Nephritis in Infectious Mononucleosis

Transcription

1 Quarterly Journal of Medicine, New Series, XLIII, No. 171, pp , July 1974 Nephritis in Infectious Mononucleosis A. J. WOODROFFE*, P. G. ROWf, R. MEADOWSJ, AND J. R. LAWRENCE From the Renal Unit and the Department of Pathology of The Queen Elizabeth Hospital, Woodville, South Australia Received October 1973 SUMMARY Three patients are presented with acute nephritis associated with infectious mononucleosis. Renal biopsy in these patients indicates that an interstitial nephritis or a focal mesangial glomerulonephritis can be present. The condition can be distinguished from post-streptococcal glomerulonephritis, and should be considered in all patients presenting with acute nephritis, particularly if other features such as fever, skin rash, 'hepatitis' or thrombocytopaenia are present. INTRODUCTION In a review of the reported renal manifestations of infectious mononucleosis Tennant (1968), showed that the incidence of abnormal urinary findings varied from 0 to 13 per cent in different series. Gross haematuria associated with infectious mononucleosis has been reported (Thompson, 1950; Lindsey and Chrisman, 1955; Taub, 1966) but significant impairment of renal function is not usual. Where renal tissue from such patients has been examined (Tennant, 1968; Taub, 1966; Ziegler, 1944; Allen and Kelinger, 1947; Custer and Smith, 1948; Peters, Flume, and Fuccillo, 1962; Utian, 1924; Brun, Madsen, and Olsen, 1970) the most consistent lesion reported has been an interstitial nephritis with aggregations of mononuclear inflammatory cells in the interstitium and foci of tubular necrosis. However, mild non-specific glomerular lesions have sometimes been reported (Tennant, 1968; Taub, 1966; Peters, Flume, and Fuccillo, 1962; Utian, 1924). Some authors have challenged the entity of nephritis in infectious mononucleosis, believing that it is secondary to a concomitant streptococcal infection (Hoaglund, 1967; Thelander, and Shaw, 1971; Wechsler, Rosenblum, and Sills, 1946). We present three patients with acute nephritis associated with infectious mononucleosis. Clinical and pathological features appear to distinguish this condition from post-streptococcal glomerulonephritis. * Senior Registrar, Renal Unit, Q.E.H. f Senior Registrar, Renal Unit, Q.E.H. j Director of Histopathology, Q.E.H. Director, Renal Unit, Q.E.H.

2 452 A. J. Woodrojfe, P. G. Row, R. Meadows, andj. R. Lawrence Case 1 (Figure 1). A 32-year-old man was admitted to hospital on 1st July, 1968, with acute nephritis. There was a past history of sore throat six weeks previously, followed ten days later by haematuria, and then by swelling of the face and legs. He was examined by his medical practitioner, who noted gross leg oedema, blood pressure 190/100, heavy proteinuria, and the presence of red blood cells and granular casts in the BUN (X10) CHEAT. (Mflmt/iOOml) ALK. PHOS. * IK* A Uni»* BIOPSY BIOPSY SGOT IK Unit. w.c.c. < ATYPICAL MONONUCLCAR Cf US > SO * 7 9W11T2OI4 13M17M SUVf 1961 AUG. NOV. MAY JULY AUG. JUIY MAY 19* FIG. 1. Biochemical enzyme and white cell studies in Case 1. urine. With bed rest the oedema resolved and blood pressure fell to 160/90. However, gross haematuria recurred three weeks later, and he was admitted to hospital for further assessment. On admission, he was febrile, but there was no pharyngitis, lymphadenopathy or splenomegaly. Blood pressure was 170/110, and fundi were normal. Macroscopic haematuria and red cell casts were noted, and 24-hour urinary protein excretion was 1-1 gm. BUN 14 mg/100 ml, serum creatinine 2-0 mg/100 ml, creatinine clearance 60 ml/min. Haemoglobin 14-4 gm/100 ml, white cell count 6600 per cmm, with 71 per cent polymorphs, 23 per cent lymphocytes, 6 per cent monocytes, Platelet count per cmm. ASOT 700 Todd units. Total serum complement 94 per cent (normal). ANF and LE cells were not detected. Blood culture, throat swab and viral studies were negative. Renal biopsy was performed on the 4th hospital day and the findings were consistent with the clinical diagnosis of post-streptococcal glomerulonephritis (Figs. 2 and 3). All the glomeruli showed mild to moderate endothelial and/or mesangial proliferation, most prominent in the axial regions, and in one glomerulus there was a small epithelial crescent.

3 Npjth.rit.is in Infectious Mononucleazis FIGS. 2 and 3. Renal biopsy on 4th day of admission from Case 1. All glomeruli show endothelial and/or mesangial proliferation. FIGS. 4 aod o. Kenal biupsy from Come 1 on 19th day of admission. Note development of focal collections of inflammatorv cells and patchy tubular necrobis.

4 454 A. J. Woodroffe, P. G. Row, R. Meadows, andj. R. Lawrence Fever, however, persisted and a generalized erythematous skin rash developed on day 8. Renal function deteriorated with BUN rising to 93 mg/100 ml and creatinine clearance falling to 32 ml/min despite a mean urine voulme of 1500 ml per 24 hours. In addition, SGOT rose to 124 K units (N 5-45) and SAP to 36 KA units (N 3-13). Atypical lymphocytes were first detected on day 10 and lymphocytosis reached 82 per cent on day 15. The platelet count had returned to normal by day 11. A Paul Bunnell test performed on day 11 was positive to 1 in 56. Hepatosplenomegaly and lymphadenopathy were clinically apparent five days later (by which time the fever and skin rash had resolved) and the diagnosis of infectious mononucleosis was established. A second renal biopsy was performed on day 19 and this showed a striking change from the first biopsy (Figs. 4 and 5). The glomeruli were still hyper cellular, but there were now focal collections of inflammatory cells (lymphocytes, macrophages, and plasma cells) in the interstitium together with patchy tubular atrophy and necrosis. Steady improvement in all parameters occurred, and by day 25, the BUN was 38 mg/100 ml, SGOT 44 K units, SAP 18 KA units, haemoglobin 10-7 gm/100 ml, white cell count 5900 per cmm with 29 per cent polymorphs, 55 per cent lymphocytes (some still atypical), 11 per cent monocytes, 5 per cent eosinophils. Platelet count per cmm. He was discharged on day 29 on no specific therapy. One month later, the lymphadenopathy and hepatosplenomegaly were no longer apparent, BUN had fallen to 13 mg/100 ml, but maximum urine osmolality following pitressin was only 528 mosm/kg. Nine months later (in May 1969) creatinine clearance was 94 ml/min and maximum urine osmolality was 925 mosm/kg. Paul Bunnell test was negative. ASOT FIGS. 6 and 7. Renal biopsy from Case 1, 9 months later. Interstitial inflammatory cells are now minimal but axial hypercellularity persists.

5 Nephritis in Infectious Mononucleosis Todd units, and total serum complement 90 per cent. A third renal biopsy was performed at this time (Figs. 6 and 7) which showed persisting axial hypercellularity and PAS positive fibrillary material in keeping with an unresolved post-streptococcal glomerulonephritis. There were still small areas of tubular atrophy with interstitial fibrosis but only a few inflammatory cells were present. In August 1971, treatment of mild hypertension was commenced. Serum creatinine was 1-3 mg/100 ml. A fourth renal biopsy was performed and this showed the features which were present on the previous biopsy, together with some thickening and hyalinization of blood vessels. Fluorescent microscopy failed to demonstrate the presence of immunoglubulins, complement or fibrin in this biopsy. Two years later, he remains well apart from mild hypertension, and his renal function is stable with a serum creatinine of 1-3 mg/100 ml. Case 2. A 19-year-old boy was admitted to hospital on 31st October, 1971, with haematuria. There was a past history of frontal headaches and nasal congestion for six weeks, lassitude and anorexia for three weeks, then haematuria and arthralgia on the day of admission to hospital. On admission he was febrile, with reddened fauces and lesions on the soft palate. Cervical lymphadenopathy and splenomegaly were noted. Blood pressure 150/95. Macroscopic haematuria and red cell casts were present, and 24-hour urinary protein excretion was 248 mg. BUN 17 mg/100 ml, serum creatinine 1-5 mg/100 ml, creatinine clearance 103 ml/min. Haemoglobin 13-9 gm/100 ml, white cell count FIGS. 8 and 9. Renal biopsy from Case 2. Glomeruli show varying degrees of axial prominence due to mesangial proliferation, and one glomerus (Fig. 9) contains a small epithelial crescent.

6 456 A. J. Woodroffe, P. G. Row, R. Meadows, and J. R. Lawrence 4000 per cmm with 63 per cent polymorphs, 20 per cent lymphocytes (atypical cells present), 12 per cent monocytes, 1 per cent eosinophils, 1 per cent basophils, 3 per cent plasma cells. Platelet count SGOT 100 K units, SAP 15 KA units. Paul Bunnell test was positive to 1 in A.S.O.T. 500 Todd units, throat swab negative. Total serum complement 96 per cent. Blc/Bla 120 mg (N ), A.N.F. negative, serum immunoglobulins normal. A diagnosis of infectious mononucleosis with acute nephritis was made and renal biopsy was performed on 2nd November, 1971 (Figs. 8 and 9). The glomeruli showed varying degrees of axial prominence due to mesangial proliferation and fibre formation. One glomerulus contained a small epithelial crescent. There were a few foci of tubular atrophy with interstitial fibrosis but no interstitial inflammatory infiltrate. Fluorescent microscopy revealed moderate staining for IgA in the mesangium of glomeruli together with mild staining for IgG and fibrin (Fig. 10). Complement was not detected. Electron microscopy showed diffuse mesangial proliferation and mesangial interposition. iig. 1U. Kenai biopsy, Case i' (fluorescent Microscopy). Mesangial staining for 1 ga. There was rapid spontaneous subjective improvement, the urinary sediment cleared, and he was discharged after ten days in hospital. Eight months later he remained well, with stable renal function, serum creatinine 1-3 mg/100 ml. Paul Bunnell positive to 1 in 7. ASOT 1250 Todd units. Total serum complement 96 per cent. A further renal biopsy performed at this time showed persisting areas of mesangial prominence in some glomeruli, and several patches of tubular atrophy and interstitialfibrosis.fluorescent microscopy revealed mesangial staining for IgA and fibrin.

7 luos. 11 and 12. Renal biopsy from Case 3. The glomeruli show mild mesangial thickening. FIGS. 13 and 14. Renal biopsy from Case 3. Collections of acute and chronic inflammatory cells are present in the interstitium.

8 458 A. J. Woodrojfe, P. G. Raw, R. Meadows, and J. R. Lawrence Case 3. A 16-year-old girl was admitted to hospital on 16th February, 1973, with acute nephritis. History of headache, myalgia, fever and facial swelling for five days. On admission, she was febrile, with reddened fauces and vesicular lesions on the left tonsil. Periorbital oedema was noted. Blood pressure 140/70. Cervical and inguinal lymph nodes were palpable and splenomegaly was detected radiologically. Urine contained hyaline casts and red blood cells. 24-hour urinary protein excretion was 756 mg. BUN was 17 mg/100 ml, serum creatinine 1-0 mg/100 ml. Total serum complement 90 per cent, Blc/Bla 130 mg, ASOT negative, throat swab negative, A.N.F. negative and FDPs 10-6 /xg/ml (N < 8 /xg/ml). Haemoglobin 120 gm/100 ml, white cell count 6000 per cmm with 11 per cent polymorphs, 86 per cent lymphocytes (atypical cells present), 3 per cent monocytes. Platelet count per cmm. Paul Bunnell test positive to 1 in 224. SGOT > 250 K units, SAP 42 KA units, prothrombin 57 per cent. A diagnosis of infectious mononucleosis with acute nephritis was considered and renal biopsy was performed on 21st February (Figs. 11 to 14). This showed occasional small areas of mesangial prominence in the glomeruli, and small foci of tubular degeneration and necrosis, associated with acute and chronic inflammatory cells in the interstitium. She was oliguric (mean volume 770 ml per 24 hours) for nine days, then recovered spontaneously and two months later is well, with serum creatinine 1-0 mg/100 ml, SGOT 40 K units, SAP 25 KA units. Paul Bunnell positive 1 in 224. DISCUSSION The first case is of particular interest because infectious mononucleosis with interstitial nephritis occurred following typical post-streptococcal glomerulonephritis, thus providing a unique opportunity to differentiate the features of the two types of renal disease. The initial clinical presentation and laboratory findings were consistent with post-streptococcal glomerulonephritis. Total serum complement was normal but the ASOT was raised. Renal biopsy showed endothelial and/or mesangial proliferation consistent with acute post-streptococcal glomerulonephritis. The tubules and interstitium were normal. Six weeks after the initial onset of haematuria, the patient became febrile, developed a skin rash, biochemical evidence of hepatocellular disease, lymphocytosis with atypical lymphocytes, a mild thrombocytopaenia, and a positive Paul Bunnell test. Lymphadenopathy and hepatosplenomegaly became apparent subsequently. Associated with the onset of infectious mononucleosis, there was a marked deterioration in renal function with BUN rising from 14 to 93 mg/100 ml and creatinine clearance falling from 60 to 32 ml/min. A repeat renal biopsy 15 days after the first biopsy showed a striking focal interstitial nephritis with patchy tubular atrophy and necrosis. The occurrence of an interstitial inflammatory infiltrate with tubular damage in infectious mononucleosis has been described by several authors (Ziegler, 1944; Allen and Kelinger, 1947; Ouster and Smith, 1948; Peters, Flume, and Fuccillo, 1962; Brun, Madsen, and Olsen, 1970) and we attributed both the interstitial nephritis and the concomitant deterioration in renal function to infectious mononucleosis in this patient. The absence of interstitial lesions in the first biopsy strongly supports the view that the interstitial nephritis of infectious mononucleosis is a significant entity and not secondary to streptococcal infection. Significant impairment of renal function is unusual in the nephritis of infectious

9 Nephritis in Infectious Mononucleosis 459 mononucleosis, but a case has been reported (Lowery and Rutsky, 1972) in which progressive renal failure occurred requiring haemodialysis. Renal biopsy showed severe tubular loss with a dense interstitial mononuclear inflammatory infiltrate. Our patient has now been followed for five years, is mildly hypertensive, but has stable renal function. Follow up renal biopsies have shown features of an incompletely resolved post-streptococcal glomerulonephritis together with residual areas of interstitial fibrosis and tubular atrophy. In the second case, haematuria, proteinuria, and red cell casts were present in association with infectious mononucleosis. The ASOT was slightly raised but serum complement was normal and renal biopsy showed a mild mesangial proliferative glomerulonephritis. There were a few foci of tubular atrophy with interstitial fibrosis but no interstitial inflammatory infiltrate. Mesangial IgA deposition was demonstrated by fluorescent microscopy. Electron microscopy confirmed the presence of mesangial proliferation. These findings were considered to be consistent with Berger's IgA disease (Berger, 1969) which in this case had apparently been 'triggered' or 'uncovered' by infectious mononucleosis. We are unaware of any previous reports documenting this association. Tennant's case (1968), showedmesangial cell swelling on electron microscopy, but fluorescent microscopy was not reported. Viral infection has been incriminated in 'focal nephritis' (Alexander, 1965), but the precise pathogenesis is not understood. Dixon, Oldstone, and Tonietti (1969) have suggested that virus-induced glomerulonephritis may be mediated either by viral antigen-antibody complexes, or by enhancement of latent autoimmune responses. In our patient, serum complement was normal, complement deposition was not detected on fluorescent microscopy, and no virus particles were seen on electron microscopy. Staining with antisera to EB virus was not attempted in this case, but in the series of Peters, Flume, and Fuccillo (1962), fluorescent antibody studies indicated the localization of a possible viral antigen in tubular cytoplasm, glomeruli, and vascular intima. The third case presented with acute oliguric nephritis associated with infectious mononucleosis. Renal biopsy revealed both glomerular and interstitial lesions. The glomeruli showed mild mesangial prominence and there was an interstitial inflammatory infiltrate with small foci of tubular degeneration and necrosis. Rapid spontaneous recovery followed, and renal biopsy has not been repeated. These cases indicate that acute nephritis can occur in patients with infectious mononucleosis and that the renal pathology can be an interstitial nephritis or a mesangial proliferative glomerulonephritis. It is probable that a mild self-limiting nephritis may be quite common in infectious mononucleosis. According to Carter and Penman (1969), 25 to 40 per cent of cases have periorbital oedema, but the significance of this observation does not seem to have been generally appreciated. Conversely, the possibility of infectious mononucleosis should be considered in patients presenting with acute nephritis. This is particularly the case if other features such as fever, skin rash, 'hepatitis' or thrombocytopaenia are present. The pathogenesis of nephritis in infectious mononucleosis is still not understood. Analogies can be made between the interstitial mononuclear infiltrate in the kidney

10 460 A. J. Woodroffe, P. G. Row, R. Meadows, and J. R. Lawrence and similar infiltrates seen in other tissues, i.e. lymph nodes, spleen, liver, adrenals, heart and meninges (Carter and Penman, 1969), but the glomerular lesion remains unresolved. There was no evidence in our cases to support an immune-complex mechanism, and although thrombocytopaenia was present in all three cases, there were no other features to suggest intravascular coagulation. More information may be gained by fluorescent microscopy using antisera to EB virus. REFERENCES ALEXANDER, E. A., Ann. intern. Med. 62, ALLEN, F. H., Jr., and KELINGEB, A., Amer. J. Path. 23, 463. BERGER, J., Trans. Proc. 1, 939. BRTJN, C, MADSBN, S., and OLSEN, S., Scand. J. Oastr. Supplement 7, 89. CARTER, R. L., and PENMAN, H. G., Infectious Monomicleosis. Oxford and Edinburgh, p. 27. CtTSTER, P. R., and SMITH, E. B., Blood, 3, 830. DIXON, F. J., OLDSTONE, M. B. A., and TONIETTI Trans. Proc. 1, 945. HOAGLTHSTD, R. J., Infectious Monomicleosis. New York, p. 65. LnsrDSEY, D. C, and CHRISMAN, W. P., Jr., J. Amer. med. Ass. 157, LOWERY, T. A., and RUTSKY, E. A., International Congress of Nephrology, Mexico. Abstract No PETERS, J. H., FLUME, J., and FTJCCILLO, D., Clin. Res. 10, 254. TATJB, E. A., J. Amer. med. Ass., 195, 175. TENNANT, F. S., Jr., Biology and Medicine, 26, 603. THELANDER, H. E. and SHAW, E. B., Amer. J. Dis. Child. 61, THOMPSON, W. T., Ann. intern. Med., 33, UTIAN, H. L., Sth. Afr. med. J. 38, 162. WEOHSLER, H. F., ROSENBIUM, A. H., and SILLS, C. T., Ann. intern. Med. 25, 113. ZIEGLER, E., Arch. Path. 36, 196.