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Limitations of creatinine in quantifying the severity of cyclosporine-induced chronic nephropathy
Insights
Cyclosporine (CsA) treatment in heart transplant patients impairs kidney function, causing a significant drop in glomerular filtration rate (GFR). Creatinine clearance is falsely elevated due to tubular hypersecretion, masking the true extent of kidney damage.
Area of Science:
- Nephrology
- Pharmacology
- Transplantation Medicine
Background:
- Cyclosporine (CsA) is a crucial immunosuppressant post-heart transplantation.
- Chronic CsA use is associated with nephrotoxicity, but its precise impact on glomerular filtration rate (GFR) and creatinine handling is not fully elucidated.
Purpose of the Study:
- To investigate the effects of long-term cyclosporine (CsA) therapy on GFR and creatinine clearance in heart transplant recipients.
- To determine the reliability of serum creatinine as a marker for CsA-induced nephropathy.
Main Methods:
- Measured GFR using inulin clearance and 99mTc-DTPA clearance in 34 heart transplant recipients on CsA for ≥12 months.
- Assessed creatinine clearance and fractional creatinine clearance relative to inulin clearance.
- Analyzed the relationship between fractional creatinine clearance and absolute inulin clearance.
Main Results:
- Inulin clearance was severely depressed, indicating significant GFR reduction.
- 99mTc-DTPA clearance mirrored inulin clearance, confirming their accuracy as filtration markers.
- Creatinine clearance was significantly enhanced (fractional clearance 1.51 ± 0.05), inversely correlating with GFR.
- Hypersecretion of creatinine by renal tubules increased as nephropathy worsened.
Conclusions:
- In CsA-induced nephropathy, 99mTc-DTPA and inulin accurately reflect GFR.
- Creatinine clearance overestimates GFR due to tubular hypersecretion, which intensifies with worsening nephropathy.
- Elevated serum creatinine (>2 mg/dL) only reliably indicates severe GFR reduction (by >2/3) in chronic CsA nephropathy.
Abstract:
The glomerular filtration rate (GFR), as measured by the clearance of inulin, was depressed severely in 34 heart transplant recipients receiving cyclosporine (CsA) for 12 months or longer. The clearance of 99mTc-DTPA, a filtration marker similar in size to creatinine, was identical to that of the larger inulin molecule. In contrast, the clearance of creatinine was enhanced (P less than .01) such that its fractional clearance (relative to inulin) averaged 1.51 +/- 0.05. Moreover, there was an inverse relationship between fractional creatinine clearance (r = 0.36, P less than .01) and absolute inulin clearance. We conclude that in CsA-induced chronic nephropathy 99mDTPA and inulin are unrestricted by the glomerular capillary wall and behave as true filtration markers, creatinine is progressively hypersecreted by renal tubules as the nephropathy worsens, and the ensuing enhancement of creatinine clearance over GFR blunts the expected rise in serum creatinine levels as GFR falls. As a result, serum creatinine in chronic CsA-induced glomerulopathy exceeds 2 mg/dL consistently, only after true GFR has become depressed below normal values by two thirds or more.