Treatment of unilateral obstruction reversing heavy and bilateral proteinuria
Behdad Afzali,
Edward Kingdon and
Stephen G. Holt
Sussex Kidney Unit, Royal Sussex County Hospital, Brighton, UK
Correspondence and offprint requests to: Stephen G. Holt, BSc MBBS MRCP PhD, Consultant Nephrologist, Sussex Kidney Unit, Royal Sussex County Hospital, Brighton BN2 5BE, UK. Email: Steve.Holt{at}bsuh.nhs.uk
Keywords: obstructive uropathy; proteinuria
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Introduction
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Proteinuria is a common finding in pregnancy and usually attributable to physiological changes that concurrently reduce serum albumin by 510 g/l. Urinary protein loss rarely exceeds 0.4 g/day, but nephrotic levels occur in up to 0.025% of all pregnancies [1], even in the absence of features of pre-eclampsia [2] or renal impairment. Many patients with pregnancy-associated proteinuria will remit spontaneously and may be managed conservatively without renal biopsy. Non-specific glomerular lesions may be seen in association with pre-eclampsia [3]. Primary glomerular disease, diabetes and renal vein thrombosis may also produce nephrotic levels of proteinuria in pregnancy. Pre-existing renal disease predisposes subjects to develop hypertension and further accelerated renal decline in pregnancy and these may be accompanied by an increase in urinary protein [4].
We present an unusual case where nephrotic syndrome was associated with unilateral ureteric obstruction.
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Case
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A 29-year-old nulliparous woman of Asian origin was referred to the renal service at 26 weeks of pregnancy with proteinuria (4.5 g/24 h) and ankle swelling. At presentation she was asymptomatic and her only past medical history was of beta-thalassaemia trait. She was normotensive (110/64 mmHg), intravascular volume replete and had mild bilateral pedal oedema. The remainder of the physical examination was non-contributory. Serum creatinine (42 µmol) was normal, but the serum albumin was reduced (24 g/l). Dipstick urinalysis at booking had been normal. Serological tests for antinuclear antibody, anti-neutrophil cytoplasmic antibody, double-stranded DNA, hepatitis B and C, HIV serology and urate levels were all negative or normal. A renal ultrasound revealed the presence of gross right-sided hydronephrosis with cortical thinning, suggestive of long-standing pelvi-ureteric junction (PUJ) obstruction. Protein permselectively index was 0.21 (relatively unselective) and, thus, we felt that this was unlikely to be a due to minimal change glomerulonephritis and most likely related to her obstructed kidney [5]. She was managed conservatively. At 37 weeks gestation the protein leak had increased to 8.5 g/24 h, serum albumin had fallen to 17 g/l and she was becoming increasingly oedematous. A healthy baby was delivered by normal vaginal delivery after induction of labour at 37 weeks.
Her protein leak failed to settle even at 6 months after completion of her pregnancy and the ongoing protein leak prompted dynamic and static renography with 99mTc-mercaptoacetyl - glycylglycylglycine (MAG3) and 99mTc-dimercaptosuccinic acid (DMSA) scans, respectively. These demonstrated an obstructed right kidney with a PUJ narrowing, but, surprisingly, 46% of total function was attributable to the right kidney. She subsequently underwent cystoscopy and selective ureteric sampling revealed that the protein leak was bilateral (left kidney: 0.7 g/l; right kidney: 2 g/l).
A laparoscopic pyeloplasty was performed on the right kidney at 16 months post-partum. Prior to the procedure her urinary proteinuria to creatinine ratio was 11.4 mg/mg and 24 h protein leak was measured separately at 6.08 g, indicative of ongoing heavy proteinuria. One month later, her protein leak had decreased remarkably to 0.4 g/24 h and protein creatinine ratio was 0.6 mg/mg. Her serum albumin returned to normal and has remained so. She became pregnant again and throughout this pregnancy showed no sign of increasing proteinuria. One week prior to delivery her urine protein creatinine ratio was 0.3 mg/mg.
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Discussion
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We have described a patient who presented with nephrotic syndrome in the second trimester in association with unilateral PUJ obstruction. Protein leak was documented from both the obstructed and unobstructed kidneys, which did not resolve spontaneously after delivery. However, remission occurred after a laparoscopic pyeloplasty.
Both tubular and glomerular proteinuria may accompany ureteric obstruction [5]. In this context nephrotic syndrome is rare and proteinuria is usually limited to the obstructed kidney [6]. Obstruction may be associated with loss of nephron mass and hyperfiltration in the remaining nephrons. An increase in urinary protein excretion occurs in
25% of children after unilateral nephrectomy [7] and it is likely that this is secondary to hyperfiltration. This effect is observed in animal models of reduced nephron mass [8] and may lead to the development of focal glomerulosclerosis [9]. In our case the obstruction was reversible and not associated with asymmetry of renal function at dynamic renography or an abnormal creatinine.
In this case, there were no symptoms of systemic disease, pregnancy-associated hypertension or renal impairment and all serological tests were negative. The dynamic renography effectively excluded hyperfiltration in the contralateral kidney. Selective sampling of the ureters demonstrated that the protein was derived from both kidneys. The high protein selectivity argues against the presence of minimal change disease. Moreover, the complete reversal of nephrotic range proteinuria by treatment of the unilateral obstruction, in the absence of any other treatment, is strongly suggestive that the obstruction itself was the cause of the proteinuria from both sides.
In animal models, unilateral increases in pressure within the renal pelvis, as in situations of PUJ obstruction, have been demonstrated to result in a pressure rise [10], diuresis and naturesis from the contralateral kidney. Neurological mechanisms may be responsible for this reno-renal reflex, as denervation of an intact kidney leads to reduced saluresis from the contralateral side [11] without reduction in renal blood flow or glomerular filtration rate [12].
We postulate two theoretical mechanisms that might account for the observations in our patient. A reno-renal reflex from the increased pressure within the right renal pelvis might have altered the properties of the left kidney, making it susceptible to protein leak. However, these responses are not uniform across species [13,14] and have not previously been described in humans. Furthermore, there is no evidence as yet that obstruction can cause contralateral proteinuria as a result of a reno-renal reflex.
The second possibility is the presence of some circulating factor that may have been derived from the obstructed kidney and that could have changed the permeability of the glomerulus or microrheology in both kidneys. The lack of proteinuria prior to pregnancy and failure of proteinuria to resolve following delivery points to the woman's pregnancy as a possible catalyst to the evolution of this problem. It is possible that obstruction might unveil cryptic epitopes and an antibody response to epithelial epitopes following unilateral obstruction has been observed previously [15]. The risks of biopsy in this patient, who had neither hypertension nor deteriorating renal function, were felt to be prohibitive during pregancy. The spontaneous resolution of the protein leak after PUJ surgery rendered this procedure unnecessary, so we do not have a histological diagnosis. A chance temporal association of the PUJ surgery and spontaneous remission of a primary glomerular pathology might explain our observations. However, we would like to speculate that a soluble factor produced by the obstructed kidney mediated the bilateral protein leak.
Conflict of interest statement. None declared.
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Received for publication: 5. 5.04
Accepted in revised form: 7.10.04