Recurrent hematuria: A novel clinical presentation of hereditary complete complement C4 deficiency

CASE REPORTS

Recurrent Hematuria: A Novel Clinical Presentation of Hereditary Complete Complement C4 Deficiency Karl Lhotta, MD, Maria Neunh~iuserer, MD, Brigitte S61der, MD, Beatrice Uring-Lambert, MD, Reinhard W(~rzner, MD, Hans J. Rumpelt, MD, and Paul KSnig, MD • A 10-year-old boy suffered from recurrent attacks of fever, vomiting, and hematuria. During disease flares, circulating immune complexes were detected in the serum. Elevated levels of Bb, Ba, and C3a indicated complement activation through the alternative pathway. Complement C4 was undetectable. C4 phenotyping by agarose gel electrophoresis showed complete C4 deficiency. Restriction fragment length polymorphism (RFLP) studies showed a homozygous deletion of the C4B and 21-hydroxylase A genes. A mild mesangioproliferative glomerulonephritis with mesangial deposits of immunoglobulin (Ig) G, IgM, IgA, Clq, C3, properdin, and terminal complement complex was probably caused by immune complex deposition and altemaUve complement pathway activation. Treatment with low-dose prednisolone substantially reduced the frequency of further episodes. © 1996 by the National Kidney Foundation, Inc. INDEX WORDS: Complement C4 deficiency; mesangioproliferative glomerulonephritis; hematuda; immune complex disease.

'EREDITARY complete deficiency of the .fourth component of complement is extremely rare. Approximately 20 cases have been described. Complete C4 deficiency severely impairs processing of immune complexes and eventually leads to classical immune complex diseases such as systemic lupus erythematosus (SLE) and Henoch-Schoenlein purpura in most affected individuals. I We have previously reported on the renal disease of our seven C4-deficient patients. 2 Here we describe our eighth patient, whose clinical presentation differs from that of the other cases.

H

CASE REPORT

Laboratory Investigations

A 10-year-old boy was admitted to a local hospital because of 39°C fever, vomiting, and macrohematuria. Except for recurrent otitis media, he had been completely healthy. He had previously experienced the same symptoms twice within

From the Departments of Internal Medicine and Pediatrics, Innsbruck University Hospital, and the Institute for Hygiene, University of lnnsbruck, lnnsbruck, Austria; the Bruneck Hospital, Bruneck, Italy; the Laboratoire de Recherches en Immunologie, University of Strasbourg, Strasbourg, France; and the Institute of Pathology, Heilbronn Hospital, Heilbronn, Germany. Received June 9, 1995; accepted in revised form September 13, 1995. Address reprint requests to Karl Lhotta, MD, Nephrologisches Labor, Medizinische Universitiitsklinik, Anichstrasse 35, A-6020 Innsbruck, Austria. © 1996 by the National Kidney Foundation, Inc. 02 72-6386/96/2 703-001753.00/0

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the last 3 months. Laboratory results showed elevated erythrocyte sedimentation rate and C-reactive protein, slightly elevated serum creatinine and blood urea nitrogen, and modest proteinuria (Table 1). Under symptomatic treatment and antibiotic therapy, the complaints resolved within the next days and blood tests became normal, but microhematuria and minimal proteinuria persisted. Four months later, an identical attack occurred, and the patient was admitted to our university hospital for renal biopsy. Within the next 9 months, symptoms recurred five times. The patient's father is a cousin of two of our patients with complete hereditary C4 deficiency, who suffer from a lupuslike illness and mild mesangioproliferative glomerulonephritis, z In an attempt to prevent further attacks, therapy with prednisolone 7.5 mg every other day was begun. Under that treatment, only one further episode occurred within the next 6 months.

The results of blood tests, urine examinations, and complement parameters obtained when the patient was asymptomatic and during one of the acute attacks are shown in Table 1. Antinuclear antibodies were positive at a fiter of 1:20. Anti dsDNA antibodies, anti-Chido, and anti-Rogers antibodies were not detected. On phenotyping of complement C4 using agarose gel electrophoresis and immunoprecipitation, C4 was completely absent from the patient's plasma (phenotype C4AQOBQ0).3 The father's C4 phenotype was C4AQOB1BQ0, and the mother's phenotype C4A3AQOB1. HLA typing of the boy and his parents showed that he was homozygous for the HLA type A24 B38 Cw7 DR13 DQ6, which must carry the C4-deficient haplotype C4AQOBQ0. The HLA type of this patient is identical to that found in his father's two cousins, who were also completely C4 deficient?"4 Analysis of the C4 and 21-hydroxylase genes was performed with TaqI restriction fragment length polymorphism (RFLP) using C4- and 21-hydroxylase-specific complementary DNA probes. 5'6 Two bands of 7.0 kb and 3.7 kb were obtained. This is consistent with a homozygous 28-kb deletion of the C4B

American Journal of Kidney Diseases, Vol 27, No 3 (March), 1996: pp 424-427

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RECURRENT HEMATURIA IN C4 DEFICIENCY Table 1. Laboratory Results During Remission and Attack

Remission Blood ESR (mm/hr) C-reactive protein (mg/dL) Serum creatinine (mg/dL) Urea nitrogen (mg/dL) CIC ~g Eq/mL) C3 (mg/dL) C3a desArg (ng/mL) Bb (#g/mL) C7 ~g/mL) TCC ~g/mL) Urine Leukocytes/#L Erythrocytes/#L Protein mg/24h GFR (mL/min/1.73m 2)

Attack

4 <0.5

46 10

0.6

1.15

14

25

0.2 81 260

7.0 80 560

0.10 106.4 0.8

>0.21 67.9 (7.4 after zym) 9.0 (174.0 after zym)

0 250 250 110

100 Macrohematuria 2,410 68

Abbreviations: ESR, erythrocyte sedimentation rate; CIC, circulating immune complexes; TCC, terminal complement complex; zym, in vitro complement activation using baker's yeast/zymosan; GFR, glomerular filtration rate.

and 21-hydroxylase A genes. The defect of the nontranscribed C4A gene has not yet been detected.

Renal Histology Twenty-six glomeruli were obtained by renal biopsy performed after the fourth attack (Fig 1). On light microscopy, the glomeruli showed minimal extension of the mesangium and modest proliferation of mesangial cells. In one glomerulus, an old segmental fibrous crescent was present. The tubuli, vessels, and interstitium were unaltered. Immunofluorescence showed focal and segmental granular deposits of immunoglobulin (Ig) G, IgM, and to a lesser extent IgA in the mesanglum. Diffuse and global staining in the mesangium was observed for Clq, C3, properdin, and terminal complement complex. Staining with C4A and C4B isotype-specific antibodies 99H7 and 1288, which recognize the C4d fragment, was negative. Electron microscopy showed few small electron-dense deposits in the mesangial matrix.

DISCUSSION

Hereditary complete deficiency of the fourth component of complement is an extremely rare disorder. Approximately 20 cases have been found so far. Most of these individuals suffer

from immune complex diseases.~ In our own series of seven patients, five were classified as SLE, one patient had Henoch-Schoenlein purpura, 7 and one individual is completely healthy. 2 The classic complement pathway plays a pivotal role in clearance of immune complexes, 8 and C4 deficiency may impair this process with the possible consequences of large immune complex lattice formation and deposition in various tissues as kidney, skin, or gut. The patient described here presented with recurrent fever, vomiting, hematuria, and mesangioproliferative glomerulonephritis. His disease cannot be classified as SLE or Henoch-Schoenlein purpura. Disease flares were accompanied by the presence of circulating immune complexes, immune complex deposition in the renal mesangium and probably also in the gut. Increased serum levels of Bb, C3a, and terminal complement complex (TCC) as well as deposition of properdin, C3, and TCC in the kidney are ample evidence of complement activation by the alternative pathway during the attacks. What triggered the attacks remains obscure. Only one of the nine flares was possibly related to an infection, namely, lymphangitis after an insect sting. Conversely, infections such as otitis media did not lead to disease flares. At least the earliest four episodes occurred after situations causing emotional stress for the boy. A similar phenomenon is well known in patients with hereditary angioedema and C1 inhibitor deficiency, who also may suffer attacks when under emotional stress.

The rather mild pathological changes found in the kidney on renal biopsy are somewhat in contrast with the severity of macrohematuria, leukocyturia, proteinuria, and the reduction in glomerular filtration rate. The biopsy was performed at the end of the fourth attack and might hence not truly represent the situation at the height of the flare. Immune complex deposition and alternative pathway activation probably lead to an influx of leukocytes in the glomeruli, causing these symptoms. The presence of a crescent in one glomerulus indicates that glomerular inflammation can at times be severe. The shortness of the attacks proves that the patient had intact control mechanisms to stop the inflammatory response. The reduction of C7 and increase of TCC during disease indicate activation of the terminal

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LHO-R-A ET AL

Fig 1. (A) Light microscopy. Modest expansion of the mesangial matrix; tubuli and interstitium are normal. (Pearse; original magnification x210.) (B) Immunofluorescence. Granular deposits of properdin in the mesangium. (Original magnification x400.) (C) Electron microscopy. Small electron-dense deposits (arrows) are visible in the mesangial matrix; M: mesanglum; GBM: glomerular basement membrane. (Original magnification x17,500.)

complement pathway. When the patient was asymptomatic, levels of TCC in his serum were well below the normal range. Active disease caused a 10-fold increase, but the absolute values of TCC were still low and in the normal range in our assay. 9 After zymosan activation of complement, a further reduction of C7 and a massive increase of TCC occurred, which was comparable to normal controls, showing that the patient did not have an impaired terminal pathway. The most likely explanation for the comparably weak activation of the lytic pathway is the lack of classic pathway activation caused by complete C4 deficiency. Thus, C4 deficiency, although causing the disease, might have some protective effect against severe complement activation and tissue damage. Although the attacks were rather short and selflimited, they caused severe discomfort to the patient. In addition, further flares may cause persistent renal damage. It was therefore decided to give

the patient prophylactic treatment to prevent or diminish further attacks. Complement C4 substitution by repeated infusion of fresh frozen plasma was considered inappropriate, because it is associated with a risk of infection and formation of antiC4 antibodies, which would prevent its repeated application. ~° We therefore decided to treat him with low-dose prednisolone, because this therapy does not cause severe side effects and is effective in preventing exacerbation in other immune complex diseases, for example, SLE. This treatment achieved a considerable decrease in the frequency of attacks, with only a single episode occurring within the following 6 months.. ACKNOWLEDGMENT

The authors thank Anna Schl~gl and Doris Kerer for technical assistance. REFERENCES

1. Hauptmann G, Tappeiner G, Schifferli JA: Inherited deficiency of the fourth componentof complement. Immunodeficiency Rev 1:3-22, 1988

RECURRENT HEMATURIA IN C4 DEFICIENCY 2. Lhotta K, Thoenes W, Glatzl J, Hintner H, Kronenberg F, Joannidis M, K6nig P: Hereditary complete deficiency of the fourth component of complement. Clin Nephrol 39:117124, 1993 3. Sim E, Cross SJ: Phenotyping of human complement component C4, a class-III HLA antigen. Biochem J 239:763767, 1986 4. Tappeiner G, Hintner H, Scholz S, Albert E, Linert J, Wolff K: Systemic lupus erythematosus in hereditary deficiency of the fourth component of complement. J Am Acad Dermatol 7:66-79, 1982 5. Carroll MC, Palsdottir A, Belt KT, Porter RR: Deletion of complement C4 and steroid 21-hydroxylase genes in the HLA class III region. EMBO J 4:2547-2552, 1985 6. Schneider PM, Carroll MC, Alper CA, Rittner C, Whitehead AS, Yunis EJ, Colten HR: Polymorphism of the human complement C4 and steroid 21-hydroxylase genes. Restriction fragment length polymorphism revealing struc-

427 tural deletions, homoduplications and size variants. J Clin Invest 78:650-657, 1986 7. Lhotta K, K6nig P, Hintner H, Spielberger M, Dittrich P: Renal disease in a patient with hereditary complete deficiency of the fourth component of complement. Nephron 56:206-211, 1990 8. Schifferli JA, Bartolotti SR, Peters DK: Inhibition of immune precipitation by complement. Clin Exp Immunol 42:387-392, 1980 9. Wiirzner R, Schulze M, Happe L, Franzke A, Bieber FA, Oppermann M, G6tze O: Inhibition of terminal complement complex formation and cell lysis by monoclonal antibodies. Complement Inflammat 8:328-340, 1991 10. Lambin P, Le Pennec PY, Hauptmann G, Desaint O, Habibi B, Salmon C: Adverse transfusion reactions associated with a precipitating anti-C4 antibody of anti-Rodgers specificity. Vo× Sanguinis 47:242-249, 1984