warfarin and Glomerulonephritis--IGA

Children with IgA nephropathy showing diffuse (>80%) mesangial proliferation are at high risk for end-stage renal failure (ESRF). A previous controlled trial showed that combination therapy consisting of prednisolone, azathioprine, heparin-warfarin, and dipyridamole early in the course of disease reduces immunologic renal injury and prevents the progression of sclerosed glomeruli. The objective of this study was to evaluate the long-term effectiveness of combination therapy in children with IgA nephropathy showing diffuse mesangial proliferation.. A secondary analysis of a multicenter, randomized, controlled trial involving 78 children with IgA nephropathy who received either 2-year combination therapy or heparin-warfarin and dipyridamole (control) therapy was conducted.. The median duration of observation was 10 years (range, 0.5 to 18). Two of 40 patients (5%) who received combination therapy and five of 34 patients (14.7%) who received control therapy developed ESRF. A Kaplan-Meier plot of renal survival showed that the outcomes of patients in the combined therapy group were better than those in the control therapy group (log-rank P = 0.03). The 10-year renal survival probability of each group was 97.1% (95% confidence interval, 81.4 to 99.6%) and 84.8% (95% confidence interval, 55.4 to 95.5%), respectively. The Cox proportional hazards model showed that the 2-year combination therapy was significantly associated with renal survival in both univariate and multivariate analyses.. Two-year combination therapy not only ameliorated the activity of the acute phase of nephritis but also improved the long-term outcome of severe childhood IgA nephropathy.

Topics: Adolescent; Anticoagulants; Azathioprine; Cell Proliferation; Child; Dipyridamole; Disease Progression; Drug Therapy, Combination; Female; Glomerulonephritis, IGA; Heparin; Humans; Immunosuppressive Agents; Japan; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Glomerulus; Male; Prednisolone; Proportional Hazards Models; Prospective Studies; Proteinuria; Risk Assessment; Risk Factors; Severity of Illness Index; Time Factors; Treatment Outcome; Warfarin

Topics: Azathioprine; Child; Dipyridamole; Drug Therapy, Combination; Evidence-Based Medicine; Glomerulonephritis, IGA; Heparin; Humans; Practice Guidelines as Topic; Prednisolone; Prognosis; Randomized Controlled Trials as Topic; Ribonucleosides; Warfarin

Various pathogenetic mechanisms are involved in IgA nephritis: immunological; platelet, coagulation and vascular injury; mesangial cell proliferation and contractility; hypertension; glomerular hyperperfusion and tubulo-interstitial injury. It is now possible to identify the subgroup of patients with IgA nephritis who have adverse prognostic features and may develop progressive glomerular scarring with renal failure. These features are proteinuria greater than 1 gm/day, non-selective proteinuria, glomerulosclerosis, hypertension, crescents and medial hyperplasia of blood vessels on renal biopsy. Controlled trials involving cyclophosphamide, anti-platelet agent (dipyridamole) and low dose warfarin; prednisolone; angiotensin converting enzyme inhibitors and eicosapentanoic acid (fish oil) appear promising. Currently, patients with bad prognostic indices in the Department are offered entry into an ongoing controlled trial of dipyridamole and low dose (anti-thrombotic dose) warfarin. Those patients with nephrotic syndrome especially with selective proteinuria are treated with a course of prednisolone and failing that, cyclophosphamide. It is important to maintain adequate blood pressure control among hypertensive patients as uncontrolled hypertension can lead to accelerated renal failure. With the onset of even mild renal impairment, dietary protein restriction should be recommended as this will help to decrease the rate of renal deterioration due to glomerular hyperfusion.

Topics: Blood Platelets; Captopril; Cyclosporins; Dietary Proteins; Eicosapentaenoic Acid; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; Hypertension, Renal; Platelet Aggregation Inhibitors; Warfarin

Two previous randomized controlled trials showed that treatment of severe childhood immunoglobulin A (IgA) nephropathy using prednisolone with azathioprine, heparin-warfarin, or dipyridamole prevented the increase of sclerosed glomeruli. Prednisolone alone, however, did not prevent further increase. These studies indicated the importance of immunosuppressants in the treatment. An additional pilot study using mizoribine instead of azathioprine enabled us to complete 2 years of combined regimen. It showed non-numerical inferior effectiveness compared with the azathioprine regimen. Further examination of the additional efficacy of warfarin and dipyridamole was required.. A randomized control trial of prednisolone and mizoribine with (group 1) or without (group 2) warfarin and dipyridamole was administered for treatment of 71 children with severe IgA nephropathy to evaluate the efficacy of additional warfarin and dipyridamole.. Thirty of 34 patients (88.2%) in group 1, and 27 of 36 patients (75.0%) showed the disappearance of proteinuria as defined by early morning urinary protein to creatinine ratio of < 0.2 during the 2-year treatment period. The cumulative disappearance rate of proteinuria determined by the Kaplan-Meier method showed that the disappearance rate of proteinuria was significantly higher in group 1 than in group 2 (log-rank P = 0.04). There was no significant difference in pathological findings, but there was a tendency of increase of global sclerosis in group1 which might be related to warfarin. Most of the adverse effects were related to prednisolone, but fortunately transient.. The balance between minimal benefits of warfarin/dipyridamole and potential adverse effects may be in favor of avoiding them in children with IgA nephropathy.

Topics: Adolescent; Biopsy; Child; Dipyridamole; Drug Therapy, Combination; Female; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Male; Prednisolone; Prospective Studies; Proteinuria; Ribonucleosides; Severity of Illness Index; Treatment Outcome; Warfarin

Children with IgA nephropathy showing diffuse (>80%) mesangial proliferation are at high risk for end-stage renal failure (ESRF). A previous controlled trial showed that combination therapy consisting of prednisolone, azathioprine, heparin-warfarin, and dipyridamole early in the course of disease reduces immunologic renal injury and prevents the progression of sclerosed glomeruli. The objective of this study was to evaluate the long-term effectiveness of combination therapy in children with IgA nephropathy showing diffuse mesangial proliferation.. A secondary analysis of a multicenter, randomized, controlled trial involving 78 children with IgA nephropathy who received either 2-year combination therapy or heparin-warfarin and dipyridamole (control) therapy was conducted.. The median duration of observation was 10 years (range, 0.5 to 18). Two of 40 patients (5%) who received combination therapy and five of 34 patients (14.7%) who received control therapy developed ESRF. A Kaplan-Meier plot of renal survival showed that the outcomes of patients in the combined therapy group were better than those in the control therapy group (log-rank P = 0.03). The 10-year renal survival probability of each group was 97.1% (95% confidence interval, 81.4 to 99.6%) and 84.8% (95% confidence interval, 55.4 to 95.5%), respectively. The Cox proportional hazards model showed that the 2-year combination therapy was significantly associated with renal survival in both univariate and multivariate analyses.. Two-year combination therapy not only ameliorated the activity of the acute phase of nephritis but also improved the long-term outcome of severe childhood IgA nephropathy.

Topics: Adolescent; Anticoagulants; Azathioprine; Cell Proliferation; Child; Dipyridamole; Disease Progression; Drug Therapy, Combination; Female; Glomerulonephritis, IGA; Heparin; Humans; Immunosuppressive Agents; Japan; Kaplan-Meier Estimate; Kidney Failure, Chronic; Kidney Glomerulus; Male; Prednisolone; Proportional Hazards Models; Prospective Studies; Proteinuria; Risk Assessment; Risk Factors; Severity of Illness Index; Time Factors; Treatment Outcome; Warfarin

We previously reported that a combined therapy with heparin/warfarin and renin-angiotensin system (RAS) inhibitors dramatically reduces proteinuria for prolonged periods in advanced IgA nephropathy (IgAN). In the present study, we prospectively analyzed whether the combined therapy can inhibit the progressive decline in renal function of patients with progressive IgAN. Patients who had a marked linearity of decline in loss of glomerular filtration rate (GFR), assessed by reciprocal serum creatinine plots vs. time for more than one year, were recruited in this study if they were histologically diagnosed as IgAN at this point of declining renal function. Twelve patients were eligible for trial entry; reciprocal serum creatinine plot suggested end-stage renal failure within 5 years. All patients were treated with continuous intravenous infusion of heparin for 8 weeks, followed by oral administration of warfarin, ACE inhibitors and/or angiotensin II receptor blockers and dypiridamole. Eight patients were further given corticosteroid for 2 years because of the presence of acute glomerular lesions such as cellular crescent or angionecrosis. All patients were followed-up for at least 12 months, and the mean follow-up period was 34 +/- 20 (range 12-79) months. After the combined therapy, urinary protein excretion was significantly reduced from 2.4 +/- 1.5 g/day at baseline to 0.7 +/- 0.5 g/day at final observation, while the mean serum creatinine was not significantly different. Of note, the mean slope of 1/serum creatinine significantly increased from -0.009 to +0.0002 dl/mg/week (p < 0.05). Moreover, histological analysis of a repeat kidney biopsy which was performed in 5 patients at 2 years after the institution of the combined therapy revealed that the percentage of cellular/fibrocellular crescent and the degree of mesangial matrix expansion were significantly attenuated (19-->0.1% and 1.6-->0.6 score, respectively) while the percentage of global sclerosis and tubulointerstitial lesion did not increase. These results indicate that our combined therapy with heparin/warfarin and RAS inhibitors can inhibit the progressive decline in renal function Combined Heparin/Warfarin and RAS Inhibitors in Progressive IgAN 115 of patients with progressive IgAN through its marked antiproteinuric and anti-inflammatory effects.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Disease Progression; Drug Therapy, Combination; Female; Glomerulonephritis, IGA; Heparin; Humans; Male; Middle Aged; Prospective Studies; Renin-Angiotensin System; Treatment Outcome; Warfarin

A previous trial showed that treatment of children with severe IgA nephropathy (IgAN) using prednisolone, azathioprine, heparin-warfarin, and dipyridamole for 2 yr early in the course of disease reduced the severity of immunologic renal injury and prevented any increase in the percentage of sclerosed glomeruli. This study compared the effects of prednisolone, azathioprine, warfarin, and dipyridamole (combination) with those of prednisolone alone in 80 children with newly diagnosed IgAN that showed diffuse mesangial proliferation. Patients were randomly assigned to receive either the combination or prednisolone alone for 2 yr. The primary end point was the disappearance of proteinuria, defined as urinary protein excretion <0.1 g/m2 per d, and the secondary end points were urinary protein excretion at the end of treatment, the change in the percentage of sclerosed glomeruli during the trial, and adverse effects. The two study groups were similar in terms of baseline characteristics. Thirty-nine of the 40 patients who received the combination and 39 of the 40 who received prednisolone completed the trial. Thirty-six (92.3%) of the 39 patients who received the combination and 29 (74.4%) of the 39 who received prednisolone reached the primary end point by the 2-yr follow-up point (P = 0.007 log-rank). The percentage of sclerosed glomeruli was unchanged in the patients who received the combination but increased from 3.1 +/- 4.8 to 14.6 +/- 15.2% in the prednisolone group (P = 0.0003). The frequency of adverse effects was similar in the two groups. It is concluded that combination treatment may be better for severe IgAN than treatment with prednisolone alone.

Topics: Azathioprine; Child; Dipyridamole; Female; Glomerulonephritis, IGA; Glucocorticoids; Humans; Male; Prednisolone; Prospective Studies; Severity of Illness Index; Warfarin

No satisfactory treatment exists for IgA nephropathy (IgAN), especially in patients with severe histologic damage. Several trials using steroids combined with other therapies such as warfarin have demonstrated unremarkable results. We investigated the renoprotective effects of warfarin and steroids in IgAN patients with crescent formation.. Fifteen Japanese patients with IgAN were followed for up to 3 years. Crescent formation was recognized in over half of their glomeruli from renal biopsy specimens. Treatments consisted of either 0.5 mg/kg per day of prednisolone, or warfarin monotherapy. Blood pressure was controlled with long-acting calcium channel blockers and alpha-beta blockers. Serum creatinine and urinary protein excretion were evaluated at least every 2 months for 36 months.. Ten of the 15 patients completed the study. The serum creatinine levels had increased in both groups by 3 years, but significantly more so in the group treated with warfarin. However, they were not significantly different between the two groups as measured at the beginning and end of the study. Blood pressure for all patients in the study was maintained below 130/85 mmHg. Excluded from the study were 5 patients who experienced either peptic ulcers (n = 2, steroid group) or bleeding problems (n = 3, warfarin group).. These results suggest that corticosteroid therapy may assist in preventing deterioration of renal function in patients with IgAN accompanied by crescent formation. However, further study would be required to decide its usefulness.

Topics: Adolescent; Adult; Aged; Anticoagulants; Biopsy; Blood Pressure; Child; Creatinine; Female; Glomerulonephritis, IGA; Glucocorticoids; Humans; Kidney; Male; Middle Aged; Prednisolone; Proteinuria; Warfarin

The most appropriate treatment for patients with IgA nephropathy is controversial. Treatment with prednisolone, azathioprine, heparin-warfarin, and dipyridamole early in the course of disease may prevent immunologic renal injury in children with severe IgA nephropathy. To determine whether similar results can be obtained with a combination of just heparin-warfarin and dipyridamole, the effects of such treatment were compared to those of treatment with prednisolone, azathioprine, heparin-warfarin, and dipyridamole in 78 children with newly diagnosed IgA nephropathy showing diffuse mesangial proliferation. The patients were randomly assigned to receive either prednisolone, azathioprine, heparin-warfarin, and dipyridamole for 2 yr (group 1) or heparin-warfarin and dipyridamole for 2 yr (group 2). All of the 40 patients in group 1 and 34 of the 38 patients in group 2 completed the trial. The mean urinary protein excretion fell in group 1 patients (P < 0.0001), but remained unchanged in group 2 patients. The mean serum IgA concentration was reduced in group 1 patients (P = 0.0002), but was unchanged in group 2 patients. BP and creatinine clearance were normal at the end of the trial in all but one group 2 patient, who developed chronic renal insufficiency. The percentage of glomeruli showing sclerosis was unchanged in group 1 patients, but increased in group 2 patients (P = 0.006). The intensity of mesangial IgA deposits decreased in group 1 patients (P = 0.02), but remained unchanged in group 2 patients. In conclusion, the present study shows that treatment of children with severe IgA nephropathy with prednisolone, azathioprine, heparin-warfarin, and dipyridamole for 2 yr early in the course of disease reduces immunologic renal injury and prevents increase of sclerosed glomeruli.

Topics: Adolescent; Azathioprine; Blood Urea Nitrogen; Child; Dipyridamole; Drug Therapy, Combination; Glomerular Mesangium; Glomerulonephritis, IGA; Hematuria; Heparin; Humans; Immunoglobulin A; Microscopy, Fluorescence; Prednisolone; Proteinuria; Warfarin

Topics: Adult; Anticoagulants; Azathioprine; Child; Dipyridamole; Drug Therapy, Combination; Glomerulonephritis, IGA; Glucocorticoids; Heparin; Humans; Immunosuppressive Agents; Platelet Aggregation Inhibitors; Prednisolone; Warfarin

This study is a 5-year post trial assessment of patients with IgA nephritis who entered a 3-year prospective controlled trial of cyclophosphamide, dipyridamole (D) and low-dose warfarin (W). Patients entered the trial from 1979 to 1981 and the trial ended in 1984 with those in the treatment group having more stable renal function and less proteinuria compared to the control group. Present reassessment of the patients in 1989 showed no difference in the renal function between those in the treatment group (n = 27) and the control group (n = 21). 6 patients in the treatment group and 7 in the control group were in ESRF. At the conclusion of the trial in 1984, among the 27 patients in the original treatment group, 13 patients elected to continue with D + W while the other 14 patients chose to cease therapy and therefore served as the new control group. 5 years later, renal function in the new treatment group (n = 13) was significantly stable compared to the new control group (n = 14), (serum creatinine 1.4 +/- 0.7 versus 4.4 +/- 3.2 mg/dl, p less than 0.01). Furthermore, all the 6 patients with ESRF in the original treatment group of 27 patients were from the new control group (n = 14) where treatment with D + W had been ceased. None of the patients still on D + W are in ESRF.

Topics: Adult; Cyclophosphamide; Dipyridamole; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulonephritis, IGA; Humans; Kidney Function Tests; Male; Prospective Studies; Time Factors; Warfarin

Of 52 patients with mesangial IgA nephropathy, 25 were allocated to treatment with cyclophosphamide (6 months), and dipyridamole and warfarin (2 years) and 27 to no treatment in a randomized prospective 2-year study. At entry, the treated and untreated groups of patients did not differ in mean serum creatinines, urinary protein excretions, quantitative urinary erythrocyte counts or blood pressure readings. At the end of the trial mean (+/- SEM) serum creatinine values had gone from 0.12 +/- 0.01 to 0.13 +/- 0.01 mmol/l (p less than 0.05) in untreated patients and from 0.10 +/- 0.01 to 0.12 +/- 0.01 mmol/l (p less than 0.05) in treated patients. Mean (+/- SEM) log values of urinary erythrocyte (rbc) counts had not changed significantly from 5.47 +/- 0.09 to 5.21 +/- 0.14 log rbc/ml in untreated patients, from 5.45 +/- 0.11 to 5.49 +/- 0.19 log rbc/ml in treated patients. However, in treated patients, mean (+/- SEM) urinary protein excretions decreased from 1.67 +/- 0.35 to 1.15 +/- 0.31 g/24 h (p less than 0.01) whereas in untreated patients urinary protein was unchanged between initial values of 1.76 +/- 0.34 and follow-up at 1.89 +/- 0.45 g/24 h. No significant changes in blood pressure occurred in either group. This study supports the observation that treatment of IgA nephropathy with cyclophosphamide, dipyridamole and warfarin is associated with a reduction of urinary protein excretion but a significant effect on preservation of renal function, at least as determined by serum creatinine values, could not be confirmed over this two-year study.

Topics: Adult; Cyclophosphamide; Dipyridamole; Drug Therapy, Combination; Female; Glomerulonephritis, IGA; Humans; Male; Prospective Studies; Time Factors; Warfarin

Topics: Adult; Clinical Trials as Topic; Dipyridamole; Female; Glomerulonephritis, IGA; Humans; Male; Nephritis; Warfarin

Fifty-two pairs of patients with idiopathic diffuse mesangial proliferative glomerulonephritis entered a controlled 3-year prospective trial of a combination regimen of cyclophosphamide, dipyridamole and warfarin. In the treatment group proteinuria decreased significantly (p less than 0.01) and renal function remained stable, but in the control group there was no change in proteinuria and creatinine clearance (Ccr) decreased significantly (p less than 0.01). The time patients with renal impairment in the control group and those in the treatment group took to reach end stage renal failure was significantly different (6.1 years versus 8.9 years, p less than 0.02). Among the patients with IgA nephritis, those in the treatment group (n = 27) had stable renal function and a significant decrease in proteinuria (p less than 0.01) but in the control group (n = 21) there was a significant fall in Ccr (p less than 0.01) and rise in serum creatinine (p less than 0.02) with no change in proteinuria. Among 23 pairs of patients in the study who were matched for renal function and degree of glomerulosclerosis, those in the treatment group had stable renal function and decrease in proteinuria (p less than 0.01) whereas those in the control group had decreased Ccr (p less than 0.01) but no change in proteinuria.

Topics: Adult; Clinical Trials as Topic; Cyclophosphamide; Dipyridamole; Drug Therapy, Combination; Female; Glomerulonephritis; Glomerulonephritis, IGA; Humans; Male; Prospective Studies; Time Factors; Warfarin

Henoch-Schönlein purpura (HSP) is a small vessel vasculitis characterized by the presence of vascular immunoglobulin A deposition that usually presents as non-thrombocytopenic palpable purpura. It primarily affects children and is less common in adults. The incidence of hemorrhagic necrotic skin lesions increases with age, similarly to renal involvement. Warfarin is a widely used oral anticoagulant drug that has rarely been associated with leukocytoclastic vasculitis and allergic interstitial nephritis. We report a patient with HSP who presented with cutaneous ulcerative plaques and proteinuria in the setting of warfarin therapy. We would like to raise the awareness of this potential adverse effect of warfarin for prompt diagnosis.

Topics: Anticoagulants; Atrial Fibrillation; Drug Substitution; Enoxaparin; Female; Glomerulonephritis, IGA; Glucocorticoids; Humans; IgA Vasculitis; Middle Aged; Prednisolone; Warfarin

The aim of this study was to determine whether serum immunoglobulin A/complement factor 3 (IgA/C3) ratio and glomerular C3 staining predict outcome in IgA nephropathy.. We collected data for 44 IgA nephropathy children treated with multi-drug combination therapy. The children were retrospectively divided into four groups based on serum IgA/C3 ratio and glomerular C3 staining: group A, IgA/C3 ratio >2.68 (median) and glomerular C3 staining ≥2.0, n = 9; group B, IgA/C3 ratio >2.68 and glomerular C3 staining <2.0, n = 7; group C, IgA/C3 ratio <2.68 and glomerular C3 staining ≥2.0, n = 7; and group D, IgA/C3 ratio <2.68 and glomerular C3 staining <2.0, n = 21. Clinical features; pathology at the first and second renal biopsy and at the latest follow up; and prognosis were analyzed for the four groups.. At the most recent follow up, urinary protein excretion, incidence of hematuria, and serum creatinine in group A were all higher than in group D. At the second biopsy, crescent absence/presence ratio; mesangial hypercellularity, segmental glomerulosclerosis or adhesion, endocapillary hypercellularity, and tubular atrophy/interstitial fibrosis as well as crescents and global glomerulosclerosis (MESTCG) score; and clonicity index in group A were higher than in group D. All patients in group D had normal urine, and the prevalence of persistent nephropathy in group A was higher than in group D.. Serum IgA/C3 ratio and glomerular C3 staining can predict outcome in IgA nephropathy.

Topics: Adolescent; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Biopsy; Child; Complement C3; Dilazep; Female; Glomerulonephritis, IGA; Glucocorticoids; Humans; Immunoglobulin A; Kidney Function Tests; Kidney Glomerulus; Male; Prednisolone; Prognosis; Retrospective Studies; Ribonucleosides; Vasodilator Agents; Warfarin

A 55-year-old man with Marfan syndrome taking warfarin for anticoagulant therapy after aortic valve replacement developed acute kidney injury (serum creatinine level of 9.01 mg/dL) and gross macrohematuria. Renal biopsy showed red cell casts in the renal tubules, glomerular crescent formation in the glomeruli with immunoglobulin A deposition, and global sclerosis. Based on these findings, the patient was diagnosed with warfarin-related nephropathy with acute kidney injury characterized by immunoglobulin A nephropathy with crescents. The warfarin was withdrawn, and his hematuria and renal function improved without immunosuppressive agents.

Topics: Acute Kidney Injury; Anticoagulants; Aortic Valve Insufficiency; Glomerulonephritis, IGA; Hematuria; Humans; Kidney; Kidney Glomerulus; Kidney Tubules; Male; Marfan Syndrome; Middle Aged; Treatment Outcome; Warfarin

A wide variety of treatments, including tonsillectomy and steroid pulse therapy (TSP), are performed for the various stages of IgA nephropathy (IgAN) in Japan. However, the current status of treatments for IgAN patients in Japan is still unclear. The objective of the present study was to investigate the current status of treatments for IgAN patients.. A nationwide survey was conducted in 2008 by sending questionnaires to the 1,194 teaching hospitals of the Japanese Society of Nephrology (JSN) via Progressive Renal Diseases Research, Research on intractable disease, from the Ministry of Health, Labour and Welfare of Japan.. Among the total 376 hospitals (31.4 %) that responded, 188 hospitals (66.2 % in the internal medicine departments) performed TSP, out of which 137 hospitals (61.4 %) had begun to perform TSP in the period from 2004 to 2008. The following two major steroid pulse protocols in TSP were used: (1) three cycles over 3 consecutive weeks and (2) three cycles every 2 months. Approximately 68 % of pediatric hospitals (68 hospitals) performed combination therapy with prednisolone, azathioprine, heparin-warfarin and dipyridamole. The clinical remission rates for hematuria and proteinuria after TSP tended to be higher than those following other corticosteroid therapies. Almost all hospitals prescribed antiplatelet agents and renin angiotensin system inhibitor (RAS-I).. In addition to popular treatments such as antiplatelet agents and RAS-I, TSP is becoming a standard treatment for adult IgAN patients in Japan.

Topics: Adult; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Azathioprine; Child; Combined Modality Therapy; Glomerulonephritis, IGA; Heparin; Humans; Japan; Platelet Aggregation Inhibitors; Prednisolone; Proteinuria; Renin-Angiotensin System; Surveys and Questionnaires; Tonsillectomy; Warfarin

The patient was an 82-year-old female. She had been treated with warfarin for atrial fibrillation that developed after a heart valve replacement operation. She was admitted because of a progressive loss of renal function together with persistent microscopic hematuria and proteinuria. Although the renal biopsy showed only focal mononuclear cell infiltration and mild mesangial expansion in the glomeruli, the occlusive red blood cell casts were remarkable in the tubules and were accompanied by inflammatory and edematous changes in the surrounding interstitial area. After the adjustment of an excessively extended prothrombin time, her renal function gradually improved in parallel with the marked decrease in the microhematuria. It was assumed that an acute kidney injury observed in this case was caused by the occlusive red blood cell casts as a result of abnormal hemorrhage in the glomeruli due to focal glomerulonephritis and a warfarin overdose. The present case, therefore, suggests that a warfarin overdose is a potential risk factor for acute kidney injury in the presence of coexisting glomerular injury.

Topics: Acute Kidney Injury; Aged, 80 and over; Female; Glomerulonephritis, IGA; Hematuria; Humans; Kidney Glomerulus; Warfarin

Topics: Acute Kidney Injury; Adult; Child; Cohort Studies; Cyclophosphamide; Dipyridamole; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulonephritis, IGA; Humans; Male; Randomized Controlled Trials as Topic; Retrospective Studies; Risk Assessment; Treatment Outcome; Warfarin

The prognosis of children with severe IgA nephropathy showing diffuse mesangial proliferation is poor. However, the prognosis can be improved by combination therapy (prednisolone + azathioprine or mizoribine + warfarin + dipyridamole) or prednisolone alone over a 2-year period, and disappearance of glomerular IgA deposits is often observed. Details of the incidence and clinicopathological significance of glomerular IgA disappearance remain unclear.. To investigate this phenomenon, we retrospectively screened and analysed 124 consecutive children (age ≤ 18 years at first biopsy) with newly diagnosed severe IgA nephropathy showing diffuse mesangial proliferation, who received combination therapy or prednisolone alone for 2 years and underwent repeat biopsies.. Among these patients, 90 received combination therapy, and 34 received prednisolone alone. After 2 years of treatment, 27 of the patients (21.8%) showed disappearance of glomerular IgA. Logistic analysis showed that IgA disappearance was associated with less severe urinary protein excretion at the end of treatment. Kaplan-Meier analysis of the long-term course revealed a significant difference in proteinuria-free survival after the 2-year treatment period between the patients with IgA disappearance and those without (P = 0.008; log-rank test). The Cox proportional hazards model showed that disappearance of glomerular IgA after the treatment was a factor significantly associated with proteinuria-free survival in both univariate and multivariate analyses.. The present results suggest that disappearance of IgA after 2 years of treatment indicates milder disease severity, even in patients with diffuse mesangial proliferation, and is a prognostic factor related to proteinuria-free survival.

Topics: Anti-Inflammatory Agents; Anticoagulants; Azathioprine; Child; Dipyridamole; Drug Therapy, Combination; Female; Glomerular Mesangium; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Immunosuppressive Agents; Kidney Glomerulus; Male; Prednisolone; Retrospective Studies; Ribonucleosides; Survival Rate; Treatment Outcome; Vasodilator Agents; Warfarin

Renal tubulointerstitial injury plays an important role in the development of IgA nephropathy (IgAN), the most common form of glomerulonephritis. Few currently in use biomarkers can sensitively detect the earliest signs of renal tubular injury, hindering our efforts to launch preventive and therapeutic measures for this disorder in a timely manner. Neutrophil gelatinase-associated lipocalin (NGAL) is an acute phase protein that is rapidly released from not only neutrophils but also a variety of cell types upon inflammation and tissue injury. Its small molecular size and protease resistance could render it an excellent biomarker of renal injury in IgAN. In this study, we tested this hypothesis by measuring urinary levels of NGAL, creatinine and N-acetyl-beta-D-glucosaminidase (NAG) in 40 healthy individuals and 70 IgAN patients with various disease severities. The urinary NGAL levels and NGAL/creatinine values were significantly upregulated in Lee grade III IgAN patients, in correlation with progressive glomerular mesangial proliferation and tubulointerstitial injury. Compared with urinary NAG levels, the urinary NGAL levels elevated much more drastically and can be readily detected even in Lee grade II IgAN patients when their NAG levels showed almost no change. Our findings suggest the promising use of urinary NGAL as an early biomarker for tubulointerstitial injury of IgA nephropathy and perhaps other types of renal disease in general.

Topics: Acetylglucosaminidase; Acute-Phase Proteins; Adolescent; Adult; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Benzazepines; Biomarkers; Female; Glomerulonephritis, IGA; Humans; Kidney Tubules; Lipocalin-2; Lipocalins; Male; Mesangial Cells; Middle Aged; Phytotherapy; Plant Extracts; Predictive Value of Tests; Proteinuria; Proto-Oncogene Proteins; ROC Curve; Tripterygium; Warfarin

We describe a patient with IgA nephropathy associated with Crohn disease. IgA nephropathy first appeared at the age of 10 years. Combined therapy with prednisolone, cyclophosphamide, warfarin, and angiotensin-converting enzyme inhibitor resulted in clinical improvement over the following year, and remission was maintained. At the age of 13 years, the patient developed Crohn disease and IgA nephropathy recurred. Significant increases in serum IgA were associated with progression of Crohn disease. An elemental diet combined with oral prednisolone resulted in clinical improvement of Crohn disease and in remission of nephropathy and normalization of serum IgA concentration. The clinical course of the two diseases was linked, suggesting a common pathogenetic mechanism involving an IgA immune response to mucosal challenge in the intestine.

Topics: Adolescent; Alkylating Agents; Angiotensin-Converting Enzyme Inhibitors; Anti-Inflammatory Agents; Anticoagulants; Crohn Disease; Cyclophosphamide; Diet; Glomerulonephritis, IGA; Humans; Immunoglobulin A; Male; Prednisolone; Recurrence; Sulfasalazine; Warfarin

Topics: Anticoagulants; Cyclophosphamide; Dipyridamole; Dose-Response Relationship, Drug; Glomerulonephritis, IGA; Humans; Platelet Aggregation Inhibitors; Randomized Controlled Trials as Topic; Warfarin

We retrospectively evaluated renal outcome in a total of 38 children and adolescents with IgA nephropathy who were selected for 6-month therapy for clinical (proteinuria > 1 g/m2/24 hour) and pathologic (mesangial proliferation, crescent formation, and tubulo-interstitial changes) features suggestive of progressive renal failure. Seventeen patients (group A) were treated with a combination of prednisolone, cyclophosphamide and dipyridamole, and the remaining patients (21; group B) were treated with the same drugs plus warfarin. All the patients were followed-up for more than 2 years (range 2-10 years, mean 4.8). In both groups, the mean urinary protein excretion value was significantly reduced after the therapy, compared with that at entry into the therapy. The significant reduction continued for up to 6 years in group A and up to 5 years in group B. Creatinine clearance was stable until 5-6 years after the trial in both groups, but 4 patients progressed to end-stage renal failure after that period. Post-therapy biopsy was performed in 14 patients, and was compared with the pre-therapy biopsy. The activity score had improved in both groups, but the chronicity score did not. These results indicate that there was a temporary effect and limited benefit with this treatment of combined drugs for children and adolescents with IgA nephropathy. The additive effect of warfarin was not substantiated.

Topics: Adolescent; Child; Child, Preschool; Cyclophosphamide; Dipyridamole; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulonephritis, IGA; Humans; Male; Prednisolone; Retrospective Studies; Warfarin

To achieve clinical remission, intensive therapy in active IgA nephropathy was conducted on a trial basis. Forty-five patients with active IgAN in which cellular crescents were present were divided into two groups. The patients in one group (Group A, N = 19) were treated with a combined regimen of steroid pulse, cyclophosphamide (4 months), dipyridamole (36 months) and warfarin. The patients in the other group (Group B, N = 26) were treated with tonsillectomy in addition to the same regimen as Group A. Three years after the initiation of treatment, proteinuria and hematuria had significantly decreased in both groups, and the renal function in Group B was significantly improved. Remission of proteinuria and hematuria was achieved in five patients (26.3%) and eight patients (42.1%), respectively, in Group A, and 14 patients (53.8%) and 20 patients (76.9%), respectively, in Group B. These results indicate that early intensive therapy combined with tonsillectomy in active IgAN is potentially of great benefit from both the medical and socioeconomic points of view.

Topics: Adolescent; Adult; Cyclophosphamide; Dipyridamole; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulonephritis, IGA; Hematuria; Humans; Male; Middle Aged; Proteinuria; Remission Induction; Tonsillectomy; Warfarin

We report the case of a 15-year-old Japanese female with severe mesangial proliferative IgA glomerulonephritis who showed a dramatic response to cocktail therapy for nephrotic syndrome. She had suddenly developed massive proteinuria and microscopic hematuria. The first renal biopsy at one month after onset revealed severe mesangial hypercellularity and podocytic detachment from the glomerular basement membrane (GBM). The cocktail therapy resulted in a decrease of proteinuria clinically, and a second biopsy demonstrated repair of the podocytic detachment. We suggest that the massive proteinuria in this case was due to destruction of the size barrier by detachment of podocytes from the GBM, and the repair of the podocytic covering on the GBM was accelerated by the cocktail therapy.

Topics: Adolescent; Basement Membrane; Cyclophosphamide; Dipyridamole; Drug Therapy, Combination; Female; Furosemide; Glomerulonephritis, IGA; Glomerulonephritis, Membranoproliferative; Humans; Kidney Glomerulus; Prednisolone; Warfarin

Topics: Cyclophosphamide; Dipyridamole; Drug Therapy, Combination; Glomerulonephritis, IGA; Humans; Warfarin

Forty-eight patients with IgA nephritis entered a 3 year controlled prospective trial using a combination regimen of cyclophosphamide for 6 months and dipyridamole and low dose warfarin for 36 months. Those in the treatment group (n = 27) had stable renal function and a significant decrease in proteinuria (p less than 0.01) but in the controlled group (n = 21) there was a significant fall in creatinine clearance (p less than 0.01) and rise in serum creatinine (p less than 0.02) with no change in proteinuria. The data suggested that the above treatment resulted in a significant reduction of proteinuria and more stable renal function. Eleven patients in the treatment group and 10 patients in the controlled group had repeat renal biopsies after the trial. Eight parameters were used in the evaluation of the renal biopsies: mesangial hypercellularity, crescents, tuft adhesion, segmental sclerosis, global sclerosis, tubular atrophy, interstitial fibrosis and vascular sclerosis. Each lesion was graded from 0 to 3 and a total scoring system used for evaluation of histological severity. In the treatment group there was no significant histological deterioration but in the controlled group there was progressive histological deterioration. Mean total histological score was 3.7 +/- 2.6 before the trial and 6.5 +/- 3.1 after the trial (p less than 0.05). This histological progression appeared to run parallel with the clinical course.

Topics: Biopsy, Needle; Cyclophosphamide; Dipyridamole; Drug Therapy, Combination; Glomerulonephritis, IGA; Humans; Prospective Studies; Warfarin

Topics: Biopsy, Needle; Cyclophosphamide; Dipyridamole; Drug Therapy, Combination; Follow-Up Studies; Glomerulonephritis, IGA; Humans; Kidney; Random Allocation; Warfarin

Topics: Adult; Age Factors; Cyclophosphamide; Dipyridamole; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulonephritis, IGA; Humans; Male; Prognosis; Sex Factors; Singapore; Time Factors; Warfarin