PEDIATRICS Vol. 111 No. 4 April 2003, pp. 785-789
Efficacy of Methylprednisolone and Urokinase Pulse Therapy for Severe Henoch-Schönlein Nephritis
From the Department of Pediatrics, Fukushima Medical University School of Medicine, Fukushima, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Objective. To evaluate the efficacy of methylprednisolone and urokinase pulse therapy (MUPT) for severe Henoch-Schönlein nephritis, we examined the clinical manifestation and prognosis of patients with MUPT on long-term observation.
Methods. We enrolled 56 patients with Henoch-schönlein nephritis who had been diagnosed with at least type IIIb from 1980 to 1998 on long-term observation and had been treated with MUPT. The clinical features, laboratory data, and pathologic findings between "pre-MUPT" and "post-MUPT," and the prognosis of these patients on long-term observation were retrospectively investigated.
Results. The mean urinary protein excretion after 6 months of treatment had decreased significantly compared with "pre-MUPT." Hypercoagulant state in "after the completion of urokinase pulse therapy" improved compared with "pre-MUPT." First renal biopsies were performed in all patients and second biopsies were performed in 27 patients. The activity index decreased significantly from 4.1 ± 1.9 at first biopsy to 2.5 ± 1.7 at second biopsy, while the chronicity index did not differ between first and second biopsy. None had renal insufficiency and renal survival rate was 100% for the decade.
Conclusions. Although uncontrolled, our study suggested that MUPT is effective for those patients with the risk of progression of their nephropathy, especially if started early during the course of the disease before the crescents become fibrous.
Key Words: Henoch-Schönlein nephritis • methylprednisolone • urokinase • prognosis
Abbreviations: HSP, Henoch-Schönlein purpura • MUPT, methylprednisolone and urokinase pulse therapy • HSPN, Henoch-Schönlein nephritis • Ig, immunoglobulin • UK, urokinase • MPT, methylprednisolone pulse therapy • 
2PI, 2 plasmin inhibitor • 24hCcr, 24-hour creatinine clearance • LM, light microscopy • IF, immunofluorescence • TAT, thrombin antithrombin III complex
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Henoch-Schönlein purpura (HSP) is an immunoglobulin (Ig) A-mediated immune-complex vasculitis affecting predominantly the skin, joints, gastrointestinal tract, and kidney. It occurs most frequently in childhood, and the prognosis of HSP patients is largely predicted by the severity of renal involvement. The proportion of patients reported to have renal involvement varies between 20% and 100%.
The majority of children with Henoch-Schönlein nephritis (HSPN) present only with hematuria and/or low-grade proteinuria have a good chance for recovery. However, patients with massive proteinuria at onset frequently show a progressive course.1,2 In specialized centers, the proportion of children with HSPN progressing to renal failure or end-stage renal disease varies from 12% to 19%.3–6 In Japan, Yoshikawa et al7 reported that HSP is a significant cause of childhood chronic renal failure, accounting for 16% of all children entering dialysis prognosis, especially 13 (52%) of 25 patients with at least grade IV had renal insufficiency.
Recently, some studies reported a beneficial effect of agents, such as intravenous methylprednisolone pulse,3 urokinase (UK) therapy,4 combined therapy with prednisolone, heparin/warfarin, dipyridamole, and cyclophosphamide8,9 or azathioprine,10 and plasma exchange therapy.11
Niaudet and Habib3 described the beneficial effect of methylprednisolone pulse therapy (MPT) in the treatment of severe HSPN. Watanabe at al4 found that UK therapy was effective in improving the prognosis of severe HSPN patients with at least grade III. As noted above, some studies concerned with MPT and UK therapy were reported. However, there were no reports concerned with the efficacy of methylprednisolone and UK pulse therapy (MUPT) for severe HSPN on long-term observation in numerous cases. To evaluate the efficacy of MUPT for severe HSPN, we examined the clinical manifestation and pathologic findings between "pre-MUPT" and "post-MUPT", and prognosis of the patients with this treatment on long-term observation.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients
Between January 1980 and December 1998, 105 children were newly diagnosed to have HSPN at the Department of Pediatrics of the Fukushima Medical University School of Medicine (Fukushima, Japan). The glomerular changes evident at initial biopsy were as follows: grade II in 26 patients, grade IIIa in 20 patients, grade IIIb in 31 patients, grade IVb in 21 patients, grade Vb in 4 patients, and grade VI in 3 patients.
We enrolled 56 patients who had been diagnosed with at least grade IIIb and had been treated with MUPT. The clinical features, laboratory data, and pathologic findings between "pre-MUPT" and "post-MUPT", and the prognosis of these patients on long-term observation were retrospectively investigated. We measured coagulant data such as thrombin antithrombin III complex (TAT), fibrinogen, 2 plasmin inhibitor (2PI), and D-dimer in serum samples between "pre-MUPT" and "after the completion of urokinase pulse therapy". These serum samples for measuring coagulant data were collected in the pre-MUPT (days 12.4 ± 7.8 at onset) and "after the completion of urokinase pulse therapy" (days 54.6 ± 24.8 at onset).
Definitions
Hematuria was defined as positive if microscopic examination showed 5 or more red blood cells per high-power field, and macrohematuria if visible with the naked eye.12 Proteinuria was evaluated by 24-hour quantitative measurement. The nephrotic syndrome was defined as the presence of proteinuria (
40 mg/m2/hour) and a serum albumin level <2.5 g/dL, with or without edema.12 Hypertension was defined as a systolic or diastolic blood pressure greater than the 95th percentile for the specific age, based on the Pediatric Task Force Recommendation.13 The acute nephritic syndrome was defined as hematuria with at least 2 conditions among hypertension, raised serum urea or creatinine, and oligouria.14 The rapidly progressive nephritic syndrome was defined as glomerular diseases characterized by extensive crescents (involving 50% of glomeruli) as the principal histologic finding and a rapid deterioration of renal function (>50% decline in glomerular filtration rate within 3 months) as the clinical correlate.
A diagnosis of HSP was made if the major manifestations of the illness consisted of a purpuric rash and abdominal pain without thrombocytopenia. Additional features including arthritis and nephritis were accepted as being consistent with the diagnosis.
The clinical status of each patient at the latest observation was classified as follows.
- Stage A-normal: the patient was normal on physical examination, with normal urine and renal function.
- Stage B-minor urinary abnormalities: the patient was normal on physical examination, with microscopic hematuria or proteinuria <40 mg/m2/hour.
- Stage C-persistent nephropathy: the patient had proteinuria of 40 mg/m2/hour or greater or hypertension, and 24-hour creatinine clearance (24hCcr) of 60 mL/min/1.73 m2 or greater.
- Stage D-renal insufficiency: the patient had 24hCcr <60 mL/min/1.73 m2 (including dialysis/transplant or death).
Pathology
First renal biopsies were performed in all patients and second biopsies at recovery phase (months 9.4 ± 6.8 at onset) were performed in 27 patients to assess the efficacy of the therapy. There was an average of 17.3 ± 8.7 (range 10–46) glomeruli. The specimens were assessed by light microscopy (LM) and immunofluorescence (IF). Material for histologic study was fixed in 20% neutral formalin and embedded in paraffin, sliced at 2 to 3 µm in thickness, and stained with hematoxylin and eosin or periodic acid-Schiff reagent.
The glomerular changes were graded according to the classification devised by the pathologists of the International Society of Kidney Disease in Children15 as follows:
- I. Minor glomerular abnormalities.
- II. Pure mesangial proliferation (a, focal; b, diffuse).
- III. Minor glomerular abnormalities or mesangial proliferation, with crescents in <50% glomeruli (a, focal; b, diffuse mesangial proliferation).
- IV. Same as no. 3 but with crescents in 50%–75% glomeruli (a, focal; b, diffuse mesangial proliferation).
- V. Same as no. 3 but with crescents in >75% glomeruli (a, focal; b, diffuse mesangial proliferation).
- VI. Membranoproliferative-like lesions.
To compare the biopsies, a histologic scoring system was modified to evaluate acute and chronic changes. Acute changes included mesangial proliferation (grade 0–3; 0 = normal, 1 = slight, 2 = moderate, 3 = severe), segmental necrosis with cellar crescent formation (scored according to the percentage of glomeruli involved; 0 = 0%, 1 = 1–20%, 2 = 20–50%, 3 = >50%), and interstitial edema with mononuclear cell infiltration (0–3).
Chronic renal injury was estimated by determining the number of glomeruli demonstrating fibrous crescents and segmental or global sclerosis. Each abnormality was scored 0–3 according to the number of glomeruli involved as for acute crescent formation. In addition, the combination of tubular atrophy and interstitial fibrosis was graded 0–3. Scoring was performed in a blinded fashion on coded. The individual scores were added to get the activity and chronicity scores.
Tissue for IF were immediately fixed in optimum cutting temperature compound and frozen at -80° until use for IF. IF was examined for IgG, IgA, IgM, C1q, C3, C4, and fibrinogen. We used fluorescein-conjugated goat antibody (IgG) toward rabbit IgG, IgA, IgM, C1q, C3, C4, and fibrinogen, respectively. The intensity of IF was graded on a scale where 0 = negative, 1 = mild, 2 = moderate, and 3 = severe.
Treatment
Following diagnostic renal biopsy, the patients with at least grade IIIb were treated with a combination of "pulse" methylprednisolone at 30 mg/kg/d intravenous bolus (maximum 1 g) for 3 consecutive days, and of "pulse" UK at 5000 u/kg/d intravenous bolus (maximum 180 000 U) for 7 consecutive days, followed by daily oral prednisolone (1 mg/kg/d) for >6 months, along with antiplatelet agents (dipyridamole 5 mg/kg/d) and anticoagulant (warfarin). Warfarin was given orally at a single morning dose of 1 mg (<7 years old) or 2 mg (>7 years old) to maintain the thrombotest at 30% to 50%. Then, the corticosteroid was reduced subsequently according to individual improvement in 24hCcr, urinary sediment, and urinary protein.
Statistics
Data are expressed as mean values ± standard error of the mean. Statistical analysis was performed on a Macintosh computer with a software package for statistical analysis (Stat View; Abacus Concepts, Berkeley, CA). Several variables, which are clearly not normal in their distribution, were compared using nonparametric statistics such as Mann-Whitney U test or Wilcoxon test. The renal survival rates were calculated using the life-table method (Kaplan-Meier). A value of P < .05 was considered significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients’ Characteristics
Age at onset was 8.6 ± 2.9 years and male-to-female ratio was 24:32. On the clinical manifestations at onset, initial clinical symptoms were purpura, 56 cases (100%); abdominal pain, 16 (29%); nephrotic syndrome, 11 (20%); arthralgia, 6 (11%); acute nephritic syndrome, 6 (11%); rapidly progressive nephritic syndrome, 2 (4%); school urinary screening, 1 (2%); and intussusception, 1 (2%).
Clinicopathologic Correlations at the Time of the First Renal Biopsy
In the prebiopsy period, hematuria was present in all patients. Proteinuria varied between 68 and 315 mg/m2/hour (mean 146 ± 62 mg/m2/hour). A nephrotic syndrome developed in 25 patients. 24hCcr was decreased in 10 patients, ranging from 9 to 57 mL/min/1.73 m2. Seventeen patients were hypertensive before treatment. Table 1 shows the correlations between the histopathologic categories observed on first biopsy and the clinical symptoms. Nephrotic syndrome, hypertension, and renal insufficiency were more frequently found in patients with grade IVb and Vb compared with patients with grade IIIb.
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Side Effects of the Treatment
Twenty-one patients showed cushingoid face change, 6 patients developed mild glaucoma, and 5 patients presented mild growth retardation. Three patients developed hypertension, which was well-controlled by treatment with nifedipine. UK pulse therapy and the doses of anticoagulants used in the treatment regimen did not result in bleeding tendency.
Most of the side effects were mild and well-controlled, and all were reversible. Severe side effects attributable to the treatment regimen were relatively rare and MUPT was well-tolerated in all patients.
Effect of Therapy on Renal Symptoms and Laboratory Data (Fig 1)
We compared the renal symptoms and laboratory data before and following therapy. The mean urinary protein excretion before initiation of treatment was 146 ± 62 mg/m2/hour. Following completion of oral steroid therapy, 6 months later, urinary protein excretion had decreased significantly (P < .01) to 33 ± 19 mg/m2/hour. 24hCcr had returned to normal values in the 10 patients who had a mild renal impairment at initiation of therapy. Two years after initiation of treatment, the mean urinary protein excretion was 14 ± 7 mg/m2/hour.
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The mean blood pressure in posttherapy was lower than that in pretherapy (70 ± 9 vs 85 ± 11 mm Hg; P < .05).
The coagulant data such as TAT, fibrinogen, D-dimer, and 2PI in "after the completion of urokinase pulse therapy" were lower than those in "pre-MUPT" (Table 2).
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Clinicopathologic Correlations at Latest Follow-up
The mean duration of follow-up was 9.7 ± 6.0 years. At the latest follow-up, 39 patients had clinically recovered, 10 had minimal urinary abnormalities, 5 had active renal disease, and 1 had renal insufficiency. The status at latest examination was analyzed in relation to first biopsy findings (Table 3). Among the 31 patients with grade IIIb, 26 had clinically recovered, 4 had minimal urinary abnormalities, and 1 had a persistent nephropathy. Among the 21 patients with grade IVb, 13 had clinically recovered, 4 had minimal urinary abnormalities, 3 had a persistent nephropathy, and 1 had renal insufficiency. Among the 4 patients with grade Vb, 1 had clinically recovered, 2 had minimal urinary abnormalities, and 1 had a persistent nephropathy. One patient with renal insufficiency at latest follow-up had been treated late after the onset of the nephropathy (15 months). None had renal insufficiency and the renal survival rate was 100% for the decade.
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Results of Repeat Renal Biopsies
IF Findings at First and Second Biopsies
On the IF findings at the first and second biopsy, deposits degree of Igs such as IgG, IgM, and IgA, complements of C1q, C3, and C4 did not differ between the first and second biopsies, but those of fibrinogen in "post-MUPT" decreased compared with "pre-MUPT" (P < 005).
LM Findings at First and Second Biopsies (Table 4)
The activity index decreased significantly from 4.1 ± 1.9 at first biopsy to 2.5 ± 1.7 at second biopsy (P < .001), whereas the chronicity index did not differ between first and second biopsy. The chronicity indices of patients in stage C and D were higher than those of stage A and B, and the activity indices did not differ among stage A, B, C, and D.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Our study suggested that MUPT significantly reduced urinary protein excretion and improved hypercoagulant state, and prevented any increase of sclerosed glomeruli in children with diagnosed severe HSPN.
The beneficial effects of MUPT were accompanied by few serious side effects specifically attributable to the drugs. There were 6 patients with mild glaucoma, 5 patients with mild growth retardation, and 3 patients with hypertension. UK pulse therapy and the doses of anticoagulants used in the treatment regimen did not result in bleeding tendency. Most of the side effects were mild and well-controlled, and all were reversible. There were no patients who discontinued the treatment because of side effects attributed to drugs.
With regard to the prognosis for severe HSPN, Counahan et al6 reviewed 88 patients with HSPN and found that 13 (20%) of 66 patients with at least grade III and 5 (13%) of 38 patients without treatment had active renal disease and/or renal insufficiency. Yoshikawa et al7 reported that HSP was a significant cause of childhood chronic renal failure, accounting for 16% of all children entering dialysis prognosis in Japan. Specially, 13 (52%) of 25 patients with at least grade IV had renal insufficiency.
In view of pathology and prognosis, pathologic features that are valuable portents of prognosis are histologic grade, especially percentage of glomeruli with crescents, and worse chronicity index.1,2,5,6 Therefore, it is necessary to perform sufficient therapy for severe HSPN patients.
Following the report of Rose et al,16 the beneficial effect of MPT in the treatment of severe glomerulonephritis was described. As for HSPN, Niaudet and Habib3 reported that MPT is effective for patients with the risk of progression of their nephropathy, especially if started early during the course of the disease before the crescents become fibrous.
In contrast, it has been suggested that activation of intraglomerular blood coagulation was 1 of the exacerbative factors in IgA nephropathy and HSPN,17 and administration of steroid for them may cause hypercoagulable state and the formation of thrombus. Miura et al18 reported that the deposition of fibrinogen and/or 2PI is an exacerbative factor in the glomeruli in patients with IgA nephropathy. Because an intraglomerular hypercoagulable state was histopathologically related to renal injury, it was considered that fibrinolytic therapy including UK therapy might be a beneficial approach to preserve the renal function in patients with IgA nephropathy.19 Watanabe et al4 found that UK pulse therapy was effective in improving the prognosis of severe HSPN patients with at least grade III in a minority of patients.
Therefore, we had treated with MUPT the patients at risk of progression of their nephropathy. Our study found that the depositions of fibrinogen on IF and activity index on LM at the first biopsy decreased significantly compared with the second biopsy, and the chronicity index was not so high at the second biopsy. On clinical manifestation, hypercoagulant state in "after the completion of urokinase pulse therapy" improved compared with pretherapy. Urinary protein excretion and the number of patients with renal insufficiency in posttherapy was lower than that in pretherapy, and side effects such as bleeding tendency were not found in patients with MUPT. These findings suggest that MUPT is effective for those patients with the risk of progression of their nephropathy.
UK, a plasminogen activator derived from fresh human urine, first attracted attention as a therapeutic agent for thrombotic diseases such as cardiovascular diseases or cerebral thrombosis. The molecular weight of UK is 54 000. UK administration has been applied to patients with chronic glomerulonephritis including IgA nephropathy with fibrinogen and/or fibrin deposition by IF. The rationale for such treatment was as follows: 1) there was stronger defibrinating activity with UK administration than that with anticoagulant drug administration; 2) specific accumulations of UK were seen in the kidney and liver despite a very short turnover rate; and 3) adverse effects were very rare even if UK was administered for a long period.20,21
Recently, Glass et al22 reported that UK may mediate proteolysis in the mesangial extracellular matrix and Yasunaga et al23 showed that plasminogen enhanced the angiogenesis of bovine capillary endothelial cells and an anti-UK antibody inhibited this effect in vitro. In our study, the improvement of hypercoagulant state and acute inflammatory responses, and the suppression of sclerotic change in glomeruli were found in patients with MUPT. These studies suggest that UK and plasminogen may regulate the repair of affected capillaries and digest the proliferated matrix in diseased glomeruli.
The renal survival rate was 100% for the decade of follow-up and the prognosis of HSPN was good, although its pathologic findings were relatively severe. The number of follow-ups from the early 1980s patients was 17 and that from the early mid-1990s was 39. In the early 1980s patients, 12 patients had clinically recovered, 3 had minimal urinary abnormalities, 2 had active renal disease, and none had renal insufficiency. In the early mid-1990s, 27 patients had clinically recovered, 7 had minimal urinary abnormalities, 3 had active renal disease, and 1 had renal insufficiency. The prognosis did not differ between the early 1980s patients and the early mid-1990s. The renal survival rate and prognosis in our study were superior to those of the studies by Counahan et al6 and Yoshikawa et al.7 Therefore, we think MUPT is effective in improving the short-term and long-term prognosis of patients with at least grade IIIb.
However, this study was prospectively uncontrolled. Furthermore, it is necessary that we perform the prospective randomized trial concerned with the efficacy of MUPT.
There were some reports concerned with the treatment for severe HSPN in childhood. Hattori et al11 mentioned that plasmapheresis as the sole therapy is effective in improving the prognosis of patients with rapidly progressive HSPN, and Iijima et al9 showed that the multiple combined therapy including prednisolone, cyclophosphamide, heparin/warfarin, and dipyridamole was effective for histologically severe HSN. Foster et al10 reported that treatment with prednisone and azathioprine prevents progressive renal damage and improves outcome. Therefore, to improve the prognosis of patients with rapidly progressive HSPN and nephrotic syndrome, we would like to try MUPT including immunosuppressive agents and/or plasmapheresis.
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CONCLUSIONS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The present study, although uncontrolled, strongly suggests that MUPT may be beneficial in patients with severe forms of HSPN.
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FOOTNOTES |
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Received for publication Apr 2, 2002; Accepted Sep 5, 2002.
Reprint requests to (Y.K.) Department of Pediatrics, Fukushima Medical University School of Medicine, 1 Hikariga-oka, Fukushima City, Fukushima 960-1295 Japan. E-mail: tomo{at}fmu.ac.jp
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REFERENCES |
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PEDIATRICS (ISSN 1098-4275). ©2003 by the American Academy of Pediatrics
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