CORRESPONDENCE

SINGLE KIDNEY FUNCTION: EFFECT OF ACUTE PROTEIN AND WATER LOADING ON MICROALBUMINURIA

We read with interest the report of Amore et al (Am J Med 1988; 84: 711-717), since our own studies have also shown that protein load- ing can induce an abnormal renal response in subjects who do not have overt renal disease [1]. The methods used by Amore and col- leagues, however, make interpreta- tion of their data rather difficult. Baseline creatinine clearance was measured by Amore and colleagues over three hours in the nonhydrat- ed state. Shannon [2] has demon- strated that, in both test and base- line studies, measures of creatinine or urea excretion must be made un- der steady urinary flow conditions with a flow rate greater than 60 ml/ hour to minimize error due to in- complete collection (bladder resid- ual). The control group in the study of Amore et al had a urine flow rate of approximately 50 ml/ hour, which may account for the large standard deviation of mea- surement in the baseline creatinine clearance. Under test conditions, significant changes in hemody- namic status may have occurred due to water loading alone. In sub- jects with a single kidney, urine

flow rate (approximately 3,600 ml/ day) appeared to be significantly different from that in the control group, and urine flow also had a lower standard deviation of mea- surement.

Work by Bosch et al [3] and our own group [4] shows a different time course of renal response to oral protein loading. In Amore and co-workers' study, subjects ingest- ed large amounts of protein (150 g) and water (1 liter) over 30 minutes. If clearance periods started at the beginning of ingestion, the post- absorptive phase would be no more than 30 minutes. Dr. Bolin (Uni- versity of South Carolina, Charles- ton, South Carolina, personal com- munication) has shown that in sub- jects given large amounts of red meat (100 g of protein) and large volumes of water (1 liter), creati- nine clearances may decrease for unknown reasons. This may also have occurred in Amore and co- workers' study two to four hours after protein ingestion.

Large amounts of protein ingest- ed in the form of cooked red meat, depending on the manner of prepa- ration, can contain large amounts of exogenous creatinine (converted from creatine), and lead to an in- crease in serum creatinine levels during test conditions [5,6]. It is not clear whether Amore et al mea-

sured serum creatinine during the study, in order to calculate accu- rate increases in creatinine clear- ance. We have followed serum cre- atinine values at 30-minute inter- vals for four hours in subjects ingesting 80 g of protein, and have not observed a significant change in serum creatinine [4] (Figure 1).

Similarly to the findings of Amo- re et al in subjects with a single kidney, we have demonstrated that type I diabetic subjects (without evidence of overt diabetic nephrop- athy or incipient nephropathy) giv- en 80 g of oral protein experienced marked microalbuminuria during peak glomerular filtration rate; a smaller increase followed water loading, consistent with previous studies on water loading and albu- min excretion in diabetic subjects [7]. Since urinary microalbumin excretion decreased in the second of two collections after water load- ing, Amore et al may also have ob- served a washout phenomenon es- pecially in the normal control sub- jects. Therefore, did water loading itself induce microalbuminuria in Amore and colleagues' subjects with a single kidney? If performed under standard conditions, protein loading may be a valid clinical tool to uncover abnormal glomerular function in patients with a variety of renal diseases [8].

Figure 1. Changes in serum creatinine in response to 80-g protein load. WLTD -- wa- ter loading; PRLD -- protein loading.

O) E (P

C =. (3

E

O U)

2

Base WTLD PRLD 30 60 90 120 150 180 240

Minutes after Protein Loading

752 November ]988 The American Journal of Medicine Volume 85

CORRESPONDENCE

ARLENE CHAPMAN, M.D. Georgetown University Hospital

3800 Reservoir Road N.W. Washington, D.C. 20007

ALISON S.M. BOYLE School of Medicine

University of Edinburgh Edinburgh, Scotland

JAMES F. WINCHESTER, M.D., F.R.C.P.

Georgetown University Hospital 3800 Reservoir Road N.W.

Washington, D.C. 20007

1. Chapman AB, Winchester JF, Eastman R, Dawn K, Lynam L: Oral protein loading induces microalbumin- uria in type I diabetics without previous evidence of nephropathy (abstr). Clin Res 1988; 36: 251. 2. Shannon J: Urea excretion in the normal dog dur- ing forced diuresis. Am J Physiol 1938; 122: 782- 787. 3. Bosch JP, Lew S, Glabman S, Lauer A: Renal hemo- dynamic changes in humans: response to protein loading in normal and diseased kidneys. Am J Med 1986; 81: 809-815. 4. Chapman AB, Mulroney S, Winchester JF, Lynam L, Haramati A: Serum atrial natriuretic peptide and urinary cyclic guanosine monophosphate are not in- fluenced by water and protein loading in normal sub- jects (abstr). Clin Res 1988; 36: 28A. 5. Sherman RA: Creatinine in the crock pot. Arch In- tern Med 1981; 141: 543. 6. Jacobsen FK, Christensen CK, Mogensen CE, et al: Pronounced increase in serum creatinine concentra- tion after eating cooked meat. Br Med J 1979; 2: 1049-1050. 7. Viberti GC, Mogensen CE, Keen H, Jacobsen FK, Jarret R J, Christensen CK: Urinary excretion of albu- min in normal man: the effect of water loading. Scand J Clin Lab Invest 1982; 42: 147-151. 8. Chan AYM, Cheng MLL, Keil LC, Myers BD: Func- tional response of healthy and diseased glomeruli to a large protein-rich meal. J Clin Invest 1988; 81: 245- 254.

Submitted June 30, 1988, and accepted August 29, 1988

The Reply: We recently reported that microal- buminuria is detectable in the ma- jority of patients with a single kid- ney and that it can be modulated by different protein intakes [1]. In these patients, mean urinary albu- min excretion--in the microalbu- minuric range--was found to be significantly decreased after one month of a "low-protein" diet (0.6 g/kg/day) and increased signifi- cantly after one month of "high- protein" intake (1.6 g/kg/day).

After acute protein and water loading, patients with a single kid- ney showed an abnormal renal re- sponse with increased urinary al- bumin excretion in the microalbu- minuric range, as we reported (Am J Med 1988; 84: 711-717).

Chapman et al [2] observed a similar phenomenon in type I dia- betic subjects without overt renal disease. Moreover, other authors have recen t ly s t ressed t ha t an acute protein load can be a good

test to uncover abnormal glomeru- lar function in subclinical renal dis- eases [3].

Besides this basic general agree- ment on the phenomenon, Chap- man et al have pointed out in their letter that a few details of our study needed further elucidation.

We found a slight increase in se- rum creatinine--determined each hour for the accurate hourly clear- ance measurement--over the test period of four hours. In control subjects, the mean serum creati- nine level was 0.83 =1:0.11 mg/dl before the test, 1.02 + 0.19 mg/dl at the second hour (p <0.02), and 0.96 =t= 0.16 mg/dl at the fourth hour (p <0.05); in patients with a single kidney, the mean serum creatinine level was 1.05 ± 0.24 mg/dl before the test, 1.28 + 0.33 mg/dl at the second hour (increase not signifi- cant), and 1.23 -~ 0.40 mg/dl at the fourth hour.

We observed a decrease in creati- nine clearance at the fourth hour after protein ingestion in three of eight healthy subjects, and in five of six patients with a single kidney. We interpreted these data as the expression of some unknown mech- anisms of rebound stimulated in response to the h e m o d y n a m i c events following protein and water loading.

The last point discussed in the letter of Chapman et al was wheth- er the water loading alone per- formed without pre-hydration may have played the most important role in increasing the microalbu- minuria in the subjects we investi- gated by the acute protein and wa- ter load test.

We measured baseline creatinine clearance under normo-hydration conditions. After a fasting over- night period, urine collection was performed over three hours in the morning immediately before the loading test. A high urinary flow, as obtained with oral hydration by 20 ml/kg of water [4], is necessary when the creatinine clearance is measured in urine collections over 30-minute periods. It is well known that errors can arise when dealing with low urinary volume because of incomplete bladder voiding. We measured baseline creatinine val- ues over three-hour urine collec- tions. The mean urinary volume was 161 ± 57 ml/three hours in con- trol subjects and 366 + 174 ml/ three hours in patients with a sin- gle kidney, sufficient for a correct

urine collection. Basal creatinine clearance in healthy subjects was not statistically related to the uri- nary flow but was likely to be influ- enced by the spontaneous protein intake. In a healthy subject (BB) with a protein intake of 1.5 g/kg/ day (urinary nitrogen excretion of 1,776 mg/hour) , the c rea t in ine c lea rance was 196 m l / m i n u t e , whereas in another subject (DR), who ingested 1 g/kg/day of protein (urinary nitrogen excretion of 834 mg/hour), the creatinine clearance was 91 ml/minute . The ur inary flow was similar in both healthy subjects.

If the changes in hemodynamic status may have been determined by water loading alone, as suggest- ed by Chapman et al, because of a lack of pre-hydration, an indirect relationship between urinary vol- ume during the baseline three-hour period and urinary albumin excre- tion after the test must have been found, at least in healthy subjects. However, we failed to observe even a tendency to this phenomenon. Moreover, patients with a single kidney who presented with high urinary flows (three times higher than that in control subjects and directed to a single kidney) showed greater peak amounts of urinary al- bumin excretion than control sub- jects.

In our study [1], we analyzed the effects of water loading alone on urinary albumin excretion and on creatinine clearance. The first hour after water loading, we observed a non-significant slight increase in urinary albumin excretion. The in- crease was significantly greater af- ter protein and water loading than after water loading alone. More- over, we reported the lack of corre- lation between beta2 microglobulin and increased urinary albumin ex- cretion the first hour after loading, indicating a lack of significant tu- bular washout phenomenon. These data were very similar to those of Viberti et al [4] after water loading in healthy control subjects.

These findings represent a satis- factory demonstration that the in- creased urinary albumin excretion found in patients with a single kid- ney was mainly due to the protein loading and only further increased by the simultaneous water load.

Common agreement exists on the clinical usefulness of this kind of test for the detection of subclini- cal abnormal glomerular function.

November 1988 The American Journal o~' Medicine Volume 85 75~