1Department of Nephrology - Aster Medcity, Kochi
2Department of Pathology – Aster Medcity, Kochi Corresponding Author:
Dr. Vinod Kumar K MD, DNB Consultant Nephrologist Aster Medcity, Cheranalloor Kochi – 682027
Tel: +91 86060 84448
E-mail: [email protected]
Abstract: A 15-year-old male presented with acute glomerulonephritis, preceded by a history of sore throat and fever. He had features of acute rheumatic fever and echocardiographic evidence of severe mitral regurgitation and aortic regurgitation. He had proteinuria, haematuria and renal failure; renal biopsy showed diffuse exudative endocapillary proliferative glomerulonephritis. Simultaneous occurrence of acute glomerulonephritis and rheumatic fever in the same patient is very rare. He responded to treatment with steroids and his renal functions recovered over three months.
Acute post-streptococcal glomerulonephritis (APSGN) and acute rheumatic fever (RF) are both well-recognized non suppurative sequelae of group A beta hemolytic streptococcus infections.¹ The serotypes of group A Streptococci can be divided into those with rheumatogenic and nephritogenic potential.² Post-streptococcal glomerulonephritis and rheumatic fever have different epidemiology and immunological features; their concurrent development in the same patient is very rare,³ because of their different pathophysiologic mechanisms.1,4
A 15-year-old male presented with history of fever of three weeks duration, associated with a sore throat. Twenty days after the onset of fever, he noticed puffiness of the face followed by progressive worsening of oedema involving the rest of the body. He had bilateral pedal oedema and abdominal disten- sion, associated with dark-coloured urine and reduced urine output. He had arthralgia involving both knee joints. Urine examination showed numerous RBCs and proteinuria; Serum creatinine was 1.8mg/dl. There was a weight gain of 8 kg.
On admission to our center, the patient was febrile, and blood pres- sure was 130/88 mm Hg correspond- ing to the 95th centile). He had pallor, facial and pedal oedema. He had gradual worsening of dyspnoea and tachypnoea, and a grade 3/6 pansystolic murmur in the mitral area radiating to the axilla.
Investigations revealed Haemo- globin: 9.9 g/dl, WBC count: 8100 / cu mm, Platelet count: 242000/cu mm, ESR: 44mm at 1 hour, CRP: 103.5mg/dl, serum creatinine: 1.77mg/ dl and serum albumin: 2.8 g/dl.
Urine analysis showed albumin 2+ and microscopic haematuria. Urine protein (24hr) was 6.1 g. The patient had elevated ASO titres (>800) and hypocomplementemia (serum C3:45 mg/dl). A chest X-ray showed bilateral blunting of the costophrenic angles, suggestive of bilateral pleural effu- sion. An electrocardiogram showed a prolonged PR interval (0.32 seconds). Renal failure worsened rapidly; serum creatinine increased to 6.9 mg/dl over 7 days. In view of this, a renal biopsy was done after initiation of dialysis. Blood and urine cultures were sterile, and a throat swab showed no growth.
The renal histology showed features of diffuse exudative proliferative glomerulonephritis with neutrophilic exudates (Figs 1A, 1B, 1C). Immunofluorescence revealed granular capillary wall staining for IgG (3+) and C3 (2+). There were no crescents. The picture was consistent with post-infectious glomerulonephritis.
A 2D echocardiogram (figs 2A, 2B) showed dilated left atrium and left ventricle, right coronary cusp prolapse and severe aortic regurgitation. The aortic valve annulus was 2.2 cm. The anterior mitral leaflet was thickened, and there was severe eccentric mitral regurgitation with chordal rupture (mitral annulus 3.4cm). A transoesophageal echocardiogram confirmed the findings. As he had one major and two minor criteria of modified Jones criteria for rheumatic fever, he was diagnosed to have acute rheumatic fever. Infective endocarditis was ruled out, as repeated blood cultures were sterile and there was no evidence of vegetations from the echocardiogram.
As the patient had diffuse proliferative glomerulonephritis, with massive proteinuria and renal failure, he was started on Prednisolone 60mg/day (1.5 mg/kg/day). Renal functions improved gradually after initiation of steroids. He was treated with oral Furosemide and antihypertensives. Benzathine Penicillin (1.2 MIU injection intramuscularly) was advised every 3 weeks. He improved remarkably on treatment with steroids. The aortic regurgitation (AR) improved from severe AR to mild AR over ten days; however moderate mitral regurgitation persisted. At the time of discharge, serum creatinine was 2.9 mg/dl. On follow-up at three months, serum creatinine was 1.1mg%, and ESR 15mm/hr. Urine analysis showed 5 RBCs/hpf and no albuminuria. A 2D echocardiogram showed persistence of mild mitral and aortic regurgitation. Steroids were tapered and stopped within three months.
APSGN can affect individuals of any age, but typically occurs usually between the ages of 5 and 15 years⁵; males are affected twice as often as females. Post-infectious glomerulonephritis is associated with a previous skin or throat infection by a group A streptococcus (Streptococcus pyogenes), or occasionally group C or G streptococci. Pyoderma associated APSGN occurs more frequently in summer. A review estimated that over 470,000 cases of APSGN occur annually worldwide. 97% of these cases are in less developed countries, with an annual incidence that ranges from 9.5 to 28.5 per 100,000 individuals7. Studies from India have reported that APSGN constitutes about 6 to 8% of all renal biopsy specimens.
Rheumatic fever can occur at any age, although most cases occur in children aged 5 to 15 years7. There are about 233,000 deaths worldwide attributable to rheumatic fever or rheumatic heart disease each year7.
The mean incidence of RF is 19 per 100,000 school-aged children world- wide10. Rheumatic fever occurs more frequently in winter months.
Two antigens have been implicated as potential causes of APSGN: the glycolytic enzyme identified as glyceraldehyde-3-phosphate dehydro- genase, and streptococcal proteinase exotoxin B (SPEB, zymogen), both of which activate the alternate pathway of the complement system8. APSGN occurs due to the antibody-mediated response to bacterial infection, typically with a nephritogenic strain of Streptococcus pyogenes, which results in glomerular deposition and/or in-situ formation of immune complexes; a glomerular inflammatory response ensues with leukocyte infiltration and complement activation⁶. Nephritogenic strains associated with the development of APSGN include M types 1, 4, 12, 15 (causing throat infection and ASPGN) and 2, 42, 49, 55, 57, 60 (causing skin infection and ASPGN).9
A streptococcal strain capable of causing a well-documented pharyngitis is almost always capable of causing rheumatic fever11. Many M types are associated with RF, including 1, 3, 5, 6, 11, 12, 14, 17, 18, 19, 24, 27, 29, 30, 32, and 4112.The lack of specific rheumatogenic strains may explain the relatively high risk of recurrent disease with new streptococcal infections, in contrast to poststreptococcal glomerulonephritis, in which only a few “nephritogenic” strains appear to be capable of inducing the disease, and hence recurrent disease is uncommon.
Acute rheumatic fever is caused by the mechanism of molecular mimicry. M protein and the hyaluronate capsule cause inflammation by inducing cross-reacting autoantibodies against human tissue proteins, stimulated by cell-mediated immunity in genetically predisposed patients. Early recognition of acute rheumatic fever is very important, because of the possibility of developing rheumatic heart disease if not treated appropriately.
Co-existent acute rheumatic fever and post streptococcal glomerulone- phritis were observed in our patient.
PSGN and RF rarely coincide, as has been previously described.¹,³ Simultaneous occurrence of APSGN and acute RF was first reported in 1981. Since then, seventeen cases have been reported. Most of the cases had acute RF preceding, or after the event of APSGN. Only six out of seventeen patients had simultaneous occurrence of acute RF and APSGN, as seen in our case13. The explanation for the co-occurrence might be that certain strains have both nephritogenic and rheumatogenic potential (e.g. M types 1 and 12), which can result in the occurrence of both conditions.³ Although some serotypes are both rheumatogenic and nephritogenic, it cannot be said with certainty whether a single pharyngeal infection resulted in both APSGN and acute RF in this case; however the possibility of a single infection causing both PSGN and rheumatic fever cannot be ruled out. We could not isolate the organism on throat swab culture.
Mitral insufficiency is frequently seen in patients with concurrent acute RF and APSGN, however only 2 cases of aortic insufficiency have been reported so far with these conditions. Our patient had both mitral and aortic insufficiency1.
In patients associated with acute RF, focal and mesangial proliferative glomerulonephritis has been re- ported; diffuse exudative proliferative glomerulonephritis which is typical of APSGN is rare; our patient had diffuse proliferative GN3.
Co-existence of RF and APSGN in the same patient is very rare. Awareness of infection risk and prevention strategies at the grass roots level is essential to lessen the burden of post-infectious glomerulonephritis in our country.
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