Pulse methylprednisolone and cyclophosphamide therapy in

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Postgraduate Journal of Medicine (January 1981) 57, 54-56




                 'Pulse' methylprednisolone and cyclophosphamide therapy in
                       idiopathic rapidly progressive glomerulonephritis
                  G. FRIEDMANt                                                  H. GRANOTt
                          M.D.                                                        M.D.

                  Y. KOPLOVIC*                                              M. FRIEDLANDERt
                          M.D.                                                 M.R.C.P., D.C.H.
                       Departments of tMedicine B, *Pathology, and tNephrology Service,
                                Hadassah University Hospital, Jerusalem, Israel



                        Summary                              renal function deteriorated rapidly to oliguria and
The clinical report of a 31-year-old man who developed       he was transferred to Hadassah University Hospital.
acute renal failure due to idiopathic rapidly progres-       On admission he was a pale, ill-looking patient, the
sive glomerulonephritis is presented.                        temperature was 37-10C, pulse 98/m, BP 180/115
   Intravenous pulse methylprednisolone therapy in           mmHg. Physical findings and urine analysis gave
combination with cyclophosphamide resulted in                results similar to those described previously. ESR
marked improvement in renal function. The literature         140 mm/hr; Hb 6-8 g/dl; WBC and thrombocyte
dealing with pulse therapy is reviewed.                      count were normal. Urea was 42 mmol/l, plasma
                                                             creatinine 2254,mol/l. Total protein was 779 g/l;
Introduction                                                 albumin 28 g/l; globulin 51 g/l. Complement deter-
   Rapidly progressive glomerulonephritis (RPGN)             minations (C3 and total haemolytic complement)
is characterized by crescent formation with protein-         were normal. Serological studies including measure-
uria, oliguria and rapid deterioration in renal func-        ment of ASO titre and detection of antinuclear
tion. Most of the patients die within weeks or need          antibody, rheumatoid factor and cryoglobulins were
dialysis (Bierne et al., 1977). Many therapeutic             negative. The electrocardiogram and chest X-ray
modalities have been attemped in RPGN but the                examination were normal. There were no other dis-
effect on the disease course was not encouraging             tinctive abnormalities of blood chemistries. Abnor-
(Briggs et al., 1979). Bolton and Couser (1979) re-          malities found in electrolyte and acid-base studies
ported recently that therapy with intravenous                were related to the degree of renal functional im-
'pulse' methylprednisolone causes favourable im-             pairment.
provement in renal function.                                    Circulating anti-glomerular basement membrane
   The present authors wish to report on another             antibodies were not demonstrated. On arrival the
patient with RPGN whose renal function improved              patient started haemodialysis, and an open kidney
dramatically after therapy with i.v. 'pulse' methyl-         biopsy was performed. Light microscopic examina-
prednisolone in combination with cyclophosph-                tion of the kidney biopsy specimen showed over 50
amide.                                                       glomeruli, all involved by epithelial proliferation and
                                                             a polymorphonuclear infiltrate with crescent forma-
Case report                                                  tion, diffuse fibrosis in the interstitium and no glomeru-
   A 31-year-old man was admitted to another hospi-          lar sclerosis (Fig. 1). Immunofluorescence showed
tal with a one-week history of chills, fever and             linear glomerular deposition of IgG, (Fig. 2). No
malaise. There was no history of renal disease, recent       electron-dense deposits were found in capillary walls
pharyngitis, diabetes mellitus, arthritis or exposure        or mesangium.
to known nephrotoxic agents. The physical findings              The histological and immunofluorescence picture
were non-specific. Urine analysis showed protein             was compatible with the diagnosis of RPGN type I.
2+, numerous red and white blood cells and red               Treatment was begun with 'pulse' intravenous ad-
cell casts per high power field. Blood urea 6 mmol/l;        ministration of one g methylprednisolone sodium
serum creatinine concentration 100 ,umol/l. Other             succinate given daily for 3 days followed by oral
laboratory results were negative. In the next 3 weeks         prednisone 60 mg/day with subsequent tapering and
                     0032-5473/81/0100-0054 S02.00 () 1981 The Fellowship of Postgraduate Medicine
                    Downloaded from pmj.bmj.com on December 11, 2011 - Published by group.bmj.com



                                                     Case reports                                                 55




                         ~
                        *.




           FIG. 1. Circumferential cellular crescent and compressed glomerular tuft (Silver methenamin x 100).




                                         - r                  4O




                                          it                         tY
                     FIG. 2. Immunofluorescence. Strong linear pattern of IgG in glomerular tuft.

cyclophosphamide 200 mg/day i.v. for 5 days, fol-              defined clinical entity. It may occur as an idiopathic
lowed by 100 mg/day orally for one month. Over the             form (Bierne et al., 1977), as well as in some systemic
next days there was a striking and dramatic im-                disease (Spargo, Ordonez and Ringus, 1977).
provement in renal function and the patient who                  The most consistent histopathological finding is
initially required haemodialysis regained sufficient           the presence of glomerular crescents resulting from
renal function to discontinue this (Fig. 3).                   proliferation of the extra-capillary epithelial cell of
   During a follow-up period of 8 months the patient           Bowman's capsule (Heptinstall, 1974). Three distinct
has remained well with a creatinine clearance of 30            immunofluorescent patterns are known: Diffuse
ml/min.                                                        linear deposits of antibody directed against the
                                                               glomerular basement membrane-type-I; diffuse
Discussion                                                     granular deposits of immune complexes accompanied
  Rapidly progressive glomerulonephritis is a well             by C3 in the glomeruli-type II; and crescents with
             Downloaded from pmj.bmj.com on December 11, 2011 - Published by group.bmj.com


 56                                                                Case reports

 sparse or no immune deposits (Glassock and Ben-                           usefulness in many forms of glomerulonephritis
 nett, 1976)-type III.                                                     (Ibels et al., 1975) and vasculitis (Fauci, 1979).
    Although there are few reports of spontaneous                             This experience suggests that the administration of
 recovery (Maxwell et al., 1979), the clinical course is                   'pulse' methylprednisolone in combination with
 characterized by rapid deterioration of renal func-                       cyclophosphamide may produce a dramatic im-
 tion so that most of the patients die within weeks,                       provement in a certain group of patients with idio-
 or need dialysis. Little benefit has been gained from                     pathic RPGN, and supports other similar experience
 various therapeutic modalities, including anti-                           in the literature. Although it is recognized that spon-
 coagulants, cytotoxic agents and steroid therapy                          taneous remission may have occurred simultane-
 alone (Briggs et al., 1979). Plasmaphoresis and im-                       ously with the initiation of therapy, the temporal
 munosuppression have been used with apparent                              relationship among therapy and recovery cannot be
 beneficial effect in Goodpasture's syndrome (Lock-                        ignored.
 wood et aL. 1977).                                                           The authors hope that controlled studies will con-
                       methyl-                                             firm their expectations of the benefit of 'pulse'
                     prednisolone                                          methylprednisolone and cyclophosphamide therapy
                    60rl                                                   in idiopathic RPGN, if started early in the course of
                    40-                                                    the disease.

                >   200k                                                   References
                                                                           BELL, P.R.F., BRIGGS, J.D., CALMAN, K.C., PATON, A.M.,
                                       Dialysis
                                                                             WOOD, R.F.M., MACPHERSON, S.G. & KYLE, K. (1971)
                                                                              Reversal of acute clinical and experimental organ rejection
                                                                             using large doses of intravenous prednisolone. Lancet, i,
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                                              /                            BIERNE, G.J., WAGNILD, J.P., ZIMMERMAN, S.W., MACKEN,
                                                                             P.D. & BURKHOLDER, P.M. (1977) Idiopathic crescentic
      2000          20
                                                                             glomerulonephritis. Medicine, 56, 349.
                                                                           BOLTON, W.K. & COUSER, W.G. (1979) Intravenous pulse
                                                                             methylprednisolone therapy of acute crescentic rapidly
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      0
      1500     'E                                                            progressive glomerulonephritis. American Journal of
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                                                                           BRIGGS, W.A., JOHNSON, J.P., REICHMAN, S., YEAGER, H.C.
 LYi 1000 _          10                                                      & WILSON, C.B. (1979) Antiglomerular basement mem-
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       500                 01-' -                                          COLE, B.R., BROCKLEBANK, J.T., KIENSTRA, R.A., KISSANE,
                    0-0                                                      J.M. & ROBSON, A.M. (1976) "Pulse" methylprednisolone
                                                                             therapy in the treatment of severe glomerulonephritis.
                            2   4      6 8 10      12   5 6 7 8
                                                                             Journal of Pediatrics, 88, 307.
                                                                           FAUCI, A.S., KATZ, P., HAYNES, B.F. & WOLFF, S.M. (1979)
                                    Time (weeks)        (Months)             Cyclophosphamide therapy of severe systemic necrotizing
  FIG. 3. Summary of the clinical course. 0- [Cr]p =                         vasculitis. New England Journal of Medicine, 301, 235.
  Plasma creatinine; Ccr = creatinine clearance; El = pred-                GLASSOCK, R.J. & BENNETT, C.M. (1976) In: The Kidney
  nisone; =cyclophosphamide.                                                 (Ed by Brenner, B.M. & Rector, F.C.), p. 212. Saunders,
                                                                             Philadelphia.
   Cole et al. (1976) suggested that a therapeutic                        HEPTINSTALL, R.H. (1974) Rapidly progressive glomerulo-
approach similar to that employed by Bell (Bell et al.,                      nephritis. In: Pathology of the Kidner, 2nd edn (Ed by
 1971) for transplant rejection might be efficacious in                      Heptinstall, R.H.), p. 371, Little Brown and Co., Boston.
severe glomerulonephritis. They described the bene-                       IBELS, L.S., PALMER,IA.A., MAHONY, J.F. & STEWART, J.H.
                                                                            (1975) Cyclophosphamide in treatment of nephrotic
ficial effect of 'pulse' methylprednisolone in 4 out of                     syndrome. British Medical Journal, 1, 268.
5 children with RPGN. O'Neill, Etheridge and                              LoCKWOOD, C.M., REES, A.J., PINCHING, A.J., PUSSELL, B.,
Bloomer (1979) found benefit in 4 out of 10 patients                        SWENY, P., UFF, J. & PETERS, D.K. (1977) Plasma-ex-
with renal failure due to idiopathic rapidly pro-                           change and immunosuppression in the treatment of ful-
                                                                            minating immune-complex crescentic nephritis. Lancet, i,
gressive glomerulonephritis. The improvement in                             63.
renal function appeared to be directly related to                         MAXWELL, D.R., OZAWA, T., NIELSEN, R.L. & LUFT, F.C.
'pulse' methylprednisolone administration.                                  (1979) Spontaneous recovery from rapidly progressive
   Recently, Bolton and Couser (1979) noted im-                             glomerulonephritis. British Medical Journal, 2. 643.
                                                                          O'NEILL Jr, W.M., ETHERIDGE, W.B. & BLOOMER, H.A.
provement in renal function in 7 of 9 patients from                         (1979) High-dose corticosteroids. Their use in treating
one to 4 weeks after 'pulse' therapy. The addition of                       idiopathic rapidly progressive glomerulonephritis. Archives
cyclophosphamide to the pulse therapy was sug-                              of Internal Medicine, 139, 514.
gested by its use as the main immunosuppressant by                        SPARGO, B.H., ORDONEZ, N.G. & RINGUS, J.C. (1977) The
                                                                            differential diagnosis of crescentic glornCrulonephritis,
Lockwood et a. (1977) and by other reports of its                           Human Pathlology, 8, 187,
     Downloaded from pmj.bmj.com on December 11, 2011 - Published by group.bmj.com




                                  'Pulse' methylprednisolone and
                                  cyclophosphamide therapy in
                                  idiopathic rapidly progressive
                                  glomerulonephritis.
                                  G. Friedman, H. Granot, Y. Koplovic, et al.

                                  Postgrad Med J 1981 57: 54-56
                                  doi: 10.1136/pgmj.57.663.54


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