Renal functional assessment in the failing renal graft: what to do where clearances show discrepancy
Giorgina Barbara Piccoli1,
Antonella Sargiotto2,
Massimo Gai1,
Giovanni Cacace2,
Elisabetta Mezza1,
Maura Rossetti1,
Francesca Bermond1,
Giorgio Soragna1,
Alberto Jeantet1,
Giacomo Lanfranco1,
Giuseppe Picciotto2 and
Giuseppe Paolo Segoloni1
1Chair of Nephrology, Depavrtment of Internal Medicine, University of Torino, Azienda Ospedaliera San Giovanni Battista della città di Torino and 2Servizio di Medicina Nucleare, Azienda Ospedaliera San Giovanni Battista della città di Torino, Italy
Correspondence and offprint requests to: Giorgina Barbara Piccoli, MD, Cattedra di Nefrologia, Dipartimento di Medicina Interna, Università di Torino, Corso Dogliotti 14, I-10126 Torino, Italy. Email: giorgina.piccoli{at}unito.it
Keywords: creatinine; cystatin C; renal clearances; renal failure; renal function assessment; renal graft
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Background
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Recently increased attention for chronic renal failure has stimulated new interest in renal function assessment by direct measurement as well as by algorithms or formulas [13]. In the failing renal graft, a situation in which pharmacological therapy may interfere with the complex adaptation mechanisms of renal failure, the assessment of renal function may be particularly difficult [4]. Studies of patients with liver or heart transplantation and advanced kidney disease suggest that creatinine-based indexes may be poor indicators of residual renal function under calcineurin inhibitors [5,6]. The following two cases, displaying a discrepancy between creatinine and urea clearances, draw attention to this rather neglected, yet clinically relevant, aspect of renal function assessment.
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Case 1
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PGL is a 30-year-old male who started renal replacement therapy (RRT) in 1994, due to chronic glomerulonephritis. He received a living donor graft in 1995 and developed an acute thrombotic microangiopathy, leading in 2001 to a rapid decrease of renal function. The decision to restart once weekly haemodialysis was taken in the presence of a high creatinine clearance (20 ml/min assessed; 19.2 ml/min calculated) and low urea clearance (4 ml/min).
Over time, the discrepancy between urea and creatinine clearances was repeatedly confirmed. A radioisotopic study (51Cr-EDTA plasma clearance 7.8 ml/min), according to the Bröchner-Mortensen method (Appendix), confirmed the overestimation of renal function by creatinine-based measurements and supported the choice of an early dialysis approach (Table 1).
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Case 2
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AM is a 37-year-old male, fully rehabilitated, well nourished at Subjective Global Assessment (SGA), sporty (previous body-builder) and with good Karnofsky score (100, working full-time). He started RRT in July 1982 due to focal segmental glomerulosclerosis and received a first cadaver graft in 1985, which failed in the following year due to recurrence of the primary disease. In 1988 he received a living donor graft, which failed in 1992 due to recurrence of glomerulosclerosis. A third graft, performed in 1997, acutely developed severe proteinuria (
35 g/24 h) in September 2002, with rapidly progressive deterioration of renal function impairment, leading to oligo-anuria (urinary output 200500 ml/day). The patient restarted an intensive dialysis schedule of four treatments per week. In October 2002, the finding of discrepant functional data, together with a renal scintiscan suggesting a vital, well-perfused renal parenchyma, was the basis for reconsidering an aggressive therapeutic approach (Table 1).
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Discussion
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In these two renal transplant patients with severe kidney failure, the quantification of renal function was attempted by the direct assessment of renal clearances using cystatin C (widely employed in Italy), whose use is under study in our laboratory, and by all of the main bedside formulas. The bedside formulas were retrieved by a search strategy combining words indicating kidney function tests as free and MeSH terms (exp kidney function test) and free terms indicating calculation (formula$, calculation$, equation$).
Both cases were characterized by a marked discrepancy between urea and creatinine clearances, reflected also by the derived bedside formulas. Both patients were young, fit, in good clinical condition and on an unrestricted diet. While urea and creatinine clearances were superimposable, cystatin C and the derived formula pointed to opposite directions (in the first case the renal clearance calculated from cystatin C was lower than the creatinine clearanceassessed or calculatedwhile it was higher in the second).
Taking the radioisotopic clearances as the gold standard of renal function assessment, in the first patient the creatinine-based formulas substantially overestimated glomerular filtration rate (GFR), in keeping with previous reports related to therapy with calcineurin inhibitors [5,6].
However, in the second case, the radioisotopic GFR corresponded closely with the creatinine clearance and the formulas taking into account the urea clearance clearly underestimated renal function. The low urea clearance may be explained by the low urinary output and by volume depletion, a result of the severe nephrotic syndrome and of the aggressive dialysis therapy.
In both cases, a correct quantification of renal function was crucial. In the first patient, relying on creatinine clearance could have lead to the first uraemic symptoms being overlooked, thus, retarding a timely start of dialysis. In the second patient, relying on the formulas usually employed in dialysis patients (also taking into account the urea clearances) would probably have supported an abstention-based therapeutic approach.
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Teaching points
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- In the failing renal graft, assessment of residual renal function based only on the commonly measured parameters (clearances, urea, creatinine and derived formulas) may be very difficult.
- Clearances may be biased in opposite ways and by different pathophysiological mechanisms (such as pharmacological interferences or dehydration plus nephrotic syndrome), potentially affecting clinical decisions. The situation may be particularly dangerous in the critical phase of renal graft failure.
- Radioisotopic clearances can be of great help in obtaining a precise quantification of renal function. The presence of discrepant functional data may support the indication for this relatively expensive and time-demanding test.
Conflict of interest statement. None declared.
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Appendix
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Procedure used for radioisotopic GFR measurement
The patients were confined to bed during the study. Oral water intake was unrestricted. A dose of commercially available 51Cr-EDTA (Amersham) was administered in an antecubital vein. The amount of injected activity was determined from the patient's weight using a standard of 37 KBq (1 µCi)/kg. A carefully weighed amount of 51Cr-EDTA drawn from the same batch used for the injection was diluted by a factor of 1000 for a standard.
Three blood samples were obtained from the contralateral arm at 180, 240 and 300 min. The blood samples were drawn through a three-way stopcock inserted into a cubital vein, which also served for infusion of saline solution. Plasma samples were centrifuged at 1500 g using a fixed-angle centrifuge, then 2 ml plasma samples and 2 ml standard solution were counted in a well crystal scintillation detector to a relative counting error of 1.0%.
According to the Bröchner-Mortensen method, the total 51CR-EDTA plasma clearance (Cl) was determined from Equation 1:
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and GFR was calculated from the correction equation:
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where E1 (ml/min) is the ratio between the injected dose and the total area under the monoexponential curve determined from the radioactivity in the plasma samples.
The plasma samples used for the fit were taken at 180, 240 and 300 min, according to the method suggested by Bröchner-Mortensen and Rödbro for patients with creatinine clearance <30 ml/min.
Clearance values were normalized to 1.73 m2 of body surface area (A). The value of A was calculated using the DuBois (1927) formula.
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