CASE REPORTS

Intravenous Pulse Methylprednisolone Therapy of Acute Crescentic Rapidly Progressive Glomerulonephritis

W. KLINE BOLTON, M.D. Charlottesville.

Virginia

WILLIAM G. COUSER, M.D.* Boston, Massachusetts

From the Departments of Internal Medicine, University of Virginia School of Medicine, Charlottesville, Virginia and the Evans Memorial Department of Clinical Research and the Department of Medicine, Boston University Medical Center, Boston, Massachusetts. Portions of the work were supported by Research Grant AM 17722 from the U.S. Public Health Service. This work was presented in part at the VIIth International Congress of Nephrology, June 22,1978, Montreal, Canada. Requests for reprints should be addressed to Dr. W. Kline Bolton, Box 133, University of Virginia School of Medicine, Charlottesville, Virginia 22901. Manuscript accepted August 1,1978. . * Recipient of NIH Research Career Development Award AM 00102.

Idiopathic acute crescentic rapidly progressive glomerulonephritis (RPGN) with oliguria, proteinuria and rapid decline of renal function is usually associated with death or the need for support by dialysis. Spontaneous recovery is rare, and various modes of therapy have been generally unsuccessful. We describe nine patients with rapidly progressive glomerulonephritis of less than six weeks’ duration whose creatinine clearance decreased over 50 per cent. All had normal-sized kidneys and were proteinuric, six of nine were oliguric, and five of nine required dialysis. Renal biopsy specimens were examined by light, electron and immunofluorescence microscopy. Rapidly progressive glomerulonephritis without immune deposits was present in six, immune complex disease in two and antiglomerular basement membrane disease in one. All were treated with intravenous pulse methylprednisolone followed by oral steroids. Serum creatinines decreased in seven of nine patients from one to four weeks after pulse therapy and remained stable or improved in six of these. Three of five patients undergoing dialysis were able to discontinue that support. The mean creatinines of 10.6 f 2.2 mg/dl before therapy decreased to 2.2 f 0.5 mg/dl after four to 24 months in the six responding patients. Two other patients died of causes unrelated to therapy. Tissue obtained from four patients four to 12 months after pulse therapy showed resolution of inflammatory changes and regression of crescents. The marked and sustained improvement of renal function in six of our nine (67 per cent) patients with rapidly progressive glomerulonephritis who were treated with pulse methylprednisolone is in sharp contrast to experience previously reported and suggests the need for further evaluation in a prospective controlled study. Acute crescentic glomerulonephritis occurs in a variety of systemic diseases [l-5] as well as in an idiopathic form [2,6]. Patients with rapid deterioration of renal function, especially with proteinuria or oliguria, usually die within weeks or require dialysis [1,4,7,8]. Numerous therapeutic modalities have been tried with little benefit [4,9-131. We describe nine patients with acute crescentic rapidly progressive glomerulonephritis who were treated with intravenous pulse methylprednisolone followed by oral steroids. This therapy was followed by a marked improvement in renal function in six of the patients. Repeat histologic examinations in four patients demonstrated improvement in renal lesions with regression of crescents.

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2

4

6

6

10 12

14

16

I

limo

6

AL%---+-

1.8 ‘u-+ c-“__.@

I

10

(weok

*.

I

12

I

14

I

16

0

6

6

10

A

FI

2

4

6

________-

\

6

10

12

14

16

~.__ ~.-___-. -~-. lgure 1. C-se of the patients from admission through the first 16 weeks of therapy. Point “A” represents either the time of admission, week 0. or b time within the preceding month when normal serum creatinine values were obtained (Cases 1, 7 and 8). Crams of methylprednisolone administered at each pulse is given above the arrows indicating the time of pulsing. Case numbers correspond to their numbers in Tables I and II.

A

-__/--.

14 F

16

INTRAVENOUS

TABLE I

PULSE METHYLPREDNISOLONE

THERAPY-BOLTON.

COUSER

Clinical Characteristics and Course of Patients

% Case

Age (ur)

NO.

and Sex

CresOliguria

cents

Proteinuria (g/24 hr) Initial

Serum Creatinine (mgldl) Peak LOW Latest

Follow-up

Follow-up (mc)

0.8

0.9

14

12.5

2.1

2.0

a

9.0

lo.8

4.0

4.0

6

2.3

la.2

3.7

2.9

6

78

0.8 -

2.0

53

0.6 -

1.7

23

3.3 -

+

60

0.6 -

39, F

+

94

1+

6’

70, M

+

70

1+

a.1

4.8

10.0

4

7’

52, M

+

75

1+

9.2

3.1

3.1

24

a*+

59, M

+

57

+

10.0

1.6

1.6

4

9

70, M

20

2.6

1

13, F

2’

61, M

3+

43, M

4’

59, M

5f

+

1.9

16.5

1

7.0

2

Outcome Stable, proteinuria Stable, proteinuria Stable, proteinuria Stable, proteinuria Hemodialysis, died Hemodialysis, died Stable, proteinuria Stable, proteinuria Hemodialysis

Diuresis with pulse therapy. 7 Immune complex disease. i Antiglomerular basement membrane disease. l

MATERIALS AND METHODS All patients were studied for the presence of antinuclear antibodies, abnormal antistreptolysin (ASO) titers, cryoglobulins. hepatitis B surface antigen levels, antiglomerular basement membrane antibodies, circulating immune complexes and rheumatoid factor [6]. Blood urea nitrogen, serum creatinine, crcatinine clearance, urinary protein (qualitative or quantitative] and complement levels were determined by standard methods. Adequate renal biopsy specimens in all were examined by light, electron and immunofluorescence microscopy as previously described [14-161, and all had crescentic cxtracapillary glomerulonephritis. One had antiglomerular basement membrane disease, two had idiopathic immune complex disease, and six had rapidly progressive glomerulonephritis without immune deposits [6]. The number of glomeruli, type and number of crescents, and amount of tubular atrophy and cellular infiltrate were noted. Glomcrular tuftal involvement was further scored in those patients from whom tissue was available after pulse therapy according to the following schema: 11) normal glomeruli or less than 25 per cent involvement with segmental sclerosis, (z] 25 to 50 per cent tuftal sclerosis, (3) greater than 50 per cent sclerosis but identifiable glomcrular bascmcnt membrane morphology and (4) totally obsolescent glomeruli. All patients were treated with intravenous pulse methylprcdnisolone, 30 mg/kg lean body weight or actual weight (whichever was less), up to 3 g, given over 20 minutes with electrocardiographic monitoring every other day for three doses, or 1 g given intravenously daily for three days. After treatment with pulse methylprednisolone. five patients [Cases 1 through 5) received prednisone every other day beginning with 2 mg/kg and subsequent tapering, whereas four patients (Cases 6 through 9) were begun on prednisone, 60 to 80 mg daily, for one to three weeks and then switched to al-

ternate day therapy. One patient (Case 7) also received cyclophosphamide, 100 mg/day, for one month. Patients were excluded from the study if they had any evidence of systemic disease or if they had been treated only with high dose oral prednisone. RESULTS

The clinicopathologic characteristics of the patients are given in Table 1. The study group consisted of seven males and two females ranging from 13 to 70 years of age (mean

f standard

error

of the mean,

51.7 f 6.1 years].

The duration of disease before presentation, as indicated by a documented decrease in renal function, proteinuria or edema, ranged from three to five weeks. Oliguria (50 per cent at the time of pulse therapy. Three patients (Cases 2,~ and 7) who initially required hemodialysis regained sufficient renal function to discontinue dialysis. Seven patients responded with a decrease in serum creatinine within one to four weeks of the first course of pulse therapy, with most responders having decrements in serum creatinine within the first two weeks. Five of the six oliguric patients responded with a brisk diuresis within four weeks. In one patient [Case 6) creatinine decreased from 8.1 to 4.8 mg/dl, but relapse occurred later and

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INTRAVENOUS

TABLE II

Case No. 1

2 4 6

PULSE

METHYLPREDNISOLONE

THERAPY-BOLTON,

COUSER

Glomafular luftal Scores and Crescentlc Fibrin Before and After Pulse Steroid Therapy

BfopSY

MonthsAfter P&Therapy (no.)

Glomeruli (no.)

DegreeofSegmental Sclerosis Crescents (%I

Fibrin

O-25%

25-50%

50%

ObsO. leecent

1 2 3

0 12

9 21 14

38 78

3+ 3+ f

12 14 18

25 5 17

50 21 8

12 48 66

1 2

14 14

53

6

3+ -

14 50

43 36

21 7

21 7

1 2

19 50

60

4.5

3+ 1+

33 42

24 17

38 16

5 25

1 2

16 210

70

4

3+ ND

43 24

28 27

7 24

21 25

NOTE: ND = not determined

dialysis was required. The six patients who responded to pulse therapy had a mean serum creatinine of 10.6 f 2.2 mg/dl, which was not different from that of the three patients who did not respond, lo.4 mg/dl. Two patients (Cases 5 and S] died of causes unrelated to therapy. One patient (Case 5) died of respiratory failure and massive fluid overload at home, and another [Case 6) of a gastrointestinal bleed. One patient (Case 9) is still maintained on dialysis. The six patients who responded have been followed from four to 24 months, with stable or improving renal function. The urinary protein excretion has increased in these patients as the creatinine clearances have improved. No side effects attributable to pulse methylprednisolone therapy were detected, nor have there been any side effects of the oral alternate day prednisone therapy. Kidney tissue was available from four patients after four to 12 months of therapy (Table II]. Tuftal necrosis was present in the first biopsy specimen in all four, and endocapillary proliferation in each of them but one (Case 6). All had a pronounced interstitial infiltrate of mononuclear cells with minimal tubular atrophy. Each demonstrated the same trend after therapy. The amount of cellular infiltrate was markedly diminished, whereas tubular atrophy increased. Cellular crescents were replaced by remnant or fibrous acellular crescents with a decrease in the intrusion on the glomerular tuft by crescents (Figure 2). The percentage of obsolescent or severely damaged glomeruli remained approximately the same for a given patient with one exception [Case 21,a patient who had fewer damaged glomeruli on repeat biopsy. Numerous glomeruli demonstrated segmental sclerosis involving variable portions of the tuft (Figure 3, Table II]. Immunofluorescence of the initial biopsy specimens demonstrated intense crescentic staining for fibrin which was diminished in four to six months (Figure I) and virtually absent in the one year specimens.

496

COMMENTS Idiopathic acute crescentic glomerulonephritis may be associated with granular deposition of apparent immune complexes in the glomerulus, linear deposits of antibody directed against the glomerular basement membrane or crescents in the absence of immune deposits [6]. Regardless of pathogenetic mechanism, the most important prognostic factors appear to be the initial clinical course and severity of any associated systemic diseases, rather than the degree of crescent formation per se [2-4,6]. Table III summarizes the outcome in previously reported cases of acute crescentic rapidly progressive glomerulonephritis. Those patients with crescents but without rapidly progressive glomerulonephritis have been excluded. Seventy-eight per cent of all patients with rapidly progressive glomerulonephritis and 93 per cent of oliguric patients with rapidly progressive glomerulonephritis in these studies died or required dialysis. Although functional improvement in acute crescentic glomerulonephritis has been well documented, this rarely occurs if oliguria and rapid loss of renal function are present [2,17].Even more unusual is recovery of sufficient renal function in patients who require dialysis so that they no longer need that support

PI. A variety of therapeutic modalities have been attempted in rapidly progressive glomerulonephritis [4]. Anticoagulants and cytotoxic agents have had little apparent effect on the disease process [lo-12,181. Plasmaphoresis has been used with steroids and cytotoxic agents with apparent beneficial effect [9]. especially in Goodpasture’s syndrome without oliguria [19,2o], However, the results of therapy in rapidly progressive glomerulonephritis have generally been disappointing. Most patients with crescentic glomerulonephritis have many common histologic features. These include an interstitial infiltrate with mononuclear cells, presence

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INTRAVENOUS

PULSE

METHYLPREDNISOLONE

THERAPY-BOLTON.

COUSER

Figure 2. Case 6. A, photomicrograph of kidney from patient before treatment illustrating cellular crescent (arrows) compressing the glomerutar tuft. Periodic acid-Schiff stain; magnification X 382, reduced by 35 percent. B, glomerulus from patient four months after therapy illustrating acellular fibrous crescent remnant (arrow) with minimally abnormal tuft. Hematoxylin and eosin stain; magnification X 382, reduced by 35 per cent.

Figure 3. Case 6. A, glomerulus from patient illustrating segmental sclerosis (arrow) with adhesions. B, glomerulus from patient illustrating segmental tuftal damage and residual fibrous crescent separating glomerular lobules (arrow). A and B, hematoxylin and eosin stain; magnification X 382, reduced by 35 per cent.

Figure 4. Case 4. A, glomerulus from patient before treatment stained with fluoroscein-labeled rabbit antihuman fibrin. A cresent surrounds and separates the tuft. Three + intensity of stafning. B, glomerulus from patient showing 1 + residual fibrin deposits four and a half months later. Exposure time and staining conditions identical to A. A and B, magnification X 410, reduced by 35 per cent.

of multinucleated giant cells, tubular increscences, defects in Bowman’s capsule, periglomerular fibrosis and gaps in the glomerular basement membrane [8,21-251. These features imply that crescentic glomerulonephritis may be a common final pathway of clinically and pathogenetically different diseases. Certain aspects of rapidly progressive glomerulonephritis are similar to allograft rejection in which cell-mediated immunity clearly plays a role. Cellular sensitivity to glomerular basement membrane has been demon-

strated in some patients with rapidly progressive glomerulonephritis [26-281. Several studies have suggested that crescents in rapidly progressive glomerulonephritis are comprised in large part of macrophages of bone marrow origin [22,29-331. A possible role for this cellular component in the pathogenesis of rapidly progressive glomerulonephritis is suggested by the observation that recurrent antiglomerular basement membrane disease in allografts is often not associated with crescents or rapid deterioration of renal function [34-361.

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INTRAVENOUS PULSE METHYLPREDNISOLONE THERAPY-BOLTON.

TABLE III

associated

Summary of Previous Studies of the Clinical Course in Rapidly Progressive Glomerulonephritis Death or

Reference

131

Proteinuria (no.)

Oliguria (no.)

Dialysis (no.)

t::;

17 8 7 6 14

1121

15

11 6

11’ 6”

Total

67

43

52

series

9

6

[:I

Present

10 4 6 6

17 a 7 3

COUSER

3+

Oliguric. + Two oliguric. l

These findings, as well as the favorable experience reported with pulse steroid therapy in other glomerular diseases [19,37-411,suggest that a therapeutic approach similar to that employed for transplant rejection might be efficacious in rapidly progressive glomerulonephritis. Six of our nine patients treated with intravenous pulse methylprednisolone appeared subsequently to improve. Five of the six oliguric patients diuresed within four weeks, and in seven of the nine creatinine clearances improved, with six of these seven showing sustained improvement. Three of five patients who were being maintained on hemodialysis recovered sufficient renal function to discontinue dialysis. Although the “poor prognosis” indicators of large numbers of crescents, necrosis, endocapillary proliferation, oliguria, proteinuria and rapid progression [l-4,7] were present, they did not portend the poor outcome seen without pulse methylprednisolone therapy. Although these results are clearly uncontrolled, the striking improvement in clinical status in the six patients with sustained improvement is in marked contrast to the almost universally poor prognosis in patients with similar lesions described by others [3,7,8,10-U]. It is difficult to assess the effect of therapy on the histology in the four patients from whom tissue was available. The small number of patients precludes definitive evaluation, but comparison with the natural histologic progression previously reported suggests a definite benefit of therapy [1,3,7,17]. Acute crescentic rapidly progressive glomerulonephritis progresses from cellular to fibrous, acellular crescents with contraction, sclerosis and, finally, obsolescence of the glomerular tuft

with interstitial fibrosis and marked tubular atrophy [1,3,7].The four tissue specimens obtained after pulse therapy suggest that therapy ameliorated this process. Tubular atrophy was present, but the mononuclear infiltrate was almost completely gone. Cellular crescents were no longer present-instead, there were fibrous and remnant crescents. Glomerular sclerosis was present in a large proportion of glomeruli but was segmental in many cases. Whereas the natural progression is to total tuftal obliteration and obsolescence, the sclerotic process in our treated patients appeared to be greatly retarded and only segmental sclerosis persisted [Table II). There was no correlation with the per cent of crescents and response to therapy. A number of effects of high dose intravenous methylprednisolone therapy might be of benefit in a disease process in which macrophages and lymphocytes are important mediators. These include a lymphocytopenia; impairment of mixed lymphocyte cultures; depression of T-cell and B-cell function; and marked monocytopenia and depressed macrophage function [42-491.Other effects that could contribute to the results observed include prevention of leakage of lysosomal enzymes, inhibition of fibroblasts and depression of circulating immune complex levels [50-531. Alteration of cardiac output, peripheral vascular resistance, renal blood flow or glomerular filtration could also play some role in the effects of methylprednisolone on renal function [54-561. Compared to patients with similar histologic and clinical findings in the literature, the patients described here appear to have benefitted significantly from high dose intravenous pulse methylprednisolone therapy and oral prednisone. The small numbers of patients with acute crescentic rapidly progressive glomerulonephritis seen in any individual center make the study of therapy with randomized trials difficult. However, our results are sufficiently encouraging to suggest that aggressive therapy with standard support procedures, high dose pulse methylprednisolone and oral steroids merits further evaluation in a prospective controlled fashion as a possible alternative to the a priori need for dialysis and transplantation in patients with acute crescentic rapidly progressive glomerulonephritis. ACKNOWLEDGMENT

We thank Dr. B. Sturgill, University of Virginia and Dr. M. Stilmant, Boston University, for assistance in interpreting the histology, and Ms. B. Parks for secretarial assistance.

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500

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Beirne GJ, Wagnild JP, Zimmerman SW, et al.: Idiopathic crescentic glomerulonephritis. Medicine (3altimore) 56: 349,1977. Whitworth JA, Morel-Maroger L, Mignon F, et al.: The sig-

INTRAVENOIJS PULSE METHYLPREDNISOLONE THERAPY-BOL’I’ON, COUSER

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‘IO. 11. 12. 13. 14.

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28. 29. 30. 31. 32. 33. 34.

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35. Lerner RA, Glassock RJ, Dixon FJ: The role of anti-glomerular basement membrane antibody in the patho~nesis of human glomerulonephrit~. 1Exp Med 126: 989.1967. 36. Couser WG. Wallace A, Monaco AP, et al.: Successful renai transplantation in patients with circulating antibody to glomerular basement membrane: report of 2 cases. Clin Neuhrol 1: 381.1973. 37. Cathdart ES, Scheinberg MA, Idelson BA, et al.: BeneficiaI effects of methylprednisolone “pulse” therapy in diffube proliferative lupus nephritis. Lancet 1: 163.1976. 38, Nibout T, SobelA, Lagrue C: Intravenous methylprednisolone pulses in diffuse proliferative lupus neDhritis (letter). _ _ Lanckt 1: 909,1977. . 39. Ponticelli C, Tarantino A, Pioltelli P, et al.: High-dose mcthylprednisolone pulses in active lupus nephritis (letter). Lancet 1: 1063,1977. 40. Cole BR, Brocklebank JT, Kienstra RA, et al.: “Pulse” methvlpr~nisolone therapy in the treatment of severe glom~~1onephritis. J Pediatf 88: 307,1976. 41. O’Neill WM, Etheridae WB, Bloomer HA: High dose corticosteroids in idiopathic rapidly-progressive glomerulonephritis (abstract). Clin Res 26: 164-A, 1978. 42. Thompson J, vanFurth R: The effect of glucocorticosteroids on the kinetics of mononuclear -__ uharocvtes. .1EXD . Med 131: 429.1970. 43. Craddock CG, Winkelstein A, Matsuyuki Y, et al.: The immune response to foreign red blood cells and the participation of short-lived lymphocytes. J Exp Med 125: 1149, 1967.

44.

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Balow JE. Rosenthal AS: Glucocorticoid suppression of macrophage migration inhibitory factor. J Exp Med 137: 1031, 1973. Rinehart JJ, Sagone AL, Balcerzak SP: Effects of corticosteroids on mono~te function. J Clin Invest 54: 1337.1974. Bach JF, Duval D, Dardenne M, et al.: The effects of steroids on T cells. Transplant Proc 7: 25.1975. Cheigh JS, Stenzel KH, Riggio RR, et al.: Effects of intravenous methylprednisolone on mixed lymphocyte cultures in normal humans. Transplant PFOC7: 31,1975. Webel ML, Ritts RE Jr, Taswell HF. et al.: Cellular immunity after intravenous administration of methylprednisolone. J Lab Clin Med 83: 383.1974. Claman HN, Moorhead JW, Benner WH: Cofiicosteroids and lymphoid cells in vitro. I. Hydrocortisone lysis of htiman, guinea pig and mouse thymous cells. ] Lab Clin Med 78: 499,1971. Leibovich Sl, Ross R: A macronhane deuendent factor that stimulates the proliferation if fybrobiasts in vitro. Am J Patho184: 501,1976.

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51. Goldstein IM: Effect of steroids on lysosomes. Transplant Proc 7: 21,1975. 52. Levinsky RJ, Cameron JS, Soothill JF: Serum immune complexes and disease activity in lupus nephritis. Lancet 1: 564, 1977. 53. Ooi YM, Ooi BS. Vallota EN, et al.: Circulating immune complexes after renal transplantation. Correlation of increased 1251~Clqbinding activity with acute rejection characterized by fibrin deposition in the kidney. J Clin

502

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Invest 60: 611,1977. 54. DeBermudez L, Hayslett JP: Effect of methylprednisolone on renal function and the zonal distribution of blood flow in the rat. Circ Res 31: 44,1972. 55. Sambhi MP, Weil MH, Udhoji VN: Acute pharmacodynamic effects of glucocorticoids. Circulation 31: 523,1965. 56. Webel ME, Donadio JV, Woods JE, et al.: Effects of large dose of methylprednisolone on renal function. J Lab Clin Med 80: 765, 1972.

Volume 66

Intravenous pulse methylprednisolone therapy of acute crescentic rapidly progressive glomerulonephritis.

CASE REPORTS Intravenous Pulse Methylprednisolone Therapy of Acute Crescentic Rapidly Progressive Glomerulonephritis W. KLINE BOLTON, M.D. Charlotte...
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