Nephrology Unit and 1 Pathology Service, Corporació Sanitaria Parc Taulí, Sabadell, Spain
Keywords: renovascular hypertension; percutaneous angioplasty; nephrotic syndrome
Introduction
Several anecdotal case reports have described an association between renal artery stenosis and the nephrotic syndrome [14]. The aetiology of this nephrotic state has been related to the hyperrreninaemia secondary to renal artery stenosis [24]. This mechanism has been supported by the evidence showing occurrence of proteinuria in experimental animals infused with renin or angiotensin II [5,6]. Resolution of proteinuria has been observed after nephrectomy [2,4,711], reconstruction of the affected renal artery [1215] or administration of angiotensin-converting enzyme inhibitor [7,1621].
We observed a case of renovascular hypertension with bilateral renal artery stenosis who presented a sudden nephrotic syndrome following a transluminal angioplasty of the functioning kidney. This observation suggests that in addition to hormonal factors, the intrarrenal haemodynamics must be decisive in its genesis.
Case report
A 72-year-old man was referred to our hospital for evaluation of hypertension and renal failure. Hypertension had been discovered incidentally 2 months before admission by his general practitioner, who started treatment with hydrosaluretil, amlodipine and lisinopril. Subsequently, blood pressure remained uncontrolled, and only a worsening of renal function was evident, so the patient was referred to the hospital for further evaluation.
He reported a 40-pack-year history of cigarette smoking. During the preceding 4 months, he had noticed a progressive weakness and claudication involving the calves. On physical examination his blood pressure (BP) was 240/120 mmHg, the left dorsalis pedis pulse was absent with a right femoral bruit. There was no peripheral oedema.
Initial laboratory investigations included: serum creatinine 1.9 mg/dl, serum sodium 141 mmol/l, serum potassium 3.9 mmol/l, fasting blood sugar 90 mg/dl, serum cholesterol 216 mg/dl. Urinalysis revealed a normal sediment and no significant proteinuria (100 mg/24 h). The creatinine clearance was 25 ml/min. The electrocardiogram showed mild left ventricular hypertrophy and the chest X-ray mild cardiomegaly. Optic fundi showed a grade 1 hypertensive retinopathy. Ultrasonography revealed reduced size of the left kidney which measured 8 cm compared to the right kidney which measured 10 cm. Based on the clinical findings renovascular disease was strongly suspected, and an arteriography performed. This examination demonstrated a complete occlusion of the left renal artery at the ostium and an 80% stenosis of the proximal portion of the right renal artery, arteriosclerotic lesions were also found in the iliac arteries with a 50% stenosis on the left side.
In the following days renal function worsened, creatinine rose to 2.6 mg/dl, and BP remained uncontrolled (between 180/90 and 210/110 mmHg.) despite treatment with frusemide 120 mg/day, nifedipine retard 60 md/day and doxazosin 12 mg/day.
In order to improve renal function and BP control, percutaneous transluminal angioplasty (PTA) of the right renal artery was successfully performed. After the PTA, BP was easily controlled, being 150/95 with only 60 mg/day nifedipine, and the patient was discharged.
Three weeks later he was seen in the outpatients ward, his BP remained controlled and he felt well, but the laboratory test disclosed serum creatinine 2 mg/dl, urea 50 mg/dl, cholesterol 602 mg/dl, serum albumin 16 g/l, and urinalysis revealed massive proteinuria amounting to 13 g/24 h. No oedema or skin lesions were observed and he looked well. A test 2 weeks later confirmed a reasonably preserved renal function with creatinine 1.7 mg/dl, urea 36 mg/dl, clearance creatinine 27 ml/min. The urinary sediment was normal and proteinuria amounted to 16 g/24 h. Renal arteriography revealed a patent right renal artery after successful dilatation.
At this time peripheral plasma renin activity was markedly elevated to 699 pg/ml (normal range <300 pg/ml) and plasma aldosterone concentration was 40 ng/ml (normal range <4.7 ng/ml). The proteinograme disclosed hypoalbuminaemia (16 g/dl) and elevated alpha-2 globulin with high cholesterol levels (614 mg/dl); viral serology (HBsAg, HIV, HVC), complement components and immunological examinations (ANCA, ANA, cryoglobulins) were normal. The patient refused further invasive examination. His BP was controlled 160/90 mmHg and renal function was maintained. Three months after the PTA the nephrotic syndrome persisted with proteinuria being 17 g/24 h and microhaematuria 510 hxhigh power field was detected.
Four months after the PTA he suddenly complained of rapidly progressing dyspnea with orthopnea. On admission his BP was 250/130 mmHg, with dyspnea at rest and clinical as well as radiological signs of pulmonary oedema. Renal function had deteriorated creatinine concentration being 5.8 mg/dl and haematocrit 30%. After treatment with high dose furosemide, vasodilators and oxygen, his clinical condition improved, but renal function worsened and haemodialysis was started. Despite dialysis treatment, he needed four hypotensive medications to control BP. Reocclusion of the main right renal artery was suspected, but the patient refused all invasive diagnostic or therapeutic interventions. Ten days after admission he suddenly developed left side cerebral haemorrage and died.
Post mortem study demonstrated extensive brain haemorrhage. Atheromatous occlusion of the left renal artery was confirmed. In the right renal artery acute dissecting haemorrhage of the vessel was noted, with a 90% occlusion of the lumen. The most striking findings were seen in the renal parenchyma (Figure 1). The left kidney was small (60 g weight), but upon microscopic examination renal parenchyma was surprisingly well preserved. The glomeruli appeared slightly reduced in size with moderate tubular atrophy and slight interstitial fibrosis (Figure 2
). The right kidney was enlarged (180 g weight). Microscopic examination disclosed severe focal segmental glomerulosclerosis with areas of hyalinosis. Severe interstitial fibrosis with scanty inflammatory focal component and marked tubular atrophy was noted (Figure 3
). No fibrinoid necrosis or cholesterol emboli were observed. Immunofluorescence study was negative.
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Discussion
Modest proteinuria is often present in renovascular hypertension, but well documented cases of nephrotic syndrome have been described in such patients as well [14]. It is commonly assumed that this is caused by activation of the reninangiotensin system. This hypothesis has been supported by experimental studies in animals [5,6] and by the observation that proteinuria may even disappear following administration of angiotensin converting enzyme inhibitors [7,1621], nephrectomy of the ischaemic kidney [2,4,711], or after revascularization procedures, i.e. surgery or angioplasty [4,1215,22].
The effects through which angiotensin II promotes proteinuria are not completely known, but it may modify vascular resistances, act directly on vascular endothelial cells producing widening of the intercellular junctions, or can modify the anionic charge or the sialoprotein content of the basement membrane. In addition, angiotensin II is pleiotropic, acting as a growth factor with proliferative, profibrogenic and inflammatory properties [23]. The most frequent histological lesion reported in cases of proteinuria and renal vascular disease is segmental glomerulosclerosis [8,10,13,15,24,25]. Separating haemodynamic from circulating and local factors in the pathogenesis of segmental glomerulosclerosis has been difficult in the human in vivo setting. Experimental studies have emphasized the relevance of haemodynamic factors in the development of these lesions [2630].
The above observation adds interesting elements to this discussion, since the patient happened to present an almost experimental model. The appearance of massive proteinuria shortly after successful angioplasty underlines the importance of haemodynamic factors. When the patient had severe hypertension, ischaemia of the kidney and excessive activation of reninangiotensin system, proteinuria was absent. In contrast, when systemic blood pressure was controlled after angioplasty, he developed a full blown nephrotic syndrome. Post mortem examination disclosed severe unilateral glomerulosclerosis in the revascularized kidney, whilst the left kidney was well preserved.
Although other explanations are not fully excluded, the observation is in-line with an important role of haemodynamic factors in the development of these lesions, as suggested by the hyperfiltration theory. Our observation is complemented by interesting observations on glomerulonephritis or diabetic nephropathy in individuals with unilateral renal artery stenosis. For instance, the existence of unilateral rapidly progressive glomerulonephritis is observed when the opposite kidney remained protected behind a renal artery stenosis [31]. Similarly, in a transplanted kidney with multiple vascular supply, areas perfused via a stenosed artery are protected and do not show histological evidence of rejection during a rejection crisis.
Undoubtedly with more frequent use of revascularization procedures, observations like the above one will be made more frequently in the future [32].
Teaching Point
In a patient who develops proteinuria after angioplasty: consider the development of focal segmental glomerulosclerosis.
Notes
Supported by an educational grant from
Correspondence and offprint requests to: Dr J. Almirall, Nephrology Unit, Corporacio Sanitaria Parc Tauli, Parc Tauli s/n, Es-08208, Sabadell, Barcelona, Spain.
References