Use of doppler ultrasonography to predict the outcome of therapy for renal-artery stenosis

Th e Ne w E n g l a nd Jo u r n a l o f Me d ic i ne USE OF DOPPLER ULTRASONOGRAPHY TO PREDICT THE OUTCOME
OF THERAPY FOR RENAL-ARTERY STENOSIS
JÖRG RADERMACHER, M.D., AJAY CHAVAN, M.D., JÖRG BLECK, M.D., ANNABEL VITZTHUM, BIRTE STOESS, MICHAEL JAN GEBEL, M.D., MICHAEL GALANSKI, M.D., KARL MARTIN KOCH, M.D., AND HERMANN HALLER, M.D.
ABSTRACT
serve renal function. However, in 20 to 40 percent Background
of patients, treatment does not improve blood pres- whose renal function or blood pressure will improve sure or renal function. There is no reliable way to iden- after the correction of renal-artery stenosis has not tify these patients prospectively.1-5 In addition, both been possible. We evaluated whether a high level of angioplasty and surgery are associated with compli- resistance to flow in the segmental arteries of both cations, including cholesterol embolism, permanent kidneys (indicated by resistance-index values of at least 80) can be used prospectively to select appro- One possible reason for a poor response to treat- ment may be structural alterations in smaller renal Methods
arteries or arterioles distal to the renal-artery steno- tension for renal-artery stenosis using color Doppler sis induced by long-standing hypertension. Such hy- ultrasonography, and we measured the resistance in- dex as follows: [1¡(end-diastolic velocity÷maximal pertension may cause nephrosclerosis or glomeru- systolic velocity)] ¬100. Among 138 patients who had losclerosis,10 reducing the intrarenal vascular surface unilateral or bilateral renal-artery stenosis of more area and increasing vascular resistance in both the af- than 50 percent of the luminal diameter and who un- fected and the unaffected kidney.11 Increased vascu- derwent renal angioplasty or surgery, the procedure lar resistance may therefore be considered the func- was technically successful in 131 (95 percent). Creati- tional equivalent of structurally altered vasculature. nine clearance and 24-hour ambulatory blood pres- In a previous study of patients with more than 50 sure were measured before renal-artery stenosis was percent stenosis of a renal artery, we found that nei- corrected; 3, 6, and 12 months after the procedure; ther renal function nor blood pressure improved af- and yearly thereafter. The mean (±SD) duration of fol- ter correction of the stenosis in patients with a resist- Results
ance-index value of at least 80 in the segmental arteries had resistance-index values of at least 80 before re- of both kidneys, as measured by Doppler ultrasonog- vascularization, the mean arterial pressure did not de- raphy.12 The resistance index is calculated with use of crease by 10 mm Hg or more after revascularization the following equation: [1¡(end-diastolic velocity÷ in 34 (97 percent). Renal function declined (defined maximal systolic velocity)]¬100. These preliminary by a decrease in the creatinine clearance of at least retrospective findings prompted us to conduct a pro- 10 percent) in 28 (80 percent); 16 (46 percent) be- spective study to evaluate whether the resistance index came dependent on dialysis; and 10 (29 percent) died can be used to predict the outcome in patients with during follow-up. Among the 96 patients (73 percent) renal-artery stenosis that is treated with angioplasty with a resistance-index value of less than 80, the mean arterial pressure decreased by at least 10 percent inall but 6 patients (6 percent) after revascularization; renal function worsened in only 3 (3 percent), all ofwhom became dependent on dialysis; and 3 (3 per- Identification of Renal-Artery Stenosis
cent) died (P<0.001 for the comparison with patients Between June 1994 and November 1999, we performed color with a resistance-index value of at least 80).
Doppler ultrasonography in 5950 patients who had hypertension Conclusions
and clinical features suggestive of renal-artery stenosis. All the pa- least 80 reliably identifies patients with renal-artery tients had at least one of the following: high blood pressure despitetreatment with three or more antihypertensive drugs; a diastolic stenosis in whom angioplasty or surgery will not im- blood pressure of more than 110 mm Hg; systolic and diastolic prove renal function, blood pressure, or kidney sur- murmurs or an isolated systolic abdominal murmur; known cor- onary, peripheral vascular, or cerebrovascular disease; hypokalemia; Copyright 2001 Massachusetts Medical Society.
retinal hemorrhages, exudates, or papilledema; or unexplained azo-temia or a history of azotemia in association with treatment withan angiotensin-converting–enzyme inhibitor. The protocol was ap-proved by the ethics committee of Hannover Medical School, andall patients provided written informed consent.
Our technique for color Doppler ultrasonography to evaluate tients with hypertension has led to an in-crease in the diagnosis of renal-artery ste- From the Departments of Nephrology (J.R., A.V., B.S., K.M.K., H.H.), nosis. Patients with stenosis of more than Radiology (A.C., M.G.), and Gastroenterology (J.B., M.J.G.), MedizinischeHochschule Hannover, Hannover, Germany. Address reprint requests to 50 percent of the luminal diameter of a renal artery Dr. Radermacher at the Department of Nephrology, Medizinische Hoch- are usually treated with angioplasty (with or without schule Hannover, P.O. Box 61 01 80, D-30625 Hannover, Germany, or at stenting) or surgery to lower blood pressure or pre- 410 · N Engl J Med, Vol. 344, No. 6 · February 8, 2001 · www.nejm.org
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renal-artery stenosis enables us to identify a reduction in the di- meters per second) and the end-diastolic velocity (V , in centi- ameter of renal arteries of at least 50 percent (i.e., a reduction in meters per second) in order to calculate the dimensionless resist- area of at least 75 percent) with a sensitivity of 97 percent and a ance-index values: resistance index =[1¡(V specificity of 98 percent.13 This method also provides an estima- resistance-index values were the average of two to three measure- tion of the severity of the stenosis that is reproducible (coefficient ments in segmental arteries from the upper, middle, and lower of variation, 4 percent) and precise. The results are closely corre- third of each kidney. The course of the main renal artery was de- lated with those of intravascular ultrasonography (correlation coef- termined with color flow imaging. The intraobserver and inter- observer coefficients of variation for the measurements of the re-sistance index were 2.0 percent for the evaluation of 14 patients Treatment of Renal-Artery Stenosis
and 3.2 percent for the evaluation of 420 patients, respectively;the coefficient of variation was 2.8 percent for the evaluation of Among the 5950 patients who underwent color Doppler ultra- 264 patients by the same observer on consecutive days.
sonography, 138 patients had stenosis of at least 50 percent ofone renal artery (in the case of 91 patients) or both renal arteries Statistical Analysis
(in the case of 47 patients), and these 138 patients subsequentlyunderwent angiography, angioplasty with or without stent place- Statistical software programs (SPSS, version 10.0.5, SPSS, Chica- ment, or surgery to correct these stenoses. Angiography, angioplas- go, and SAS, version 8.0, SAS Institute, Cary, N.C.) were used for ty, and stent placement were performed as described previously.14 all statistical analyses. Unpaired t-tests with Bonferroni’s adjustment The operative techniques usually consisted of the placement of an for multiple tests at different time points or chi-square analysis was aortorenal-vein or synthetic graft or thromboendarterectomy. The used, as appropriate, to assess differences between groups. Odds 138 patients were classified into two groups according to their seg- ratios for the worsening of renal function in association with var- mental-artery resistance-index values: those with values of 80 or ious risk factors were calculated from two-by-two contingency ta- more and those with values of less than 80.12 In a further 16 pa- bles with use of Fisher’s exact test. For multivariate analysis, the tients who met the criteria for renal-artery stenosis, angioplasty was effects of the resistance index; the degree of renal-artery stenosis; not performed but an angiotensin-converting–enzyme inhibitor mean ambulatory 24-hour systolic and diastolic blood pressures; was given because of occlusion of the renal artery (10 patients), pulse pressure; the presence or absence of a nocturnal decrease in stenosis of intrarenal vessels (3 patients), stenosis in a kidney sched- blood pressure (a decrease in blood pressure of more than 10 per- uled to be removed because of a tumor (1 patient), or refusal to cent as compared with the daytime value); creatinine clearance; age; undergo angioplasty (2 patients, both of whom had resistance-in- sex; the size of the kidney with stenosis; peripheral venous renin activity; the presence or absence of atherosclerosis in the heart,legs, or central nervous system; the presence or absence of diabetes Base-Line Studies
mellitus; smoking status; serum uric acid concentrations; the blood-pressure response to treatment with angiotensin-converting– Before renal-artery stenosis was corrected, blood pressure was enzyme inhibitors; the number of years since the onset of hyper- measured with a 24-hour ambulatory blood-pressure monitor tension; and urinary protein excretion were analyzed in all 131 (model 90217, Spacelab, Redmond, Wash.), creatinine clearance patients in whom revascularization was successful. In the stepwise (expressed in milliliters per minute per 1.73 m2, or milliliters per forward logistic-regression analysis, variables with a P value of 0.1 minute) was determined, and 24-hour urinary protein excretion, or more were removed from the analysis and variables with a P val- serum cholesterol concentration, and serum uric acid concentration ue of 0.05 or less were retained. Unless stated otherwise, all data were determined by standard laboratory methods. Plasma renin ac- tivity was measured with the use of a radioimmunoassay for an-giotensin I in which the temperature was 37°C and the pH was 7.4.15 Follow-up Studies
Among the 138 patients with renal-artery steno- sis, the stenosis was corrected in 131. The stenosis was After renal-artery stenosis was corrected, the measurements of blood pressure and creatinine clearance and the ultrasonographic corrected with angioplasty alone in 81 patients, with procedure were repeated at 3, 6, and 12 months and yearly there- angioplasty and stent placement in 42 patients, and after. The end points of the study were the blood pressure and re- with surgery in 8 patients (placement of an aorto- nal function at the time of the last follow-up evaluation, renal status, renal-vein graft in 6, placement of a synthetic graft in and vital status. An improvement in blood pressure was definedas a decrease in the mean arterial pressure of at least 10 mm Hg 1, and thromboendarterectomy in 1). The changes in with no change or a decrease in the number of antihypertensive 24-hour blood pressure and renal function after tech- drugs. We defined diuretics and nitrates as antihypertensive drugs, nically successful correction were therefore determined even though they may have been given for other reasons. An im- in these 131 patients (Table 1). In seven patients an- provement in renal function was defined as an increase in creati- gioplasty was unsuccessful; these patients were consid- nine clearance of at least 10 percent, and worsening was defined asa decrease of at least 10 percent. The need for dialysis and vital ered poor candidates for surgery and were therefore status were ascertained by contact with the patients or their rela- tives. The mean (±SD) duration of follow-up was 32±21 months.
After correction of renal-artery stenosis, the 35 pa- tients with resistance-index values of at least 80 be- Renal Ultrasonography
fore revascularization had decreases in renal function The 5950 patients were scanned in the supine position with an (Fig. 1) and little improvement in blood pressure de- ultrasound machine (Ultramark 9 HDI, Advanced Technology Lab-oratories, Bothell, Wash.) with the use of either a multifrequency spite increased numbers of antihypertensive drugs curved-array transducer (2 to 4 MHz) or a multifrequency sector (Fig. 2), whereas both outcomes improved in the 96 transducer (2 to 3 MHz) with a 2.5-MHz pulsed Doppler frequen- patients with resistance-index values of less than 80.
cy and a focal zone at the depth of the renal arteries. Intrarenal In the latter group, the resistance index had a high Doppler signals were obtained from segmental arteries because a sensitivity (96 percent) but a low specificity (53 per- clear signal can always be obtained from these arteries.16 A clearsignal is needed for the measurement of the resistance index to cent) for predicting an improvement in renal func- be reliable. We determined the peak systolic velocity (V tion (Table 2). When the 78 patients who had im- N Engl J Med, Vol. 344, No. 6 · February 8, 2001 · www.nejm.org · 411
Downloaded from nejm.org on February 6, 2013. For personal use only. No other uses without permission. Copyright 2001 Massachusetts Medical Society. All rights reserved. Th e Ne w E n g l a nd Jo u r n a l o f Me d ic i ne TABLE 1. BASE-LINE CHARACTERISTICS OF 131 PATIENTS IN WHOM RENAL-ARTERY
STENOSIS WAS SUBSEQUENTLY CORRECTED, ACCORDING TO RESISTANCE INDEX
RESISTANCE INDEX
VALUE »80
VALUE <80
CHARACTERISTIC
P VALUE†
History of severe atherosclerosis —no. (%) No. of packs of cigarettes smoked — ¬10¡3‡ 24-Hr ambulatory blood pressure — mm Hg Nocturnal fall in blood pressure — no. (%) Good control of blood pressure with an ACE Size of the kidney with the stenotic renal Difference in size between kidneys — mm *Plus–minus values are means ±SD. To convert the values for serum uric acid to micromoles per liter, multiply by 59.5. To convert the values for serum cholesterol to millimoles per liter, multiply by0.026. Blood for the determination of plasma renin activity was drawn from a peripheral vein after15 minutes of rest with the patient in the supine position.
†P values were calculated with use of an unpaired t-test or the chi-square test.
‡This calculation included current and former smokers.
§A total of 18 patients with a resistance-index value of at least 80 and 36 patients with a resistance- index value of less than 80 were not taking an angiotensin-converting–enzyme (ACE) inhibitor atbase line.
paired renal function before revascularization (defined stenosis or spontaneous stenosis was similar among as a creatinine clearance that was less than 75 per- patients who received a stent and those treated by cent of the age-adjusted normal value17) or the 45 angioplasty alone; this rate averaged about 10 per- patients with a creatinine clearance of less than 40 ml per minute at base line were considered, the overall On univariate analysis a number of factors present accuracy of the resistance index was improved. In the before revascularization were associated with an in- patients with resistance-index values of less than 80 creased likelihood of a decline in renal function (Fig.
before revascularization there was no significant dif- 3 and Table 3). However, a resistance-index value of at ference in the degree of improvement in blood pres- least 80 had the strongest association. On multivari- sure or renal function among the methods used to ate analysis (Table 3), only a resistance-index value correct the renal-artery stenosis, whereas in patients of at least 80 (P<0.001), not smoking (P=0.01), a with resistance-index values of at least 80, renal func- creatinine clearance of less than 40 ml per minute tion deteriorated less after stent placement than after (P=0.01), and male sex (P=0.05) remained inde- angioplasty alone (data not shown). The rate of re- pendently associated with a higher risk of a decline 412 · N Engl J Med, Vol. 344, No. 6 · February 8, 2001 · www.nejm.org
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Day 7 Month 3 Month 6Month 12Month 24Month 36Month 48Month 60 Figure 1. Mean (±SE) Changes in Creatinine Clearance after the Correction of Renal-Artery Stenosis,
According to the Resistance-Index Value before Revascularization.
Asterisks indicate a significant difference (P<0.05) between the two groups with use of an unpairedt-test with Bonferroni’s adjustment.
in renal function after revascularization. Resistance- than 80). In a multivariate analysis, an initial resist- index values of less than 80 (P<0.001) and smoking ance-index value of at least 80 (risk ratio, 19; 95 per- (P=0.02) were associated with the likelihood of an cent confidence interval, 6 to 58) and a creatinine improvement in renal function. Similar findings were clearance of less than 40 ml per minute (risk ratio, 8; obtained in the univariate analysis with respect to the 95 percent confidence interval, 3 to 21) were inde- prediction of an improvement in blood pressure: oth- pendent predictors of the risk of renal failure or death.
er than a resistance-index value of less than 80, the The mean rate of renal failure at two years among best predictor was a urinary protein excretion of less patients with a resistance-index value of at least 80 than 1 g per day (odds ratio, 4.5; 95 percent confi- before revascularization was 50 percent, as compared dence interval, 1.7 to 12). On multivariate analysis, with a rate of 5 percent among patients with a re- only a resistance-index value of less than 80 was sig- sistance-index value of less than 80. The rate of re- nificantly associated with the likelihood of an improve- stenosis or spontaneous stenosis was similar in the two resistance-index groups and averaged about 10 per- Of the 96 patients with a resistance-index value of less than 80 before revascularization who underwent After the correction of renal-artery stenosis, major correction of renal-artery stenosis, 3 (3 percent) died complications occurred in 8 patients (6 percent) and during follow-up and 3 (3 percent) required dialysis minor complications in 10 patients (8 percent). The (all 3 of whom had an initial creatinine clearance of major complications consisted of aortic dissection af- less than 15 ml per minute). In contrast, among the ter angioplasty (one patient; resistance-index value, 35 patients who had a resistance-index value of at 75), myocardial infarction during angioplasty with least 80 before revascularization, 10 (29 percent) died subsequent death (one patient; resistance-index value, during follow-up and 16 (46 percent) became de- 81), renal-artery or intrarenal-vessel occlusion (three pendent on dialysis (P<0.001 for the comparison patients; resistance-index values, 75, 80, and 80), false with the patients with a resistance-index value of less aneurysm requiring operative repair (one patient; re- N Engl J Med, Vol. 344, No. 6 · February 8, 2001 · www.nejm.org · 413
Downloaded from nejm.org on February 6, 2013. For personal use only. No other uses without permission. Copyright 2001 Massachusetts Medical Society. All rights reserved. Th e Ne w E n g l a nd Jo u r n a l o f Me d ic i ne Resistance index <80Resistance index »80 Figure 2. Mean (±SE) Change in Mean Arterial Pressure and the Number of Antihypertensive Drugs Taken after the
Correction of Renal-Artery Stenosis, According to the Resistance-Index Values before Revascularization.
In the group of patients with a resistance index of less than 80 before revascularization, mean (±SD) blood pressurewas 150±22/89±12 mm Hg initially and 135±14/80±10 mm Hg at the last follow-up visit (P<0.001); the respective valuesin the group of patients with a resistance index of at least 80 before revascularization were 164±21/83±16 mm Hg and163±19/86±10 mm Hg (P=0.73). The antihypertensive drugs included angiotensin-converting–enzyme inhibitors, an-giotensin II–receptor blockers, beta-blockers, calcium antagonists, alpha-blockers, direct vasodilators, diuretics, and ni-trates. Asterisks indicate a significant difference (P<0.05) between the two groups with use of an unpaired t-test withBonferroni’s adjustment.
sistance-index value, 89), and dislocation of the stent atinine rather than creatinine clearance, and the pa- into or beyond the aorta (two patients; resistance- tients had relatively normal renal function (mean se- index values, 75 and 80). Minor complications con- rum creatinine concentration, 1.2 mg per deciliter sisted of intimal dissections that were corrected with [106 µmol per liter]) as compared with our patients stent placement (nine patients) and a false aneurysm (mean serum creatinine concentration, 2.1 mg per deciliter [186 µmol per liter]). Finally, far fewer pa-tients were treated by stenting (4 percent, vs. 32 per- DISCUSSION
We found that a renal resistance-index value of at In patients with renal-artery stenosis who are not least 80 before revascularization was a strong predictor treated with angioplasty or surgery, normalization of of worsening renal function and a lack of improve- blood pressure, especially with use of an angiotensin- ment in blood pressure despite the correction of re- converting–enzyme inhibitor or a beta-blocker, is not nal-artery stenosis. Conversely, lower resistance-index an invariable indicator of the preservation of renal values were associated with an improvement in both function.20 On the other hand, angioplasty or surgery renal function and blood pressure after the correction is not without risk, as we found. Thus, the develop- of renal-artery stenosis. These results contrast with ment of methods to identify patients who will ben- those of a recent study of similar patients, in which an- efit from the intervention or, perhaps more impor- gioplasty was not found to be superior to treatment tant, those who would only be harmed by it, should with antihypertensive drugs alone in terms of reduc- ing blood pressure or maintaining renal function.19 Among other noninvasive tests, captopril scintig- However, in that study no effort was made to identify raphy has been reported to be of value in identifying patients according to their likelihood of a response, patients in whom blood pressure is likely to decrease blood pressure was measured during an office visit after successful correction of renal-artery stenosis, with rather than at home over a period of 24 hours, renal a sensitivity of 92 percent (range, 84 to 100 percent) function was assessed by measurements of serum cre- and a specificity of 78 percent (range, 62 to 100 per- 414 · N Engl J Med, Vol. 344, No. 6 · February 8, 2001 · www.nejm.org
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TABLE 2. SENSITIVITY, SPECIFICITY, AND POSITIVE AND NEGATIVE PREDICTIVE VALUE
OF THE RENAL RESISTANCE INDEX AS A MEANS OF IDENTIFYING THE RESPONSE OF RENAL FUNCTION AND BLOOD PRESSURE TO SUCCESSFUL REVASCULARIZATION.* POSITIVE
NEGATIVE
PREDICTIVE
PREDICTIVE
SENSITIVITY
SPECIFICITY
Resistance index <80 before revascu- 96 (68/71) 53 (32/60) clearance below normal before re-vascularization clearance <40 ml/min before re-vascularization Resistance index »80 before revascu- 90 (28/31) 93 (93/100) clearance <40 ml/min before re-vascularization Resistance index <80 before revascu- 99 (90/91) 85 (34/40) *An improvement in renal function was defined as an increase in the creatinine clearance of at least 10 percent, and worsening as a decrease of at least 10 percent. The creatinine clearance was consid-ered to be below normal if it was less than 75 percent of the age-adjusted normal value. The age-adjusted normal value was calculated according to the formula of Keller.17 An improvement in bloodpressure was defined as a decrease in the mean arterial pressure of at least 10 mm Hg with no changeor a decrease in the number of antihypertensive drugs.
Size of kidney with stenotic renal artery <9 cm Lack of blood-pressure control with ACE inhibitor Figure 3. Univariate Odds Ratios for a Worsening of Renal Function after Correction of Renal-Artery Stenosis, with 95 Percent Con-
fidence Intervals, Associated with Various Factors before Revascularization.
The absence of a nocturnal fall in blood pressure was determined from measurements of 24-hour ambulatory blood pressure. Theodds ratio for captopril scintigraphy was calculated from published data.4,18 A “sudden increase in blood pressure” refers to recentworsening of hypertension or recent onset of hypertension. To convert the value for serum uric acid to micromoles per liter, multiplyby 59.5. CAD denotes coronary artery disease, AOD arterial occlusive disease of the legs, CVD cerebrovascular disease, and ACEangiotensin-converting enzyme.
N Engl J Med, Vol. 344, No. 6 · February 8, 2001 · www.nejm.org · 415
Downloaded from nejm.org on February 6, 2013. For personal use only. No other uses without permission. Copyright 2001 Massachusetts Medical Society. All rights reserved. Th e Ne w E n g l a nd Jo u r n a l o f Me d ic i ne TABLE 3. FACTORS ASSOCIATED WITH AN INCREASED RISK OF WORSENING
RENAL FUNCTION OR AN INCREASED LIKELIHOOD OF AN IMPROVEMENT IN RENAL FUNCTION OR BLOOD PRESSURE AFTER THE CORRECTION OF RENAL-ARTERY STENOSIS UNIVARIATE
MULTIVARIATE
ODDS RATIO
ODDS RATIO
(95% CI)†
Likelihood of improvement in renal function Likelihood of improvement in blood pressure *An improvement in renal function was defined as an increase in the creatinine clearance of at least 10 percent, and worsening as a decrease of at least 10 percent in the 78 patients with impaired renalfunction (a glomerular filtration rate that was less than 75 percent of the age-adjusted normal rate17)before correction of renal-artery stenosis. An improvement in blood pressure was defined as a de-crease in the mean arterial pressure of at least 10 mm Hg with no change or a decrease in the numberof antihypertensive drugs. CI denotes confidence interval.
†Stepwise logistic-regression analysis was used. Only findings that remained independent predictors after stepwise forward logistic-regression analysis are listed.
cent).4,5,21-25 However, this approach is less accurate Renal-artery angioplasty is associated with major in patients with renal impairment, patients with bi- complications in about 10 to 15 percent of patients lateral renal-artery stenosis, and patients with unilat- and a death rate of 1 to 5 percent.27-30 Renal-artery eral renal-artery stenosis.4 Furthermore, the value of surgery has complication rates of 8 to 11 percent and captopril scintigraphy as a means of identifying pa- a death rate of 2 to 8 percent.30-32 Our results were tients in whom renal function is likely to improve af- within these ranges. Intervention should therefore be ter the correction of renal-artery stenosis has not been reserved for patients in whom renal function is likely assessed prospectively. The ability to identify such pa- to improve or at least stabilize or in whom blood tients is particularly important, because preservation pressure is likely to decrease. We conclude that pa- of renal function is the main rationale for performing tients with renal resistance-index values of at least 80 angioplasty or corrective surgery in patients with re- should be excluded from these interventions.
nal-artery stenosis and reduced renal function.
The use of various risk factors has been proposed to differentiate between patients who are likely to ben- We are indebted to Dr. Friedrich C. Luft and Dr. Jürgen Wester- efit from the correction of renal-artery stenosis and mann for their help in preparing the manuscript; to Dr. Jürgen those unlikely to benefit. We found that urinary pro- Schaeffer, Markus Hiß, and Dr. Oliver Eberhard for their technical tein excretion of at least 1 g per day, hyperuricemia, assistance with the investigation; and to Dr. Hartmut Hecker, Dr.
Birgit Wiese, and Dr. Hartmut Herrmann for their assistance with creatinine clearance of less than 40 ml per minute, an age of more than 65 years, pulse pressure of at least70 mm Hg, the absence of a nocturnal fall in blood REFERENCES
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