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TRANSLATIONAL PHYSIOLOGY
Indiana University School of Medicine and Richard L. Roudebush VA Medical Center, Indianapolis, Indiana
Submitted 19 April 2007 ; accepted in final form 11 June 2007
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ABSTRACT |
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chronic kidney disease; circadian variation; proteinuria; ambulatory blood pressure
Patients with chronic kidney disease (CKD) have a high prevalence of nondipping, that is, the lack of fall of blood pressure during sleep (9). In a large cross-sectional analyses of patients with CKD, nocturnal dipping was associated with higher estimated GFR, higher serum albumin, younger age, and lesser proteinuria (4). In longitudinal studies, increase in blood pressure is strongly associated with increase in proteinuria (7). However, it is not known how circadian changes in blood pressure relate to circadian changes in proteinuria. The purpose of this study was to describe the pattern of circadian variation in urinary protein excretion in hypertensive patients with CKD and examine its relationship with circadian variation in blood pressure. Whether circadian pattern in variation of blood pressure is related to circadian changes in urine sodium excretion rate was also analyzed.
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METHODS |
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Nondialysis-dependent CKD patients between the ages of 18 and 80 years with proteinuria of 
1 g/day and/or GFR <60 ml·min–1·1.73 m–2 were the subjects of the study. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers were required to be kept at a constant dose for at least 3 mo before entry. All patients had baseline measurements of GFR. Then they were asked to collect a 24-h urine specimen in two urine jugs, one until bedtime on the first experimental day and the other overnight as outpatients. Urine was analyzed for protein, creatinine, sodium, potassium, chloride, and urea. Ambulatory blood pressures were recorded simultaneously in all patients by the Spacelabs 90207 monitor as detailed below. The entire study was repeated after 1 mo in a subgroup of 15 patients without changing blood pressure therapy, diet, or drugs. In these 15 patients, plasma renin and aldosterone were also measured after 30 min of supine rest. The study was approved by the Institutional Review Board, and all patients gave written, informed consent.
Measurements
Ambulatory blood pressure monitoring. Ambulatory blood pressures were recorded every 20 min during the day (6:00 AM to 10:00 PM) and every 30 min during the night (10:00 PM to 6:00 AM) by the Spacelab 90207 ABP monitor (SpaceLabs Medical, Redmond, WA). The accuracy of ambulatory blood pressure was determined by auscultatory methods using a T-piece connected to a mercury sphygmomanometer. Data were analyzed by ABP Report Management System software, version 1.03.05 (SpaceLabs Medical). Ambulatory blood pressure and heart rates were averaged by the caliper function of the software over the exact interval during which the urine collections were made. These readings were designated as day and night recordings for the purposes of these analyses.
GFR. GFRs were measured by iothalamate clearance as previously described (2). A continuous subcutaneous infusion at a rate of 125 µl/h was started after a bolus intravenous injection 24 h before the actual measurements. The following day, six samples of plasma were collected at 0, 1, 1.5, 2, 2.5, and 3.0 h while the subjects were water loaded. Plasma iothalamate concentrations were analyzed with the use of a previously reported high-performance liquid chromatography technique (1). The ratio of infusion rate to steady-state plasma concentration yielded the iothalamate clearance. Average of these six collections was expressed as the GFR.
Plasma renin activity and plasma aldosterone. Plasma renin activity was measured with a Clinical Assays GammaCoat radioimmunoassay kit (Baxter Healthcare). Plasma aldosterone concentration was measured by radioimmunoassay with antiserum from Diagnostic Products (Los Angeles, CA).
Laboratory analysis. Urine protein, electrolytes, urea, and creatinine were measured by our hospital laboratory using routine methods.
Statistical Analysis
Hourly protein excretion rates (mg/h) were calculated separately for day and night intervals. These values were loge transformed to approximate a normal distribution. We tested the mean level of proteinuria across participants after accounting for correlated observation for subjects by fitting a mixed straight line model using the full-maximum-likelihood approach. A mixed model is necessary over ordinary least-squares regression to allow for correlated observations within individuals. Next, the effect of average systolic blood pressure during the day and during the night was modeled, and the intercept and slope of this model were calculated. Similar analyses were performed for diastolic, mean arterial pressure, and pulse pressure. Model comparisons were made by testing the –2 log-likelihood statistics by a chi-squared test (10). This was a pilot study, and no sample size was calculated a priori. All tests were two sided at an 
-level of 0.05. Statistical analyses were carried out by standard procedures using SPSS software (version 14; SPSS, Chicago, IL).
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RESULTS |
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30–40% higher at night. The parallel changes in protein and creatinine excretion rates resulted in an unchanged protein-to-creatinine ratio from day to night.
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DISCUSSION |
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Circadian Renal Rhythms in Normal Subjects
In normal subjects (8, 12), GFR is highest during the day and lowest during the night. However, the tubular secretion of creatinine has a rhythm that is opposite to that of GFR (12). In normal subjects, urinary electrolyte excretion during the night is decreased (8). Thus urine sodium excretion rate falls from 19 ± 5.2 to 6.0 ± 2.9 mmol/h and urine potassium excretion rate from 5.4 ± 1.8 to 0.79 ± 0.32 mmol/h at night. Urine flow rate falls from 211 to 60 ml/h at night following the GFR rhythm. The magnitude of changes in the urinary electrolytes is much larger than the GFR rhythms. Urine albumin and 
-2 microglobulin excretion rates in normal individuals follow the GFR rhythm. The fractional reabsorption of sodium and water are maximal at night. It follows that circadian changes in hemodynamics and tubular function are responsible for the normal pattern of excretion in urinary electrolytes, water, creatinine, and protein. Thus tubular function is maximized during the night for reabsorption of electrolytes.
Circadian Renal Rhythms in Patients with CKD
Handling of electrolytes and protein by the diseased nephron may change with progression of CKD. For example, in 20 patients with early type 1 diabetic nephropathy with persistent albuminuria and daytime GFR of 82 ml/min, Hansen et al. (6) found no change in albuminuria from day to night, but diurnal variations in GFR were present. Electrolyte excretions were not reported. In 26 Japanese patients with various nondiabetic glomerulopathies and mean serum creatinine of 1.1 mg/dl, night-time excretion of sodium and protein was lower than that shown at daytime (5). However, the night-to-day ratio of urinary sodium excretion in those with lower creatinine clearance (16–62 ml/min) was more than twice that seen in the higher creatinine clearance group (106–151 ml/min). Night-to-day ratio of protein excretion was also higher in those with lower kidney function. Thus the patterns of electrolyte excretion and protein excretion may change with advancing kidney disease.
Few data exist for patients with more advanced kidney disease. Our data extend the above findings to a group of patients with more severe kidney disease, where reversal of diurnal rhythms was noted. Thus the nocturnal excretion of urine electrolytes, creatinine, urea, and protein exceeded that during the day. Importantly, protein excretion was related to pulse pressure in a log-linear way regardless of the time of the day. Daytime protein excretion was related to systolic and mean arterial pressures. Night-time protein excretion was not related to systolic and mean arterial pressure. Furthermore, the relationship between proteinuria and blood pressure was not shared by blood pressure and sodium excretion.
Some investigators have proposed that the rise in nocturnal blood pressure elevation with progressive loss of kidney function leads to natriuresis and proteinuria (5, 11). Our results do not support this notion. Systolic, diastolic, and mean arterial pressures were similar during the day and night. There was no relationship between the nocturnal systolic, diastolic, and mean blood pressures and proteinuria. Furthermore, we found no relationship between the night-to-day ratio of systolic or diastolic ambulatory blood pressures and the night-to-day ratio of any of the electrolyte, protein, creatinine, or urea excretion rates seen in this study. What could be the reason underlying the lack of relationship between blood pressure at night and proteinuria?
Nocturia, thought to be mediated by the loss of concentrating ability of the kidney, is an early feature of CKD. A generalized disturbance of tubular function may exist early in CKD. Renin-angiotensin-aldosterone system, the sympathetic nervous system, and vasopressin modulate sodium and water reabsorption in the kidney. These systems undergo a diurnal variation. Diurnal variability may be impaired in CKD. Our patients either had overt proteinuria or low GFR, indicating the presence of CKD. CKD may simultaneously be associated with the loss of normal circadian rhythms of electrolyte excretions as well as loss of nocturnal dipping. The steeper relationship of blood pressure and proteinuria during the day may be related to activity-induced changes in blood pressure and protein excretion rate. Orthostatic proteinuria may then form an important component of proteinuria in patients with CKD.
Limitations
There are some limitations to the study design. We had a small number of patients, and we had no normal controls. Thus we can only compare our data to those published in the literature for normal controls. Although we measured GFR in all patients, we could measure this only during the day for logistical reasons. Thus we cannot comment on the diurnal changes in GFR in the population of patients with more advanced kidney disease. The dietary sodium intake and water intake of our subjects was not controlled, and urine was collected as outpatients. These factors may influence the conclusions if the study is repeated in a controlled environment and fixed dietary intake. The antihypertensive drug therapy may have influenced circadian rhythms. However, in CKD patients with hypertension, it may be unethical to withdraw antihypertensive therapy for a significant length of time before making these measurements. Nonetheless, our data gathered in free-living CKD patients point out the inverted circadian rhythms of renal electrolyte and protein excretion rates.
Clinical Implications
This study demonstrates that, unlike normal healthy volunteers, patients with proteinuric kidney diseases taking a self-selected diet have an inverted rhythm of urinary electrolyte, creatinine, urea, and protein excretions. This inversion of rhythm is not related to the diurnal variation in blood pressure. There are several clinical research implications of these findings. Proteinuria can have a damaging effect on the renal tubules, and reduction in proteinuria may reduce tubular damage or alternatively signal tubular repair. The relationship of pulse pressure and proteinuria was not confounded by circadian rhythms. If pulse pressure and proteinuria are causally related, then measures directed to reduce pulse pressure such as through diuretics or ACE inhibitors may improve proteinuria regardless of the time of the day. On the other hand, reduction of mean arterial pressure during the day may be more useful in reducing proteinuria due to its steeper relationship with protein excretion rate during the day. It is also possible that these altered rhythms, like nondipping, may have prognostic significance. However, altering these rhythms with diet or drugs to demonstrate linkage with outcomes would require clinical trials.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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, Observed data points during the day; 
, observed data points during the night. Because the data were obtained on 2 occasions in 15 patients, least-squares regression was not performed. The observed data points are simply shown for descriptive purposes.