Impaired creatinine secretion after an intravenous creatinine load is an early characteristic of the nephropathy of sickle cell anaemia

José Herrera1, Estela Ávila2, Crispín Marín1 and Bernardo Rodríguez-Iturbe1,3,

1 Renal Service, and 2 Haematology Service, Hospital Universitario, Universidad del Zulia, Medical School and 3 Instituto de Investigaciones Biomédicas (INBIOMED), Maracaibo, Venezuela



   Abstract
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Background. The capacity to increase the tubular secretion of creatinine (TScr) after an intravenous creatinine load (stimulated TScr) has been found to be impaired in subclinical reduction of renal mass. We decided to investigate if this response was impaired in sickle cell anaemia (SCA) patients before there was evidence of deterioration of renal function.

Methods. Studies were done in 16 patients with homozygous SCA who had normal or supranormal glomerular filtration rate (GFR) and in 20 normal controls of similar median age (23 years). The tubular stress test (TST) consisted of 30-min clearance periods ([125I]iothalamate and creatinine) done before (baseline) and after (three successive post-stimulation periods) the intravenous infusion of 88.4 µmol (10 mg) of creatinine per kg of body weight.

Results. Baseline studies showed that the SCA patients had higher GFR and lower serum creatinine concentration. After stimulation there were no changes in GFR. In contrast, creatinine clearance increased 2.3 times in normal but not in SCA patients (P<0.001) and the TScr in the first post-stimulation period was 161±83 nmol/kg/min in SCA patients vs 286±93.2 in normal controls (P<0.001). The mean TScr post-stimulation was also reduced in patients with SCA (123±52 nmol/kg/min vs 179±50 in normal controls, P<0.001). Since SCA patients had lower Pcr values, separate analysis was made of post-load clearance periods in which Pcr was comparable in patients and in normal controls (range 177–265 µmol/l or 2–3 mg/dl) and the reduction in TScr was also present in SCA patients in these study periods.

Conclusion. Patients with SCA have impaired response to the TST before there are reductions in glomerular filtration. Therefore, a reduction in the tubular secretory reserve capacity represents an early event in the nephropathy of this condition.

Keywords: creatinine secretion; sickle cell anaemia; tubular stress test



   Introduction
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
We have recently reported that the tubular secretion of creatinine is increased several-fold after a creatinine load, and that this response is impaired in conditions associated with reduction in renal functioning mass [1,2]. Studies in normal individuals demonstrated that maximal U/P creatinine and creatinine clearance/inulin clearance ratios were found with acute elevations of serum creatinine to 500–700 µmol/l and that these levels were obtained with a single intravenous bolus of 88.4 µmol (10 mg) of creatinine per kg of body weight [2]. On the basis of these results, a relatively simple tubular stress test (TST) was developed to evaluate the capacity of the kidney to increase its creatinine secretion. This test proved useful to discriminate between groups of individuals with normal levels of serum creatinine but a different number of nephron units: normal individuals with two kidneys, normal individuals with one kidney (kidney donors), and transplant patients with normal renal function [2]. These findings suggested that loss of the secretory reserve capacity for creatinine anteceded the impairment of glomerular filtration in the natural history of progressive renal disease. Consequently, it raised the possibility that the TST could have clinical relevance in the evaluation of the non-azotaemic patient.

A group of patients in whom it could be explored if the reserve capacity for creatinine secretion is impaired in hyperfiltering kidneys is the group of patients with sickle cell anaemia (SCA). The patients with homozygous sickle haemoglobin (SS) disease present a variety of renal haemodynamic, functional and structural abnormalities [recently reviewed in 35], but, pertinent to this investigation, these patients have increased glomerular filtration rate (GFR) and renal plasma flow, and reduced serum creatinine levels in childhood and adolescence [67], followed by a subsequent deterioration of renal function that is usually abnormal after the age of 40 [8,9]. When significant proteinuria or azotaemia are present, approximately half of the patients with SCA will go on to end-stage renal disease in less than 2 years [10]; renal failure still accounts for 18% of the deaths in adult patients with SCA [11]. Therefore, the detection of abnormalities in renal function that precede proteinuria and changes in GFR may not only give some insight on the mechanisms of progression of renal damage but also may have clinical importance.

The present study was done to answer a specific question: is the capacity to increase creatinine secretion in response to a creatinine load impaired in patients with SCA who still have a normal or supranormal levels of GFR? To address this issue we evaluated the response to the TST in young patients with SS haemoglobin disease.



   Patients and methods
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients with sickle cell anaemia and normal controls
The patients with SCA (homozygous haemoglobin SS disease) were volunteers recruited from the outpatient Sickle Cell Clinic in the Hospital Universitario and Instituto Hematológico de Occidente, Maracaibo. They were 16 patients with a median age of 23 years (range 15–40 years) with normal renal function. Their haemoglobin ranged from 7.4 to 11.6 g/dl. The routine urine analyses were dipstick negative for protein in 14 patients and trace positive in one and +1 in one. They all had negative serologic markers for viral hepatitis and human immunodeficiency virus. All had normal fasting blood sugar and their blood pressure was normal.

The normal controls were 20 volunteers, median age 23.5 years (range 18–43 years) with normal haematological and biochemical blood profiles and normal urine analysis. Fourteen of these normal subjects had been reported as a control group in a previous study of the TST [2]. All individuals studied denied voiding difficulties and complete bladder emptying by voluntary voiding was documented by ultrasound sonography.

For at least 2 weeks prior to the studies, the patients and the controls were not allowed to take medications that modify renal haemodynamics or block the renal response to a protein or creatinine load, such as non-steroidal anti-inflammatory drugs, nor drugs that interfere with the tubular secretion of creatinine, such as trimethoprin sulfamethoxasol or cimetidine, nor drugs that interfere with the Jaffe's reaction, such as cephalosporins or ascorbic acid. The urine of all subjects in the study was strip test negative for ketones.

The protocol of the study was approved by the Ethics Committee of the Department of Medicine.

Tubular stress test (TST)
The patients arrived at 8 am to the Renal Laboratory. The last meal was eaten 12 h before the studies (8–9 pm the previous night) and after this meal only free water intake was permitted. Diuresis was stimulated by the ingestion of 20 ml/kg body weight of water and maintained by drinking every 30 min the amount eliminated in the previous 30-min period. Upon arrival, 30 µCi of [125I]iothalamate (Gliofil-125, Cypros Pharmaceutical Corp., Carlsbad, CA), in 0.05 ml saline solution with 0.02 ml 1:1000 epinephrine solution was injected subcutaneously in the forearm. As reported previously [2], this resulted in stable serum cpm counts throughout the study. Forearm veins were cannulated and 1 h after the subcutaneous injection of [125I]iothalamate, three 30-min clearance periods were done as baseline (unstimulated, PRE) studies. All urinary collections were done by supervised voluntary voiding. Then, 88.4 µmol of creatinine (Sigma Chemical Co. St. Louis, MO) per kg body weight were dissolved in 100 ml of 5% dextrose and water sterile solution for intravenous use, passed through a single-use millipore filter (sterile acrodisk 0.2 µm, Gelman Sciences) and administered intravenously in 10 min. The creatinine infusion was well tolerated and there were no pyrogenic reactions.

After the creatinine bolus, urinary collections were done, first from time 0 (end of the creatinine infusion) to 15 min and then, in three successive collections periods of 30 min each. Clearance calculations were done in these three collection periods using blood samples that bracketed each urinary collection.

As described previously [2], the initial 15 min after the end of the creatinine infusion are unreliable for clearance studies because during this time there is a steep exponential decrease in serum creatinine (Pcr), but after the initial 15 min the Pcr decreases slowly in almost linear fashion and, as reported previously [2], clearance calculations using the averaged Pcr(a-Pcr)=[Pcri+Pcrf]/2, where i and f are initial and final, respectively, creatinine concentrations of the corresponding clearance period) are practically similar to the calculations using the exponential expression (e-Pcr=exp[(lnPcri+lnPcrf)/2]. Therefore, calculations of GFR, creatinine clearance (Ccr), urinary creatinine excretion rate (UcrV) and tubular secretion of creatinine (TScr) were done in 30-min successive clearance periods 15–45 min post-load (Period A), 45–75 min post-load (Period B) and 75–105 min post-load (Period C). Data was evaluated separately for Period A and for the mean of the three stimulated periods ([A+B+C]/3).

[125I]iothalamate clearance and Ccr were calculated by the standard formula (UxV/Px). [125I]iothalamate clearance was considered equivalent to the GFR. The TScr was estimated by the difference between the UcrV and the filtered creatinine (GFRxPcr): TScr=UcrV-(GFRxPcr).

The clearance of creatinine by secretion is CTScr=TScr/Pcr.

The clearances were corrected by 1.73 m2 surface area. UcrV and TScr were corrected for body weight.

The per cent excreted of the exogenous creatinine load was estimated subtracting the baseline (pre-load) urinary creatinine excretion from the post-load urinary creatinine excretion in the corresponding period: (Stimulated UcrV-Baseline UcrV)x100/creatinine load.

Chemical determinations
I125 radioactivity in plasma and urine was counted with a gamma counter (LKB 1282 Compugamma). Creatinine determinations were done by autoanalyser methodology (Express Ultra Plus, Ciba-Corning) since studies in our laboratories with oral creatinine loads had previously shown that the ratios of ‘true’ (chromogen free) Ccr/Autoanalyser Ccr were not significantly different from 1 [1].

Statistical calculations
Comparisons between the patient and control groups were done by unpaired analysis of variance (ANOVA) followed by multiple comparisons Tukey-Kramer post-tests. Changes from baseline determinations of Ccr and Cin in SCA patients and in controls were evaluated with repeated measures ANOVA followed with Dunnett post-tests. A commercial statistical package (GraphPad Instat, San Diego, CA) was used for statistical analysis. Data are expressed as mean values±SD. Two-tailed P values <0.05 were considered statistically significant.



   Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
The SCA patients were of comparable age with the control group but had a lower body weight (Table 1Go). Their urinary osmolarity after 12-h water deprivation was 427±45.8 mOsm/l. Their systolic blood pressure was 117±7.2 mmHg and their diastolic blood pressure 65±8.8 mmHg.


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Table 1.  Baseline studies

 
The baseline data in the SCA patients and in the control group are shown in Table 1Go. Patients with haemoglobin SS disease had higher GFR and Ccr and lower Pcr and TScr in the baseline studies than the control individuals. Urinary creatinine excretion and Ccr/GFR ratio were not different in control and patients (Table 1Go).

The GFR did not change during the TST in SCA patients nor in controls (Figure 1Go). In contrast, the Ccr increased significantly in SCA patients and in controls with respect to pre-test baseline levels, but the increment in Ccr found in the SCA patients (Period A/Pre=1.17±0.19) is significantly less (P<0.05) than the increment observed in controls (Period A/Pre=1.30±0.14) (Figure 2Go).



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Fig. 1.  Serial determinations of glomerular filtration rate ([125I]iothalamate clearance) before and after the intravenous administration of 88.4 µmol of creatinine/kg (tubular stress test) demonstrate no significant changes in GFR. Patients with sickle cell anaemia (n=16, closed squares) had higher values of glomerular filtration than normal controls (n=20, open squares) throughout the study. Values are mean±SD. **P<0.01.

 


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Fig. 2.  Serial changes in creatinine clearance (Ccr) after the intravenous administration of 88.4 µmol of creatinine/kg (tubular stress test, TST). Patients with sickle cell anaemia (closed squares) had higher levels of Ccr than normal controls (open squares) before the creatinine administration. Both SCA patients and controls increased the Ccr after the creatinine load with respect to baseline (pre-test) values (P<0.05 and P<0.01, respectively), significance not shown in the figure), but the increment in SCA patients (Period A/Pre=1.17±0.19) was significantly less (P<0.05) than the increment observed in controls (Period A/Pre=1.30±0.14). Values are mean±SD. *P<0.05, **P<0.01 vs controls.

 
Results obtained with the TST are shown in Table 2Go. Pcr levels at time 0 (end of creatinine infusion) are similar in SCA patients (628±228 µmol/l) and in normal controls (621±155 µmol/l). The Pcr values decreased to levels of 168±38.5 µmol/l in the patients and only to 267±52.2 µmol/l in normal controls in Period A (P<0.01). However, these values represented similar increments with respect to pre-test values shown in Table 1Go; the period A/baseline Pcr ratios were 3.07±0.57 in the SCA patients and 3.15±0.75 in controls. As shown in Table 2Go, TScr resulting from the TST was decreased in the SCA patients in Period A (P<0.001) and in the mean post-stimulation determinations (P<0.001), (Table 2Go). Serial determinations of TScr are shown in Figure 3Go.


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Table 2.  Tubular stress test in patients with sickle cell anaemia and controls

 


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Fig. 3.  Tubular secretion of creatinine (TScr) after the administration of 88.4 µmol of creatinine/kg (tubular stress test, TST). Patients with sickle cell anaemia (closed squares) had reduced TScr with respect to normal controls (open squares) in Period A (15–45 min after the administration creatinine). Values are mean±SD. ***P<0.001.

 
During Period A, the increment in urinary creatinine resulted in the excretion of 10.9±4.8% of the administered creatinine in control individuals, and 12.2±3.7% in SCA patients (P NS). However, as shown in Figure 4Go, the increment in UcrV in the control individuals (81.5±26.6%) was principally the result of tubular secretion of creatinine while in the SCA patients, the contribution of tubular secretion was significantly less (42.6±16.6%). During the TST, controls and the SCA patients eliminated 40.4±8.5% and 40.2±14.5%, respectively, of the creatinine administered in the test, but as noted before, the contribution of the TScr to the UcrV was significantly lower in the SCA patients.



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Fig. 4.  Per cent of the creatinine administered that is excreted during Period A (15–45 min after the administration creatinine). The total amount excreted is comparable in patients with sickle cell anaemia (SCA) and in normal controls. However, the contribution of tubular secretion to the excretion of the administered creatinine in SCA patients is only 42.6±16.6% while in controls is 81.5±26.6%. ***P<0.001.

 
To evaluate the possibility that the decreased TScr in the SCA patients was the result of insufficient stimulation of the tubular secretory capacity due to lower Pcr values during the post-stimulation periods, a separate analysis was made restricted to the data obtained during those study periods in which a similar range of Pcr levels existed in control individuals and in SCA patients. These data are given in Figures 5AGo and 5BGo, showing respectively the TScr and the CTScr in seven SCA patients and 16 control individuals in periods in which Pcr ranged from 176.8 µmol/l to 265.2 µmol/l (2–3 mg/dl). To avoid over-representation of a given individual, we used in each case the average of the data obtained in a given individual in the selected Pcr range. In this manner, each individual (control or SCA patient) contributed with no more than one point for analysis. As demonstrated in these figures (5AGo and 5BGo), SCA patients had significantly (P<0.001) lower stimulated tubular secretion of creatinine than normals.



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Fig. 5.  Seven patients with sickle cells anaemia (SCA) and 16 normal controls are compared in post-stimulation periods in which the plasma creatinine (Pcr) concentration was in the range of 176.8 to 265.2 µmol/l (2–3 mg/dl). Panel 5A shows the TScr and panel 5B shows the contribution of TScr to the creatinine clearance (CTScr=TScr/Pcr), both of which are reduced in SCA patients. Each data point represents one patient. ***P<0.001.

 



   Discussion
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patients with SCA have a variety of renal structural and functional abnormalities that progress with age. Young patients with haemoglobin SS disease have increased renal plasma flow and glomerular filtration rate, which is frequently reduced after the age of 40 [8,9]. The ultrafiltration coefficient (Kf) has been found to be decreased in association with renal insufficiency [12] as well as increased in proteinuric SCA patients [13]. Studies from several other groups have demonstrated several distal nephron alterations, including decreased concentrating ability [14], incomplete renal tubular acidosis [15], and impaired potassium secretion [16]. In contrast, certain proximal tubular functions, such as the secretion of PAH and uric acid [17,18] have been found to be increased above normal levels.

In agreement with previous studies, our baseline data showed that SCA patients had normal or supranormal levels of GFR and lower than normal Pcr levels (Table 1Go).

The baseline TScr was lower in the SCA patients than in controls. This finding is contrary to the increased values that are quoted in literature reviews [5,18] and deserve some considerations. To our knowledge, the only study that evaluated the tubular secretion of creatinine (unstimulated) is the study of de Jong et al. [7]. This elegant investigation explored the haemodynamic effects of prostaglandin synthesis inhibition in SCA and found that the baseline tubular secretion of creatinine was increased in these patients. However, the discrepancy in the conclusions regarding the baseline TScr in their work [7] and in this investigation may be due, at least in part, to the method of estimation of creatinine secretion. De Jong et al. [7] evaluated the fractional creatinine excretion [(Ccr/Cin)x100] and their data showed that it was 134% in SCA patients and 108 in controls. We estimated TScr as the difference between urinary creatinine excretion minus filtered creatinine (see methods) and found it decreased in SCA patients. Ccr/Cin ratios in our baseline studies indicate that fractional creatinine excretion in our patients was 118±24% and 124±19% in our control subjects, and this difference is not statistically different. Furthermore, if we compare our baseline Ccr/Cin ratios with those of de Jong et al. [7], we find that the values in SCA patients are not statistically different (de Jong et al. =134±31, present work =118±24, P=0.13), while in contrast, the control group in de Jong et al.'s work [7] had fractional creatinine clearances lower than in the present studies (de Jong et al. =108±14, present work =124±19, P=0.02). Therefore, it appears that when our data is calculated in a similar manner as in de Jong et al.'s, the difference is in the control subjects, rather than in the SCA patients.

Maximal stimulation of the creatinine secretory capacity has been found to be impaired in conditions associated with subclinical reduction in nephron mass and a tubular stress test, consisting in the sequential evaluation of the TScr after a single intravenous bolus of creatinine, has been proposed to test the tubular functional reserve [2]. The clinical usefulness of this test depends on the premise that renal patients have abnormal responses before their Pcr is elevated and, ideally, before their glomerular filtration rate is reduced. Since young SCA patients frequently have supranormal GFR before many of them develop progressive segmental glomerulosclerosis [19], we decided to test if TST would be impaired in these patients.

The administration of a standardized dose of 88.4 µmol of creatinine per kg (TST) given intravenously resulted in similar levels of Pcr in controls and SCA patients at the end of the infusion (Time 0 in Table 2Go). Nevertheless, the SCA patients had significantly lower Pcr levels than controls in the clearance periods of the TST due to their increased GFR.

Several observations were made with the TST. The first observation was that GFR remained unchanged during the TST at values that were uniformly higher in the SCA patients than in controls (Figure 1Go). Reasonably stable GFR levels during the TST were expected from the initial description of the test [2]. In contrast to the GFR findings, a clear difference existed in the response of Ccr to the TST (Figure 2Go): while a supranormal Ccr increased slightly in the SCA patients, the normal controls increased sharply the Ccr during period A, at which time their Ccr reached levels that were similar to those of the SCA patients (Table 2Go and Figure 2Go) and, subsequently, decreased towards pre-stimulation values.

The principal parameter explored with the TST is the TScr. As shown in the serial values of TScr in Figure 3Go and in the summarized data in Table 2Go, the patients with SCA had about 40% reduction in their creatinine secretory rate in Period A with respect to the normal response. A reduction of the TScr in the TST could be due to decreased tubular reserve capacity or to insufficient stimulation of TScr during the TST. While it is conceivable that maximal tubular secretion of creatinine in SCA nephropathy would require higher levels of Pcr or longer periods of creatinine administration, the data obtained in normal subjects and in subjects with reduced renal mass indicates that maximal Ucr/Pcr ratios are associated with a bolus of intravenous creatinine that produces, at the end of the infusion, Pcr values of 500–700 µmol/l [2]. In fact, Pcr levels at the end of the creatinine infusion (time 0, Table 2Go) were in the desired range. Nevertheless, the subsequent reduction of Pcr was more pronounced in SCA patients (period A and mean post-stimulation values in Table 2Go), likely resulting from their higher filtration rate. Therefore, the possibility of insufficient stimulation of creatinine secretion has to be considered in SCA patients. It should be realized that while the Pcr are lower in SCA patients in Period A (Table 2Go), the increment with respect to baseline values (Period A/Baseline) is similar in patients and controls (SCA patients =3.15±0.75, controls 3.07±0.57). Nevertheless, it is possible that the absolute level of Pcr, rather than its increment, is the determining stimulus for the secretion of creatinine. Therefore, to evaluate the TScr at comparable levels of Pcr, we analysed the individual clearance periods in which both the SCA patients and the normal controls had Pcr in a similar range: 176.8–256.2 µmol/l (2–3 mg/dl). These data are shown in Figures 5AGo and 5BGo, and demonstrate that in this analysis the TScr and the CTScr were also significantly reduced in SCA patients. In addition, tubular secretory response was not related to the GFR levels in early SCA nephropathy since patients with GFR >120 ml/min did not have significantly different stimulated TScr than patients with lower GFR values.

The cause of impaired TST in SCA cannot be defined from the present studies. The nephropathy of SCA is a complex condition in which certain tubular functions, such as negative water clearance, potassium secretion and urinary acidification are impaired and other tubular functions, such as renal plasma flow and uric acid secretion are augmented. It must be emphasized that our findings concern specifically the capacity of the tubule to respond to creatinine stimulation, rather than to the unstimulated status of tubular creatinine secretion. In this sense, a TST is more alike to a water deprivation test that uncovers impairment in the capacity to maximally concentrate the urine. Such a defect is also an early characteristic of SCA nephropathy and was in fact demonstrated in our patients who had a mean urinary osmolarity of 427 mOsm/l after 12-h dehydration. Recent investigations indicate that repeated periods of ischaemia are associated with local inflammatory reaction in tubulointerstitial areas in the transgenic sickle cell mice [20]. If similar episodes occur in the human they could conceivably affect earlier the capacity to respond to stimulation than the baseline function.

In conclusion, the TST demonstrates that young SCA patients with normal or supranormal GFR have a reduced capacity to increase their TScr. A diminished tubular secretory functional reserve represents an early event in the nephropathy of patients with haemoglobin SS disease. While it is temping to consider that abnormal TST could predict subsequent deterioration of glomerular filtration in the subset of SCA patients that develop end-stage renal disease, there is no evidence at the present time to support this possibility.



   Acknowledgments
 
Financial support for the study was obtained from the Asociación de Amigos del Riñón (Maracaibo) and Fundacite-Zulia.



   Notes
 
Correspondence and offprint requests to: Dr B. Rodríguez-Iturbe, Apartado Postal 1430, Maracaibo 4001-A, Venezuela. Email: bri{at}iamnet.com Back



   References
 Top
 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 

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Received for publication: 19. 6.01
Accepted in revised form: 27.11.01





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