Cystatin C Kidney Functional Reserve: A Simple Method to Predict Outcome in Chronic Kidney Disease

Daniel Christiadi; Charles Simpson; Kate O'Brien; Kylie Taylor; Grant Luxton; Monica Rossleigh; Jonathan Erlich; Zoltán H. Endre


Nephrol Dial Transplant. 2022;37(6):1118-1124. 

In This Article

Abstract and Introduction


Graphical Abstract

Background: Kidney functional reserve (KFR), the only clinical kidney stress test, is not routinely measured because the complexity of measurement has limited clinical application. We investigated the utility of plasma cystatin C (CysC) after oral protein loading (PL) to determine KFR in Stages 3 and 4 chronic kidney disease (CKD).

Methods: Following a 24-h low-protein diet, KFR was measured after oral protein by hourly plasma CysC and compared with simultaneous creatinine clearance (CrCl) and radionuclide 99technetium diethylenetriaminepentaacetatic acid (Tc-99m-DTPA) measured glomerular filtration rate (mGFR) measurement in an observational, single-centre cohort study of adults with CKD Stages 3 and 4. Subjects were followed for 3 years for fast (F) or slow (S) CKD progression, dialysis requirement or death or a combination of major adverse kidney events (MAKEs).

Result: CysC, CrCl and Tc-99m-DTPA mGFR measurements of KFR in 19 CKD Stage 3 and 21 CKD Stage 4 patients yielded good agreement. KFR was not correlated with baseline kidney function. Eight CKD Stage 3 (42%) and 11 CKD Stage 4 (52%) subjects reached their lowest serum CysC concentration 4 h after PL. CysC KFR and baseline serum creatinine (sCr) predicted death or dialysis or MAKE-F with a respective area under the curve (AUC) of 0.73 [95% confidence interval (CI) 0.48–0.89] and 0.71 (95% CI 0.51–0.84). Including CysC KFR, age, baseline sCr and nadir CysC predicted a decrease in sCr-estimated GFR >1.2 mL/min/year (MAKE-S) with an AUC of 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.


The global burden of chronic kidney disease (CKD) and CKD-attributable deaths has increased greatly.[1] However, a reliable method of predicting major adverse kidney events (MAKEs; death, end-stage kidney disease and CKD progression) is lacking and interpretation of risk factors for progression of CKD remains controversial, particularly in older subjects.[2–4]

Kidney functional reserve (KFR, i.e. renal reserve) is analogous to cardiac functional reserve.[5] KFR is defined as the increase in glomerular filtration rate (GFR) from baseline during physiological stress, for example, pregnancy,[6] or following renal vasodilators or protein loading (PL).[7] A reduced KFR predicts AKI after cardiac surgery, despite a normal serum creatinine (sCr).[8] KFR is likely reduced during the progression of CKD[9] and following AKI.[10]

Despite the absence of a useful alternative stress test of kidney function, KFR has not entered routine clinical practice, in part because it is an unfamiliar measure; the complexity and time commitment in KFR testing restrict its use. Brief duration creatinine clearance (CrCl), before and after oral PL, is the most common method of measuring KFR.[5] Changes in GFR can occur within 1 h after PL, with a maximal GFR increase reported as 2–2.5 h in healthy subjects.[5] It remains uncertain when GFR is maximal in subjects with reduced GFR. KFR accuracy also depends on the accuracy of urine collection and timing, which is difficult in uncatheterized patients.

Cystatin C (CysC) is an endogenous non-glycosylated protein, freely filtered at the glomerulus. Serum CysC levels correlate inversely with GFR and are better than sCr when compared with plasma clearance of iohexol.[11] Serum CysC is produced at a constant rate by all nucleated cells and appears unaffected by age, gender or muscle mass.[12] The shorter half-life and smaller volume of distribution of serum CysC versus creatinine suggest greater sensitivity to acute changes in GFR.[13] These attributes allow prediction of early kidney transplant function[14] and suggest predictive utility in determining KFR.[15,16]

We hypothesized that CysC KFR might provide an accurate but simpler method of KFR measurement that could facilitate adoption into clinical practice. We compared KFR measurements by three different methods: CrCl, 99technetium diethylenetriaminepentaacetatic acid (Tc-99m-DTPA) measured GFR (mGFR)] and serial serum CysC. This study was conducted in patients with CKD Stage 3 and 4 (CKD 3 and CKD 4), where data are scarce and where a lower GFR [sCr-estimated GFR (eGFR)] could test the clinical utility of CysC in measuring KFR. We further hypothesized that KFR could predict progressive CKD and examined the prediction of death, dialysis or transplantation and progression of CKD and composites of these MAKEs 3 years after KFR measurement.