Nutcracker syndrome combined with IgA nephropathy in a child with recurrent hematuria

IgA nephropathy is the most common chronic glomerular disease worldwide with a prevalence of about 15% in hematuric children.1 The prevalence of childhood nutcracker syndrome is not known, but it is increasing because of the development of non-invasive diagnostic methods. In this report we describe a patient whose nutcracker syndrome is combined with IgA nephropathy. Such a combination in childhood has not been reported so far. A 9-year-old girl presented for the evaluation of isolated hematuria. Microscopic hematuria was detected through mass urinary screening 15 months ago, but has not been evaluated. At 8 days before visiting the Nephrology unit, Severance Hospital, Seoul, Korea, she had had gross hematuria preceded by upper respiratory infection for 1 day without any dysuria or flank pain. She had no family history of congenital or acquired kidney diseases. Other physical findings were normal. Blood pressure was 105/60 mmHg, pulse rate 86/min and body temperature within normal limits. Laboratory tests including complete blood cell count, electrolytes, biochemistry, and the coagulation profile were normal. Other blood examinations were also normal, including serology for hepatitis B and tests for antinuclear antibody, anti-streptococcal O titer and complement C3 and C4. Urinalysis revealed numerous red blood cells (RBC) per high power field with no casts. Urine culture was sterile and urinary calcium excretion was normal. 2-D ultrasonography and excretory urography demonstrated no reason for this hematuria. Renal Doppler ultrasound was performed with this patient in the supine position using an HDI 3000 sonography system with 4–6 MHz convex transducers (Philips, Ultrasound, Bothell, Washington, DC, USA). Peak velocity was measured at two points in the left renal vein (LRV), one at the lateral portion of the LRV near the hilum and the other where the LRV courses between the aorta and the superior mesenteric artery (aortomesenteric portion). The peak flow velocity in the aortomesenteric portion of the LRV (95.2 cm/s) was significantly faster than that in the hilar portion (20.1 cm/s; Fig. 1). The peak velocity ratio between aortomesenteric and hilar portions was 4.74. Therefore, the patient was diagnosed as having nutcracker syndrome. However, we did not perform further diagnostic examinations such as cystoscope or renal venography since the parents were reluctant to allow these procedures. Urinalysis was performed monthly and it showed 10–20, 0–2 and 3–5 RBC/high power field (HPF) for 3 months. (a) The peak velocity of the left renal vein in the hilar portion measured 20.1 cm/s. (b) The peak velocity of the left renal vein in the aortomesenteric entrapped portion was 95.2 cm/s. At this time, the child had the second episode of pinkish gross hematuria for 3 days after exercise, and a renal biopsy was performed to evaluate the recurrent hematuria. Light microscopy showed focal mesangial proliferation with normal tubulointerstitial structures, and immunofluorescence demonstrated moderate mesangial deposition of IgA, and trace depositions of IgG, IgM, C3, and fibrinogen. The biopsy findings were consistent with IgA nephropathy (Fig. 2). (a) A glomerulus showing segmental mild mesangial proliferation Periodic Acid-Schiff (×400). (b) Immunofluorescence showing moderate mesangial IgA deposits (×400). IgA nephropathy is one of the most common forms of glomerulonephritis and a major cause of persistent microscopic and recurrent gross hematuria with or without proteinuria.1 Compression of the LRV between the aorta and the superior mesenteric artery, known as nutcracker syndrome, may cause gross or microscopic hematuria, proteinuria, or a combination of these symptoms.2,3 Because IgA nephropathy is relatively common in childhood, and the prevalence of nutcracker syndrome is recently increasing due to the development of non-invasive diagnostic methods, some patients will have both diseases. Although coexistence of these two diseases in children has not been reported, this association is not rare and is sometimes experienced in the pediatric nephrology unit. In addition, there is one report in the literature of two adults with nutcracker syndrome and IgA nephropathy.4 Ozono et al. described two adult patients with nutcracker syndrome complicated by IgA nephropathy, who showed aggravation of hematuria after upper respiratory infections, urinary red cell morphology indicating hematuria of glomerular origin, elevation of serum IgA, persistence of proteinuria, and granular casts in the urine compared to those with nutcracker syndrome alone.4 However, these are not consistent findings since even patients with nutcracker syndrome alone can show recurrent gross hematuria after upper respiratory infections and persistent recumbent proteinuria.5 Although urinary RBC morphology may be normal with non-glomerular bleeding and dysmorphic from glomerular bleeding, cell morphology does not reliably correlate with the site of hematuria.6 Furthermore, Kim et al. demonstrated the percentage of isomorphic RBC was considerably variable (range, 2–90%) in patients with nutcracker syndrome confirmed by venography.7 In our case, the patient showed only microscopic hematuria at first visit and the next day the degree of hematuria was reduced (0–2 RBC/HPF). At second visit, the degree of hematuria was not severe (3–5 RBC/HPF) since she visited our unit some days after gross hematuria had stopped. Therefore, we could not check urinary RBC morphology. In addition, serum IgA levels have no diagnostic value in children because they are elevated in only 15% of patients.6 Loin pain associated with gross hematuria is also possible in both conditions.8 Therefore, a clinician may find it difficult to identify whether IgA nephropathy is combined with nutcracker syndrome with clinical findings alone, and a renal biopsy is necessary for a final diagnosis in a patient with recurrent hematuria. In our patient, nutcracker syndrome was diagnosed with renal Doppler ultrasound. Park et al. calculated the normal peak velocity ratios between aortomesenteric and hilar portions in 27 normal children aged 6–16 years.9 The mean peak velocities ± 2 SD in the LRV at aortomesenteric and hilar portions were 45.41 ± 11.59 and 18.04 ± 2.80 cm/s, respectively, and the mean ratios of peak velocity between the two portions of the LRV were 2.57 ± 0.70 (range, 1.3–3.9). They set the cut-off level of peak velocity ratios for the diagnosis of childhood nutcracker syndrome at 3.98. Although a confirmatory diagnostic method is left renal venography with pressure measurement, it is rarely indicative of children since nutcracker syndrome in childhood generally resolves spontaneously with time.10 Hematuria induced by nutcracker syndrome can be confirmed by typical venographic (pressure gradient between inferior vena cava and LRV >3 mmHg) and cystoscopic findings (left-sided hematuria), but we could not perform these procedures since the parents were reluctant to allow them. However, nutcracker syndrome might also cause hematuria in this case. IgA nephropathy has a generally favorable long-term prognosis unless aggravated by hypertension, heavy proteinuria or impairment of renal function, but about one-third of patients reach end-stage renal disease after 20 years.1 Therefore, it is very important to detect this disease at an early stage and to treat with immunosuppressive drugs, which may improve the clinical outcome. Renal biopsy should be considered in cases with recurrent gross hematuria or association of persistent proteinuria when nutcracker syndrome was initially diagnosed. Although the combination of nutcracker syndrome and IgA nephropathy is by chance in our case, coexistence of these two diseases is possible in a patient with isolated hematuria. Therefore, patients with nutcracker syndrome who experience the relapse of gross hematuria should be evaluated for glomerular disease.