Q J Med 1999; 92: 515-518
© 1999 Association of Physicians
Proteinuria in atherosclerotic renovascular disease
From the Department of Nephrology and Transplantation, Guy's Hospital, London, and 1 Department of Nephrology, Hope Hospital, Salford, UK
Received 19 March 1999 and in revised form 17 June 1999
Dr A.D. Makanjuola, Department of Nephrology and Transplantation, Guy's Hospital, London SE1 9RT
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Summary |
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Proteinuria is well described in atherosclerotic renovascular disease (ARVD), but the prevalence is unknown, and the pathogenesis may vary between patients. Substantial proteinuria (>2 g/day) however, would be regarded by many as atypical of ARVD. We studied 94 patients (52 male) with ARVD, median age 67 years (range 49–87). Digital subtraction angiography was performed on all patients. Protein was assayed in 24-h urine samples and GFR derived using the Cockroft-Gault formula. Forty-nine patients (52%) had proteinuria <0.5 g/24 h. Proteinuria increased with worsening renal function. Biopsies from seven non-diabetic patients with substantial proteinuria showed: minimal changes (1); glomerular sclerosis with marked ischaemic changes (3); focal glomerulosclerosis (2); and athero-emboli (1). Proteinuria, rather than being indicative of other pathology, is often a marker of severity of parenchymal disorder in atherosclerotic nephropathy, which itself is the major determinant of renal dysfunction in patients with ARVD.
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Introduction |
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In 1988, Jacobson defined the reversible renal impairment due to renal artery narrowing as ischaemic nephropathy.1 It is now recognized that the renal disease associated with atherosclerotic renal artery stenosis is more complex than just a direct response to ischaemia,2 and the processes may include focal segmental glomerulosclerosis (FSGS)3 and athero-embolic disease.3,4 In many forms of renal disease, proteinuria is a predictor of progressive renal dysfunction.5 Although there are individual case reports or series, there has been no investigation into the frequency of proteinuria in atherosclerotic renovascular disease (ARVD). We investigated the prevalence and magnitude of proteinuria in patients with ARVD.
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Methods |
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Patients from two renal centres with angiographically-confirmed ARVD were investigated to determine their renal function and degree of proteinuria. Protein was quantified from 24-h urine samples collected prior to or 4–8 weeks following angiography. The majority of patients had been referred for investigation of renal dysfunction rather than solely for investigation of hypertension. There was often a suspicion of renovascular disease at the time of referral.
To ensure uniformity between the two centres during data analysis, GFR was calculated using the Cockroft-Gault formula:6
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Arterial anatomy was determined by digital subtraction angiography. Radiological findings were reported either as `normal', `stenosis' or `occlusion'. Stenoses were graded as mild (<25%), moderate (25–50%), or severe (>50%). Patients with proven ARVD were scored between 0 and 2, according to a `patency index' as follows: 0, occlusion in one vessel; 1, normal vessel; with intermediate values derived as 1 minus the degree of stenosis. A patient with 50% stenosis on one side and occlusion on the other would therefore score 0.5 (0.5+0), and a patient with bilateral 50% stenosis would score 1 (0.5+0.5).
Data were also obtained for age at presentation, sex, and the presence or absence of diabetes and hypertension.
Correlation of GFR and proteinuria
Patients were arbitrarily stratified into four groups according to their GFR (ml/min): <10 (n=9); 10–25 (n=36); 25–50 (n=33); and >50 (n=16). Mean proteinuria as well as the standard error of the mean (SEM) was calculated for each group (Figure 1
). Statistical analysis was done using ANOVA, comparing all four groups of patients.
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Correlation of proteinuria and patency index
Mean proteinuria was plotted against patency index in the scatter diagram shown in Figure 2
. There was no correlation between the parameters (r=0.05).
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Results |
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Patient characteristics are shown in Table 1
. Ninety-four patients were available for study, 52 males and 42 females (M : F=1.2 : 1), of whom 87 (92.6%) were on treatment for hypertension. Some were on angiotensin-converting-enzyme inhibitors (ACEIs) prior to diagnosis, but these were usually discontinued on suspicion or confirmation of the diagnosis of ARVD. The mean age of the patients was 66 years (range 49–87).
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There were 20 diabetic patients, all of whom were type II diabetics. Five had substantial proteinuria (mean 1.37 g) and all underwent renal biopsy. Features in keeping with diabetic nephropathy were present in four, and these patients were excluded from data analysis. In the fifth patient, the biopsy showed athero-emboli, but no evidence of diabetic nephropathy. The other 15 diabetics had lesser degrees of proteinuria (mean 0.58 g) and lacked clinical features such as retinopathy or peripheral neuropathy, which argued against diabetic nephropathy being comorbidly present with ARVD, but as renal biopsies were not performed on these patients, it is impossible to be certain.
The proteinuria increased significantly (p<0.0325) in magnitude as GFR declined in these patients. We were concerned that the diabetic patients included in the study might skew these results. Subgroup analysis however, showed that there was an even distribution between groups, as seven of the 15 diabetics included had GFRs <25 ml/min. Similarly, there was no difference in prevalence of treated hypertension between the groups.
Biopsies were performed on seven non-diabetic patients who had substantial proteinuria; especially where there was a suspicion that there might be coincident intrinsic glomerular pathology unrelated to renovascular disease. Minimal changes were detected in one patient with unilateral renal artery stenosis who had a biopsy performed on the contralateral kidney. FSGS was found in three patients (the immunofluorescence pattern suggested that this was secondary, rather than idiopathic FSGS), glomerulosclerosis with marked ischaemic changes in two patients, and athero-embolic disease with cholesterol clefts in one diabetic patient in the absence of overt diabetic changes (Table 2).
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Discussion |
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This paper is a survey of patients followed by two renal centres interested in ARVD. Most of our patients had some degree of renal impairment, and as such might not be representative of the overall spectrum of ARVD. Biopsy findings were not available on most of these patients, and thus the precise nature of the parenchymal disease causing the proteinuria could not be confirmed. However, these results do suggest that urine protein excretion above the normal range is common in patients with ARVD. Indeed, proteinuria, even in excess of 2 g/day, may be a marker for atherosclerotic nephropathy, rather than an indicator of some other pathology as previously thought.
The features of interest are the relationships between proteinuria, renal function and patency index. The degree of proteinuria increased strikingly with declining renal function, and we believe this reflects the severity of parenchymal damage in these patients. These findings are noteworthy, as in most glomerulopathies, proteinuria tends to decline with worsening renal function. This relationship between GFR and proteinuria is reminiscent of that seen in advanced diabetic nephropathy, the late stages of membranous nephropathy and `chronic rejection' of renal allografts.
Data from Suresh et al. shows that there is no correlation between renal function and the patency index in patients with ARVD.7 This is in keeping with the lack of correlation between proteinuria and patency index demonstrated in our study. The poor correlation between proteinuria and the patency index suggests that the proteinuria is due to events `downstream' from the proximal arterial lesion rather than a reflection of the degree of narrowing of the renal artery.
Proteinuria has been recognized as an important predictor of renal dysfunction in the best-studied progressive renal disease, diabetic nephropathy.8 In some studies, the magnification of the risk of progression of renal disease by proteinuria is as great in non-diabetic patients as it is in those with diabetes.8 Other investigators have observed the importance of proteinuria as a predictor of mortality in the general population.9 Could this be due to occult atherosclerotic nephropathy in these patients?
The mechanism of proteinuria in these patients is complex. The case that Chen et al.10 reported, of removal of a kidney with renal artery occlusion curing nephrotic range proteinuria, lends support for a central role for hyper-reninaemia. In their patient, proteinuria fell gradually rather than instantaneously after the nephrectomy, suggesting that the proteinuria did not originate solely from the kidney with the occluded renal artery. In athero-embolic disease, the regular occurrence of proteinuria suggests a more direct response, perhaps due to cholesterol crystal embolization, which is occasionally associated with an acute-phase response. That FSGS can develop in a kidney with renal artery stenosis provokes interesting mechanistic hypotheses, which however, are difficult to prove.3 Although we only obtained biopsy material in a minority of our patients with ARVD, a spectrum of parenchymal disorders were observed. As the renal histological changes can be focal, we suggest that pathogenetic mechanisms can vary, and that several distinct changes may co-exist in the individual patient. We therefore feel the term `atherosclerotic nephropathy' is a more appropriate term to describe the spectrum of renal disease associated with ARVD.
ACEIs are useful agents for attenuating proteinuria, but we have been reluctant to initiate the liberal use of these agents in our patients pre- or post-angioplasty. This is because of the progressive nature of the renal artery narrowing11 and the risk of restenosis following intervention.12 However, it is interesting that in Mikhail et al., three of the patients with progressive renal dysfunction after angioplasty actually had 24-h urine protein values well above the normal range.13 Single kidney GFR estimations on these patients showed that progressive renal dysfunction occurred independently of restenosis.13 Significant proteinuria not uncommonly accompanies such functional deterioration, and as such, there may yet be a rationale for ACEIs or angiotensin II receptor antagonists in the long-term treatment of subgroups of patients with ARVD. The challenge for the nephrologist will be to identify such subgroups.
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References |
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TopSummaryIntroductionMethodsResultsDiscussionReferences |
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1. Jacobson HR. Ischaemic renal disease: an overlooked clinical entity? Kidney Int 1988; 34:729–43.[Web of Science][Medline]
2.
Scoble JE, Cook GJR. Individual kidney function in atherosclerotic nephropathy. Nephrol Dial Transplant 1998; 13:842–4.
3. Thadhani R, Pascual M, et al. Preliminary description of focal segmental glomerulosclerosis in patients with renovascular disease. Lancet 1996; 347:231–3.[Web of Science][Medline]
4. Thadhani RI, Camargo CA, et al. Atheroembolic renal failure after invasive procedures: Natural history based on 52 histologically proven cases. Medicine 1995; 74:350–8.[Medline]
5. Williams PS, Mallick NP. The natural history of chronic renal failure. In: El Nahas AM, Mallick NP, Anderson S. The prevention of progressive chronic renal failure. Oxford University Press, Oxford, 1993:210–58.
6. Cockroft D, Gault MK. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16:31–41.[Web of Science][Medline]
7. Suresh M, Laboi P, Mamtora S, Kalra PA. Severity of proximal renal artery lesions does not predict renal dysfunction in patients with atherosclerotic renovascular disease. Kidney Int 1998; in press.
8. Damsgaard EM, Froland A, et al. Eight to nine year mortality in known non-insulin dependent diabetics. Kidney Int 1992; 41:731–5.[Web of Science][Medline]
9.
Pontremoli R. Microalbuminuria in essential hypertension—its relation to cardiovascular risk factors. Nephrol Dial Transplant 1996; 11:2113–15.
10. Chen R, Novick AC, Pohl M. Reversible renin mediated massive proteinuria successfully treated by nephrectomy. J Urol 1995; 153:133–4.[Web of Science][Medline]
11. Zierler RE, Bergelin RO, Isaacson JA, Strandness DE. Natural history of atherosclerotic renal artery stenosis: a prospective study with renal ultrasonography. J Vasc Surg 1994; 19:250–8.[Web of Science][Medline]
12. Tullis MJ, Zierler RE, Glickerman DJ, et al. Results of percutaneous transluminal angioplasty for atherosclerotic renal artery stenosis: a follow up study with duplex ultrasonography. J Vasc Surg 1997; 25:46–54.[Web of Science][Medline]
13. Mikhail A, Cook GJR, Reidy J, Scoble JE. Progressive renal dysfunction despite successful renal angioplasty in a single kidney. Lancet 1997; 349:926.[Web of Science][Medline]
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