Tohoku

J. exp.

Med.,

1967, 91, 323-330

Differential Renal Function Test for the Diagnosis Renovascular Hypertension, with Special Reference to Urinary Potassium/Sodium Ratio Chikara

Suzuki, Takashi Furuyama, Hiroshi Saito and Hiroshi

of

Ryuji Shioji, Ito

Departmentof Internal Medicine (Prof. T. Torikai), Tohoku UniversitySchoolof Medicine,Sendai Differential renal function test was made on thirty-four hypertensive patients without abnormalities of renal arteries and thirteen patients with renovascular hypertension. The diagnostic significance of these studies was evaluated, and new criteria consisting of two indices, tubular rejection fraction ratio (TRFR, Rapoport) and left/right ratio of UK/UNa were presented. In patients without abnormalities of renal arteries both indices of TRFR and left/right ratio of UK/UNa remained close to 1.0. In four of ten patients with unilateral stenosis of renal artery, the values of TRFR overlapped the normal range. In contrast, the left/right ratios of UK/UNa were distinctly deviated from 1.0. In one of three patients with bilateral renal artery stenosis, both indices showed a pattern of the unilateral stenosis, suggesting that the stenosis of renal artery was severer in degree on one side than on the other. It was found that, although TRFR had a fairly good diagnostic value, false negative results could not be completely avoided and that since UK/UNawas higher on the side of stenosis, the left/right ratio of UK/UNawas a helpful para meter for the diagnosis of the unilateral stenosis of renal artery. The diagnostic value of the differential renal function test was found to be more reliable when TRFR and left/right ratio of UK/UNa were simultaneously evaluated.

Hypertension due to the stenosis of renal artery in man is called 'renovascular hypertension' and constitutes the group of the highest incidence among cases of the secondary hypertension which are curable by surgical procedures.1,2 Many tests have been reported for the diagnosis of this disease. Among them the followingtwo are currently used: the differential renal function test and renal arteriography.3.4 The purpose of this report is to evaluate the diagnostic value of differential renal function test into which a new index, urinary potassium/ sodium ratio is introduced by us. MATERIAL AND METHOD

Forty-seven subjects were studied. They were divided into the following groups: Group 1 including 34 hypertensive patients without abnormalities of Received

for

publication,

December

21,

1966.

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renal arteries (essential hypertension); Group 2 including 6 cases with renovas cular hypertension due to stenosis of the right renal artery; Group 3 consisting of 4 cases of renovascular hypertension due to stenosis of the left renal artery; and Group 4, including 3 cases with renovascular hypertension due to bilateral stenosis of the renal arteries. All the patients were examined by routine clinical tests including excretory urograms, 131I renograms and renal arteriographies. In all the patients with renovascular hypertension, stenosis of the renal artery was ascertained by means of renal arteriography and/or surgical operation. Differential renal functions were studied under water diuresis by using ureteral catheterization. Diets of normal sodium content were given to the patients for four to five days prior to the study. Administration of all diuret ics was discontinued. The patients were given 500 ml of tap water orally one hour before the catheterization was performed. When the rate of urine flow became adequate, simultaneous collection of urine specimens from both kidneys was started. Since an excessive leakage of urine around the ureteral catheters could not be prevented in some patients, the urinary volume thus determined was used only for a reference in our study. Urinary sodium, potassium and creatinine were determined with each specimen and expressed in mEq/L for sodium and potassium and in mg/100 ml for creatinine. Urinary sodium and potassium were measured by using a flame photometer. Urinary creatinine was measured by the method of Brod and Sirotas by using a spectrophotometer. The potassium/sodium ratio in the urine (UK/ UNa)was calculated. The difference of UK/UNabetween both sides was expressed in a left/right (L/R) ratio. The diagnostic value of this ratio was compared with that of tubular rejection fraction ratio* of Rapoport6 (TRFR).

UNa: Sodium concentration in the urine (mEq/L) Ucreat: Creatinine concentration in the urine (mg/100 ml) V: Urinary volume (ml/min) PNa: Sodium concentration in the plasma (mEq/L) Pcreat: Creatinine concentration in the plasma (mg/100 ml) Ccreat: Creatinine clearance (ml/min) L: Left, R: Right

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RESULTS

Table 1, Figs. 1 and 2 show TRFR and the L/R ratio of UK/UNain forty sevenpatients subjected to our present study. Urinary volume and concentrations of sodium, potassium and creatinine were not described here, because, as was previously reported, these values had no diagnostic significancewhen they were evaluated without calculation of the L/R ratio.7 TABLE 1.

Results of ureteral catheterization studies

L=left, R=right, TRFR=Tubular rejection fraction ratio UK=Urinary potassium concentration, UNa=Urinary sodium concentration * Mean value was calculated from the logarithms of individual values. Standard deviations calculated on the logarithms of individual values and reduced to the original scale of TRFR and of L/R ratios of UK/UNa in 34 hypertensive patients without stenosis of renal artery were from +0.15 to -0.12, and from +0.10 to -0.08, respectively.

Subjects without abnormalities of the renal arteries

TRFRs were found to be ranging from 0.82 to 1.87 (mean value calculated in logarithm was 1.04). The L/R ratios of UK/UNa ranged from 0.89 to 1.36(mean value was 1.02). Both indicesremained closeto 1.0. In one casein which TRFR showed a relatively high value of 1.87, the L/R ratio of UK/UNawas 0.90. Stenosis of the right renal artery In six patients with stenosis of the right renal artery TRFRs were found to be between 1.08 and 6.45. In three of them TRFRs were distinctly higher than 1.0. But in the remaining three (Cases 3, 5 and 6) the values were close to 1.0. The L/R ratios of UK/UNa in these six cases were distinctly lower than 1.0. In three cases in which TRFRs were close to 1.0, the L/R ratios of UK/UNawere 0.75, 0.58 and 0.67, which were considered to be significantly deviated from 1.0.

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Fig.

1.

Results

of

TRFR

in

•›

-Patients

without

renal

•œ

-Patients

with

right

•£

-Patients

with

left

•¡

-Patients

with

bilateral

et al.

four

groups.

artery renal

renal

stenosis

artery artery renal

stenosis stenosis artery

stenosis

Fig. 2. Results of L/R ratio of UK/UNain four groups . Explanations of symbols are given in the legend for Figure 1.

Differential

These value criteria

results

in some the

cases

TRFR

indicated

that

TRFR

of renovascular values

from

Renal

Function

alone

hypertension,

Test

was

327

not

since

0.60 to 1.60 are regarded

of

definite

according as the

diagnostic

to Rapoport's normal

range.6

Stenosis of the left renal artery

In 4 patients with stenosis of the left renal artery the values of TRFR and L/R ratio of UK/UNawere ranging from 0.22 to 0.61 and from 1.60 to 2.76, respectively. In one of them (Case 8) the diagnosis could not be established by TRFR alone. Bilateral stenosis of renal artery

Cases 11, 12 and 13 belonged to this group. In Case 11, TRFR was 0.44. This value indicated the stenosis of the left renal artery. The L/R ratio of UK/ UNain this case was 9.10. The renal arteriography of this case revealeda bilateral stenosis of renal arteries which was severer on the left side. In Case 12, although TRFR was 2.18 which was considered a significantlyhigh value the L/R ratio of UK/UNa remained close to 1.0. In Case 13,the values of both TRFR and L/R ratio of UK/UNaremained close to 1.0.

Fig. 3. Relation of TRFR and L/R ratio of UK/UNa in four groups. Explana tions of symbols are given in the legend for Figure 1. Note that the solid circles of right renal artery stenosis distribute in the left upper quadrant, and that the solid triangles of left renal artery stenosis, in contrast, in the right lower quadrant.

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In summary, these results indicated that TRFR alone was not of such definite diagnostic significance as asserted by Rapoport in some cases of unilateral stenosis of renal artery, since the results of the test might partly cover the normal range, but that the L/R ratio of UK/UNacould give an information of diagnosticvalue in such cases. Fig. 3 shows the relationshipbetween TRFR and L/R ratio of UK/UNa. In patients with stenosis of the right renal artery, the dots are distributed in the left upper quadrant. In patients with stenosis of the left renal artery, in contrast, the dots are distributed in the right lower quadrant. This finding suggests that the L/R ratio of UK/UNais as much useful as TRFR in diagnosis of unilateral stenosisof the renal artery. COMMENT

Since 1957, when Howard and his associates8reported the differentialrenal function test, it has been well recognized that this test is a valuable procedure for detecting correctable hypertension due to obstructive diseases of the renal artery. The basic concepts of the clinical utility of this test were based on an earlier experimental work of Muelleret al.9 They constricted partially one renal artery of the dog and noted that a correspondingreduction in glomerularfiltration rate on the constricted side was associated with a more striking decrease in urinary flow and sodium concentration. A positive result in the original Howard test is defined as a reduction in urinary volume of 50 per cent or more and a reduction in sodium concentrationof 15 per cent or more in urine from the kidney with the stenosed renal artery. However, several conflicting results have been obtained by this procedure. First , although reduction of urinary volume on one side is a useful parameter for detecting an ischemic kidney, the urinary volume determined may frequently be inaccurate because of urinary leakage around the catheter. Secondly, some investigators reported the cases in which sodium concentrationin urine was higheron the stenosed side.10,11This finding indicated that the criteria of Howard were not necessarilyof absolute validity. Thirdly, some investigators preferred to perform this test under osmotic diuresis, by using intravenous loading of osmotically active solutionswith the purpose of increasing urinary volume and to avoid the errors in the collection of urine.12,13Howard, however, criticized these procedures, because osmotic diuresis might diminish the difference between normal and stenosed sides.15 Concerningthe first and the second problems,many modifiedtests have been proposed.10-14Rapoport6 regarded increased reabsorption of sodium and water in the tubules as a functional characteristic of the ischemic kidney, and he con sidered that this must be reflected in the decrease of tubular rejection fraction of sodium (TRF-Na). He definedthe left/right ratio of TRF-Na as tubular rejec tion fraction ratio (TRFR) and advocated it as a valuable index for the diagnosis of unilateral stenosisof renal artery , becauseit is not influencedby urinary volume.

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According to his report, TRFR remained between 0.60 and 1.60 in subjects whose renal arteries were normal. In patients with stenosis of the right renal artery, TRFRs were higher than 2.33. In patients with stenosis of the left renal artery, in contrast, TRFRs were below 0.52. In our series of observations, the results obtained from four of ten patients whose renal arteries were unilater ally stenosed did not fully accord with Rapoport's criteria. The results indicated that although TRFR was a usefuldiagnostic index, even the criteria of Rapoport were not necessarilyof absolute validity. There has been no report presenting the potassium/sodium ratio in the urine as a diagnosticparameter for the stenosisof renal artery. Our results showed that the potassium/sodiumratio was distinctly higher in the urine obtained from the stenosed side than in that from the non-stenosedside. For the purpose of simplification,the left/right ratio was presented. If this index remains close to 1.0, the potassium/sodium ratio in the urine on both sides was almost equal. The left/right ratio higher than 1.0 shows that the potassium/sodiumratio in the urine is higher in the left kidney, and the ratio lower than 1.0 the reverse. In our observations, the left/right ratio of potassium/sodiumin the urine remained close to 1.0 in subjects with normal renal arteries. In contrast, in patients with stenosisof the right renal artery, this index had values lowerthan 1.0, and in those with stenosisof the left renal artery the values were higher than 1.0. It must be noticed that evenin casesin which TRFRs werewithin the normal range the left/right ratio of potassium/sodiumin the urine deviated from 1.0. These results indicate that if two indices, TRFR and left/right ratio of potassium/ sodium in the urine, are employedtogether, the diagnostic value of differential renal function test will be greater than with TRFR alone. The mechanism whereby the potassium/sodiumratio in the urine is higher on the stenosed side is considered as follows: When a renal artery is partially constricted, the glomerular filtration rate is reduced, resulting in a decrease in the speed of intratubular flow. This results in a prolongation of 'contact time' in sodium reabsorption in the proximal tubule. In the course of this process,reab sorption of sodium and water is increased, and tubular rejection fraction of sodium is decreased.'s In the distal system also, the quantity of intratubular flow is reduced for the reason mentioned above and 'contact time' between fluid and tubular wall may be prolonged.17 This process may promote the sodium potassium exchangewith resultant rise of the potassium/sodiumratio in the urine. Thus the functional characteristics of 'ischemickidney' consist in a decrease in tubular rejection fraction of sodium and an increase in the potassium/sodium ratio in the urine. The most important requisite for the diagnosis of unilateral stenosisof renal artery by using differentialrenal function test is the detection of the unique functional pattern of the involved kidney, namely, a decrease in tubular rejection fraction of sodium and a rise in the potassium/sodiumratio in the urine, and therefore the combination of two indices, TRFR (Rapoport) and

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the left/right ratio of potassium/sodium in the urine, is considered to meet satisfactorily the requirement for the diagnosis of renovascular hypertension. References

1) Winter, C.C. Correctable Renal Hypertension. Lea & Febiger, Philadelphia, 1964. 2) Hocken, A.G. Renovascular hypertension. Arch. intern. Med., 1966, 117, 364-372. 3) Poutasse, E.F. & Dustan H.P. Arterioslcerosis and renal hypertension: Indication for aortography in hypertensive patients and result of surgical treatment of obstructive lesions of renal artery. J. Amer. med. Ass., 1957, 165, 1521-1525. 4) Meaney, T.F. & Dustan, H.P. Selective renal arteriography in the diagnosis of renal hypertension. Circulation, 1963, 28, 1035-1041. 5) Brod, J. & Sirota, J. H. The renal clearance of endogenous "creatinine" in man. J. clin. Invest., 1948, 27, 645-654. 6) Rapoport, A. Modification of the "Howard test" for the detection of renal artery obstruction. New Engl. J. Med., 1960, 263, 1159-1165. 7) Suzuki, C. Clinical and experimental studies on the separated renal function test with reference to the diagnosis of renovascular hypertension. Jap. J. Nephrol. (Jap. with Engl. abst.), 1964, 7, 373-388. 8) Connor, T.B., Berthrong, M., Thomas, W.C. JR. & Howard, J.E. Hypertension due to unilateral renal disease-with a report on a functional test helpful in diagnosis. Bull. Johns Hopk. Hosp., 1957, 100, 241-276. 9) Mueller, C.B., Surtshin, A., Carlin, M.R. & White, H.L. Glomerular and tubular influences on sodium and water excretion. Amer. J. Physiol., 1951, 165, 411-422. 10) Brown, J.J. Diagnosis and treatment of renal artery stenosis. Brit. med. J., 1960, 2, 327-338. 11) Birchall, R., Batson, H.M. & More, C.B. Hypertension due to unilateral renal arterial obstruction: preliminary observation on the contribution of differential renal clearance studies. Amer. Heart J., 1958, 56, 616-628. 12) Page, I.H., Dustan, H.P. & Poutasse, E.F. Mechanisms, diagnosis and treatment of hypertension of renal vascular origin. Ann. intern. Med., 1959, 51, 196-211. 13) Schlegel, J.U., Savlov, E.D. & Gabor, F. Some studies in renal hypertension. J. Urol., 1959, 81, 581-595. 14) Stamey, T.A., Nedelman, I.J., Good, P.H., Schwentker, F.N. & Hendricks, F. Functional characteristics of renovascular hypertension. Medicine, 1951, 40, 347 394. 15) Howard, J.E. & Connor, T.B. Hypertension produced by unilateral renal disease. Arch. intern. Med., 1962, 109, 62-71. 16) Selkurt, E.E. Effect of pulse pressure and mean arterial pressure modification on renal hemodynamics and electrolyte and water excretion. Circulation, 1951, 4, 541 551. 17) Pitts, R.F. Physiology of the Kidney and Body Fluids . Year Book Medical Publi shers, Chicago, 1964, p. 104.