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April 2002, Volume 16, Number 4, Pages 275-280
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Original Article
Hypertension and renovascular disease: follow-up on 100 renal vein renin samplings
P Hasbak1, L T Jensen2 and H Ibsen3 The East Danish Study Group on Renovascular Hypertensiona

1Department of Clinical Physiology and Nuclear Medicine, Glostrup Hospital, Denmark

2Department of Clinical Physiology and Nuclear Medicine, Gentofte Hospital, Denmark

3Department of Internal Medicine, Glostrup Hospital, Denmark

Correspondence to: P Hasbak, MD, Department of Clinical Physiology and Nuclear Medicine, Glostrup Hospital, DK-2600 Glostrup, Denmark. E-mail: philip@post1.tele.dk

aMembers of the study group: H Dige-Petersen, A Leth, M Brahm, S Schifter, S Rasmussen, Glostrup Hospital; S Strandgaard, S Dorph, F Rasmussen, Herlev Hospital; JK Christoffersen, JO Lund, S Just, N Baekgaard, LP Jensen Gentofte Hospital; A Høegholm, Naestved Hospital; K Rasmussen, Roskilde Hospital.

Abstract

The clinical value of renal vein renin sampling (RVRS) as a prognostic tool in the treatment of renovascular hypertension was evaluated. One hundred consecutive patients were included over a 4-year period of time. About half of the patients (49%) were treated interventionally by PTRA (21%), nephrectomy (20%), or vascular surgery (8%). Seven patients (15%) were cured and 15 (32%) had improved (reduction in antihypertensive medicine) after 6 months follow-up, whereas three patients (6%) were cured and 12 (26%) improved after 3-4 years follow-up. Thus, the number of patients cured or improved is comparable with the results from our department reported 20 years ago. However, in the present report, more than twice as many patients were enrolled, leading to double costs. Different indices of lateralisation of the renin generation were calculated for the use in cases of a shrunken kidney (functional share 15%). None of the indices clearly discriminated between the patients who did benefit from intervention, and those who did not. The only positive finding was that a peripheral renin concentration lower than 8 mlU/l predicted no effect of intervention, which might lead to the exclusion of 11% of the patients before entering the diagnostic programme. We conclude that the RVRS demands a very restrictive referral pattern if it should be of prognostic value for the blood pressure outcome after intervention. No indices of lateralised renin concentrations proved high predictive value. However, a peripheral renin concentration low in the normal range seems useful as an indicator of no benefit from intervention.

Journal of Human Hypertension (2002) 16, 275-280. DOI: 10.1038/sj/jhh/1001365

Keywords

renovascular hypertension; renal vein renin sampling; cure and improvement rate

Introduction

More than 20 years ago, the results of interventional treatment of renovascular hypertension in our department were published.1 At that time, nephrectomy (82%) and vascular surgery (18%) were the treatments of choice. Since then, the percutaneous transarterial renal angioplasty (PTRA) has become the preferred treatment of renal artery stenosis. In the same period of time, the antihypertensive drugs have become increasingly effective. The introduction of calcium channel blockers and ACE inhibitors, in addition to beta-adrenoreceptor blockers, have made the pharmacological management of arterial hypertension a possible competitor to interventional treatment of renovascular hypertension.2,3 Furthermore, the prevalence of renovascular hypertension is now estimated to be less than 0.5%4 of the hypertensive population, in contrast to earlier estimates up to 5-10%.2 The therapeutic changes combined with the conflicting reports on the clinical usefulness of renal vein renin sampling (RVRS) and on the long term effects of PTRA on hypertension,5,6,7,8,9,10 recently addressed by van Jaarsveld and colleagues,11 prompted us to evaluate our strategy in diagnosing and predicting the outcome of interventional treatment of renovascular hypertension.

The study was retrospectively made on 100 consecutive patients who underwent RVRS. The aim of the study was to investigate if optimisation of indices calculated from the RVRS data would improve the prognostic power to predict the outcome of PTRA or nephrectomy on arterial hypertension, and to estimate the cost of curing renovascular hypertension.

Subjects and methods

The study population consisted of 100 patients consecutively referred to Glostrup County Hospital for RVRS from 1994 to 1997. For basic data, see Table 1. The study was initiated in April 1998, and with a late follow-up in 2000. The reference population was 1.3 million people in the East of Denmark, excluding the city of Copenhagen. Approximately 700000 people were older than 40 years. Thirteen percent (91000 people) received antihypertensive drugs, with 0.5% of the population (3500 people) receiving three or more different drugs.12

Diagnostic procedures

The diagnosis of renovascular hypertension was based on the history of severe hypertension (three or more different antihypertensive drugs/rapid onset of hypertension), renography, renography with acute angiotensin-converting enzyme-inhibition (ACE-I), renal artery angiography and renal vein renin sampling. Usually renal artery angiography was carried out before RVRS except in cases where the referring physician believed that the outcome of RVRS could lead to a decision as far as intervention was concerned.

The renographies (without and with acute ACE-I) were carried out according to the international recommendations,13 and interpreted by the same panel of four experts in nuclear medicine.

The renal angiographies were made with a right and a left view of 15 degrees from centre. In two patients the angiography was not technically possible due to extensive atherosclerosis, and in one patient the angiography was performed via translumbal catheterisation of the aorta, owing to occlusion of both femoral arteries. The remaining angiographies were performed with aortic catherisation from the right femoral artery. The same two radiologists, who also performed the PTRA procedures, interpreted all angiographies.

The RVRS was successful in all patients. Treatment with alpha-/beta-adrenoreceptor blockers, ACE-I and angiotensin 2 receptor (AT2) antagonists was withdrawn for at least 2 weeks prior to RVRS. Owing to a thrombotic inferior caval vein, the catheterisation procedure was performed from the right cubital vein in two patients. The remaining patients all had two catheters, from the left and right femoral vein to the left and right renal vein. The correct position of the catheters was ensured by fluoroscopy, measurement of oxygen tension, and by measuring 51Cr-EDTA in the renal veins in comparison with the reference sample (iliac vein blood). At start of the procedure, 51Cr-EDTA (3.7 MBq) was given intravenously. Simultaneously blood samples were taken before and after stimulation with furosemide. Plasma renin concentration was determined using the principle of antibody trapping,14 as modified by Millar et al.15 The standard renin preparation, 68/356, was obtained from the National Institute for Biological Standards and Control (Hertfordshire, UK) and antibodies against angiotensin I were raised in rabbits. The decision for a 'positive RVRS' was based on a significant renin gradient across the ipsilateral kidney and significant suppression of renin secretion on the contralateral site. An expert panel of physicians and surgeons made the decision about intervention after presentation of all clinical and diagnostic data.

Follow-up and evaluation

After PTRA, vascular surgery or nephrectomy the patients were followed at their local hospital for blood pressure controls and evaluation. To determine possible benefit of the intervention, the patient files were reviewed regarding post treatment blood pressure and antihypertensive therapy. If the information was available the blood pressure is given as the mean value of three consultations around the time of intervention or RVRS, at 6 months and 3-7 years after intervention/RVRS.

A patient was considered 'cured' if he/she became normotensive (diastolic blood pressure 90 mm Hg) in the absence of any antihypertensive medication for at least 6 months. Improvement was defined as a reduction in the need for antihypertensive medication. If none of these conditions were fulfilled the patient's hypertension was considered 'unchanged'.

Database, calculations and statistical analysis

Data were collected in a base containing the following on each patient: age, gender, serum creatinine (prior to intervention), renography data (functional share/shape of renograms), renin values from the RVRS (basal conditions and after stimulation with furosemide), antihypertensive medication (at time of RVRS and at follow up), result of renal angiography, interventional procedure (PTRA, nephrectomy, vascular surgery), and blood pressure (mean of three consultations before intervention, and at follow up).

Four different indices to quantify the lateralisation of the renal renin out-put were calculated, attempting to optimise the prognostic value of the RVRS (Figure 1). One of the indices was the 'Renin-Generation-Index', estimating the net renin release from each kidney by correcting the net renal vein renin production (difference between renal vein and reference) with the renographically determined functional share (Figure 1).16

The Mann-Whitney U-test was used to test differences between subgroups. P-values less than 0.05 were considered statistically significant. Data are expressed as medians and ranges.

Results

One hundred patients entered the study and underwent RVRS. Baseline characteristics are presented in Table 1. Four patients died before the first follow-up, and two settled in other parts of Denmark. The remaining 94 patients all had an abnormal renography/ACE-I-renography (Figure 1). In 60 patients their RVRS was considered 'positive' and in 34 'negative'. In 85 patients renal angiography were performed. Seventy-two patients had renal artery stenosis (46 unilateral and 26 bilateral), diagnosed by selective renal angiography (Figure 1). Of the remaining 22 subjects, 13 had normal renal angiography and in nine patients the renal angiography was omitted, owing to one shrunken kidney and normal contralateral renogram, where the question was whether a nephrectomy should be performed. In all patients, arteriosclerosis was the cause of the stenosis, and none due to fibromuscular dysplasia. Interventional treatment was applied in 47 patients (Figure 1, Table 2) and the result on blood pressure was seven cured, 15 improved and 25 unchanged after 6 months follow-up, whereas only three remained cured and 12 improved at the 3-4 years follow-up (Figure 1). In 27 patients with angiographically verified stenoses, intervention was omitted either because the RVRS was considered negative or the degree of renal artery stenosis was not sufficient for PTRA, the complexity of the patient or refusal to participate.

The indices for lateralisation of renin secretion, given in Figure 2, were calculated, and different cut off levels tested. However, none of them showed to be more valid for the prediction of blood pressure outcome after interventional treatment, than the often used lateralisation index of 1.5 (Figure 3).1,17 The peripheral renin, used as reference value in the RVRS, showed to be the most effective parameter. All patients considered cured or improved had peripheral renin concentrations above 8 mlU/l (normal range 6-60 mlU/l).

The estimated cost of 4000 renographies of 100 US$, 1200 ACE-I-renographies of 120 US$, 250 angiographies of 600 US$, 100 renal vein renin samplings of 720 US$, and 47 PTRA/surgical intervention of 2400 US$ in our patient population was in total about 720000 US$. Hence, the net cost of each cured patient was 90000 US$, or 30000 US$ for each cured or improved. These costs are clearly underestimated. If the total costs should be estimated (buildings, diagnostic utensils, heat, electricity etc) the cost could be multiplied with at least a factor of two. If so, the cost is still lower, but comparable with those of Blaufox et al2 in 1996. The cost for the society in lost working hours because of hospitalisation was not estimated.

Discussion

The renal vein renin sampling procedure (RVRS) has for several decades been one of the main diagnostic tests for renovascular hypertension. It has been argued that although the diagnostic value is good,4,18 the prognostic value of the test varies widely between centres.3,5,7 Recent reviews do not even mention the RVRS as a method of evaluating patients suspected of renovascular hypertension.2,19 Throughout the years our group has been a strong proponent for RVRS and it has a strong position in our decision-making. However, it should be stressed that a proper comprehensive study to define the predictive value of a positive versus negative RVRS has so far not been carried out.

The results of 100 renal vein renin samplings from our department show a low predictive value for the outcome of interventional procedures. The rate of cure (15%) and improvement (32%) of 47 treated patients after 6 months follow-up is significantly lower than it was 20 years ago. However, the number of patients benefiting from intervention is unchanged about six per year per one million citizens. The characteristics of the patients does not seem to have changed considerably; we still diagnose very few or none with fibromuscular dysplasia or arteriitis. The predominant underlying disease continues to be atherosclerosis. The only clear-cut difference is the increasing number of patients suspected of renovascular hypertension referred for RVRS. In the mid-nineties we performed more than twice as many renal vein renin samplings as in the seventies. It is tempting to conclude that the more liberal access to renography, angiography and renal vein renin sampling, has led to a less critical referral pattern, with an unchanged population benefiting from the tests, but for the inconvenience of more patients. The consequence of referring the double number of patients seems just to be the double cost for each cured patient. In the present study the estimated net cost of one cured patient is at least 90000 US$.

The treatment of hypertension with renovascular disease has dramatically changed. Twenty years ago the treatment in most cases was nephrectomy and in a few patients surgical angioplasty, with a cure and improvement rate of 86%.1 Our rate of cure and improvement are of the same magnitude as reported in several other studies2,7,9,20 but much lower than reported from the centres with the highest success.5,6,21 Several factors might explain this difference, but especially the clinical selection for the first renography seems important. It has been calculated that the probability of renovascular hypertension should be higher than 30% to obtain reasonable cost benefit of the diagnostic programme.2,19 It is tempting to speculate that not only structural vascular changes in the contralateral kidney might determine the outcome of PTRA, ie restoring the renal artery blood flow by PTRA might not result in normotension because of structural vascular changes in smaller arteries distal to the renal artery stenosis, perpetuating the hypertension. This might explain why a high renal resistance index at the stenosis side seems to be a highly reliable predictor for non-improvement after PTRA.22

The most positive report concerning RVRS within the recent years6 shows that the RVRS is the test with the highest prognostic value. This certainly is based on a much more restrictive referral pattern, resulting in the diagnosis and treatment of approximately one patient per 100000 citizens, whereas we have applied the programme on three times as many patients, with the same result, approximately one cured or improved per 100000. The difference between one and three patients investigated is tremendous, looking at the inclusion investigation: instead of 4000 renographies, 1200 ACE-I-renographies, and 250 angiographies, we should only make one-third. So it may very well be possible that 0.5% of all hypertension are renovascular, but also that only about 0.1% are curable.

Our attempt to optimise the prognostic value of RVRS by calculating more indices of lateralised renin release was not successful. Even the assumption that the 'Renin-Generation-Index' would be valuable when dealing with shrunken kidneys was not correct. There was no difference between patients with a shrunken kidney and patients with just moderately diminished functional share of one of the kidneys. The only positive finding was that peripheral renin concentrations of less than 8 mlU/l were not found in any patient cured or improved after intervention. Using this cut-off level, 10 (11%) of the 94 patients could be spared for the total investigatory programme. If correct, even more patients could be excluded before entering the diagnostic programme at all, diminishing the costs significantly. However, due to the retrospective character of our study, the finding has to be tested prospectively.

It is worth noting that up to 10% of all renal artery stenoses will occlude within 2 years and the renal function will deteriorate in about 30%.19,20 The preservation of kidney function by PTRA is to our knowledge not investigated in detail despite it being a highly important issue. It is known that the PTRA does not prolong the life expectancy, but perhaps the quality of life.23

Conclusion

In conclusion, the same number of patients benefit from PTRA as previously described 20 years ago. The referral pattern has changed, so now too many are suspected for renovascular hypertension. The centres with high curerates and high benefit of renal vein renin sampling seem to be the most restrictive. For the optimal use of RVRS, we advocate a more restrictive referral pattern and the need for multicentre clinical databases. Especially, there is a need for studies elucidating the effect of PTRA on renal function. There is an urgent need for measures of a higher predictive value than RVRS such as the renal resistance index.

References

1 McNair A et al. A follow-up study of hypertensivepatients after operative treatment of unilateral renovascular or renal disease. Acta Med Scand 1979; 205: 569-574. MEDLINE

2 Blaufox MD, Middleton ML, Bongiovanni J, Davis BR. Cost efficacy of the diagnosis and therapy of renovascular hypertension. J Nucl Med 1996; 37: 171-177. MEDLINE

3 Derkx FH et al. Renal artery stenosis towards the year 2000. J Hypertens Suppl 1996; 14: S167-S172. MEDLINE

4 Mann SJ, Pickering TG. Detection of renovascular hypertension. State of the art: 1992 Ann Intern Med 1992; 117: 845-853.

5 Bergrem H, Jervell J, Solheim DM, Flatmark A. Prognostic value of renal vein renin determination in suspected renovascular hypertension. Acta Med Scand 1982; 211: 387-391. MEDLINE

6 Jensen G et al. Treatment of renovascular hypertension: one year results of renal angioplasty. Kidney Int 1995; 48: 1936-1945. MEDLINE

7 Kuhlmann U et al. Long-term experience in percutaneous transluminal dilatation of renal artery stenosis. Am J Med 1985; 79: 692-698. MEDLINE

8 Roubidoux MA et al. Renal vein renins: inability to predict response to revascularization inpatients with hypertension. Radiology 1991; 178: 819-822. MEDLINE

9 Sellars L, Shore AC, Wilkinson R. Renal vein renin studies in renovascular hypertension - do they really help? J Hypertens 1985; 3: 177-181. MEDLINE

10 Svetkey LP et al. Prospective analysis of strategies for diagnosing renovascular hypertension. Hypertension 1989; 14: 247-257. MEDLINE

11 van Jaarsveld BC et al. The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis. Dutch Renal Artery Stenosis Intervention Cooperative Study Group. N Engl J Med 2000; 342: 1007-1014. MEDLINE

12 Rasmussen S. Unpublished data from the Glostrup Population Survey: MONI 10 study. Unpublished data from the Glostrup Population Survey: MONI 10 study 1998.

13 Taylor A et al. Consensus report on ACE inhibitor renography for detecting renovascular hypertension. Radionuclides in Nephrourology Group. Consensus Group on ACEI Renography. J Nucl Med 1996; 37: 1876-1882. MEDLINE

14 Poulsen K, Jorgensen J. An easy radioimmunological microassay of renin activity, concentration and substrate in human and animal plasma and tissues based on angiotensin I trapping by antibody. J Clin Endocrinol Metab 1974; 39: 816-825. MEDLINE

15 Millar JA et al. A microassay for active and total renin concentration in human plasma based on antibody trapping. Clin Chim Acta 1980; 101: 5-15. MEDLINE

16 Sato K et al. Renal vein plasma renin activity inpatients, with unilateral renovascular hypertension. Jpn Circ J 1988; 52: 431-436. MEDLINE

17 Vaughan ED et al. Renovascular hypertension: renin measurements to indicate hypersecretion and contralateral suppression, estimate renal plasma flow, and score for surgical curability. Am J Med 1973; 55: 402-414. MEDLINE

18 Pickering TG, Sos TA, Vaughan EDJ, Laragh JH. Differing patterns of renal vein renin secretion inpatients with renovascular hypertension, and their role in predicting the response to angioplasty. Nephron 1986; 44 (Suppl 1): 8-11. MEDLINE

19 Radermacher J, Brunkhorst R. Diagnosis and treatment of renovascular stenosis - a cost-benefit analysis. Nephrol Dial Transplant 1998; 13: 2761-2767. MEDLINE

20 Morganti A. Renal angioplasty: better for treating hypertension or for rescuing renal function? J Hypertens 1999; 17: 1659-1665. MEDLINE

21 Pedersen EB et al. Renovascular hypertension. Ability to renal vein ratio to predict the blood pressure level 18-24 months after surgery. Nephron 1986; 44 (Suppl 1): 29-31. MEDLINE

22 Radermacher J et al. Use of Doppler ultrasonography to predict the outcome of therapy for renal-arterystenosis. N Engl J Med 2001; 344: 410-417. MEDLINE

23 Isles C et al. Survival associated with renovascular disease in Glasgow and Newcastle: a collaborative study. Scott Med J 1990; 35: 70-73. MEDLINE

Figures

Figure 1 Flow-chart illustrating the 100 patients in the study population undergoing renography, renal vein renin sampling, angiography and intervention. Numbers in boxes represent number of patients.

Figure 2 Renal vein renin indices are calculated using the renin concentration of the renal vein with the highest renin concentration (Abnormal), the renin concentration from the contralateral renal vein (Normal), the renin concentration from the infrarenal vena cava (Reference) and renograms without angiotensin- converting enzyme inhibition determined the functional Share of each kidney.

Figure 3 Renal vein renin values for each of the 94 patients in the study population are plotted using the lateralisation and suppression indices defined in Figure 2.

Tables

Table 1 Basic characteristics of the study population

Table 2 Intervention on 47 patients and number of patients cured and improved after 6 months follow-up

Received 7 August 2001; revised 29 October 2001; accepted 29 October 2001
April 2002, Volume 16, Number 4, Pages 275-280
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