P&S Medical Review: Apr 1995, Vol.2, No.2
The Role of the Surgical Intervention in Atherosclerotic Ischemic Nephropathy

JEFFREY S. STRINGER
Columbia University College of Physicians and Surgeons, New York, N.Y.

Since the time of Goldblatt's classic experiments in 1934¹, scientific inquiry into occlusive disease of the renal artery has concerned itself primarily with the resultant hypertension and elucidation of the underlying "humoral mechanism" now known as the renin-angiotensin-aldosterone axis. Working with the dog model, Goldblatt et al observed that hypertension could be produced in a graded and reversible fashion by constriction of the renal arteries. Renovascular hypertension has thus long been recognized as an important, potentially curable disease, numerous large studies having demonstrating the clear benefits of surgical revascularization.² However, a second pathologic sequelum of renal artery occlusive disease is currently under investigation. This entity, known as ischemic nephropathy, refers to clinically significant reduction in glomerular filtration rate due to a proximal stenosis of the renal artery. Inasmuch as it involves the development of chronic renal failure, ischemic nephropathy is distinct from renovascular hypertension; indeed, many of these patients are not hypertensive. There is, however, considerable overlap of these disease states, especially in the early stages of renal artery stenosis when the renin-angiotensin system is still able to maintain renal plasma flow. In such cases, the institution of a medical antihypertensive regimen will likely produce some decline in excretory function. Typically, this is manifested only in a slight rise in serum creatinine concentration, but there are reports of such regimens making patients dialysis dependent.^3,4

A growing literature suggests that surgical revascularization procedures can secure improvement of renal excretory function (or a decrease in the rate of its decline) in certain patients.

PREVALENCE OF ISCHEMIC NEPHROPATHY

Atherosclerotic renal artery disease is a frequent concomitant of generalized atherosclerosis obliterans and accounts for the majority of renal artery lesions.^5-8 While the exact incidence of atherosclerotic ischemic nephropathy is not known, a large study by Olin et al has documented significant stenosis (defined as >50%) of the renal artery in 38% of patients with abdominal aortic aneurysms, 39% of patients with aorto-occlusive disease, and 33% of patients with occlusive disease of the lower extremity.⁹ A smaller, more recent study¹⁰ examined the prevalence of ischemic nephropathy in patients with renal insufficiency: Of 25 randomly selected patients with serum creatinines greater than 2.0 mg%, 3 patients (14%) evidenced ischemic nephropathy. Zierler's¹¹ recent study which used duplex ultrasonography to evaluate 80 patients estimates the prevalence of renal artery stenosis in individuals with peripheral vascular disease to be 30-40%. Thus, while presently ill-defined, there seems to be a significant patient population that could benefit from intervention.

COURSE OF DISEASE

Renal artery atherosclerosis is similar in its pathogenesis and clinical course to other atherosclerotic lesions, typically consisting of a concentric intimal plaque containing a core of cholesterol-protein complexes and a fibrous covering. The lesions occur most commonly at or within 2 cm of the renal artery aortic ostium, and can give rise to thrombus, sub-intimal hemorrhage, and cholesterol microemboli.^6,8,12

Unfortunately, many such lesions progress. Several investigators have documented the natural history of renal artery atherosclerosis as a progressive one.^3,11,13-15 Schreiber et al14 studied serial angiograms of 85 patients over a ten year period. Documenting significant progression in 44% and complete occlusion in 16%, they estimated an overall reduction in caliber of the renal artery to progress at 1.5% per month. In the subgroup of patients who had pre-existing high grade stenoses (which Schreiber defined as >75%), progression to occlusion was shown to occur in 40% of cases within one year. Other recent studies using duplex ultrasound corroborate these data.^11,15,16 Zierler's study demonstrated a 20% per year reduction in caliber of the renal artery.¹¹These studies clearly indicate that the patient with atherosclerotic renal artery stenosis is at significant risk of experiencing a worsening of his or her condition.

SURGICAL REVASCULARIZATION

Patency of a stenotic renal artery can be re-established by either balloon angioplasty or surgical reconstruction. Percutaneous transluminal renal angioplasty (PTRA), once believed universally appropriate, has of late been relegated to very specific populations, namely those patients with either single-sided, non-ostial lesions or stenosis due to fibromuscular dysplasia. PTRA will not be discussed here; however the reader is referred to the excellent reviews by Sos and Pickering¹⁷and Libertino¹⁸for further information. In the majority of patients, surgery remains the treatment of choice.^18,19

In1962 Morris et al²⁰described eight case reports in which severely stenotic renal arteries were repaired for the purpose of kidney salvage. All eight patients experienced marked improvement in their azotemia. Since then, numerous published series have agreed with these findings.^5,21-24In general, investigators have accepted a 20% change in estimated glomerular filtration rate as an arbitrary indicator of significant change in excretory function. The results of five recent studies appear in Table 1. One should bear in mind that each of these studies are retrospective reviews performed at major referral centers for renovascular disease. A given patient in this population would have a 42-58% chance of improvement in renal function, a 26-54% chance of no change in renal function, and a 4-22% chance of deterioration of renal function. In order to facilitate meaningful comparison of data, patient deaths that were considered by some authors as "operative complications" have been calculated as "deteriorated" in Table 1.

Table 1: Results of Surgical Revascularization for Atherosclerotic Ischemic Nephropathy
Study	Patients	Improved	Unchanged	Deteriorated
23Novick, 1987	161	58%	31%	11%
21Dean, 1991	58	53%	26%	15%
22Libertino, 1992	97	46%	32%	22%
24Zucchelli, 1993	13	69%	23%	8%
5Chaikof, 1994	50	42%	54%	4%
Results of retrospective reviews performed at major referral centers for renovascular disease, showing the typical patient to have between a 42% and 58% chance of improved function.

Interestingly, some investigators have demonstrated that those patients who do benefit from the procedure benefit significantly, ^5,21a finding that suggests the presence of a heterogeneous patient population with heterogeneous pathology.

There is some disagreement as to which actual revascularization technique is superior. As might be expected, this is center-dependent. Table 2 summarizes the procedural choices made by the authors of the larger published series, given the specifics of their particular referral populations. Dean et al at Bowman Gray report the use of aorto-renal bypass in 49% of procedures, having employed autologous saphenous vein grafts 71% of the time, and polytetrafluoroethylene (Teflon) 29% of the time. They likewise performed thromboendarterectomy in 46% of cases. Novick et al did not distinguish between aorto-renal bypass and endarterectomy in their article, and were likewise unclear as to the frequency of use of prosthetic materials. Libertino and Novick, both urologists, seem more willing to use alternate bypass methods, especially if able to avoid clamping a diseased aorta,¹⁸while Dean, a vascular surgeon, prefers aorto-renal bypass. In a study of patients with disease of both the renal artery and abdominal aorta, Chaikof et al⁵at Emory report the use of dacron bypass grafting in almost every case, presumably because the majority of their patients underwent concomitant aortic reconstruction.

Table 2: Operative Techniques of Various Surgeons
	21Dean	23Novick	22Libertino
Technique	(Bowman Gray)	(Cleveland Clinic)	(Lahey Clinic)
Aorto-Renal Bypass	49%	54% †	23%
Endarterectomy	46%	54% †
Spleno-Renal Bypass		17%	39%
Hepato-Renal Bypass		11%	26%
Ilio-Renal Bypass		7%
Other	4%	5%	12%
Summary of the revascularization techniques used by the authors of the larger published series. The patient demographics in each study are essentially identical; thus the above data reflect to some degree each center's personal preference. † Novick did not distinguish between these two.

Morbidity and mortality constitute a significant concern that is confounded by the advanced age and concomitant medical problems present in this population. In 1988, Mailloux et al²⁵reported on survival and risk analyses performed on 532 patients referred for dialysis over a fifteen year period. Their analysis indicated not only that patients with renovascular disease are increasing among the dialysis population, but they also have the poorest survival estimates of all sub-groups studied, with a 27-month median and 12% five-year survival. At present, the operative mortality of renal revascularization to correct either ischemic nephropathy or hypertension is between 2-8.6%.^5,6,21,22Novick²³has published data reporting 5/241 operative deaths in patients with atherosclerotic ischemic nephropathy and 0/104 operative deaths in patients with fibromuscular dysplasia. This discrepancy is thought to be due to differences in the two patient populations, the latter being, on average, considerably younger and healthier.

PATIENT SELECTION

One of the difficulties with surgical treatment of this disease is that there are no reliable predictors of which patients will have improved function. Certainly, some screening measure having the capacity to differentiate would be of great utility. This need has prompted several investigators to examine their data for predictors of positive functional outcome, and although speculation abounds, unfortunately little conclusive evidence is available. The power of preoperative serum creatinine concentration as a predictor of surgical success is at best questionable. Although many investigators^6,26,27have shown a positive correlation, a more recent study by Chaikof ⁵and a seminal study by Dean²¹disagree with these findings. Chaikof has, however, shown that while preoperative creatinine concentration fails to predict immediate surgical outcome, a high serum creatinine does correlate with increased likelihood that a patient will require dialysis in the long term.

This confusion has led Dean et al to examine the actual rate of deterioration in estimated GFR (EGFR, as estimated by the Cockcroft and Gault method²⁸) as a possible predictor of successful intervention. Figure 1 represents a graphic depiction of the pre- and post-operative EGFR over time in two patient groups: those who experienced improvement as the result of revascularization and those who did not.

Figure 1
(reprinted with permission from Dean et al, 1991

Likewise, other parameters, such as demonstration of collateral circulation by retrograde filling on angiogram,^{6,19,20,26,29-32}bilateral stenosis or unilateral stenosis of a solitary kidney,^{3,6,19,26,29,31}renal size,^6,19,26,31positive functional tests including captopril renography,^{4,6,19,26,31,33}biopsy-proven preservation of tubules and glomeruli,^{4,6,19,22,24,31,32}rapidly declining renal function,^3,29and anatomic extent of disease^3,5,29have all been investigated as possible predictors of agreeable functional outcome. Unfortunately, the literature in this area is very confusing, showing significant direct contradiction, sometimes even between papers of the same author.

A MODEL

Clearly, the area of patient selection presents a real problem. Although no single variable has emerged as universally valuable, it seems reasonable that any indicator of the presence of ischemic, but viable renal parenchyma would predict success. In the absence of such a marker, the clinician must make an individualized judgment, based upon intuition and the entire clinical picture. The following model is hypothetical and may be helpful in directing one's thinking about the problem in light of the available clinical data:

As the atherosclerotic lesion progresses, renal plasma flow declines, and the kidney maintains filtration by constriction of the efferent arteriole. With continued progression of stenosis, the maximum filtration fraction is reached, and GFR begins to fall. However, the kidney is unlike other tissues such as brain or myocardium in that its metabolic requirements are largely flow-dependent. Its energy requirements come from the processes of absorption, secretion, and ion transport, and thus a gradual decrease in renal plasma flow does not cause infarction because it represents a decrease in energy requirements as well.

It might therefore be useful to think of a window of opportunity that exists as the renal artery becomes progressively stenotic. The affected renal parenchyma is at first still viable, with many nephrons maintained at a certain baseline, non-functioning level. This is salvageable renal mass. With continued disuse, the tissue eventually undergoes nephrosclerosis, tubular atrophy, interstitial fibrosis, and the various other pathologic sequelae of chronic ischemia.⁸

A Model for Renal Salvageability in Ischemic Nephropathy

Figure 2 graphically demonstrates the idea of the window of opportunity. In the presence of a fixed, discrete stenosis, the proportion of ischemic, but salvageable renal mass to non-viable parenchyma is fairly large. As time passes, this proportion diminishes. Thus, as Dean's evidence³suggests, the patient with rapidly declining renal function would be most likely to have a larger proportion of salvageable to non-salvageable tissue. Unfortunately, current functional tests, such as captopril renography and intravenous pyelogram, are unable to make this differentiation.³³

CONCLUSIONS

With some 120,000 US patients on chronic dialysis,¹⁹ overwhelming evidence suggests the existence of a significant patient population that can benefit greatly from renal revascularization procedures. Now that current surgical techniques are refined sufficiently to provide acceptable morbidity and mortality, the real challenge seems to lie in astute patient selection. Almost certainly, much of the disagreement in the literature regarding which patients are most likely to benefit from these procedures is due to the heterogeneity of the patient population and the making of unjustified comparisons. Likewise, the presence of myriad comorbid features, such as hypertension and its various medications, hyperlipidemia, cigarette use, and diabetes make it difficult if not impossible to sort out the degree of renal insufficiency attributable solely to a proximal renal artery stenosis.

Thus, despite the increased attention to this interesting disease, there remains tremendous need for further investigation. Certainly a large, prospective study which investigates predictors of positive surgical outcomes is in order. How, for instance will assessments such as renal biopsy and Dean's rate of change in GFR play out? As the available data continue to increase, along with our ability to categorize our patients more intelligently, it is likely that a more definitive understanding of the interplay of these various factors will emerge. The next real challenge in this area lies in the development of better screening techniques and reliable patient selection.

From the Columbia University College of Physicians and Surgeons, Class of 1995. Address correspondence to author.

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