinine > 1.5 mg%), high proteinuria, hematuria (> 50 in sight), the presence of synechia and TIC in renal biopsy, location of immune deposits both in the mesangium and basal glomerular membranes. The responders to the immunodepressive therapy had 10-year renal survival 100%. Positive results of immunodepressive therapy were observed significantly more frequently in patients with normal level of creatinine, moderate hematuria, absence of synechias and TIC in renal biopsy, given large total course dose of corticosteroids and cytostatics. Efficiency of oral cyclophosphamide and its intravenous pulse-therapy did not differ significantly. In pulse therapy an average cumulative dose was lower 6 times, side effects occurred 3 times less frequently. CONCLUSION: The importance of morphological information for prognosis and predicting sensitivity of MPGN patients to immunosuppressive therapy necessitates renal biopsy before therapy. Intravenous pulse therapy with cyclophosphamide is preferable as an active treatment in patients with sclerosis in renal biopsy.

Correlation between the expression of DNA topoisomerases I and IIalpha and clinical parameters in kidney disease.

Multiple factors interact during the evolution of renal diseases. In the present study, we examined the expression of DNA topoisomerases type I and IIalpha, which reflect gene transcription and DNA replication, respectively. Enzyme content was assessed by immunohistochemistry using two specific monoclonal antibodies, C21 and Ki-S4, on 81 archival punch-biopsy specimens from patients with renal diseases, including minimal change disease (MCD; n = 10), focal segmental glomerular sclerosis (FSGS; n = 6), mesangial proliferative glomerulonephritis (MPGN; n = 11), membranous glomerulonephritis (MGN; n = 10), mesangial capillary glomerulonephritis (MCGN; n = 7), rapidly progressive glomerulonephritis (RPGN; n = 12), lupus nephritis (LN; n = 15), and tubulointerstitial nephritis (TIN; n = 10). Both enzymes were strongly expressed in diseases tending to rapid progression, notably RPGN and LN, whereas MCD and MGN showed low protein levels in both the glomerular and tubular compartments. Moreover, topoisomerase expression was significantly associated with the density of monocytogenic infiltrates (monitored by means of the monoclonal antibody Ki-M1p), such pathogenesis-associated factors as antinuclear antibodies and paranuclear antineutrophilic antibodies, and serum immunoglobulin levels. There also was a positive correlation with serum creatinine levels and an inverse association with proteinuria and nephrotic syndrome. We conclude that the expression of DNA topoisomerases may be linked to pathogenetic mechanisms and may provide prognostic information. Because of their comparatively low nephrotoxicity, topoisomerase inhibitors might prove to be useful therapeutic agents in the treatment of renal diseases.

[Kidney damage in primary antiphospholipid syndrome]. / Porazhenie pochek pri pervichnom antifosfolipidnom sindrome.

AIM: To characterize clinical manifestations, course and laboratory signs of nephropathy in primary antiphospholipid syndrome (PAS). MATERIAL AND METHODS: 6 patients with PAS and renal affection were observed for 10 years since 1991. They were examined for anticardiolipin antibodies and/or lupus anticoagulant. Renal tissue was studied morphologically in one patient. RESULTS: In all the patients renal damage manifested with arterial hypertension associated with isolated proteinuria. The majority of the patients had renal dysfunction. All of them had elevated level of antibodies to cardiolipin primarily in combination with lupus anticoagulant. Histological changes of renal tissue presented with thrombotic microangiopathy of glomerular and extraglomerular vessels, intimal proliferation and vascular wall thickening with occlusion of their lumen which combined with morphological indicators of focal segmental glomerulosclerosis. CONCLUSION: The thrombotic process in the intrarenal vessels in PAS dictates the necessity to develop novel approaches to treatment of such patients. In addition to immunodepressants the treatment should include indirect anticoagulants and antiaggregants.

[Renal and uterine hemodynamics in pregnant women with hypertension]. / Pochechnaia i matochnaia gemodinamika u beremennykh s gipertonicheskoi bolezn'iu.

AIM: To study gestational alterations of renal and uterine hemodynamics, their relationships with systemic and intracardiac hemodynamics in pregnant women (PW) with essential hypertension (EH). MATERIAL AND METHODS: Echocardiography, ultrasound dopplerography of renal and uterine arteries, roll-over test were made in the course of trimester II-III and 3 months after the delivery in 48 PW with EH degree 1-2 and control 20 healthy PW. Hemodynamic parameters in pregnancy were compared to postpartum ones. The latter were supposed to be basal. RESULTS: Changes in systemic and intracardiac hemodynamics in EH and control women were in many respects similar but systolic blood pressure in EH changed insignificantly, minute volume increased owing to increased heart rate. PW with EH of the second degree have in the III trimester more frequent positive roll-over test this evidencing for high pressor reactivity of the vascular system. PW with EH showed higher speed of the blood flow in the renal arteries in unchanged resistance. With growing gestation time the resistance of the uterine arteries declined. The resistance of the main stem of the renal artery went up in enhanced cardiac contraction regardless of total peripheral vascular resistance (TPVR). Blood flow in the uterine arteries worsened in elevation of arterial pressure, TPVR, lowering of the heart rate and systolic function of the heart. Renal and uterine hemodynamics were independent. CONCLUSION: Hemodynamic changes in control and EH PW were similar in many respects but higher arterial pressure, abnormal systolic function of the left ventricle, bradycardia disturb uterine blood flow. Renal circulation was independent of systemic and intracardiac hemodynamics and is unrelated to changes in the uterine circulation.

Expression of DNA topoisomerases in chronic proliferative kidney disease.

BACKGROUND: Circulating autoantibodies to human topoisomerases have been reported in glomerular kidney disease associated with scleroderma and systemic lupus erythematosus. However, limited information is available about the expression of topoisomerases in the kidney under normal and pathological conditions. METHODS: The expression of DNA topoisomerases I and IIalpha was studied by immunohistochemistry on archival biopsies from 70 patients with chronic renal diseases. Normal kidney tissue was examined for comparison. Topoisomerase I was detected by means of monoclonal antibody (mAb) C21, and topoisomerase IIalpha was detected by means of mAb Ki-S4. In addition, mAb Ki-M1p was used to assess the density of monocytic infiltrates. All parameters were assessed in a semiquantitative manner. RESULTS: Glomerular topoisomerase IIalpha levels were increased in mesangial proliferative glomerulonephritis (MPGN), rapidly progressive glomerulonephritis (RPGN), and lupus nephritis (LN) and were reduced in membranous glomerulonephritis (MGN), chronic transplant nephropathy (CTN), and tubulointerstitial nephritis (TIN). Tubular epithelia displayed high topoisomerase IIalpha levels in mesangiocapillary glomerulonephritis (MCGN), RPGN, TIN, miscellaneous entities (MISC) and LN, and displayed low levels in MPGN and CTN. Topoisomerase I expression was high in the glomeruli of focal segmental glomerulosclerosis (FSGS), MCGN, and RPGN and was extreme in LN, whereas it was strikingly diminished in the glomeruli of MGN, CTN, and TIN. Almost all conditions displayed lower tubular topoisomerase I levels than normal kidney, except for LN, in which the enzyme content was markedly increased. Increased glomerular monocytic infiltrates were found in FSGS, MCGN, RPGN, TIN, and LN, and tubulointerstitial Ki-M1p+ cells were seen at high numbers in MCGN, RPGN, TIN, MISC, and LN. The expression of the topoisomerases I and IIalpha was significantly correlated; also, topoisomerases showed a positive association with the density of monocytic infiltrates. The parameter profiles exhibited significant differences between distinct types of chronic renal disease. CONCLUSION: Topoisomerase IIalpha expression is tightly linked to cell cycling, and topoisomerase I is likely a reflection of gene transcription. Rapidly progressing glomerular disease therefore appears to be accompanied by active mesangial cell proliferation and increased metabolic activity in glomerular cells. The correlation with inflammatory infiltrates is likely to reflect a positive feedback mechanism involving cytokines, growth factors, and adhesion molecules. Assessment of topoisomerases may therefore be of diagnostic help and might allow prognostic predictions. Provided that our observations are supported by clinicopathological follow-up studies, one might envisage the use of topoisomerase inhibitors in the therapy of chronic proliferative renal disease refractory to current treatment protocols.

[Primary focal segmental glomerulosclerosis: clinical and morphological prognostic factors]. / Pervichnyi fokal'no-segmentarnyi glomeruloskleroz: klinicheskie i morfologicheskie faktory prognoza.

AIM: To retrospectively analyze clinical course and results of immunodepressive therapy of patients with primary focal-segmental glomerulosclerosis (FSGS), to reveal prognostic factors of the disease progression and patients' sensitivity to immunosuppressive therapy. MATERIAL AND METHODS: Morphological diagnosis was specified, morphological indices of activity and sclerosis were estimated, renal survival was analysed, mono- and multivariate analysis of prognostic factors was made by the evidence obtained in the study of 135 biopsy specimens from CRF patients meeting the criteria of FSGS. RESULTS: At the moment of the disease onset only age of the patients was related to FSGS: 5- and 10-year survival was 100% if the disease started under 16 years of age, if older--the survival was 80 and 65%, respectively. Nephrotic syndrome, hematuria, high creatinine, racemose alterations in the glomeruli worsened the disease prognosis. When cytostatics and corticosteroids were used in combination they produced better results and were associated with better prognosis than each of them in monotherapy. Patients with marked hematuria and low proteinuria were less sensitive to therapy than those with weak hematuria and high proteinemia. Patients with FSGS having high IA and SI required more aggressive therapy for response. CONCLUSION: Renal biopsy with quantitation of IA and IS increases the prognosis accuracy and is important for choice of the treatment policy in patients with primary FSGS.

[Lupus nephritis and pregnancy]. / Volchanochnyi nefrit i beremennost'.

AIM: To evaluate effects of pregnancy on the course and prognosis of lupus nephritis and fetal outcome, in particular, in patients with lupus nephritis (LN) and antiphospholipid syndrome (APS). MATERIAL AND METHODS: A retrospective analysis was made of the course of LN in 31 females (44 pregnancies). RESULTS: A favorable outcome of pregnancy is possible in LN women if they had a persistent remission at conception. However, one third of these women had exacerbations of LN in pregnancy and early postpartum period. Pregnancy developing in active LN aggravated LN course in all the women. Fetal outcome was unfavorable. LN was especially severe if it arose in the course of pregnancy or early postpartum period. It seems that the presence of APS affected pregnancy outcome in a less degree than LN activity. CONCLUSION: Both in pregnancy and postpartum period, LN showed frequent exacerbations, but if the conception takes place during a persistent remission of LN, under adequate care and treatment, a delivery of a viable child is possible without an extraordinary risk for the mother.

Role of matrix metalloproteinases in development of diabetic nephropathy.

This review considers molecular mechanisms that underlie disorders in the structure and metabolism of renal extracellular matrix in diabetic nephropathy. The contribution of the increased synthesis of renal extracellular matrix proteins in the accumulation of renal mesangial matrix is considered, and the important role of the degradation system of the extracellular matrix proteins in the development of fibrosis is also shown. Data on changes in mRNA expression for the matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) in various forms of diabetic nephropathy are presented. A correlation is established between changes in the balance of MMP proteolytic activity and TIMP activity and the accumulation of extracellular matrix.

[Polymorphism studies of angiotensin converting enzyme gene in chronic glomerulonephritis]. / Izuchenie polimorfizma gena angiotenzinprevrashchaiushchego fermenta pri khronicheskom glomerulonefrite.

AIM: To investigate the relationship between polymorphism of angiotensin-converting enzyme (ACE) gene and predisposition to chronic glomerulonephritis (CGN) as well as antihypertensive and anti proteinuric response to ACE inhibitors (ACEI) treatment, therapy with angiotensin II receptor antagonists. MATERIALS AND METHODS: Genotype was determined in 57 CGN patients and 113 subjects free of chronic diseases. Effects of ACE gene polymorphism on antihypertensive and antiproteinuric efficiency of ACEI and cozaar were studied in 35 CGN patients on monotherapy. 24-h proteinuria, levels of creatinine, potassium in the serum, arterial pressure, glomerular filtration rate were measured in all the patients. RESULTS: No significant differences were found between incidence of ACE gene genotypes and alleles in patients with CGN and controls. Maximal antihypertensive response to therapy was observed after a month treatment in patients with genotypes II and ID. Lowering of arterial pressure in patients with genotype DD was observed on month 6-12 of continuous therapy. Proteinuria diminished on the treatment month 1-3 in patients with genotypes II and ID, in genotype DD proteinuria rose for the same period of time. Proteinuria dropped similarly in all the groups by month 6-12. CONCLUSION: Relations between ACE gene polymorphism and genetic predisposition to CGN were not found. Patients with genotype II were most sensitive to IACE and cosaar treatment. Lack of an early anti proteinuric response in homozygotes DD does not determine effectiveness of long-term IACE treatment and should not be a reason for the above drug discontinuation.

[Platelet dysfunction and pregnancy in gestational exacerbation of chronic glomerulonephritis]. / Disfunktsiia trombotsitov i iskhody beremennosti pri gestatsionnom obostrenii khronicheskogo glomerulonefrita.

AIM: To evaluate platelet dysfunctions and pregnancy outcomes in females with gestational exacerbation of chronic glomerulonephritis (CGN) and the disease remission. MATERIALS AND METHODS: Platelet metabolism was studied by activity of intraplatelet LDG, platelet secretory activity by plasm beta-TG and ADP-aggregation in 75 gravidae. Of them 16 had exacerbation of CGN, 40 females were in remission of CGN and 19 healthy pregnant women served control. RESULTS: Enhanced LDG activity and intensity of maximal ADP aggregation, high beta-TG levels compared to control were recorded in gravidae with CGN both in exacerbation and remission. The frequency of preterm deliveries, intrauterine growth retardation, neonatal hypotrophy was greater in women with gestational exacerbation of nephritis compared to pregnant women with stable nephritis. CONCLUSION: Metabolic and functional platelet hyperactivity with platelet intravascular activation in pregnancy in aggravated CGN suggest contribution of platelets to onset of the disease gestational exacerbation. Pregnancy-induced overactivation of platelets in CGN exacerbation stimulates intravascular coagulation in placental circulation with resultant microthrombi in placental vessels responsible for high rate of unfavorable pregnancy outcomes in relevant patients.

[Hemodynamic mechanisms of lupus nephritis progression]. / Gemodinamicheskie mekhanizmy progressirovaniia volchanochnogo nefrita.

AIM: To study the role of abnormal intrarenal hemodynamics (IRHD) in progression of lupus nephritis (LN) and its response to therapy with inhibitors of angiotensin-converting enzyme (ACE). MATERIALS AND METHODS: The trial included 30 LN patients (27 females, 3 males; age 29.8+(-)10.4 years). 19 had aggravation of active LN. All the patients were free of chronic renal insufficiency. IRHD was studied with estimation of renal functional reserve (RFR) using protein loading, evaluation of clinical activity of LN and renal function, blood pressure. The tests were repeated after 6 months of treatment with ACE inhibitors (captopril and ramiprilol) in 13 patients (11 of them had exacerbation of active LN). RESULTS: Disturbed IRHD was found in 37% of the patients. Blood hypertension deteriorated this condition. Treatment with ACE inhibitors in 6 months brought about a significant decrease in blood pressure and improvement of IRHD. Before treatment RFR was absent in 46% of patients, after treatment in 1 patient. CONCLUSION: Defects in IRHD occur in LN frequently. These are related with the presence of blood hypertension and activity of LN. Inhibitors of ACE seem perspective in management of essential hypertension in LN patients but this hypothesis needs confirmation by the results of further studies.

[Comparison of two cyclophosphamide treatment regimens in nephrotic patients with chronic glomerulonephritis]. / Sravnenie dvukh metodov lecheniia tsiklofosfanom bol'nykh khronicheskim glomerulonefritom s nefroticheskim sindromom.

AIM: Comparison of two cyclophosphamide (CPA) treatment regimens in chronic glomerulonephritis (CGN) patients: oral daily CPA versus intravenous CPA pulses (IV-CPA) MATERIALS AND METHODS: 31 nephrotic patients entered the trial: 12, 16 and 3 with membraneous, mesangial proliferative and mesangiocapillary CGN, respectively. The patients were randomized into two groups. 13 patients of group 1 received oral CPA (1.5-2.0 mg/kg/day for 6 months, while 18 patients of group 2 received IV-CPA pulses (20 mg/kg/monthly, at least 6 pulses) combined with oral prednisolone (40-6-mg/day during 1.5 mo with subsequent tapering). At entry, no statistical differences (p > 0.05) were found between groups 1 and 2 by age, gender, duration of the renal disease, serum creatinine levels, frequency of arterial hypertension. Mean duration of follow-up was 27.6 and 22.6 mo (p > 0.05) for group 1 and 2, respectively. RESULTS: After 6 months of follow-up there was no difference in the rate of complete and partial remission between the groups (69 and 83% for group 1 and 2, respectively). The rate of renal function deterioration was also similar. Side effects occurred 3 times more frequently in group 1 than group 2. The mean cumulative course dose of CPA per 1 patient in group 1 was 35.6 g, in group 2--5.6 g. CONCLUSION: The effectiveness of methods was similar irrespective of CGN morphological form, but in spite of similar rates of remission of nephrotic syndrome, pulse CPA is preferable being more safe as to possible complications.

[Arterial hypertension in lupus nephritis]. / Arterial'naia gipertoniia pri volchanochnom nefrite.

Incidence of arterial hypertension (AH), its relation with activity of lupus nephritis (LN), other factors (antiphospholipid syndrome, old age, disturbances of purin and lipid metabolism), prognostic implication of AH were studied in a trial performed from 1957 to 1996. A total of 398 patients with LN were divided into 3 groups according to immunosuppressive therapy practiced in different time periods. Overall AH incidence and that of severe AH were similar at present and in the past. AH occurred frequently in patients with rapidly progressing LN and active LN with nephrotic syndrome. In remission of nephrotic syndrome AH incidence was on the decrease. This suggests that hypertension may be a criterion of LN activity. AH was also associated with the presence of antiphospholipid syndrome and old age. AH was a separate prognostic indicator in respect to overall and renal survival. Hemodynamic mechanisms may contribute to LN progression.

[Nitric oxide: its role in the development of pregnancy complications and in their prevention in women with hypertension and chronic glomerulonephritis]. / Oksid azota: rol' v razvitii oslozhnenii beremennosti i v ikh profilaktike u zhenshchin s gipertonicheskoi bolezn'iu i khronicheskim glomerulonefritom.

The activity of NO-synthase and formation of NO (EDRF) were assessed by an increase in the activity of NO-dependent hyanilate cyclase in response to L-arginine in vitro in platelets of 61 pregnant females (39, 8 14 with essential hypertension, preeclampsia and healthy controls, respectively) and in 9 hypertensive nonpregnant females. Compared to healthy pregnant females, EDRF synthesis activity was inhibited in hypertensive gravidas but enhanced in preeclampsia patients. Effectiveness of exogenic donator NO (transdermal nitroglycerine, Nitroderm NNS 5) was studied in a randomised trial of 76 gravidas with essential hypertension (EH), EH and chronic glomerulonephritis (GN). 39 of them were given transdermal nitroglycerine, 37 received acetylsalicilic acid and curantil. The number of treatment failures was the same in both groups. The conclusion is made that nitro compounds are adequate for use in EH and chronic GN gravidas.