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Pediatric Nephrology

, Volume 19, Issue 1, pp 51–56 | Cite as

Henoch-Schönlein purpura nephritis: course of disease and efficacy of cyclophosphamide

  • Penina TarshishEmail author
  • Jay Bernstein
  • Chester M. EdelmannJr
Original Article

Abstract

Nephritis in Henoch-Schönlein purpura (HSP) is the primary cause of morbidity and mortality. Although many therapeutic regimens have been reported to be effective, no therapy has been shown in a controlled trial to be beneficial. Fifty-six patients with histopathologically severe HSP nephritis were randomized to receive supportive therapy with or without cyclophosphamide, 90 mg/m2/day for 42 days. Patients were classified according to status at final follow-up: Fully Recovered 48.2%, Persistent Abnormalities 39.3%, or ESRD/Death 12.5%. There were no differences in onset data or outcome between the two trial groups or in outcome between trial and 23 non-trial patients followed concurrently. Therefore, data from trial and non-trial patients were combined for further analysis. There was no correlation between outcome and age, blood pressure, serum total protein, or serum albumin. Although rates of proteinuria did not correlate with outcome, all those with progression to ESRD had nephrotic levels of proteinuria at onset. Only five of 28 patients with nephrotic levels of proteinuria and severe onset histopathology recovered fully. No patient with crescents in 50% or more of glomeruli went on to full recovery. Recurrence of non-renal symptoms did not correlate with outcome. Nephrotic syndrome, decreased GFR, and more severe histopathology at onset, as well as persistence of urinary abnormalities for several years, are ominous signs.

Keywords

Purpura Henoch-Schönlein Cyclophosphamide Nephritis Natural history Pediatrics Clinical trial 

Introduction

Henoch-Schönlein purpura (HSP) is primarily a disease of children [1, 2, 3, 4, 5]; the disease appears in some patients as young as 6 months [6, 7]. Renal involvement, HSP nephritis, has been reported in 15–62% of patients [2, 6, 7, 8, 9, 10, 11, 12, 13], the wide range related to the origin of some reports from renal referral centers and others from the general pediatric population.

Although most children with HSP recover completely, a serious risk of progression to end-stage renal disease exists. This study was initiated in 1973 by the International Study of Kidney Disease in Children, based on the prevailing belief that adrenal corticoid therapy was of only symptomatic benefit and on the lack of controlled studies of the efficacy of cyclophosphamide. Follow-up data were last available in 1990. Patients with severe HSP nephritis were entered into a randomized trial, comparing cyclophosphamide plus supportive therapy with supportive therapy alone. The data from the trial patients plus an additional group of children followed concurrently but not entered into the trial provided an opportunity to study the long-term course of the disease.

Materials and methods

Entry criteria for trial

  1. 1.

    HSP, defined as purpura plus urticaria, characteristically affecting lower limbs and possibly buttocks and elbows, plus one or more of the following: joint pain and swelling, renal involvement, abdominal pain, and intestinal bleeding.

     
  2. 2.

    Age>12 weeks<16 years.

     
  3. 3.

    Estimated GFR [14] of at least 35 ml/min/1.73 m2, demonstrated on two consecutive occasions separated by an interval of at least 1 month.

     
  4. 4.

    Biopsy-proven HSP nephritis histopathology ≥Grade III based on a biopsy done at entrance to the trial, according to the classification established by the ISKDC pathologists at the onset of the trial (see “Definitions” below) with heavy proteinuria persisting for at least 1 month, and/or reduced GFR demonstrated by two consecutive serum creatinine measurements separated by at least 1 month.

     

Exclusion criteria

  1. 1.

    Prior use of immunosuppressive or cytotoxic drugs other than corticosteroids.

     
  2. 2.

    Concurrent disease, such as systemic lupus, diabetes mellitus, amyloidosis, syphilis, malaria, sickle cell, congenital cyanotic heart disease, blood coagulation disorder.

     
  3. 3.

    Any renal disease preexisting the onset of HSP.

     
  4. 4.

    Symptoms of HSP present for more than 3 months prior to qualification for entry into the trial.

     

Trial design

Fourteen centers, as listed in the “Acknowledgements,” participated in this trial. Patients were randomly allocated by the central office to a control group receiving supportive therapy only or to treatment with supportive therapy plus cyclophosphamide, 90 mg/m2 per day as a single dose given in the morning for 42 days of actual drug intake. This duration of treatment and dosage were based on the prevailing practice and to avoid potential toxicity from a longer course of therapy. Supportive therapy was limited to diet modification, diuretics, exchange resins, or vitamins. Frequency of proteinuria determination was at time of entry into the trial, 12 weeks later, and every 6 months thereafter for the length of the study. Patients were scheduled to have a second renal biopsy at 18–24 months after entry into the trial, and were to be followed for a minimum of 5 years. Written informed consent was obtained from the parents of all participants.

Definitions

Heavy proteinuria: ≥40 mg/h/m2 determined quantitatively on an overnight collection using sulfosalicylic acid.

Proteinuria: >4 mg/h/m2 in an overnight specimen or ≥2+ by dipstick

Protein-free urine: ≤4 mg/h/m2 in an overnight collection, or negative or trace by dipstick.

Hematuria: Addis count >30,000 rbc/h/m2, or ≥1+ by dipstick, or ≥3 rbc/hpf in a spun specimen, or >2 rbc/mm3.

Reduced GFR: <80 ml/min/1.73 m2

Histopathology: ISKDC classification

  1. 1.

    Minor glomerular abnormalities (mesangial cell proliferation 0–1+)

     
  2. 2.

    Pure diffuse mesangial proliferation (2–3+)

     
  3. 3.
    Occluding crescents1/segmental lesions2/global sclerosis in <50% glomeruli
    a)

    With minor glomerular abnormalities

    b)

    With diffuse mesangial proliferation

     
  4. 4.
    Occluding crescents/segmental lesions/global sclerosis in 50–75% glomeruli
    a)

    With minor glomerular abnormalities

    b)

    With diffuse mesangial proliferation

     
  5. 5.

    Occluding crescents/segmental lesions/global sclerosis in >75% glomeruli

     
  6. 6.

    Membranoproliferative-like glomerulonephritis

     
The histopathologic severity was quantified, using the following formula:
$$ {\text{Histopathologic severity index}} = \frac{{{\left( {{\text{\# glob sclerosis + \# occluding cresc + \# seg lesions + \# bridges}}} \right)}}} {{{\text{Total number of glomeruli}}}} \times {\text{100 + mesang prolif }}{\left( {{\text{1 - 3 + }}} \right)} $$

Proportion of glomeruli with crescents = (no. occluding + segmental crescents) × 100 : no. total glomeruli.

Outcome classification

Recovered: normal GFR and no urinary abnormalities.

Persistent abnormalities: decreased GFR, or any level of proteinuria and/or hematuria.

Severe persistent abnormalities (a subgroup of “Persistent abnormalities”): decreased GFR, moderate or severe persistent proteinuria.

End-stage renal: disease (ESRD) or death.

Statistical methods

A power analysis was performed, assuming recovery in 50% of the treatment group and 15% of the control group. At 80% power, and probability of 0.05, 32 patients would be needed in each group. The two treatment groups were compared with regard to outcome, classified as above, using Fisher’s exact test. To determine the relationships between characteristics and outcome, trial and non-trial participants were combined (n=79). Analyses of variance were done with adjustment for multiple comparisons by the Bonferroni procedure. Correlations among variables were obtained. Multiple logistic regression models were run with the dependent variable being the outcome groups and independent variables being all onset data. All differences were considered significant at p≤.05.

Results

Onset characteristics

Fifty-six patients were entered into the cyclophosphamide trial between 1973 and 1980, 28 to the control group and 28 to the treatment group. Twenty-three additional patients with biopsy-proven HSP nephritis, who either did not qualify for the trial or whose parents declined to participate, were followed concurrently. The 79 patients, 53% male and 47% female, were followed for up to 14 years. There were no differences in onset characteristics between the treatment and control groups (Table 1). Initial renal biopsy characteristics were similar with respect to proportions of crescents and histopathologic severity. There were also no differences in onset characteristics between trial and non-trial patients (Table 1), except for significantly lower values of serum total protein and albumin and higher levels of urinary protein excretion in the trial patients. These findings were expected, because most of the non-trial patients did not meet the trial’s strict entry criteria.
Table 1

Clinical and laboratory data at onset

Blood pressure

Serum

Estimated GFR

Urinary

Renal biopsy

Age

Syst.

Diast. change

Diast. disapp.

Cr

Total protein

Albumin

Protein (mg/h/m2)

RBC per h/m2

Percent crescent

Histopath. severity index

Trial control (n=28)

Mean

8.02

112

75

66

0.81

5.26

2.45

93.9

134.8

3,557,000

36.0

45.2

SD

2.99

27.61

20.47

18.22

0.33

1.36

0.82

35.6

78.3

4,111,000

31.2

32.3

Trial treatment (n=28)

Mean

7.68

109

73

66

0.74

5.05

2.46

103.4

128.1

3,275,000

31.7

41.5

SD

3.22

29.92

23.80

21.45

0.35

1.44

0.85

48.5

70.4

3,608,000

29.0

29.6

Non-trial (n=23)

Mean

8.17

111

69

70

0.89

6.42a

3.51a

96.9

68.6a

2,496,000

18.3

29.9

SD

3.04

18.92

17.58

20.18

0.71

0.88

0.75

35.1

78.0

3,822,000

21.9

26.7

aNon-trial patients significantly different from trial patients, p≤.05

Outcome data

Mean follow-up time was 6.93 (SD=3.32) years in the Recovered group, 6.57 (SD=4.14) years in the group with Persistent Abnormalities, and 3.71 (SD=2.14) years in the group that progressed to ESRD. No toxicity from cyclophosphamide was reported. No differences in outcome were found between the control and treatment trial groups or between the trial and non-trial patients (Table 2). Therefore, for the analysis of correlations between onset characteristics and long-term outcome, the trial and non-trial patients were combined (Table 2). Based on status at final follow-up, the series was subdivided into three groups (Recovered, Persistent Abnormalities, ESRD) as described above. In these 79 patients, there was no correlation between outcome and age, blood pressure, serum total protein, serum albumin, or urinary protein (Table 3).
Table 2

Clinical status at last follow-up

Cyclophosphamide trial

All patients

Control

Treatment

Trial

Non-trial

Recovered

14

13a

27

16a

Pers. abnormal:

22

6a

  Mild

6

8a

-

-

  Moderate or severe

4

4a

-

-

ESRD

4

3a

7

1a

aNS, Fisher’s exact test

Table 3

Onset characteristics and outcome

Blood pressure

Serum

Estimated GFR

Urinary protein (mg/h/m2)

Renal biopsy

Age

Syst.

Diast. change

Diast. disapp.

Cr

Total protein

Albumin

Percent crescent

Histopath. severity index

Recovered

  Mean

7.6

111

71

66

0.72b

6.03

3.19

116.6b

99.2

12.30a,b

22.27a,b

  SD

3.03

14.8

16.4

18.3

0.56

0.90

0.81

44.05

88.7

11.46

14.33

Persistent abnormalities

  Mean

7.6

111

71

66

0.75c

5.75

2.98

104.6

109.4

34.35a

43.39a,c

  SD

3.03

14.8

16.4

18.3

0.27

0.87

0.83

36.07

67.9

28.59

29.18

ESRD

  Mean

8.0

114

75

78

1.2b,c

5.53

2.90

73.2b

151.2

44.52b

70.89b,c

  SD

2.76

19.2

9.0

17.1

0.64

1.10

0.59

35.18

100.7

26.88

18.81

All patients

  Mean

7.9

109

70

66

0.90

5.80

3.11

103.8

104.2

23.32

34.02

  SD

3.09

25.0

19.8

21.7

0.95

1.12

0.97

44.94

82.3

23.49

25.88

aRecovered vs persistent abnormalities, p<.05

bRecovered vs ESRD, p<.05

cPersistent abnormalities vs ESRD, p<.05

Because of the common belief that nephrotic levels of proteinuria at onset are of prognostic significance, patients were divided into those with ≥40 mg/h/m2 and those with <40 mg/h/m2. While the difference between the two groups did not achieve the conventional p value of 0.05 (chi-square p=0.053, Fisher’s exact test p=0.12), the analysis strongly suggests that heavy proteinuria is an ominous sign. Although many patients with nephrotic levels of proteinuria recovered completely, it should be noted that all patients with ESRD had nephrotic levels of proteinuria at onset and half of the others with nephrotic levels of proteinuria at onset had persistent abnormalities at last follow-up.

Onset levels of serum creatinine were significantly higher in the ESRD patients than in the Recovered or Persistent Abnormalities patients. Baseline estimated GFR was significantly lower in the ESRD group compared to the Recovered group (Table 3).

An analysis was made of the patients with Severe Persistent Abnormalities, a subgroup of 15 of the 28 patients with Persistent Abnormalities, to assess the significance of continuing proteinuria, hematuria, and decreased GFR. None of these had hematuria as the sole abnormality. Ten of the 15 were followed for 4–11 years, providing a sufficient period of observation to suggest that these patients would not ultimately recover fully. Comparison of onset data between these ten patients and those in the Recovered group followed for a similar period of time showed significantly higher levels of serum creatinine (p=0.05), a greater percentage of crescents, and a greater histopathologic severity (p<0.02). These ten patients with persistent abnormalities also showed greater onset values of proteinuria and hematuria and lower levels of estimated GFR and serum protein concentration (p=0.06–0.07).

The predictive value of the onset renal biopsy was examined by comparing the proportion of glomeruli containing crescents and the histopathologic severity index among the three outcome groups. The proportion of crescents was significantly greater in the Persistent Abnormalities and ESRD groups than in the Recovered group. No correlation existed between the percentage crescents on renal biopsy at onset and years to recovery. The histopathologic severity index at onset increased significantly from Recovered, to Persistent Abnormalities, to ESRD, but did not correlate with years to recovery.

Despite these findings, the overlap among the three outcome groups in both proportion of glomeruli with crescents and the histopathologic severity index, as shown in Figs. 1 and 2, renders individual values of little prognostic value. Therefore, we evaluated patients with nephrotic levels of proteinuria, crescents ≥50%, and histopathologic severity index ≥40 at onset to identify possible predictors of outcome. None of the patients with ≥50% crescents went on to full recovery. Twenty-eight patients had nephrotic levels of proteinuria at onset and histopathologic severity index ≥40. This group contained all the patients with progression to ESRD, and only 5 of the 28 recovered fully.
Fig. 1

Proportion of glomeruli with crescents, based on the initial renal biopsy, in patients who recovered fully, had persistent abnormalities at the time of last follow-up, or who died or developed end-stage renal disease

Fig. 2

Histopathologic activity index, based on the initial renal biopsy, in patients who recovered fully, had persistent abnormalities at the time of last follow-up, or who died or developed end-stage renal disease. The formula for the histopathologic activity index is given under “Materials and methods

Forty patients, comprising about half of the patients in each of the outcome groups, underwent follow-up biopsy. Only one of 20 patients who recovered fully showed progression in renal histology grade (grade 2–3). Of the 16 patients with Persistent Abnormalities who had a follow-up biopsy, 12 had histopathologic improvement or remained the same and 4 had histopathologic deterioration. All four patients who had histopathologic deterioration were in the Severe Persistent Abnormalities subgroup. The difference in histopathologic progression between patients with Severe Persistent Abnormalities and those who recovered or had mild Persistent Abnormalities is statistically significant (p<0.05). As expected, among patients with progression to ESRD, three showed histopathologic deterioration and one (grade 5) remained the same.

A total of 31 patients had recurrence of purpura, urticaria, abdominal pain, arthritis, arthralgia, or intestinal bleeding, occurring mostly within the first 6 months to 1 year after onset. There was no significant difference in outcome between patients who did and who did not have recurrence of symptoms (p>0.1) (Table 4).
Table 4

Recurrence of non-renal symptoms and outcome

Recurrence

No recurrence

Total

No.

%

No.

%

Recovered

17

40

26

60

43

Persistent abnormalities

9

32

19

68

28

ESRD

5

63

3

38

8

No significant differences

The rate of progression to ESRD was variable, ranging from 1 to 7 years, with six out of eight patients in ESRD by 4 years after onset.

Discussion

Children with HSP nephritis constitute 1.4% of the pediatric transplant population in the United States [15] and 1.7% of children who develop ESRD in Europe [16]. The current study incorporated a clinical trial of the efficacy of cyclophosphamide in children with severe HSP nephritis, representing the population considered to be at risk of progression to renal failure. Our study differs from most other reports in that patients were newly diagnosed, underwent renal biopsy at entry, and were followed prospectively.

Our study is the only randomized, controlled trial of cyclophosphamide therapy. The negative results are consistent with most of the reports in the literature, although some authors have claimed a beneficial effect based on small retrospective uncontrolled series [1, 3, 13, 17, 18, 19, 20]. It could be argued that initiation of treatment earlier after onset of disease might have been successful in demonstrating efficacy. However, our trial was designed to exclude patients with apparently severe nephritis who would recover quickly.

No other treatment regimen has been evaluated in a randomized, controlled trial. Recent publications using combination drug therapy show promising results, although in the absence of controlled data there is no definitive proof that they are effective [1, 3, 17, 18, 19, 20, 21, 22, 23, 24].

Several studies have suggested a correlation between outcome and age at onset, with children older than 5–10 years of age having a worse prognosis [2, 4, 5, 6, 18, 22]. This correlation may have been obscured in the present study since most of the patients had severe disease. However, our findings are in agreement with a recent long-term follow-up study [12].

Nephrotic syndrome at onset has been found to augur a poor prognosis [1, 3, 8, 12, 13, 18, 19, 21, 25, 26, 27, 28]. In the current study, although the rate of proteinuria overall did not correlate with outcome, half of the patients who had heavy proteinuria at onset failed to recover, including all patients who developed ESRD, confirming heavy proteinuria at presentation as ominous.

Many studies have considered the prognostic significance of glomerular crescents shown by renal biopsy, and most reports appear to agree that more than 50% crescents at onset predicts a poor outcome [3, 4, 18, 19, 21, 29]. In the current series, the percentage of crescents and the histopathologic severity index were highly correlated with outcome. None of the patients with ≥50% crescents went on to full recovery. However, there were large overlaps among the outcome groups, as shown in Figs. 1 and 2, so that only an extreme value would be of help in predicting an individual patient’s outcome.

With regard to other baseline clinical characteristics, only lower GFR and (as expected) higher plasma creatinine were predictive of worse outcome, in agreement with prior studies [12, 18, 25, 27, 29]. However, in contrast to these studies, we did not find hypertension to correlate with poor outcome.

The rates of full recovery from HSP nephritis reported in the literature range from 65% to 95%, and the incidence of ESRD ranges from 2.5% to 20% [1, 3, 8, 12, 18, 19, 25, 26, 29]. Although only 54% of our patients were classified to have fully recovered, our data are within these ranges, if patients with persistent but minimal urinary abnormalities are included as “recovered.”

Recurrence of urinary abnormalities after apparent recovery was noted in one patient. This has been reported in other series as well, with new onset or reappearance of clinical renal disease as long as 2–10 years after onset [2, 9, 10, 12, 25, 29]. Therefore, we recommend prolonged follow-up of all patients, including those who seem to have recovered.

Although recurrence of non-renal symptoms is worrisome to parents, we failed to find any correlation between recurrence up to 2 years from onset and a poor outcome. Many studies do correlate recurrence of extrarenal symptoms with longer duration and greater severity of renal disease [3, 6, 18, 22], but generally do not address the issue of outcome. Counahan et al. examined only recurrence of rash and noted that it did not correlate with poor outcome [25].

Meadow et al. considered the clinical status at 2 years to be a reliable prognostic index; they found deterioration to be rare and improvement slower at 2 years after onset [4]. In the current series, patients with persistence of urinary abnormalities for at least 4 years had more severe findings at onset, suggesting a guarded prognosis. Ten of the patients in this group with persistent abnormalities for at least 4 years and followed up to 9 years, had moderate to heavy proteinuria, with or without decreased GFR at last follow-up, suggesting that recovery would not occur. Unfortunately, further follow-up data could not be obtained.

In conclusion, although it is possible on the basis of onset characteristics and the findings on renal biopsy to identify most, if not all, patients who will fail to recover completely, no therapy, including cyclophosphamide as used in the current study, has been proven to be effective. Decisions regarding therapy, therefore, must rely on small, nonrandomized series, which have yielded conflicting results [1, 3, 13, 17, 18, 19, 20, 21, 22, 23, 24].

Footnotes

  1. 1.

    Crescents that occupy Bowman’s space almost completely

  2. 2.

    Segmental thrombosis/necrosis, crescents, and sclerosis

Notes

Acknowledgements

Work performed: Albert Einstein College of Medicine. Financial support by National Institutes of Health Research Grant 1-RO1-AM18234, the National Kidney Foundation of New York, the Kidney Disease Institute of the State of New York, the William Beaumont Hospital Pathology Projects Fund, the John Rath Foundation, the National Kidney Research Foundation (United Kingdom), and the Kidney Foundation of the Netherlands. Participants in the ISKDC who contributed to this study were as follows: Central Office (New York): H.L. Barnett and C.M. Edelmann Jr. (Directors), I. Greifer (Associate Director), D.I. Goldsmith and A. Spitzer (Directors of Coordinating Center), P. Tarshish (Data Coordinator), G. Laddomada (Project Administrator), and J. Massaro (Secretarial Assistant); Regional Coordinators: I.B. Houston, R.H. Kuijten, and L.B. Travis; Directors of Participating Centers: R.H.R. White (Birmingham, Alabama), I.B. Houston (Manchester, United Kingdom), J.G. Mongeau (Montreal, Canada), N. Hallman and J. Vilska (Helsinki), S.R. Meadow (Leeds, United Kingdom), M.J. Schoeneman and R. Weiss (New York-Albert Einstein), S. Roy (Memphis, Tennessee), G. Gordillo (Mexico City, Mexico), J. Lewy (New York-New York Hospital), O. Oetliker (Bern, Switzerland), Bowman Gray Hospital (North Carolina, USA), M. Nash (New York-Columbia Presbyterian), M. McVicar (North Shore University Hospital-New York), A. Fanconi (Zurich, Switzerland); Consultants: J. Bernstein, J. Churg, R. Habib, and R.H.R. White (Pathology) and S.M. Wassertheil-Smoller (Biostatistics).

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Copyright information

© IPNA 2003

Authors and Affiliations

  • Penina Tarshish
    • 1
    • 3
    Email author
  • Jay Bernstein
    • 2
  • Chester M. EdelmannJr
    • 1
  1. 1.Albert Einstein College of MedicineNew YorkUSA
  2. 2.Department of Anatomic PathologyWilliam Beaumont HospitalRoyal OakUSA
  3. 3.Room 803Jacobi Medical CenterBronxUSA

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