RENAL FUNCTION CHANGES AFTER ELECTIVE CARDIAC SURGERY WITH CARDIOPULMONARY BYPASS

Abstract

Cardiac surgery can either induce acute renal failure or improve GFR by improving the cardiac performance. In order to study renal function changes after elective cardiac surgery (CS) with cardiopulmonary bypass (CPBP), 21 patients undergoing valvular CS (VCS) or coronary artery bypass (CAB) were prospectively evaluated in three time periods: before, 24 hours after surgery and 48 hours after surgery. Patients were divided in 2 groups according to the GFR percent change in comparison to the baseline value found 24 hours after CS (ΔGFR₂₄): Group 1, ΔGFR₂₄ decrease higher than 20% (n = 11) and Group 2, ΔGFR₂₄ decrease ≤ 20% or ΔGFR₂₄ increase (n = 10). In Group 1, 73% of the patients underwent VCS (p = 0.05 vs. Group 2) and all of them had previous VCS in sharp contrast with Group 2, where none of the patients had previous CS (p = 0.006). Patients in Group 1 required more volume replacement than Group 2 during the first 24 hours after CS: 2,699 ± 704 mL versus 217 ± 603 mL respectively, p = 0.019. Despite similar baseline GFR, Group 1 presented lower GFR 24 hours after CS when compared to Group 2 (39 ± 5 versus 75 ± 8 mL/(min × 1.73 m₂), p = 0.001) and a significantly different ΔGFR 48 hours after CS as compared to Group 2 (−21 ± 11 versus +88 ± 36%, p < 0.01). Baseline sodium fractional excretion (FE_Na) in Group 1 was lower than in Group 2 (0.27 ± 0.04 versus 0.70 ± 0.12%, p = 0.01). No changes were observed after CS in urinary osmolality (U_osm) and urinary pH (U_pH) in both groups. The ΔGFR₂₄ showed positive correlation with baseline FE_Na (r = 0.44 p = 0.04) and negative correlation with volume balance during the first 24h after CS (r = −0.63, p = 0.007). More patients in Group 1 required nitroprusside than in Group 2 (66% vs. 14%, p = 0.04). Anesthesia time was shorter in Group 1 as compared to Group 2: 323 ± 21 vs. 395 ± 26 min, p = 0.04. No significant hemolysis occurred during CS in either group. There were no differences in age, gender, CPBP time, need for dopamine and/or dobutamine between the two groups.

In conclusion, patients who presented GFR decrease after CS underwent VCS more frequently, had more prevalence of previous CS, presented lower baseline FE_Na, required more volume infusion and more nitroprusside use. On the other hand, no tubular dysfunction was detected in the early follow-up of CS. These results suggest that the observed renal function changes should be the result of an appropriated renal response to a low effective blood volume. In fact, a low baseline FE_Na anticipated a GFR decrease in these patients. Consistently, CAB patients that usually improve their cardiac output after surgery showed a clear GFR improvement.

• Renal function
• Glomerular filtration rate
• Tubular renal function
• Cardiac surgery
• Cardiopulmonary bypass

INTRODUCTION

In the 90's, the reported incidence of acute renal failure (ARF) after cardiac surgery (CS) ranged widely from 0.7% to 15% (1,2,3,4). In a recent prospective study (5) the risk for developing ARF requiring dialysis after CS was 1.1% with mortality rate of 63.7%, strikingly higher when compared to the mortality rate of 4.3% among the patients without ARF. In our university tertiary hospital a survey of cardiovascular surgery performed for 3 months showed that 365 surgeries (coronary artery bypass, valvular cardiac surgery and aortic aneurism) were carried out: 7.3% of the patients developed ARF requiring dialysis with a mortality rate of 85% (Abdulkader RC, unpublished data). In other paper Chertow et al. [[6]] showed that the presence of ARF increased 7.9 times the risk for death after CS, even after all the adjustment for comorbidity and postoperative complications.

However, there are few recent studies assessing the mechanisms of renal changes after elective CS with cardiopulmonary bypass (CPBP), an issue clearly necessary in order to prevent CS-induced ARF. Mazzarella et al. [[7]] studying patients with normal glomerular filtration rate (GFR) before CS whose did not develop ARF afterwards, showed that GFR was not different from the baseline in the 9th postoperative day. Nevertheless, GFR response to protein infusion was impaired, indicating there was renal functional reserve loss. A recent study [[8]] of 40 patients with risk factors for ARF who underwent coronary artery bypass (CAB), showed that even though there was no increase in postoperative serum creatinine, an important increase in urinary excretion of retinol binding protein was found in the early postoperative period, indicating that a tubular injury occurred. Conversely, CS may improve cardiac function and, as a consequence, GFR may also improve.

Thus, this prospective study was designed in order to identify some of the possible mechanisms related to GFR and tubular function changes after elective CS.

PATIENTS AND METHODS

From November 1994 to April 1997, 21 patients (11 men and 10 women), undergoing elective CS with CPBP, aged 49 ± 3 years were studied. Inclusion criteria were: age > 15 years, no complains of micturition, baseline P_creat ± 2 mg/dL, no insulin-dependent diabetes mellitus, no myocardial infarction within 6 months before the study. Ten patients underwent coronary artery bypass (CAB) and 11 patients valvular CS (VCS) and 6 patients of this last group had undergone previous CS. All patients undergoing CAB were hypertensive and two were diabetic. The protocol was approved by the Ethics Committee, and all patients gave post-informed consent.

Protocol: All patients were studied throughout their hospitalization in two phases: Phase 0: before the CS and Phase 1: 10 to 25 hours after CS. Sixteen patients were also studied in a third phase, Phase 2, 31 to 45 hours after the CS. In Phase 0 all patients were on low sodium diet. Mass index was calculated by the usual formula (Kg/m₂) in all patients in Phase 0. In the 3 phases, systolic and diastolic arterial blood pressure, (BP_s and BP_d, mmHg), and pulse (P, beats/minute) were measured. GFR was evaluated by two-hour creatinine clearance. The fractional excretion of sodium and potassium (FE_Na and FE_K), urinary osmolality (U_osm) and pH (U_pH) were assessed. The GFR percent change in Phase 1 and 2 relative to Phase 0 was calculated (ΔGFR₂₄ and ΔGFR₄₈, %). The urinary volume (V, mL/min) was measured for 2 hours, by spontaneous micturition, in Phase 0 and by bladder catheterization in Phases 1 and 2. No patient received diuretics within 12 hours before any phase. In Phase 1 haptoglobin, serum hemoglobin and fraction 1 of lactic dehydrogenase (LDH₁) were measured in order to evaluate hemolysis. Arterial pH, bicarbonate and base excess were registered only in Phase 1. Anesthesia time, (Δt _anesth, minutes), CPBP time (Δt _CPBP, minutes), the mean of all mean arterial blood pressure measurements performed during CS (MBP_m, mmHg) and the CS nadir temperature (T_min, °C) were recorded. The need for vasoactives drugs, sodium nitroprusside (SNP), dobutamine (DB) or dopamine (DP), from the end of CS to Phase 1 and from Phase1 to Phase2 was also registered.

Patients were divided in 2 groups according the GFR percent change in comparison to the baseline value found 24 hours after CS (ΔGFR₂₄): Group1, ΔGFR₂₄ decrease higher than 20% (n = 11) and Group 2, ΔGFR₂₄ decrease ≤ 20% or ΔGFR₂₄ increase (n = 10).

Statistical analysis: The following tests were used as appropriated: Student's “t” test or Mann-Whitney test for quantitative variables, Fischer or χ₂ for qualitative variables and Spearman correlation to verify association between two variables. The adopted significant level was ≤ 0.05. Data are presented as mean ± SE.

RESULTS

General Data

There was no difference between the 2 groups regarding age (53 ± 5 in Group 1 vs. 45 ± 5 years in Group 2, p = 0.219), gender (46% males in Group 1 vs. 70% in Group 2, p = 0.188) or mass index (25 ± 1 in Group 1 vs. 26 ± 2 kg/m₂ in Group 2, p = 0.397).

Surgery Type

The 2 groups were different regarding the surgery type: 73% of Group 1 undergone VCS while only 30% of Group 2 (p = 0.050). All the six patients with previous CS were in Group 1 (p = 0.006) and all underwent VCS.

Surgery Data

Studying all patients together the registers of CS showed: Δt _anesth: 360 ± 77 minutes, Δt_CPBP: 91 ± 37 minutes, MBP_m: 63 ± 5 mmHg, T_min: 29 ± 3 °C.

The Δt _anesth was shorter in Group 1 than in Group 2: 323 ± 21 and 395 ± 26 minutes respectively, p = 0.042. No difference was found between the 2 groups in the other CS parameters.

Vasoactive Drugs Use and Volume Balance

From CS to Phase 1, 76% of the patients needed SNP, 62% DB and 48% DP. During the period between Phase 1 and Phase 2, the need for vasoactive drugs decreased: 41% of the patients needed SNP, 59% DB and 6% DP. The need for each drug was not different between the 2 groups in the period from CS to Phase 1, but in the period between Phase 1 and 2, 66% of Group 1 required SNP while only 14% of Group 2 patients needed it (p = 0.060).

During the period from CS to Phase 1, volume balance was +1531 ± 550 mL and between the Phase 1 and Phase 2, −471 ± 270 m/L. The volume balance from CS to Phase 1 was higher in Group 1 than in Group 2: respectively, 2699 ± 704 and 217 ± 603 mL, p = 0.018. No other differences were found.

Hemolysis Evaluation

Blood hemoglobin decreased significantly from Phase 0 to Phase 1: 14.3 ± 0.2 vs. 11.4 ± 0.3 g/L, p < 0.001) as well as the hematocrit (43 ± 1 vs 34 ± 1%, p < 0.001). Haptoglobin levels were bellow the normal range in 14 of the patients (66%): 9 of Group 1 (82%) and 5 of Group 2 (50%) with no statistical difference between the groups (p = 0.183). Serum hemoglobin was above the normal range in 3 patients (14%), one of Group 1 and 2 of Group 2. No patient showed serum hemoglobin higher than 21 mg/dL. LDH₁ values above the normal range were found in 14 patients (67%): 7 of each group.

Hemodynamic Data

These data are presented in table 1. In Phase 1 there was a clear BP_d decrease (p = 0.002) and the BP_s showed a trend to decrease (p = 0.064). Pulse rate increased either in Phase 1 (p = 0.010) as in Phase 2 (p = 0.001). No hemodynamic differences between the 2 groups were found in either phase.

Table 1. Hemodynamic data in Phases 0, 1 and 2

	Phase 0	Phase 1	Phase 2
BPs (mm Hg)	115 ± 5	125 ± 5	125 ± 4
BPd (mmHg)	73 ± 2	65 ± 2^*	73 ± 2
P (beats/min)	66 ± 2	105 ± 4^*	89 ± 4^*

BP_s and BP_d: respectively, systolic and diastolic blood pressure. P: pulse.

^* p < 0.05 versus phase 0.

Renal Function Data

Urinary volume increased in Phase 1 as compared to phase 0: 1.28 ± 0.22 vs. 0.69 ± 0.10 mL/min, p = 0.014. In Phase 2, V was also higher (1.25 ± 0.30 mL/min) than in phase 0 but this difference did not reach statistical significance (p = 0.104). No differences between the 2 groups were found in V in any of the studied phase.

Taking all patients together GFR did not change in Phase 1 (56 ± 6 mL/(minx1.73m₂), p = 0.785) or Phase 2 (58 ± 8 mL/(minx1.73m₂), p = 0.808) as compared to phase 0 (57 ± 5 mL/(minx1.73m₂)). For all the patients ΔGFR₂₄ and ΔGFR₄₈were respectively +6 ± 14% and −20 ± 20%. However, when Group 1 and Group 2 were compared, there were statistically significant differences. Group 1 showed lower GFR in Phase 1 as compared to phase 0 (p = 0.015) or to Phase 1 of Group 2 (p = 0.001). ΔGFR₂₄ and ΔGFR₄₈ were negative in Group 1 while positive in Group 2 (p ± 0.01 for both). The values of GFR, ΔGFR₂₄and ΔGFR₄₈for Group 1 and Group 2 are presented in table 2.

Table 2. Glomerular filtration rate in Phases 0, 1 and 2 and changes in glomerular filtration rate in Phase 1 and Phase 2 relative to Phase 0 in Group 1 and Group 2

		Phase 0	Phase 1	Phase 2
GFR	Group 1	62 ± 7	39 ± 52-3^*,#	47 ± 9
(mL/(min × 1.73 m2))	Group 2	52 ± 6	75 ± 8	73 ± 12
ΔGFR	Group 1		−39 ± 4^*	21 ± 11^*
(%)	Group 2		+55 ± 20	+88 ± 36

GFR: glomerular filtration rate. ΔGFR: change in glomerular filtration rate in Phase 1 and 2 relative to phase 0, %.

^* p < 0.01 versus Group 2

^# p < 0.05 versus Phase 0.

Considering the patients as a whole, arterial pH, bicarbonate and base excess were respectively 7.38 ± 0.03, 22.6 ± 3.3 mEq/L and 1.8 ± 3.1 mEq/L in Phase 1. These data show that the patients did not present significant acid-base alterations. No differences in these parameters were found between the 2 groups.

Tubular function data are summarized in table 3. No significant changes were found regarding U_osmand U_pH either in Phase 1 or Phase 2 when all the 21 patients were studied together. FE_Na increased significantly in Phase 1 relative to phase 0 (p = 0.005) with a trend to remain increased in Phase 2 (p = 0.064). FE_K also increased in Phase 1 (p < 0.001) but not in Phase 2 (p = 0.144). When the tubular function of the 2 groups was compared it was found that the FE_Na was lower in Group 1 than in Group 2 in phase 0: 0.27 ± 0.04 versus 0.70 ± 0.12 %, p = 0.010 and that the U_osm in Phase 2 had a trend to be lower in Group 1: 492 ± 73 versus 683 ± 51 mOsm/kg, p = 0.063. A positive correlation between FE_Na and FE_K (r = 0.69, p < 0.001) was found in Phase 1 but not in Phase 2 (r = 0.46, p = 0.07). In Phase 1 there was a positive correlation between pH and U_pH (r = 0.46, p = 0.04) and between U_pHand GFR (r = 0.44, p = 0.04). In Phase 1 and Phase 2 there was significant negative correlation between U_osm and respective FE_Na (Phase 1: r = −0.47, p = 0.03 and Phase 2: r = −0.54, p = 0.03).

Table 3. Tubular function in Phases 0, 1 and 2

	Phase 0	Phase 1	Phase 2
Uosm	647 ± 52	632 ± 35	575 ± 51
UpH	5.7 ± 0.2	5.6 ± 0.2	6.1 ± 0.2
FENa	0.47 ± 0.08	1.67 ± 0.32^*	2.33 ± 1.19
FEK	16 ± 2	43 ± 5^*	29 ± 6

U_osm: urinary osmolality, mOsm/kg. U_pH: urinary pH. FE_Na and FE_K: fractional excretion of sodium and potassium, respectively, %.

^* p < 0.05 versus Phase 0.

A significant positive correlation was found between ΔGFR₂₄ and FE_Na in phase 0: r = 0.44, p = 0.04 and between ΔGFR₄₈and FE_Na in phase 0: r = 0.71, p = 0.003. A negative correlation was found between ΔGFR₂₄ and volume balance from CS to Phase 1: r = −0.63, p = 0.007. There was no statistically significant correlation between ΔGFR₂₄or ΔGFR₄₈ and age, renal parameters in Phase 0 (GFR, V and U_osm), CS data (Δt _anesth, Δt _CPBP and T_min) and hemolysis data (values of haptoglobin, serum hemoglobin and LDH₁).

DISCUSSION

Severe ARF induced by CS is not very frequent but when present has a poor prognosis and a high morbidity rate [[2]], [[5]]. The optimal ARF prophylaxis in these patients is hampered by the lack of knowledge about the mechanisms of renal changes after CS. To get this information the best population to be studied is the low ARF risk patients undergoing elective CS.

The type of CS and the presence of a previous CS are known risk factors for ARF. [5-6] VCS was showed to be an independent risk factor for ARF requiring dialysis. [[5]] Consistently, in the present study it was observed that 73% of Group 1 patients underwent VCS in striking contrast with Group 2, where only 30% of the patients underwent this type of surgery. Moreover, all VCS patients with previous CS were in Group 1. A well-known risk factor for ARF is a low basal GFR [[1]], [[5]], [9-10] but a low basal GFR can be either a normal renal response to a low cardiac output or an intrinsic renal impairment. The decrease in GFR after CS found in Group 1 patients, was probably related to a baseline poor cardiac function, consequent to the valvular disease and to the presence of previous CS surgery. It is interesting to point out that the 3 patients of Group 2 with valvular disease underwent their first VCS, emphasizing that previous CS might be more important as ARF risk factor than CS type for these patients. Usually CAB patients are older and with diseases that can impair GFR as diabetes and arterial hypertension. However, in the present study all the patients with the above diseases where in Group 2. Probably CAB in these patients acutely improved their cardiac performance and consequently the GFR, despite the presence of hypertension and diabetes in some of them. The sum of these data indicates that in patients with previous CS undergoing another VCS, ARF is an expected complication.

Unfortunately only few of the studied patients had a quantitative evaluation of cardiac ejection fraction before CS and so it was not possible to have a more precise baseline cardiac function evaluation in the present paper. For example, there was a patient with GFR of 37 mL/(minx1.73m₂) in phase 0 with respective U_osm of 479 mOsm/kg and FE_Na of 0.91% and another with a similar GFR: 34 mL/(minx1.73m₂) but with U_osm of 709 mOsm/kg and FE_Na of 0.04%. The low GFR found in the last one was probably due to a normal renal response to a low effective blood volume caused by a poor cardiac condition (high U_osm ad low FE_Na). It was not the case for the first patient who showed lower U_osm and higher FE_Na. The lack of correlation found between ΔGFR₂₄ or ΔGFR₄₈ with GFR in Phase 0 was probably because these two kinds of patients were pooled together. The positive correlation of ΔGFR₂₄with the respective FE_Na in phase 0 and the negative correlation between the ΔGFR₂₄ with the volume balance before Phase 1 are consistent with the hypothesis that the observed GFR changes after an elective CS are a normal renal response to the effective blood volume in each Phase. Thus, even in elective CS it is very important to measure baseline GFR and FE_Na in all patients in order to identify those at risk for GFR worsening taking into account that normal or mildly increased P_creat can represent deeply impaired GFR and a very low FE_Na may be a significant risk factor for GFR decrease after CS.

There are few studies about tubular function after CS. The finding of increased FE_Na in Phase 1 could suggest a tubular impairment. However, there was no correlation between FE_Na in Phase 1 and the ΔGFR₂₄ as expected in the presence of tubular lesion, when a more negative ΔGFR is related to a higher FE_Na. An explanation for the FE_Na increase in Phase 1 might be a positive volume balance or the diuretic effects of dopamine and nitroprusside increasing renal blood flow. [[11]] These drugs were administered, at least one of them, to almost all patients after the CS. In 1979 Hilberman et al. [[10]] found a FE_Na < 1% 24 hours after CS, despite BUN levels. The difference between our results (FE_Na of 1.64 ± 1.46%) and theirs could be explained by the nowadays routine administration of these cit890-ed vasoactive drugs.

The other changes in tubular function found after CS in the present study are also likely the result from normal physiological response to the clinical condition of the patients. In Phase 1 there was a positive correlation between FE_Na and FE_K demonstrating that the distal tubular portions were able to secret more potassium in response to an increased distal sodium delivery. Urinary acidification seems to be intact. A positive correlation was found between urinary and blood pH and between urinary pH and GFR. These findings indicate normal tubular function. In fact, in the presence of systemic acidosis an inappropriate high urinary pH is found in acute tubular necrosis but not in pre-renal ARF [[13]].

Although an urinary concentration impairment after CS had been previously reported, [14-15], in the present study the urinary concentration capacity was apparently preserved. Besides no decrease in U_osm was found in Phase 1 and Phase 2, a negative correlation between FE_Na and U_osm was present in both Phase 1 and Phase 2: the lower was the FE_Na, the higher was the U_osm. These data indicate a normal tubular response increasing either sodium absorption or urinary concentration capacity. However, Tang et al. [[8]] reported increased urinary retinol-binding protein excretion after CS with preserved GFR, showing that some isolated tubular dysfunction can occur, with indeterminate clinical role.

A prolonged anesthesia is one of the usually cit890-ed risk factor for ARF. In the 70's a prospective study [[10]] showed that anesthesia time was not different in 4 groups of patients with different levels of postoperative P_creat ranging from ≤ 1.5 to > 5.0 mg/dL. A recent prospective paper [[5]] on risk factors for dialysis-dependent ARF after CS also did not find anesthesia time as an independent risk factor. In the present study, Δt _anesth did not shown correlation with ΔGFR₂₄. Moreover, in Group 1 Δt _anesth: was even shorter than in Group 2, indicating that the usual anesthesia time (around 6 hours) can not be incriminated for GFR impairment after CS.

There is some controversy about how long CPBP can last without inducing ARF. Hilberman et al. [[12]] showed a positive association between CPBP time and BUN levels 24 hours after CS: for CPBP time of 124 ± 44, 135 ± 44 and 168 ± 77 minutes the respective BUN levels were 21 ± 6, 42 ± 18 and 111 ± 30 mg/dL. Yeboah et al. [[9]] noticed that a CPBP time up 60 minutes was able to induce GFR worsening. In a recent study, Suen et al. [[16]] showed that CPBP time more than 140 minutes is an independent risk factor for ARF requiring dialysis. The above cit890-ed data and the present results of a Δt_CPBP of 91 ± 3 7 minutes with no correlation with ΔGFR₂₄, suggests that a CPBP time up to 120 minutes is not an important factor for GFR decrease after CS.

Hemolysis is another well-known cause of ARF and it can be ascribed to CPBP. In the 60's, it was reported that among 29 patients with ARF after CS with CPBP, only 3 of them (10%) had plasma hemoglobin levels lower than 50 mg/dL [[17]]. In the 90's, in order to prevent ARF, Tanaka et al. [[18]] recommended haptoglobin administration only when serum hemoglobin concentration reaches 30 mg/dL or more. In the present study, the maximum serum hemoglobin level found was 21 mg/dL, lower than the above cit890-ed value. There was also no correlation between any of the evaluated hemolysis parameters and ΔGFR₂₄in this study. Furthermore, the presence of abnormally high serum hemoglobin or LHD₁ and of low haptoglobin concentration were similar in the 2 studied groups. The decrease in blood hemoglobin and hematocrit found in Phase 1 was probably due to blood losses during CS and/or hemodilution during CPBP. During a non complicated CS with an usual CPBP time, mild hemolysis may occur as that found in the present study with no contribution to GFR decrease.

Age has not been found as a factor associated with GFR decrease after CS. Abel et al. [[10]] found that the patients who presented P_creat > 5 mg/dL after CS were older (58 ± 8 years) than those with P_creat < 1.5 mg/dL (47 ± 17 years) but the first group also had more hemodynamic instability during CS. Chertow et al. [[5]] showed that dialysis-dependent ARF prevalence increased with increasing age, but age itself was not an independent risk factor for ARF. In the present study no correlation between age and ΔGFR₂₄ was found. Also, no difference in age was found between the two studied groups. These data strongly indicate that age is not an important ARF risk factor.

In conclusion, in elective CS in patients with low ARF risk factors, a low baseline GFR represents probably more a poor cardiac condition than a true renal impairment. Early GFR improvement can be expected after CS for most of the patients undergoing CAB surgery, probably due to the improved cardiac performance. Otherwise, close attention and careful ARF prophylaxis must be given for patients with low baseline FE_Na, because these patients are on high risk for ARF development after CS.