Cystatin C kidney functional reserve: a simple method to predict outcome in chronic kidney disease

Abstract

Background Kidney Functional Reserve (KFR), the only clinical kidney stress test, is not routinely measured because complexity of measurement has limited clinical application. We investigated the utility of plasma cystatin C (CysC) after oral protein loading to determine KFR in stage 3 and 4 CKD. Methods Following a 24 hour low protein diet, KFR was measured after oral protein by hourly plasma CysC and compared with simultaneous creatinine clearance (CrCl) and radionuclide Tc-99m-DTPA (mGFR) measurement in an observational, single-centre cohort study of adults with CKD 3 and CKD 4. Subjects were followed for three years for fast (F) or slow (S) CKD progression, dialysis requirement or death or a combination of major adverse kidney events (MAKE-F or -S). Result CysC, CrCl and Tc-99m DPTA mGFR measurements of KFR in 19 CKD 3 and 21 CKD 4 patients yielded good agreement. KFR was not correlated with baseline kidney function. Eight CKD 3 (42%) and 11 CKD 4 (52%) subjects reached their lowest serum CysC concentration four hours after protein loading. CysC KFR and baseline serum creatinine (sCr) predicted (death or dialysis) or MAKE-F with respective AUC = 0.73 (95% CI: 0.48 to 0.89) and 0.71 (95% CI: 0.51 to 0.84). Including CysC KFR, age, baseline sCr and nadir CysC predicted a decrease in sCr-eGFR greater than 1.2 mL/min per year (MAKE-S) with AUC = 0.89. Conclusions Serial CysC avoided timed urine collection and radionuclide exposure and yielded equivalent estimates of KFR. Serial CysC may facilitate monitoring of KFR in clinical practice.

Potential utility of renal functional reserve testing in clinical nephrology

“…Hourly urine collection without an indwelling bladder catheter may be inaccurate, and selection of the baseline GFR as the lower of the two CrCl before stimulation, and the peak GFR as the highest CrCl within 3 h post stimulation, needs further validation [5]. Replacement of creatinine with the more accurate filtration marker cystatin C did show conflicting results, questioning whether changes in plasma levels of creatinine and cystatin C reflect the stimulation-induced filtration dynamics fast enough to be detected within an hour [35,38]. More work is therefore required to standardize stimulation and GFR and to optimize the detection of dynamic changes in GFR to improve robustness of RFR measurement.…”

The complexity of kidney disease and diagnosing it – cystatin C, selective glomerular hypofiltration syndromes and proteome regulation

“…Ingestion of meat increases GFR in the healthy kidney, and a protein load is one way of determining kidney functional reserve, that is renal reserve [ 28 ]. Although the kidney functional reserve has been shown to be useful in the clinical assessment of the severity of kidney disorders [ 29 ], it has not been extensively used because of the requirement to measure GFR by invasive methods after a protein load [ 30 ]. Cooked meat does not contain any undenatured cystatin C, and the increase in kidney function after such a meal is reflected in the cystatin C level, which will be reduced.…”

“…Cooked meat does not contain any undenatured cystatin C, and the increase in kidney function after such a meal is reflected in the cystatin C level, which will be reduced. This observation has been used to devise a simple way of estimating kidney functional reserve by measuring this reduction in the cystatin C level after a protein load [ 30 , 31 ].…”

Definitions, phenotypes, and subphenotypes in acute kidney injury—Moving towards precision medicine

“…Recent studies in cardiothoracic surgery demonstrated that among patients with a normal sCr those with low KFR (<15 ml/min) were at higher risk of development of postoperative AKI 94 and that the AKI episode itself reduced postoperative KFR 95 . Thus, reduced KFR highlights a potential vicious cycle of AKI risk followed by CKD, which itself increases further risk of AKI that will further reduce KFR 96 . There are few clinical studies of KFR, since testing usually involves hourly creatinine clearance measurements, which is cumbersome in non‐catheterised patients.…”

“… 95 Thus, reduced KFR highlights a potential vicious cycle of AKI risk followed by CKD, which itself increases further risk of AKI that will further reduce KFR. 96 There are few clinical studies of KFR, since testing usually involves hourly creatinine clearance measurements, which is cumbersome in non‐catheterised patients. However, serial serum cystatin C measurements before and after a liquid protein meal has simplified KFR measurement in healthy and CKD subjects 96 , 97 and should allow easier detection of subclinical CKD in clinical settings associated with high AKI risk.…”