Hyperuricosuria, hematuria, and novel bladder images with IgA nephropathy

Abstract

Episodic (recurrent) macroscopic hematuria in patients with IgA nephropathy is usually associated with a benign prognosis, although some patients experience a transient fall in glomerular filtration rate during the episodes. We present a 15-year-old girl with mild IgA nephropathy who had multiple episodes of macroscopic hematuria associated with severe but transient decreases in estimated glomerular filtration rate, low levels of serum uric acid, and marked increases in fractional excretion of uric acid. Ultrasound studies showed marked inflammatory changes in the bladder, especially involving the trigone. Cystoscopic findings were consistent with these changes. We hypothesize that the macroscopic hematuria may have resulted, at least in part, from hyperuricosuria causing acute irritation of the bladder mucosa in the trigone area.

Many studies report that patients with IgA nephropathy (IgAN) who have recurrent episodes of macroscopic hematuria (MH) paradoxically enjoy a good prognosis compared to patients who have only microscopic hematuria (mH),^1–5 although at least one report refuted these findings.⁶ One mechanism that may be responsible for this unusual observation is that the MH in these cases may be precipitated by intermittent hyperuricosuria.^7,8 In this report, we describe a patient in whom sonography findings and laboratory features support the hypothesis that episodic MH may have been caused by hyperuricosuria.

CASE DESCRIPTION

A 15-year-old girl was experiencing cyclical vomiting, recurrent urinary tract infections, enuresis, and vesico-ureteral reflux. She had been seen at 11 years of age for evaluation of positive antinuclear antibodies, low C4 complement levels, and hypertension. Her estimated glomerular filtration rate (eGFR) was 136 mL/min/1.73 m², and her kidney biopsy showed mild mesangial IgAN. Over the next 4 years, she had multiple episodes of abdominal pain, cyclical vomiting, and voiding dysfunction. Urodynamic studies demonstrated high bladder pressures, weak stream, and incomplete emptying. She was treated with intermittent catheterization. She also had MH on some of these occasions, with the urine described as “pink with blood clots.” The patient experienced an acute, reversible fall in eGFR during three of these hospitalizations (Table 1). Repeat renal biopsy again revealed mild mesangial IgAN.

Table 1.

Laboratory studies during and between multiple episodes of macroscopic hematuria

Age (years)	SCr (mg/dL)	eGFR (mL/min/ 1.73 m2)	UPCR (mg/mg)	SUA (mg/dL)	UUA/UCr (mg/mg)	FEUA (%)
12.0	2.6MH	24	2.0
12.9	0.47	132	0.15
13.6	0.74		2.8
14.5	4.1MH	15		4.9–6.2
14.7	3.22MH	19		4.1–1.5
15.2	0.7MH	115		2.2	0.41	12.9
15.25	0.83	97		4.4	0.42	7.9
15.3	0.64GLH	126	0.68	3.1	0.28	5.8
15.35	0.81	100	1.26	3.6	0.40	9.1
15.4	0.6MH	126	0.63	2.8	0.54	15.3

eGFR indicates estimated glomerular filtration rate; FEUA, fractional excretion of uric acid; GLH, glomerular hematuria; MH, macroscopic hematuria; SCr, serum creatinine; SUA, serum uric acid; UPCR, urine protein to urine creatinine ratio; UUA/UCr, urine uric acid to urine creatinine ratio.

When the patient was 15 years old, she presented with a history of five to six episodes of vomiting each day and nickel-sized clots with every void, but her urine culture showed no growth. Her vital signs and physical examination were normal apart from suprapubic tenderness and mild volume depletion. Laboratory studies showed a normal eGFR but a low serum uric acid (SUA) (2.2 mg/dL) and a high fractional excretion of uric acid (12.9%). Two weeks later, the fractional excretion rate fell to 7.9%, and then 5.8%, and the SUA rose to 4.4 mg/dL. Sonography revealed significant abnormalities in the posterior bladder wall with thickening up to 1.5 cm and hyperemia marginated by the ureteral insertions extending to the urethra (Figure 1). Cystoscopy confirmed the significant inflammatory changes in the trigone. The mucosa was edematous and heaped up, with a polypoid appearance. There were mild ecchymotic changes around the bladder neck, but the dome and lateral walls of the bladder were spared of these changes. Between episodes, her bladder wall returned to normal.

Figure 1.

(a) Transverse grayscale ultrasound of the bladder (B) at the level of the mid-trigone (arrows) with bladder wall thickening isolated to the trigone, measuring 1.5 cm centrally and tapering laterally. (b) Transverse Doppler ultrasound of the bladder at the level of the mid-trigone demonstrating increased color Doppler flow in the trigone, indicating hyperemia. (c) Transverse grayscale ultrasound of the bladder at the inferior trigone. The bladder wall thickening of the trigone extends to the urethra. The urethra is seen posterior to the bladder in this image because of the angle of the ultrasound probe. The central echogenic mucosa (short arrow) and the peripheral muscular layer (long arrow) of the urethra are thickened. (d) Transverse Doppler ultrasound of the bladder at the level of the superior trigone demonstrating focal thickening at the right and left ureteral insertions (arrows).

DISCUSSION

In many reports of patients with IgAN, investigators have stated that patients who had recurrent episodes of MH enjoyed a better prognosis than those who had only mH.^1–4 This apparently paradoxical relationship was also reported by Yoshikawa et al in 119 Japanese children.⁵ The patient described in this report appears to be similar to those described by Yoshikawa et al. It has been proposed that the mechanism responsible for at least some of the episodes of MH in patients with IgAN may be intermittent hyperuricosuria. In 1990, Muira et al reported that a group of 34 adult IgAN patients with recurrent MH had lower SUA levels but higher fractional excretion of uric acid than a group of 79 patients who had persistent mH.⁷ Serum creatinine levels were initially not different between the two groups, but 3 years later, they were lower in patients who had MH (P < 0.005). The relationship between recurrent MH and hyperuricosuria was also studied in 12 Polish children with IgAN by Konopielko et al in 1996. They showed that the fractional excretion rate of uric acid was higher during episodes of MH (9.8 ± 5.1%) than during remissions (5.5 ± 1.2%).⁸ This was similar to our patient, in whom the rate ranged from 9.1% to 15.3% during episodes of MH but only 5.8% to 7.9% between episodes.

Why do patients with IgAN and hyperuricosuria develop MH? Some authors have proposed that hyperuricosuria causes “microcalculi” that injure the tubular epithelium.⁹ Alternatively, the ultrasound and cystoscopic findings in our patient suggest that the reaction of the bladder mucosa to a high concentration of uric acid may also be a viable possibility, explaining the hyperemia and irritation on imaging. Visible toxic effects of uric acid on the urinary bladder were first described by Etheridge in the late 19th century¹⁰ and subsequently reinforced by Ravogli in 1906.¹¹ Our patient had trigone thickening during her episodes with intervening normal ultrasounds, supporting bladder irritation as the source of macroscopic hematuria. Isolated trigone thickening, as in this case, also raises the question of why this irritation self-isolates to this region alone. One plausible consideration may stem from embryological development of the bladder. When the bladder is forming, the trigone is derived from mesodermal tissue. The remainder of the bladder is derived from the ectoderm. It can be speculated that the different properties of these various layers could lead to different responses to irritation.

The fact that our patient had two kidney biopsies that showed only mild lesions over 4 years despite multiple significant falls in eGFR is an encouraging sign for her ultimate prognosis. The bladder is not always included in renal ultrasound evaluation. The novel bladder sonography findings reported herein underline the importance of sonographic examination of the bladder in patients passing red or pink urine and blood clots, even in those with known glomerular diseases, since it may be a source of pathology.