Plasma Exchange in Patients With Rapidly Progressive Idiopathic IgA Nephropathy: A Report of Two Cases and Review of Literature

Plasma Exchange in Patients With Rapidly Progressive Idiopathic IgA Nephropathy: A Report of Two Cases and Review of Literature Kar Neng Lai, MD, MRCP, Fernand Mac-Moune Lai, MD, Antony C.T. Leung, MBBS, MRCp, Chung Ping Ho, MBBS, MRCP, and John Vallance-Owen, MD, FRCp, FRCPI, FRCPath • Primary IgA nephropathy is generally considered an indolent disease, but progression to chronic renal failure is not uncommon, and a rapidly progressive course is observed in some cases, especially when extensive fibrocellular crescents are present. The therapeutic benefit of immunosuppression and plasma exchange remains controversial. We described two patients with primary IgA nephropathy and rapidly progressive renal failure. Both patients showed extensive glomerulosclerosis and crescent formation in their renal biopsies. Corticosteroid and immunosuppressive therapy failed to control the progression of the disease, and plasma exchanges were performed. In both cases, the serum creatinine and creatinine clearance initially improved with plasma exchange and the rapid progression of renal failure was apparently halted. In one patient, the serum creatinine rose when treatment was discontinued and fell again when plasma exchange was recommenced. Nevertheless, the long-term benefit of plasma exchange in crescentic IgA nephropathy was unsatisfactory as the renal function continued to deteriorate in the following 12 months despite an initial stabilization. © 1987 by the National Kidney Foundation, Inc. INDEX WORDS: IgA nephropathy; crescentic glomerulonephritis; plasma exchange; prognosis.

I

NITIAL REPORTS suggested that primary IgA nephropathy has a benign course, but progression to end-stage renal failure (ESRF) was subsequently observed in from 8 % to 33 % of the cases, \,2 and a small proportion of patients even showed a rapidly progressive deterioration of renal function. 3.4 The immunopathogenesis of IgA nephropathy is not completely defined but available clinical data suggest that circulating IgA-containing immune complexes play an important role 5 ,6 and the levels of circulating immune complexes correlate with the extent of glomerular crescent formation.? Treatment was previously reported to be uniformly ineffective in IgA nephropathy.8 Plasma exchange has been tried with some success in patients with glomerulonephritis (GN) of HenochSchoenlein purpura. 9 - 11 A preliminary case report has been published recently suggesting the likelihood that plasma exchange is effective in patients with rapidly progressive IgA nephropathy.12 In this report, we describe two patients with rapidly progressive IgA GN undergoing immunosuppresFrom the Renal Unit, Prince of Wales Hospital, Chinese University of Hong Kong, Address reprint requests to Kar Neng Lai, MD, MRCp, Senior Lecturer in Medicine, Department of Medicine, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, New Territory, Hong Kong. © 1987 by the National Kidney Foundation, Inc, 0272-6386/8711001-0012$3,00/0 66

sive treatment and plasma exchange, and review previously reported cases of plasma exchange treatment in rapidly progressive IgA nephropathy. CASE REPORTS

Case 1 A 24-year-old previously healthy college student was admitted to the Renal Unit, Prince of Wales Hospital. in April 1985. Four months prior to admission, she noticed loin pain, easy fatigability, and general malaise, Laboratory data revealed a hemoglobin of 7,9 g/dL, serum creatinine of 450 ",moIlL, and creatinine clearance of 32 mLimin. Ultrasonography of kidneys showed no hydronephrosis and the kidney sizes were normal. Physical examination revealed pallor and the BP was 120170 nun Hg. The following pathological laboratory data were found: hemoglobin 7.6 g/dL, erythrocyte sedimentation rate (ESR) 65 mm/h, serum creatinine 727 ",moIlL, BUN 27.2 nunollL, and serum phosphate 2.24 mmollL. The serum IgA and serum albumin concentrations were normal. Cryoglobulin, anti-DNA antibody, and hepatitis B surface antigen were not detected, Urinalysis revealed a protein excretion of 1.8 g/d and the creatinine clearance was 13 mLi min, Phase contrast urinary microscopy revealed 10 to 15 glomerular RBCs per high power field (HPF) and RBC casts. A renal biopsy specimen revealed that 13 of the 20 glomeruli were obsolescent and that the remaining seven glomeruli showed large circumferential cellular and fibrous crescentic lesions at various stages of organization. The tubules and interstitium showed severe damage, atrophy, and mononuclear cellular infiltration, No vasculitic changes were observed. Immunofluorescence studies showed coarse granular deposits of IgA (3 +) predominantly in the mesangium, IgM (I +), and C3 (2 +) in similar distribution as IgA deposits. Electron microscopy revealed mesangial electrondense deposits. A crescentic primary IgA nephropathy was diagnosed,

American Journal of Kidney Diseases, Vol X, No 1 (July), 1987: pp 66-70

PLASMA EXCHANGE IN CRESCENTIC IGA NEPHROPATHY AZATHIOPRINE

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Fig 1. Time course of serum creatinine and creatinine clearance for our first patient. Note that the progression of renal deterioration was temporarily halted by plasma exchange (arrows) on three occasions.

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Case 2 A 21-year-old woman was admitted to the hospital in 1982. Three years previously, macroscopic hematuria and proteinuria were detected during a routine examination. An intravenous urogram showed normal findings. Four months before admission, she noticed ankle-swelling and loin pain. Urinalysis revealed macroscopic hematuria and proteinuria. The serum creatinine was then normal. The following pathological laboratory data were found on admission: creatinine clearance 60 mLlmin and ESR 45 mm/h. Urinalysis showed a protein excretion of 0.89 g/d with 9.6 million erythrocytes/d. Serum creatinine, IgA , and albumin were normal; cryoglobulin, anti-DNA antibodies , and hepatitis B surface antigen were not detected. Renal biopsy revealed mesangial proliferative ON with mesangial IgA deposition , but no crescent formation. Three of the 30 glomeruli were sclerotic. The patient was admitted to the hospital in April 1985 because of malaise and headache. The BP was 150/90 mm Hg . Laboratory investigations revealed hemoglobin 7.0 g/dL, BUN 21.0 mmollL, and serum creatinine 425 !LmollL. Urinalysis revealed a protein excretion of 2.6 g/d and the creatinine clearance was 20 mLlmin. Phase contrast urinary microscopy showed 15 to 20 glomerular RBCs/HPF and numerous RBC casts. Ultrasonography of the kidneys showed no hydronephrosis and the kidney sizes were normal. Renal biopsy demonstrated IgA nephropathy with large fibrocellular crescent formation in ten of the 15 glomeruli and the remaining five glomeruli were completely sclerotic. Three daily doses of I g of methylpredniso-

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On the tenth day after admission, the serum creatinine rose to 802 !LmollL while the creatinine clearance feli to 10 mLlmin. Prednisolone, 40 mg/d, and azathioprine, 100 mg/d, were started . The BP was elevated to 160/110 mm Hg after 2 weeks. The dosage of prednisolone was reduced to 20 mg/d and antihypertensive treatment was commenced. Four 3-L plasma-exchange treatments were performed within the following eight days and the serum creatinine decreased to 550 !LmoIlL. The patient was then discharged and was observed regularly as an outpatient. The serum creatinine remained stable at 400 to 450 !Lmol/L for 2 months before rising to 850 !LmollL associated with increased malaise. Four 3-L plasma-exchange treatments were performed again during the following week with a fall of the serum creatinine to 510 !Lmol/L. The BP was well controlled with the cessation of steroid therapy. Azathioprine was discontinued because of leukopenia. The serum creatinine and creatinine clearance remained stable for 10 weeks before deteriorating again after an episode of macroscopic hematuria. The serum creatinine rose to 910 !LmollL with a simultaneous fall of creatinine clearance to 8 mLlmin. Following another four 3-L plasma-exchange treatments performed on alternate days, the serum creatinine and creatinine clearance improved to 590 !LmoIlL and 18 mLlmin, respectively. The patient received another eight 3-L plasma-exchange treatments in February 1986 following deterioration of renal function after another episode of macroscopic hematuria. Renal function failed to improve, and the patient has recei~ed regular maintenance hemodialysis since April 1986. The clinical course of this patient is presented in Fig I. AZATHIOPII;IN[

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68

LAI ET AL

lone were given intravenously and the patient was maintained on prednisolone, 20 g/d, and azathioprine, 100 mg/d. Over the following 3 weeks, the serum creatinine and creatinine clearance deteriorated to 720 /LmollL and 8 mLlmin, respectively, despite immunosuppression and good control of BP. Six 3-L plasma exchanges were performed on alternate days after which the serum creatinine fell to 405 /LmollL and the creatinine clearance rose to 23 mLlmin. The renal function remained stable for 7 months, but started to deteriorate progressively in March 1986 after an episode of macroscopic hematuria. The clinical course of case 2 is presented in Fig 2.

DISCUSSION

Since it was originally described by Berger and Hinglais, 13 IgA nephropathy has emerged as a heterogeneous disease with a wide spectrum of clinical presentation. While many patients retain good renal function, some follow a progressive course to chronic renal failure.1.2 Patients with rapidly progressive IgA nephropathy have recently been reported, and the renal deterioration is frequently

associated with episodes of macroscopic hematuria, accompanied by crescents on biopsy. 3.4.12 Available clinical data suggest that circulating IgAcontaining immune complexes play the most important role in the pathogenesis of rapidly progressive IgA nephropathy, and high levels of IgA-containing immune complex correlate significantly with the extent of florid glomerular crescent formation in the renal biopsy. 7 The two young women in this study were very similar. Both presented with recurrent loin pain, proteinuria, and macroscopic hematuria. The second patient had a renal biopsy 3 years previously that revealed mesangial IgA nephropathy with no crescents or glomerulosclerosis. Both patients had rapid deterioration of renal function with no apparent precipitating factor. The ultrasonography showed normal-sized kidneys , suggesting that the progression of disease activity was recent and

Table 1. Clinical and Pathologic Data of Seven Patients With Rapidly Progressive IgA Nephropathy Receiving Plasma Exchange Known History Duration of of MacroCase Sex! Illness scopic No. Age (mo) Hematuria M/22

19

+

2

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45

+

3

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36

+

4

M/54

26

+

5

F/18

Renal Biopsy (Light Microscopy) 13/15 Glomeruli sclerotic, remaining 50% (1/2) with

cellular crescent Focal segmental proliferative GN; 14/31 Glomeruli sclerotic, 8/31 Glomeruli crescentic 25/28 Glomeruli sclerotic, 2/28 Glomeruli crescentic, 1128 Glomerulus advanced segmental scarring Diffuse mesangial proliferative GN, 6/30 Glomeruli with epithelial crescent 2/12 Glomeruli hyalinized, 10/12 glomeruli epithelial

Steroid ImmunePlasma Therapy suppression Exchange

F/24

12

+

13/20 Glomeruli sclerotic, 7/20 Glomeruli with fibro-

eycl

2 mo

Rapid progression to ESRD

4

+

eycl

2 mo

4

+

eycl

1 mo

Renal function stabilized for 3 mo, then progressed to ESRD Renal function stabilized for 2 mo; progressed to ESRD in 10 mo

+

eycl

4wk 12 PE

+

eycl

+

Aza

+

Aza

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Outcome

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Decrease of IgA 12 immune complexes; complete recovery of renal function 35 PE Decrease of IgA 17 in 30 immune complexes; weeks complete recovery of renal function 4 PE Renal function stabilized x 5 with PE for 10 mo; over progressed to ESRD 8 mo in 1 yr 6 PE Renal function stabilized in for 9 mo; thereafter pro2wk gressive deterioration

Abbreviations: eycl, cyclophosphamide; Aza, azathioprine; + , present; -, absent; PE, plasma exchange; ESRD, endstage renal disease. * Present study.

PLASMA EXCHANGE IN CRESCENTIC IGA NEPHROPATHY

rapid. Renal biopsy of both the patients showed typical features of IgA nephropathy with extensive crescent formation (> 50 %) in the nonsclerotic glomeruli. Although two cases ofIgA nephropathy with fibrocellular crescents resolving spontaneously have been reported, crescents were only present in < 30% of the glomeruli in these biopsies. 3 Natural recovery in rapidly progressive GN with over 50 % crescent formation is less likely. 14 Corticosteroid and immunosuppressive therapy was administered to our patients with no improvement of the renal function, and the treatment was complicated with hypertension and leukopenia in the first patient. Plasma exchange therapy has been tried with clinical improvement in patients with a rapidly progressive course in GN caused by HenochSchoenlein purpura. 911 Repeated plasma exchange therapy will remove circulating immune complexes, procoagulant, and most inflammatory mediators such as complement components C3, C4, and factor B,15 and this may theoretically reduce the extent of tissue injury. The therapeutic value of plasma exchange in IgA nephropathy, with a relentless and slowly deteriorating renal function, remains uncertain. 10.11.16 A review of the medical literature reveals only five cases of rapidly progressive idiopathic IgA nephropathy treated with plasma exchange,4.12.17 and the clinical and pathologic findings of these seven patients (including the two patients reported here) are presented in Table 1. Except for one, all patients with rapidly progressive primary IgA nephropathy had a history of recurrent macroscopic hematuria. The disease activity in these patients usually runs an indolent course initially, as in our second patient, yet rapid deterioration can occur in 6 to 8 months, not uncommonly associated with hypertension and episodes of macroscopic hematuria. Although the initial renal biopsy specimen may show focal segmental mesangial proliferative IgA nephropathy with no significant sclerosis or crescent formation, renal biopsy during the phase of rapidly progressive GN often shows diffuse mesangial proliferation with significant glomerulosclerosis and with fibrocellular crescents in 50% to 100% of the nonsclerotic glomeruli. Corticosteroid and immunosuppressive therapy apparently is not effective in controlling the rapid progression of the disease. The beneficial effect of intensive plasmaexchange therapy is not confirmed in the patients

69

that we have reviewed. The two patients reported by Coppo and co-workers I2.17 had clinical recovery after plasma-exchange treatment but the renal biopsy in one of their patients showed epithelial crescent in only 20% of the glomeruli, and one may argue that spontaneous resolution of the crescentic GN occurred as in patients described by Feltis and co-workers. 3 The three patients described by Nicolls et al 4 developed ESRF despite plasma-exchange therapy. In our study, the progression of renal failure appeared to be temporarily halted by plasma-exchange therapy, but complete recovery of renal function is most unlikely in these patients with advanced glomerulosclerosis and fibrous crescent formation. Our limited experiences and that of Nicolls et al 4 suggest that plasma-exchange therapy may be beneficial in delaying the rapid progression of crescentic primary IgA nephropathy, thus temporarily delaying the onset of ESRF and the need for dialysis therapy. The long-term benefit is unfavorable, however, as most patients progress to ESRF in the next 12 months. Our experience emphasizes the need for a controlled trial of immunosuppressive therapy and plasma exchange in IgA nephritic patients undergoing a rapidly progressive course with crescents in more than 60% of glomeruli, 18 and a multicenter trial is warranted because of the relatively small number of patients treated at individual centers.

REFERENCES 1. Nicolls K, Fairley K, Dowling J, et al: The clinical course of mesangial IgA associated nephropathy in adults. Q J Med 53:227-250, 1984 2. D'Amico G, Imbasciati E, Di Belgioioso G, et al: Idiopathic IgA mesangial nephropathy. Medicine 64:49-60, 1985 3. Feltis JT, Churg J, Holley KM, et al: Active and chronic phases of Berger's disease (IgA nephropathy). Am J Kidney Dis 3:349-356, 1984 4. Nicolls K, Walker RG, Dowling Jp, et al: Malignant IgA nephropathy. Am J Kidney Dis 5:42-46, 1985 5. Rifai A, Small P, Teague P, et al: Experimental IgA nephropathy. J Exp Med 150:1161-1173, 1979 6. Isaacs K, Miller F, Lane B: Experimental model for IgA nephropathy. Clin Immunol Immunopathol 20:419-426, 1981 7. Coppo R, Basolo B, Martina G, et al: Circulating immune complexes containing IgA, IgG, and IgM in patients with primary IgA nephropathy and with Henoch-Schonlein nephritis. Correlations with clinical and histological signs of activity. Clin Nephrol 18:230-239, 1982 8. Clarkson AR, Seymour AE, Chan Y, et al: Clinical, pathological and therapeutic aspects of IgA nephropathy, in Kin-

70 caid-Smith P, d'Apice A, Atkins R (eds): Progress in Glomerulonephritis. New York, Wiley, 1979, pp 247-258 9. Kauffman RH, Houwert DA: Plasmapheresis in rapidly progressive Henoch-Schoenlein glomerulonephritis and the effect on circulating IgA immune complexes. Clin Nephrol 16:155-160, 1981 10. Hene RJ , Kater L: Plasmapheresis in nephritis associated with Henoch-Schoenlein purpura and in primary IgA nephropathy. Plasma Ther Transfus Technol 4: 165-173 , 1983 II. Chalopin JM , Tanter y, Rifle G: Plasma exchange and IgA nephropathies. Eur J Clin Invest i3:A45 , 1983 (abstr) 12. Coppo R, Basolo B, Giac hino 0, et al: Plasmapheresis in a patient with rapidly progressive idiopathic IgA nephropathy: Removal ofIgA-containing circulating immune complexes and clinical recovery. Nephron 40:488-490, 1985

LAI ET AL 13. Berger J, Hinglais N: Les depots intercapillaries d'IgAIgG. J Urol Nephrol (Paris) 74:694-695, 1968 14. Couser WG: Idiopathic rapidly progressive glomerulonephritis. Am J Nephrol 2:57-69 , 1982 15. Lockwood CM, PussellB, Wilson CB, et al: Plasma exchange in nephritis. Adv Nephrol 8:383-418, 1979 16. Pasquali S, Cagnoli L, Ferrari G, et al: Plasma exchange in rapidly progressive glomerulonephritis. Eur J Clin Invest i3:A44, 1983 (abstr) 17 . Coppo R, Basol0 B, Roccatello D , et al: Plasma exchange in primary IgA nephropathy and Henoch-Schiinlein syndrome nephritis. Plasma Ther Transfu s TechnoI6:705-723, 1985 18 . D'Amico G: Natural history and treatment of idiopathic IgA nephropathy, in Robinson RR (ed): Nephrology-Proceedings of the IXth International Congress of Nephrology. New York, Springer-Verlag, 1984, pp 686-701