Exploration of Chronic Kidney Disease Prevalence Estimates Using New Measures of Kidney Function in the Health Survey for England

BackgroundChronic kidney disease (CKD) diagnosis relies on glomerular filtration rate (eGFR) estimation, traditionally using the creatinine-based Modification of Diet in Renal Disease (MDRD) equation. The Chronic Kidney Disease Epidemiology Collaboration (CKDEPI) equation performs better in estimating eGFR and predicting mortality and CKD progression risk. Cystatin C is an alternative glomerular filtration marker less influenced by muscle mass. CKD risk stratification is improved by combining creatinine eGFR with cystatin C and urinary albumin to creatinine ratio (uACR). We aimed to identify the impact of introducing CKDEPI and cystatin C on the estimated prevalence and risk stratification of CKD in England and to describe prevalence and associations of cystatin C.LimitationsCross sectional study, single eGFR measure, no measured (‘true’) GFR.ConclusionsIntroducing the CKDEPI equation and targeted cystatin C measurement reduces estimated CKD prevalence and improves risk stratification.     

Circadian Variability of Cystatin C,Creatinine, and Glomerular Filtration Rate (GFR) in Healthy Men during Normal Sleep and after an Acute Shift of Sleep

The estimation of the glomerular filtration rate (GFR) is essential for the evaluation of patients with kidney disease and for the treatment of patients with medications that are eliminated by the kidneys. Plasma cystatin C has been shown in several studies to be superior to plasma creatinine for the estimation of GFR. However, there is limited information on the circadian variation of cystatin C and estimated GFR using cystatin C (eGFR_CystC) or “The Modification of Diet in Renal Disease Study” (MDRD) (eGFR_MDRD) equations. We studied the circadian variation of cystatin C and creatinine during night‐ and day‐sleep conditions in seven healthy volunteers. Serum samples were collected every hour (48 samples per individual) to evaluate the effect of different sampling times on the test results. The median intra‐individual coefficients of variations for the studied markers were 4.2% for creatinine, 4.7% for eGFR_MDRD, 5.5% for cystatin C, and 7.7% for eGFR_CystC. Neither cystatin C nor creatinine differed significantly between the night‐ and day‐sleep conditions. Cystatin C differed significantly with time of day (p=.0003), but this was not the case for creatinine (p=.11). The circadian variation of cystatin C was minor. Small but significant increases in creatinine values and a decrease of eGFR_MDRD were observed after food intake. Thus, cystatin C and creatinine sampling does not have to be restricted to specific times of the day.     

Assessment of serum beta-trace protein (BTP) measurement in the prediction of glomerular filtration rate. Comparison with serum cystatin C

Serum BTP measurement is sometimes believed to be an alternative marker of glomerular filtration rate (GFR) assessment. The aim of the present work was to investigate the correlation between creatinine, cystatin C, and BTP values in sera and to compare the diagnostic efficacy for serum BTP and cystatin C with the glomerular filtration rate estimate. 25 individuals were tested. GFR was estimated from creatinine clearance, serum cystatin C and BTP and urine alpha-1 microglobulin, albumin, GMT and creatinine were measured. BTP values correlated with cystatin C (r = 0.75; p < 0.01), creatinine (r = 0.73, p < 0.01), GFR (r = -0.46; p = 0.02), urine alpha-1-microglobulin (r = 0.66; p < 0.01). The diagnostic efficacy of BTP for reduced GFR was insufficient and the calculation of GFR with BTP was not included in the regression model.     

Mechanisms Underpinning Increased Plasma Creatinine Levels in Patients Receiving Vemurafenib for Advanced Melanoma

Context

Serum creatinine has been reported to increase in patients receiving Vemurafenib, yet neither the prevalence nor the mechanism of this adverse event are known.

Objective

We aimed to evaluate the frequency and the mechanisms of increases in plasma creatinine level in patients receiving Vemurafenib for advanced melanoma.

Methods

We performed a retrospective monocentric study including consecutive patients treated with Vemurafenib for an advanced melanoma. We collected clinical and biological data concerning renal function before introduction of Vemurafenib and in the course of monthly follow-up visits from March 2013 to December 2014. Cystatin C-derived glomerular filtration rate was evaluated before and after Vemurafenib initiation, as increase in serum cystatin C is specific to a decrease in the glomerular filtration rate. We also performed thorough renal explorations in 3 patients, with measurement of tubular secretion of creatinine before and after Vemurafenib initiation and a renal biopsy in 2 patients.

Results

70 patients were included: 97% of them displayed an immediate, and thereafter stable, increase in creatinine (+22.8%) after Vemurafenib initiation. In 44/52 patients in whom Vemurafenib was discontinued, creatinine levels returned to baseline. Serum cystatin C increased, although proportionally less than serum creatinine, showing that creatinine increase under vemurafenib was indeed partly due to a renal function impairment. In addition, renal explorations demonstrated that Vemurafenib induced an inhibition of creatinine tubular secretion.

Conclusion

Thus, Vemurafenib induces a dual mechanism of increase in plasma creatinine with both an inhibition of creatinine tubular secretion and slight renal function impairment. However, this side effect is mostly reversible when Vemurafenib is discontinued, and should not lead physicians to discontinue the treatment if it is effective.     

Methods of Estimating GFR - Different Equations Including CKD-EPI

The initiative for estimating glomerular filtration rate (GFR) derives from the limitations of interpreting plasma creatinine alone, the cost and complexities of determining a gold standard GFR with either inulin or radionuclides, and the inaccuracies inherent in measuring a 24 h urine creatinine clearance. In August 2005, the Australasian Creatinine Consensus Working Group recommended that an eGFR based on the abbreviated MDRD (Modification of Diet in Renal Disease) formula shall be automatically calculated for every request for creatinine in people over 18 years. Uptake was almost universal, though with appropriate caveats in place regarding potential limitations. Updated recommendations in 2007 recognised uniform standardisation of the plasma creatinine assay. A recent development is the CKD-Epidemiology Collaboration (CKD-EPI) equation which confers less underestimation of GFR in subjects with normal renal function. Cystatin C and its derivative equations may have advantages in some situations.     

Use of Cystatin C and Serum Creatinine for the Diagnosis of Contrast-Induced Nephropathy in Patients Undergoing Contrast-Enhanced Computed Tomography at an Oncology Centre

ObjectiveOur aim was to assess renal function using as laboratory measurements serum creatinine and cystatin C concentrations before and after administration of low-osmolarity (nonionic) iodinated contrast medium in patients with cancer undergoing computed tomography (CT).MethodsThis prospective study included 400 oncologic outpatients. Serum creatinine and cystatin C concentrations were measured before and 72 h after contrast administration. Glomerular filtration rates (GFRs) were estimated using serum creatinine–based [Modification of Diet in Renal Disease (MDRD) and Cockroft-Gault and cystatin C based (Larsson) equations. Exploratory data analysis was performed. The nonparametric Wilcoxon test was used to compare pre and post contrast of test results and estimated clearance. The confidence interval used in the analysis was 95%.ResultsCompared with the pre-contrast values, the mean serum creatinine concentration was significantly higher and average GFRs estimated using MDRD and Cockcroft-Gault equations were significantly lower after the administration of contrast (p <0.001). It was also observed a significant increase after contrast in the concentration of Cystatin C (p = 0.015). In addition, a decrease in GFR estimated using the average Larsson (p = 0.021) was observed between time points. However, none of the patients presented clinically significant nephropathy.ConclusionsAssessment using serum creatinine and cystatin C concentrations showed changes in renal function among patients with cancer undergoing contrast-enhanced CT examination in this study. No significant renal damage related to the use of low-osmolarity iodinated contrast medium of the type and dosage employed in this study was observed. This contrast medium is thus safe for use in patients with cancer.     

Evaluation of cystatin C as an early biomarker of cadmium nephrotoxicity in the rat

Cadmium (Cd) is a nephrotoxic environmental pollutant that causes insidious injury to the proximal tubule that results in severe polyuria and proteinuria. Cystatin C is a low molecular weight protein that is being evaluated as a serum and urinary biomarker for various types of ischemic and nephrotoxic renal injury. The objective of the present study was to determine if cystatin C might be a useful early biomarker of Cd nephrotoxicity. Male Sprague–Dawley rats were given daily injections of Cd for up to 12 weeks. At 3, 6, 9 and 12 weeks, urine samples were analyzed for cystatin C, protein, creatinine, β₂ microglobulin and kidney injury molecule-1. The results showed that Cd caused a significant increase in the urinary excretion of cystatin C that occurred 3–4 weeks before the onset of polyuria and proteinuria. Serum levels of cystatin C were not altered by Cd. Immunolabeling studies showed that Cd caused the relocalization of cystatin C from the cytoplasm to the apical surface of the epithelial cells of the proximal tubule. The Cd-induced changes in cystatin C labelling paralleled those of the brush border transport protein, megalin, which has been implicated as a mediator of cystatin C uptake in the proximal tubule. These results indicate that Cd increases the urinary excretion of cystatin C, and they suggest that this effect may involve disruption of megalin-mediated uptake of cystatin C by epithelial cells of the proximal tubule.     

Use of cystatin C determination in clinical diagnostics

This paper presents a current view of the possible clinical uses of cystatin C determination. Cystatin C is an inhibitor of cysteine proteases, and relatively stable in the systemic circulation it is comparatively easily determined. Although in clinical practice it is known primarily as a relatively reliable and endogenous marker for glomerular filtration, lately cystatin C analysis has been discussed in connection with the diagnostics of a variety of diseases such as early atherosclerosis, Alzheimer's dementia, vascular aneurysms, hyperhomocysteinaemia and other neurodegenerative diseases.     

Potential Contribution of Adipose Tissue to Elevated Serum Cystatin C in Human Obesity

Cystatin C, an endogenous inhibitor of cathepsin proteases has emerged as a biomarker of cardiovascular risk and reduced renal function. Epidemiological studies indicate that serum cystatin C increased in human obesity. Here, we evaluated the contribution of adipose tissue to this elevation, based on our previous observation that cystatin C is produced by in vitro differentiated human adipocytes. We measured serum cystatin C in 237 nonobese (age: 51 ± 0.8 years; BMI: 22.8 ± 0.11 kg/m²) and 248 obese subjects (age: 50 ± 0.8 years; BMI: 34.7 ± 0.29 kg/m²). Creatinine‐based estimated glomerular filtration rate (eGFR) was calculated to account for renal status. Cystatin C gene expression and secretion were determined on surgical adipose tissue biopsies in a distinct group of subjects. Serum cystatin C is elevated in obese subjects of both genders, independently of reduced eGFR. Cystatin C mRNA is expressed in subcutaneous and omental adipose tissue, at twice higher levels in nonadipose than in adipose cells. Gene expression and cystatin C release by adipose tissue explants increase two‐ to threefold in obesity. These data confirm elevation of serum cystatin C in human obesity and strongly argue for a contribution of increased production of cystatin C by enlarged adipose tissue. Because cystatin C has the potential to affect adipose tissue and vascular homeostasis through local and/or systemic inhibition of cathepsins, this study adds a new factor to the list of adipose tissue secreted bioactive molecules implicated in obesity and obesity‐linked complications.     

Cystatin C,a novel urinary biomarker for sensitive detection of acute kidney injury during haemorrhagic fever with renal syndrome

To explore the value of cystatin C for evaluating acute kidney injury (AKI) in haemorrhagic fever with renal syndrome (HFRS), the concentrations of cystatin C in serum and urine samples from HFRS patients were determined. The serum and urinary cystatin C concentrations significantly increased in HFRS patients compared with normal controls (p?<?0.001). In the acute phase of HFRS, urinary cystatin C increased to higher levels than serum creatinine, especially in severe or critical cases in the oliguric stage. Furthermore, higher levels of urinary cystatin C in the acute phase positively correlated with increased severity of the subsequent kidney injury. In conclusion, urinary cystatin C is a more sensitive clinical marker for AKI in HFRS, which may enable us to initiate treatment measures as early as possible.     

A New Equation to Estimate Muscle Mass from Creatinine and Cystatin C

Background

With evaluation for physical performance, measuring muscle mass is an important step in detecting sarcopenia. However, there are no methods to estimate muscle mass from blood sampling.

Methods

To develop a new equation to estimate total-body muscle mass with serum creatinine and cystatin C level, we designed a cross-sectional study with separate derivation and validation cohorts. Total body muscle mass and fat mass were measured using dual-energy x-ray absorptiometry (DXA) in 214 adults aged 25 to 84 years who underwent physical checkups from 2010 to 2013 in a single tertiary hospital. Serum creatinine and cystatin C levels were also examined.

Results

Serum creatinine was correlated with muscle mass (P < .001), and serum cystatin C was correlated with body fat mass (P < .001) after adjusting glomerular filtration rate (GFR). After eliminating GFR, an equation to estimate total-body muscle mass was generated and coefficients were calculated in the derivation cohort. There was an agreement between muscle mass calculated by the novel equation and measured by DXA in both the derivation and validation cohort (P < .001, adjusted R² = 0.829, β = 0.95, P < .001, adjusted R² = 0.856, β = 1.03, respectively).

Conclusion

The new equation based on serum creatinine and cystatin C levels can be used to estimate total-body muscle mass.     

Mechanisms Underlying Early Rapid Increases in Creatinine in Paraquat Poisoning

Background

Acute kidney injury (AKI) is common after severe paraquat poisoning and usually heralds a fatal outcome. The rapid large increases in serum creatinine (Cr) exceed that which can be explained by creatinine kinetics based on loss of glomerular filtration rate (GFR).

Methods and Findings

This prospective multi-centre study compared the kinetics of two surrogate markers of GFR, serum creatinine and serum cystatin C (CysC), following paraquat poisoning to understand and assess renal functional loss after paraquat poisoning. Sixty-six acute paraquat poisoning patients admitted to medical units of five hospitals were included. Relative changes in creatinine and CysC were monitored in serial blood and urine samples, and influences of non-renal factors were also studied.

Results

Forty-eight of 66 patients developed AKI (AKIN criteria), with 37 (56%) developing moderate to severe AKI (AKIN stage 2 or 3). The 37 patients showed rapid increases in creatinine of >100% within 24 hours, >200% within 48 hours and >300% by 72 hours and 17 of the 37 died. CysC concentration increased by 50% at 24 hours in the same 37 patients and then remained constant. The creatinine/CysC ratio increased 8 fold over 72 hours. There was a modest fall in urinary creatinine and serum/urine creatinine ratios and a moderate increase in urinary paraquat during first three days.

Conclusion

Loss of renal function contributes modestly to the large increases in creatinine following paraquat poisoning. The rapid rise in serum creatinine most probably represents increased production of creatine and creatinine to meet the energy demand following severe oxidative stress. Minor contributions include increased cyclisation of creatine to creatinine because of acidosis and competitive or non-competitive inhibition of creatinine secretion. Creatinine is not a good marker of renal functional loss after paraquat poisoning and renal injury should be evaluated using more specific biomarkers of renal injury.     

Carp ovarian cystatin binds and agglutinates spermatozoa via electrostatic interaction

A sperm-agglutinating factor was purified from ovulated carp eggs and the conditioned medium (CM) of cortical-reacted eggs. It was identified to be the carp ovarian cystatin. Three cystatin isoforms were found. The cystatin isolated from the CM had a higher sperm-agglutinating activity than that isolated from eggs, although the cystatins have identical N-terminal amino acid sequences, masses, and positive charges. Differences in sperm-agglutinating activity between the cystatins of the CM and eggs may be caused by the different conformations because they differed in circular dichroism spectrum and tryptic map. Cystatin was discharged from cortical granules to the perivitelline space after fertilization and is abundant in the perivitelline fluid (PVF) of early stage embryos. Cystatin rapidly agglutinated spermatozoa via an electrostatic interaction. Other basic proteins also agglutinated carp spermatozoa. Their activities were inhibited by salt and high pH. Cystatin bound to the entire surface of carp spermatozoa. The PVF of early embryos agglutinated carp spermatozoa. The activity was related to the cystatin content and influenced by ionic strength and pH. Therefore, cystatin is the major sperm-agglutinating factor of PVF. Owing to the rapid action of cystatin on spermatozoa agglutination and the presence of a high concentration of cystatin in PVF, cystatin is considered important for preventing polyspermy in carp eggs.     

Cystatin C: a candidate biomarker for amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurologic disease characterized by progressive motor neuron degeneration. Clinical disease management is hindered by both a lengthy diagnostic process and the absence of effective treatments. Reliable panels of diagnostic, surrogate, and prognostic biomarkers are needed to accelerate disease diagnosis and expedite drug development. The cysteine protease inhibitor cystatin C has recently gained interest as a candidate diagnostic biomarker for ALS, but further studies are required to fully characterize its biomarker utility. We used quantitative enzyme-linked immunosorbent assay (ELISA) to assess initial and longitudinal cerebrospinal fluid (CSF) and plasma cystatin C levels in 104 ALS patients and controls. Cystatin C levels in ALS patients were significantly elevated in plasma and reduced in CSF compared to healthy controls, but did not differ significantly from neurologic disease controls. In addition, the direction of longitudinal change in CSF cystatin C levels correlated to the rate of ALS disease progression, and initial CSF cystatin C levels were predictive of patient survival, suggesting that cystatin C may function as a surrogate marker of disease progression and survival. These data verify prior results for reduced cystatin C levels in the CSF of ALS patients, identify increased cystatin C levels in the plasma of ALS patients, and reveal correlations between CSF cystatin C levels to both ALS disease progression and patient survival.     

Estimating glomerular filtration rate in diabetes using serum cystatin C

Chronic kidney disease (CKD) is a major public health problem, especially for people with diabetes. Not only is it a risk factor for end-stage renal disease (ESRD) but it is also a major cardiovascular disease (CVD) risk factor. Methods that accurately and simply estimate glomerular filtration rate (GFR) are therefore needed to optimise the detection and management of CKD in people with diabetes. One of the main failures of commonly used creatinine-based methods for estimating renal function is that they lack applicability across the full range of GFR values and underestimate GFR levels >60 mL/min/1.73m(2). Methods for accurately estimating an early pathological decline in GFR (i.e. ΔGFR >3.3 mL/min/year before reaching a GFR <60 mL/min/1.73m(2)) are especially needed as appropriate interventions have been shown to retard progression to ESRD and reduce CVD risk in people with diabetes. In contrast, recent studies have suggested that estimates of GFR based on serum cystatin C concentration might provide a simple and accurate method for detecting and monitoring an early decline in renal function.     

Is Increased Echogenicity Related to a Decrease in Glomerular Filtration Rate? Objective Measurements in Pediatric Solitary Kidney Patients—A Retrospective Analysis

Quantitative measurements of renal echogenicity using a graphic program show close correlation with renal histology in adult patients, but this has neither been applied in pediatric patients nor correlated with glomerular filtration rate (GFR). To determine the direct relationship between echogenicity and GFR, we retrospectively analyzed 91 patients with a solitary functioning kidney under the age of 10, who underwent ultrasonography and serum cystatin C evaluation on a single day between January 2013 and December 2014. Echogenicity was quantified as previously reported. Echogenicity and kidney length were correlated with age-matched values of serum cystatin C-based GFR. Evaluation was performed at a median age of 17.1 months. GFR was low for age in eight of 54 right solitary kidney patients and four of 37 left solitary kidney patients. The right kidney-liver ratio was significantly elevated in the right decreased GFR group, while the left kidney-spleen ratio was not different in the left decreased GFR group. Age-matched longitudinal kidney length ratios were similar between the decreased and normal GFR groups for both sides. This is the first report to objectively prove the relationship between echogenicity and renal function in patients with a right solitary kidney. The right kidney-liver echogenicity ratio, measured objectively, showed feasibility in clinical practice as it showed a close relationship with decreased renal function when increased. However, absolute kidney echogenicity values, or the left kidney-spleen echogenicity ratio, were not independent markers for decreased renal function.     

Regulated expression and intracellular localization of cystatin F in human U937 cells.

Cystatin F is a cysteine peptidase inhibitor recently discovered in haematopoietic cells by cDNA cloning. To further investigate the expression, distribution and properties of the native human inhibitor the promyeloid cell line U937 has been studied. The cells expressed relatively large quantities of cystatin F, which was found both secreted and intracellularly. The intracellular levels were unusually high for a secreted cystatin ( approximately 25% of the cystatin F in 2- or 4-day culture medium). By contrast, U937 cells contained only 3-4% of the related inhibitor, cystatin C. Cystatin F purified from lysates of U937 cells showed three major forms carrying two, one or no carbohydrate chains. Immunocytochemistry demonstrated a marked cytoplasmic cystatin F staining in a granular pattern. Double staining with a marker for endoplasmic reticulum revealed no colocalization for cystatin F. Analysis of the promoter region of the cystatin F gene (CST7) showed that it, like that of the cystatin C gene (CST3), is devoid of typical TATA- and CAAT-box elements. In contrast to the cystatin C promoter, it does not contain multiple Sp1 binding sites, but has a unique site for C/EBPalpha, possibly explaining the restricted expression of the cystatin F gene. Cells stimulated with all-trans retinoic acid to differentiate them towards a granulocytic pathway, showed a strong ( approximately 18-fold) down-regulation of intracellular cystatin F and almost abolished secreted levels of the inhibitor. Stimulation with tetradecanoyl phorbol acetate, causing monocytic differentiation, also resulted in down-regulation (two fold to threefold) of cystatin F expression, whereas the cystatin C expression was essentially unaltered in both experiments. The results suggest that cystatin F as an intracellular cysteine peptidase inhibitor with readily regulated expression, may be a candidate to control the cysteine peptidase activity known to be essential for antigen presentation in different blood cell lineages.     

Intérêts et limites de l’estimation du débit de filtration glomérulaire avec des formules qui utilisent la créatinine ou la cystatine C dans une population âgée dénutrie

Renal function is often altered in elderly patients. A lot of formulae are proposed to estimate GFR to adjust drug posology. French guidelines recommend the Cockcroft-Gault formula corrected with the body surface area, but the initially described unadjusted Cockcroft-Gault equation is mainly used in geriatric clinical practice. International recommendations have proposed the modification of diet in renal disease (MDRD) formula, since several authors recommended the Rule formula using cystatin C in particular population. To appreciate the most accurate GFR estimation for posology adaptation in an elderly polypathological population, a cross-sectional study with prospective inclusion was carried out in Charles Foix Hospital. Plasma glucose levels, creatinine levels and serum cystatin C, albumin, transthyretin. C-reactive protein, orosomucoid, total cholesterol levels were determined among 193 elderly patients aged 70 and older. The results showed that in a malnourished, inflamed old population, CG, MDRD and Rule formulae resulted in different estimations of GFR, depending on nutritional and inflammatory parameters. Only cCG estimation was shown to be independent from these parameters. To conclude, cCG seems to be the most accurate and appropriate formula in a polypathological elderly population to evaluate renal function in order to adapt drug posology.     

Fibrillogenic oligomers of human cystatin C are formed by propagated domain swapping

Cystatin C and the prion protein have been shown to form dimers via three-dimensional domain swapping, and this process has also been hypothesized to be involved in amyloidogenesis. Production of oligomers of other amyloidogenic proteins has been reported to precede fibril formation, suggesting oligomers as intermediates in fibrillogenesis. A variant of cystatin C, with a Leu68-->Gln substitution, is highly amyloidogenic, and carriers of this mutation suffer from massive cerebral amyloidosis leading to brain hemorrhage and death in early adulthood. This work describes doughnut-shaped oligomers formed by wild type and L68Q cystatin C upon incubation of the monomeric proteins. Purified oligomers of cystatin C are shown to fibrillize faster and at a lower concentration than the monomeric protein, indicating a role of the oligomers as fibril-assembly intermediates. Moreover, the present work demonstrates that three-dimensional domain swapping is involved in the formation of the oligomers, because variants of monomeric cystatin C, stabilized against three-dimensional domain swapping by engineered disulfide bonds, do not produce oligomers upon incubation under non-reducing conditions. Redox experiments using wild type and stabilized cystatin C strongly suggest that the oligomers, and thus probably the fibrils as well, are formed by propagated domain swapping rather than by assembly of domain-swapped cystatin C dimers.     

Modulation of phagocytosis-associated respiratory burst by human cystatin C: role of the N-terminal tetrapeptide Lys-Pro-Pro-Arg

Cystatin C, a cysteine protease inhibitor, has recently been suggested to be a potent regulator in inflammatory processes. Human cystatin C was isolated from the urine of one patient suffering from tubular disorders and was tested for its effects on two functions of human polymorphonuclear neutrophils (PMN): O2- release and phagocytosis. Slow-form or (des 1-4) cystatin C and fast-form or (des 1-8) cystatin C differed by the presence in (des 1-4) cystatin C only of the N-terminal tetrapeptide Lys-Pro-Pro-Arg. Whereas (des 1-8) cystatin C did not seem to interfere with PMN functions at physiological concentrations, (des 1-4) cystatin C induced an inhibition of PMN phagocytosis-associated respiratory burst in response to opsonized zymosan particles. The inhibition may be attributed to the tetrapeptide Lys-Pro-Pro-Arg which has been synthesized and shown to have the same inhibitor effects, at concentrations similar to those required for (des 1-4) cystatin C. These results support a potential role for cystatin C as a modulator during inflammation.