Department of Nephrology, Guy's Hospital, London
Correspondence and offprint requests to: A. David Makanjuola, Department of Nephrology and Transplantation, Guy's Hospital, London SE1 9RT, UK.
Bright's observations in 1836 [1] highlighted the link between proteinuria and renal disease. More recently, ischaemic renal disease was described by Jacobson [2] as `a clinically significant reduction in glomerular filtration rate in patients with haemodynamically significant obstruction to renal blood flow in the renal artery of a solitary kidney or in both renal arteries if both kidneys are present'. As a means of differentiating ischaemic renal disease from other glomerular diseases, Jacobson used the 24-h protein excretion rate as a discriminatory clinical feature. He stated that ischaemic renal disease would produce 24-h protein excretion rates of less than 1 g.
Atherosclerotic renal disease
Atherosclerotic renal disease is the major cause of renal artery stenosis in Europe and the USA. It is recognized as a cause of hypertension, and it is also possibly the single most common cause of end-stage renal failure in patients over the age of 60 years in the USA [3]. There are reports, however, of patients who satisfy the definition of ischaemic renal disease, presenting with significant proteinuria, sometimes in the nephrotic range [4]. The difficulty in interpreting some of these reports is that although the renovascular lesion is easily demonstrable by angiography, the precise nature of the glomerular/tubular lesion and its relation to ischaemia is rather more difficult to substantiate. Greco and Breyer [5] point out this fact, stating that `there is no definitive way to determine a causal relationship between the renovascular lesion and the decrement in glomerular filtration rate'. They also note that it is often difficult to distinguish between the degree of renal insufficiency due to the decrease in perfusion, and that due to hypertension and/or chronic ischaemia. Like Jacobson, they list heavy proteinuria as an indicator of other aetiologies of chronic renal insufficiency.
Heavy proteinuriapotential aetiologies
Clinical experience however, is at variance with this. Indeed, to use heavy proteinuria as a discriminating factor is to ignore the fact that it is well described in patients who satisfy the criteria for ischaemic renal disease. The question is not whether it excludes the diagnosis of ischaemic renal disease, but rather, why it occurs.
The reninangiotensin system is one of the potential causes of proteinuria in these patients, and renin associated proteinuria is well described [6,7]. Proteinuria in some of these cases has been succesfully treated with ACE inhibitors [8], by restoration of blood flow to [9], or by removal of [10], the ischaemic renin producing kidney.
There is experimental evidence, which shows that renin mediated proteinuria is glomerular, rather than tubular in origin [11]. Some authors have postulated that angiotensin II might cause proteinuria due to selective arteriolar vasoconstriction and systemic hypertension leading to increased glomerular capillary hydrostatic pressure and filtration fraction. The consequent increase in concentration of plasma proteins along the length of the glomerular capillary may thus lead to increased trans-glomerular passage of proteins [3]. Angiotension II infusions have been shown to induce glomerular hypertrophy, vascular and interstitial damage [12], and glomerulosclerosis [13]. These actions might be secondary to stimulation of extracellular matrix synthesis by induction of transforming growth factor-ß [14].
Apart from the reninangiotensin system, there are other possible explanations for heavy proteinuria in these patients. The patient with renal disease secondary to atherosclerosis is quite likely to have a clinical phenotype which predisposes to hypertension, hypertensive nephrosclerosis, and athero-embolic disease; conditions which are associated with varying degrees of proteinuria, occasionally in the nephrotic range. This is most marked in athero-embolic renal disease, the clinical manifestations of which are very similar to those of a systemic vasculitis. These patients have eosinophilia and eosinophiluria, the plasma complement levels may fall, and renal failure in these patients is often accompanied by a very poor overall prognosis.
Proteinuria in patients with athero-embolic renal disease is usually modest, but there are reports of significant, even nephrotic range proteinuria [15]. In addition to this, there may be associated specific glomerular lesions. Greenberg et al. [16] showed a 63% incidence of focal segmental glomerulosclerosis (FSGS) in 24 patients with athero-embolic disease. Those patients with nephrotic range proteinuria were more likely to have the `collapsing' variant of FSGS. It is interesting to note that this variant was found in areas of ischaemic glomerular collapse. The authors speculate that this lesion may have developed as a response to direct glomerular injury from ischaemia. Thadhani et al. [17] have presented data which suggests that in patients over the age of 65 years, 30% of patients with FSGS also have renal artery stenosis, which in this age group will be almost exclusively of the atherosclerotic variety.
The histological lesions
In hypertensive nephrosclerosis, the histological features include focal ischaemic collapse of glomerular tufts, arterial hyalinosis, myo-intimal hyperplasia, and corrugation of the capillary basement membrane. The arterial hyalinosis and myo-intimal hyperplasia can lead to a reduction in luminal diameter, with consequent distal ischaemia. In keeping with Sealey's theory of nephron heterogeneity [18], one would expect increased intra-renal secretion of renin from these ischaemic glomeruli. This, as well as hyperfiltration in neighbouring glomeruli would lead to proteinuria. It is difficult to be sure which mechanism is more important. There are reports of patients with unilateral renal artery stenosis, where FSGS was present in the contralateral kidney, but the ipsilateral kidney seemed to have been protected [19]. There are also reports, however, of patients with unilateral renal artery stenosis, where FSGS was found in both kidneys [20]. Alkhunaizi suggests a possible causal relationship between chronic ischaemia, and the development of secondary FSGS, with consequent severe proteinuria in patients with ipsilateral lesions, while hyperfiltration produces similar effects in patients with contralateral lesions [19]. Textor makes the important point that atherosclerotic disease of the renal arteries commonly supervenes on longstanding hypertension, and the renal histological findings compatible with ischaemic renal disease are often interspersed with vascular changes suggestive of `nephrosclerosis' [21].
The heterogeneity of atherosclerotic renovascular disease
The fact that the renal lesions secondary to atherosclerotic renovascular disease can be diverse and multiple within the individual patient is of significant clinical importance. These patients should be viewed in a similar fashion to patients with nephritis due to systemic lupus erythematosus, where the histological features though varied, are nonetheless compatible with the single diagnosis, and patients may present with one or other histological type at different stages in the evolution of their disease.
It is partly for this reason that the term ischaemic nephropathy does not rest comfortably with quite a few nephrologists. It is, we feel, more appropriate to describe these patients as having atherosclerotic nephropathy, rather than ischaemic nephropathy, as it is clear that the mechanisms by which atherosclerotic renovascular disease causes renal impairment are complex, and not just a simple response to diminution of renal blood flow.
Conclusion
Proteinuria ranging from modest amounts up to nephrotic proportions as in many published reports is compatible with the diagnosis, and should not of itself necessitate further investigation for a different glomerular pathology.
References