Cyanotic congenital heart disease associated with glomerulomegaly and focal segmental glomerulosclerosis: remission of nephrotic syndrome with angiotensin converting enzyme inhibitor
Kazuyuki Hida,
Jun Wada,
Hiroko Yamasaki,
Yoshio Nagake,
Hong Zhang,
Hitoshi Sugiyama,
Kenichi Shikata and
Hirofumi Makino
Department of Medicine III, Okayama University Medical School, Okayama, Japan
Keywords: angiotensin converting enzyme inhibitor; cyanotic congenital heart disease; glomerulomegaly; focal segmental glomerulosclerosis; glomerular hyperfiltration
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Introduction
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Glomerular injury has been recognized as a prominent complication of cyanotic congenital heart disease (CCHD). The structural hallmark of glomerular injury in patients with CCHD has been described as glomerulomegaly, capillary dilatation, thickening of the capillary walls, focal or diffuse proliferation of mesangial cells, and segmental or global glomerulosclerosis [1]. Although proteinuria is the major urinary abnormality in patients with CCHD, nephrotic syndrome is an uncommon complication and renal biopsy has been seldom performed [2]. Flanagan et al. [3] reported that nephrotic syndrome with symptomatic oedema developed in five of 83 patients with CCHD (6%) after the age of 21 years. Here, we report on a patient with CCHD complicated by nephrotic syndrome that was successfully treated with an angiotensin converting enzyme inhibitor (ACEI).
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Case
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A 26-year-old female with CCHD was referred to our hospital for evaluation and management of nephrotic syndrome. She was cyanotic at birth and was diagnosed as having pulmonary atresia (PA) and ventricular septal defect (VSD). She had undergone heart surgery on five occasions. Urinalysis at age 18 revealed + to 2+ score test for proteins and repeated tests had shown that proteinuria persisted for 8 years. On admission, she had pretibial oedema, her blood pressure was 112/78 mmHg, heart rate 66/min, and respiratory rate 16/min. Urinalysis revealed nephrotic range proteinuria, 410 g/day, with no haematuria or hyaline casts. Peripheral blood counts indicated polycythaemia, haemoglobin at 15.9 g/dl and haematocrit was 47.4%. Total protein was 4.83 g/dl, albumin 2.4 g/dl, and total cholesterol 324 mg/dl. Glomerular filtration rate (GFR) was 71.8 ml/min. Blood gas analysis revealed the presence of hypoxaemia, arterial oxygen saturation 92%, oxygen partial pressure 62.4 mmHg, and carbon dioxide partial pressure 45.1 mmHg.
Percutaneous needle renal biopsy was performed. Immunofluorescence imaging revealed focal segmental deposition of IgM and C3 in mesangial areas. Twelve glomeruli were evaluated using light microscopy. The size of the glomeruli was prominently increased; three glomeruli showed global sclerosis and three had focal and segmental glomerulosclerosis (FSGS). Focal and segmental hyalinosis was noted in glomeruli (Figure 1A
) and axial hypercellularity associated with expansion of mesangial matrix was also observed (Figure 1B
). Electron microscopy showed focal segmental hyalinosis in the glomeruli (Figure 2A
and B
). Although podocyte hypertrophy was observed, the segmental area of glomeruli was affected and the degree of foot process fusion was rather mild. In addition, glomerular endothelial cells were detached from glomerular basement membranes and subendothelial lucent areas were observed (Figure 2C
).

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Fig. 1. Light micrographs of renal biopsy specimens from the patient with CCHD. The size of the glomeruli is prominently increased, indicating glomerulomegaly. FSGS of glomeruli was also observed. (A) The glomerulus reveals focal and segmental hyalinosis (arrow head). (B) The glomerulus shows axial hypercellularity associated with expansion of mesangial matrix. PAS, periodic acid-Schiff; original magnifications: (A) x200, (B) x200.
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Fig. 2. Electron micrographs of renal biopsy specimens from the patient with CCHD. Focal and segmental hyalinosis is seen in the glomerulus (asterisk, A and B). A thickening of glomerular basement membranes and FSGS are also observed (A). Although hypertrophy of podocytes is observed (big arrows, A), the degree of foot process fusion is rather mild (small arrows, C). Glomerular endothelial cells are detached from glomerular basement membrane and subendothelial lucent area is observed (arrow heads, C). Abbreviations: US, urinary space; CAP, capillary lumen. (A, bar=20 µm; B, bar=10 µm; C, bar=5 µm.)
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As ACE inhibition may exert anti-proteinuric effects through a direct influence on glomerular hyperfiltration and hypertension, we prescribed temocapril (2 mg) to decrease hydraulic pressure in glomeruli. Temocapril administration caused a gradual decrease in proteinuria and the 24-h urinary protein excretion was within 1 g/day without an aggravation of renal function after a year.
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Discussion
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Although pathogenesis of glomerulomegaly and FSGS associated with CCHD is still unclear, a large number of reports have described potential mechanisms. Many causative factors, such as elevated haematocrit, hyperviscosity, chronic hypoxia, increased venous pressure, and glomerular hyperfiltration, seem to be involved in the glomerulopathy associated with CCHD.
Phlebotomy in a CCHD patient not only reduced haematocrit but also decreased proteinuria [45]. A reduced blood viscosity seems to exert beneficial effects on hypoxia and glomerular permeability [6], because arterial oxygen transport was higher at normal haematocrit compared with high volumes of packed red cells [7]. Pathological features of glomerulomegaly observed in CCHD patients are similar to the lesions found in cor pulmonale and massive obesity. In both CCHD and cor pulmonale, the patients are exposed to chronic hypoxia. Similarly, individuals with massive obesity are often complicated with sleep apnea syndrome [8] and exposed to hypoxia. An association between glomerular damage and duration of cyanosis was reported in CCHD patients [9,10]. However, the glomerular lesions were not always correlated with the degree of oxygen desaturation or polycytaemia in CCHD, in cor pulmonale or in massively obese patients [11], and massively obese patients do not always show sleep apnea syndrome (8). Hypoxia, elevated haematocrit, and polycytaemia may be contributory factors for glomerulopathy in CCHD, but they may not be necessary conditions.
FSGS and glomerulomegaly are frequently observed in patients with massive obesity, and it has been reported that patients with massive obesity have markedly increased GFR [12]. Increased glomerular capillary plasma flow initiates capillary dilatation, increased glomerular capillary hydraulic pressure and glomerular sclerosis. Hyperfiltration has been implicated as one of the most plausible pathological entities associated with FSGS and glomerulomegaly. In this regard, the effectiveness of ACEI in the present case may be due to reductions in intraglomerular pressure, as ACEI may exert anti-proteinuric effects through direct influences on glomerular haemodynamics, such as through preferential dilatation of efferent arterioles.
Many factors, such as hypoxia, elevated haematocrit, polycythaemia, and hyperdynamic circulation, could play pathogenic roles in the glomerulopathy associated with CCHD. In the present case, glomerular hyperfiltration was probably the most important factor as ACEI produced partial remission of the nephrotic syndrome. In a retrospective analysis between 1973 and 1989, Flanagan et al. [3] did not report any nephrotic syndrome cases in 83 CCHD patients, with or without urinary abnormalities, that were treated with ACEI (captopril). Clinical trials using ACEI treatment in a large group of patients with CCHD with proteinuria will be necessary to investigate the effectiveness of ACEI.
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Acknowledgments
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We gratefully thank Mrs T. Hashimoto and Mrs Y. Saito for assistance with the electron microscopy and for their excellent work.
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Notes
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Correspondence and offprint requests to: Jun Wada, MD, PhD, Department of Medicine III, Okayama University Medical School, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. Email: junwada{at}md.okayama\|[hyphen]\|u.ac.jp 
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Received for publication: 3. 2.01
Revision received 14. 6.01.