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Longevity Library · Lab reference

Written by Daniel Tagge, MD
Updated October 10, 2026
Reviewed October 12, 2026
28 sources · Measured in mL/min/1.73 m²

System: Metabolism & Metabolomics

eGFREstimated glomerular filtration rate · Cystatin C

eGFR is an estimate of kidney filtration calculated from creatinine, a muscle by-product, and in pooled cohorts of more than a million people mortality was flat between about 75 and 105 and rose only below about 60, with albumin in the urine an independent second axis. A low result that does not fit the person is checked with cystatin C, a second marker that does not depend on muscle.

eGFR estimates how much blood the kidneys filter each minute, from a creatinine level plus age and sex. Laboratories flag results under 60; the guideline calls 90 and above normal and 60 to 89 mildly decreased, which on its own is not disease. Risk in the large cohorts was flat from about 75 to 105 and climbed below 60. Because creatinine comes from muscle and meat, a second marker, cystatin C, is the check.

01 · The scale

Where the laboratory range and the evidence sit.

In pooled general-population cohorts, mortality was unrelated to eGFR between 75 and 105 and rose below that: 1.18 times at 60, 1.57 at 45 and 3.14 at 15 compared with 95. Albumin in the urine raised risk independently at every eGFR. Measured by cystatin C instead of creatinine, the same gradient was steeper and the J-shape at high eGFR disappeared.

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  1. Flagged as low on most reports: under 60

    0 to 59 mL/min/1.73 m² · KDIGO 2024 laboratory standards

  2. G2 mildly decreased, not disease without kidney damage: 60 to 89

    60 to 89 mL/min/1.73 m² · KDIGO 2024

  3. G1 normal or high: 90 and above

    90 and above mL/min/1.73 m² · KDIGO 2024

  4. Mortality flat: 75 to 105

    75 to 105 mL/min/1.73 m² · CKD Prognosis Consortium 2010, 1.2 million people

  5. Mortality 1.18 times at 60, 1.57 at 45, 3.14 at 15

    0 to 59 mL/min/1.73 m² · CKD Prognosis Consortium 2010

  6. Above 105 by creatinine alone, risk rose again: low muscle or hyperfiltration

    106 and above mL/min/1.73 m² · KDIGO 2024 (CKD-PC); Park 2015

  • Laboratory range
  • Evidence supports
  • Guideline goal or unstudied
  • Higher risk in studies
Scale in mL/min/1.73 m². eGFR is reported per 1.73 m² of body surface area so that people of different sizes can be compared. It is an estimate, calculated from blood creatinine or cystatin C with age and sex, not a measurement. Cystatin C itself is reported in mg/L. Bands show where studies found something, not a recommendation for any one person.

02 · What it is

What eGFR measures.

Glomerular filtration rate is the volume of blood the kidneys filter each minute. It is rarely measured directly; most reports estimate it from blood creatinine with age and sex, using the 2021 CKD-EPI equation that no longer includes race. In the validation data set of 4,050 participants, the earlier equation with a race coefficient overestimated measured GFR in Black participants by a median of 3.7 mL/min/1.73 m², and for every equation tested 85 percent or more of the estimates fell within 30 percent of the measured value, which means a reported 60 can sit anywhere from about 42 to 78.1,2Grade A

Creatinine is a breakdown product of muscle, so its blood level depends on how much muscle a person has and what they ate, not only on the kidney. Cystatin C is a small protein made by every nucleated cell at a steady rate, and the equations that combine creatinine and cystatin C were more accurate than creatinine alone, with smaller differences between race groups. The 2024 kidney guideline recommends creatinine-based eGFR as the first test and, where cystatin C is available, staging from the combination of the two (recommendation 1.1.2.1, grade 1B).1,2Grade A

Chronic kidney disease is defined as abnormalities of kidney structure or function present for at least 3 months with implications for health. The GFR categories are G1, 90 and above (normal or high); G2, 60 to 89 (mildly decreased); G3a, 45 to 59; G3b, 30 to 44; G4, 15 to 29; and G5, under 15 (kidney failure). Albuminuria is the second axis: A1 under 30 mg/g, A2 30 to 300, A3 over 300. The guideline is explicit that without evidence of kidney damage, neither G1 nor G2 meets the criteria for chronic kidney disease, so an eGFR of 75 with a normal urine albumin is not a diagnosis.2Grade A

03 · Origins

Where it came from, and where it sits in the network.

The glomerulus is a filter under pressure, and the standard account of why vertebrates have one is Homer Smith's: a reconstruction rather than a tested fact, but one that has held. Our fish ancestors moved from the sea into fresh water, where water poured in and had to be pumped back out; a high filtration rate followed by a tubule that reabsorbs most of the filtrate did the job, and the segments that concentrate urine were added for the move onto land. The bill is still paid: human kidneys are about 1 percent of body weight and use about 10 percent of the body's oxygen, mostly to reclaim 99 percent of what they filter. Two further trades follow. Nephron number at birth varies about tenfold between people, and mammals, unlike fish, amphibians and reptiles, cannot form new nephrons as adults; what we are born with is what the rest of life draws down.3Grade C

Creatinine is a muscle molecule that the kidney happens to clear. Muscle keeps its energy reserve as creatine phosphate, a pool of up to 30 millimolar that creatine kinase uses as an immediately available buffer to rebuild ATP, and creatine closes into a ring spontaneously, with no enzyme, until a chemical equilibrium of roughly two parts creatinine to one part creatine is reached. It became the kidney test because it is abundant and easy to measure, and the same equilibrium is why creatine supplements nudge it upward without any injury to the kidney. Cystatin C has a different pedigree. It belongs to a family of cysteine protease inhibitors that arose in the ancestor of all eukaryotes; its branch gained a signal peptide early and became secreted proteins that restrain protein breakdown outside the cell, the first vertebrate cystatins date to about 650 million years ago, and cystatin C itself appeared in the ancestor of bony vertebrates and still inhibits the proteases it was built against. Every nucleated cell makes it at a fairly steady rate, so its blood level follows filtration with little regard for muscle or diet, which is why it is the check on creatinine.4,5,2Grade C

eGFR stands in for the one thing it cannot measure, how much plasma the glomeruli clear, and it is read beside the urine albumin-to-creatinine ratio because the two fail in different ways: the filtration rate says how much filter is left, albumin in the urine says whether the filter that remains is intact, and in the pooled cohorts each predicted death and kidney failure independently of the other, with risk flat from about 75 to 105 and rising below. Uric acid rides on the same number because it is retained as filtration falls; whether a high urate also drives the decline is an open hypothesis, revived by rat experiments in which raising urate produced glomerular hypertension and scarring without crystals, and its proponents say the trials to settle it are still needed. Hypertension, the metabolic syndrome and type 2 diabetes are the usual proximate causes of nephron loss. Age is the hard case. Nephron number falls by about half over the last decades of life and whole-kidney GFR falls with it, while the filtration rate and size of each surviving glomerulus stay about constant, so healthy aging looks like attrition rather than a sick filter. In older adults without albuminuria, an eGFR under 60 carried very modest to no increase in age-standardized mortality or kidney failure, and the reviewers who assembled those data ask openly whether labeling an age-related decline a disease is appropriate; the guideline keeps 60 at every age, and the range section of this entry lays out both positions.6,7,8,3,9,2Grade C

04 · The laboratory range

What a laboratory calls normal.

Printed as a number or as "above 60" (some laboratories "above 90"), with results under 60 flagged as low; cystatin C about 0.6 to 1.0 mg/L, depending on the laboratory.

The 60 on most reports is not a statistical reference interval drawn from healthy people. It is the guideline's threshold for decreased GFR, and the guideline's laboratory standards ask that reported eGFR levels under 60 be flagged as low and that eGFR be rounded to a whole number relative to 1.73 m². Many laboratories print values above 60 only as "above 60", which hides the 60 to 89 range entirely.2Grade A

Creatinine is one of the steadier blood tests. In 91 healthy adults aged 21 to 69 bled weekly for 10 weeks, within-person variation of creatinine was 4.4 percent by the enzymatic method and 4.7 percent by the older alkaline picrate method, lower than the 5.9 percent previously quoted; the picrate method added analytical imprecision of 4.4 percent against 1.1 percent for the enzymatic assay. The guideline puts within-person variation of eGFR itself at about 5 percent for creatinine, cystatin C and combined equations, and states that for people with chronic kidney disease a change of more than 20 percent between tests exceeds the expected variability and warrants evaluation.10,2Grade B

Even a healthy creatinine moves with a meal. In 32 adults, median creatinine rose from 80.5 to 101.0 micromol/L one to two hours after a cooked-meat meal and median eGFR fell from 84 to 59.5, recovering to 64 by three to four hours, while a meat-free meal had little effect and cystatin C was generally uninfluenced by food. The guideline's practice point is that interpreting a creatinine requires knowing what was eaten, and that waiting at least 12 hours after meat or fish best avoids the effect.11,2Grade B

05 · The evidence

What the studies support.

The CKD Prognosis Consortium pooled 14 general-population cohorts with 105,872 participants who had urine albumin-to-creatinine ratios and 7 cohorts with 1,128,310 participants who had dipstick protein. In the albumin cohorts, mortality was unrelated to eGFR between 75 and 105 mL/min/1.73 m² and increased at lower values: compared with 95, adjusted hazard ratios for all-cause death were 1.18 at 60, 1.57 at 45 and 3.14 at 15. Albuminuria rose with risk linearly on the log-log scale with no threshold, 1.20 at 10 mg/g, 1.63 at 30 and 2.22 at 300 compared with 5 mg/g, and the two measures multiplied without interaction. Cardiovascular mortality behaved the same way. These are associations in people whose eGFR was estimated from creatinine with an older equation, not a trial.6Grade A

For kidney failure itself the curve is the same shape and far steeper. Across 9 general-population cohorts with 845,125 participants, the risk of end-stage renal disease was unrelated to eGFR between 75 and 105 and rose exponentially below: hazard ratios of 4 at 60, 29 at 45 and 454 at 15 compared with 95, after adjustment for albuminuria and cardiovascular risk factors. Albumin-to-creatinine ratios of 30, 300 and 1,000 mg/g carried 5, 13 and 28 times the risk of 5 mg/g. Acute kidney injury and progressive disease followed the same pattern.7Grade A

Age changes the relative risk but not the direction. In 2,051,244 participants from 46 cohorts, both low eGFR and high albuminuria carried higher mortality and kidney-failure risk in every age group. The adjusted hazard for death at an eGFR of 45 versus 80 fell from 3.50 at ages 18 to 54 to 2.21 at 55 to 64, 1.59 at 65 to 74 and 1.35 at 75 and over, while the absolute excess rose with age, from 9.0 to 27.2 extra deaths per 1,000 person-years. The consortium's own reading was that the data support the current 60 threshold at all ages; the difference between age groups lay in the slope between 45 and 75, and below 45 the slopes ran parallel.12Grade A

Cystatin C sorts risk better than creatinine. In 4,637 community-dwelling adults aged 65 and over followed for about 9 years, death rose step by step with cystatin C, from a hazard of 1.08 in the second fifth to 2.58 in the top third of the highest fifth, while the creatinine relationship was J-shaped. Compared with the lowest two fifths (cystatin C 0.99 mg/L or less), the top fifth (1.29 mg/L or more) carried 2.27 times the cardiovascular mortality, 1.48 times the myocardial infarctions and 1.47 times the strokes; the top fifth of creatinine was not independently associated with any of the three.13Grade B

In a meta-analysis of 11 general-population cohorts (90,750 participants) and 5 kidney-disease cohorts, cystatin C-based eGFR called 13.7 percent of the general population under 60 against 9.7 percent by creatinine, and everyone the cystatin C result moved to a lower category had higher risk of death, cardiovascular death and kidney failure, while everyone it moved up had lower risk. Net reclassification improvement for death was 0.23. The authors attribute the creatinine equation's reverse J-shape to low creatinine in people in poor health, who make less of it. The 2024 guideline's own pooled analysis found the same: creatinine eGFR showed a J-shaped association with risk rising above 105, and the creatinine-cystatin C estimate was linear throughout.14,2Grade A

A very high eGFR is not automatically good news. Among 43,503 Korean adults screened with a baseline eGFR of 60 or more and followed a median of 12.4 years, hyperfiltration, defined as an eGFR above the 95th percentile after adjustment for age, sex, muscle mass measured by bioimpedance, diabetes and blood pressure treatment, carried 1.37 times the all-cause mortality after adjustment for known risk factors, and it was more likely in people with the most muscle (odds ratio 1.31), which argues it was not only a low-muscle artifact. One cohort, and a finding its own authors ask to see confirmed.15Grade C

06 · What moves it

The levers with evidence behind them.

What is listed here has been tested. The size of each effect, and the size of the study, are in the sentence, so a small effect reads as a small effect.

  • Blood pressure control

    protects the kidney and the person; a small early dip in eGFR is expected

    In the prespecified kidney-disease subgroup of the SPRINT trial, 2,646 adults with chronic kidney disease and hypertension without diabetes were randomized to a systolic target under 120 mm Hg or under 140. Over a median of 3.3 years the intensive group had a hazard of 0.81 for the cardiovascular composite and 0.72 for all-cause death, and the main kidney outcome (a 50 percent fall in eGFR or kidney failure) occurred in 15 versus 16 participants. After the first 6 months eGFR fell slightly faster in the intensive group (0.47 versus 0.32 mL/min/1.73 m² per year), a hemodynamic effect rather than injury. The 2024 guideline suggests a systolic target under 120 when tolerated, using standardized office measurement (recommendation 3.4.1, grade 2B), with less intensive treatment in frailty, falls risk or symptomatic postural hypotension.16,2Grade A

  • Glucose control in diabetes

    lowers the risk of kidney events

    Pooling individual data from four randomized trials (ACCORD, ADVANCE, UKPDS and VADT, 27,049 adults with type 2 diabetes, median 5 years), more intensive glucose control lowered hemoglobin A1c by 0.90 percentage points and reduced kidney events, a composite of kidney failure, renal death, an eGFR falling under 30 or overt nephropathy, by 20 percent (hazard ratio 0.80), with a 13 percent reduction in eye events and none in nerve events. Trial evidence in people with diabetes; no trial has tested glucose lowering for kidney protection in people without it.17Grade A

  • Weight loss in obesity

    lowers protein leak and blood pressure; brings a hyperfiltering eGFR down

    Across 13 studies of intentional weight loss in people with chronic kidney disease, nonsurgical interventions that lowered body mass index by 3.67 kg/m² reduced proteinuria by 1.31 g per day and systolic blood pressure, with no further decline in GFR over a mean of 7.4 months. In people with severe obesity (BMI over 40) and hyperfiltration (GFR over 125), surgery lowered GFR by 25.56 mL/min, which the authors read as normalization, with lower albuminuria and blood pressure. Small, short studies; no study measured kidney failure.18Grade C

  • Smoking

    raises the risk of new kidney disease

    In a meta-analysis of 15 prospective cohorts with 65,064 incident cases, current smokers had 1.34 times the risk of new chronic kidney disease and former smokers 1.15 times compared with never-smokers; for end-stage renal disease the figures were 1.91 for current and 1.44 for former smokers. Heterogeneity was considerable and no trial has tested whether quitting lowers the risk, but former smokers sat between current and never in both outcomes.19Grade B

  • Pain relievers of the anti-inflammatory class

    high doses raise the risk of faster decline

    A systematic review of observational studies in adults aged 45 and over found that regular-dose nonsteroidal anti-inflammatory use did not change the odds of accelerated decline (an eGFR fall of 15 or more; pooled odds ratio 0.96), while high-dose use raised them (odds ratio 1.26), with the definition of high dose unclear across studies. The 2024 guideline prefers low-dose colchicine or glucocorticoids over this drug class for gout flares in people with chronic kidney disease, and lists the class among the medications to review when kidney function falls. An association in observational data; which product and dose is a question for the prescriber.20,2Grade C

  • Protein restriction

    slows progression to kidney failure only at very low intakes in advanced disease; no evidence in healthy kidneys

    In the Cochrane review of 17 randomized trials and 2,996 adults with nondiabetic chronic kidney disease, a low-protein diet (0.5 to 0.6 g/kg per day) made little or no difference to death or to reaching kidney failure compared with a normal intake of 0.8 g/kg or more (risk ratio for kidney failure 1.05). A very low-protein diet (0.3 to 0.4 g/kg) probably reduced progression to kidney failure in stage 4 and 5 disease (risk ratio 0.65, 165 fewer per 1,000) without changing death, with limited data on malnutrition and none on quality of life. The trials enrolled stages 3 to 5; they say nothing about protein intake in people with normal kidney function.21Grade A

  • Drinking more water

    no effect on eGFR decline in the one trial

    In the CKD WIT trial, 631 adults with stage 3 chronic kidney disease and albuminuria were randomized to coaching to drink more water or to keep their usual intake. The hydration group raised urine output by 0.6 L a day, yet eGFR fell 2.2 mL/min/1.73 m² over a year against 1.9 in controls, a difference of 0.3 that was not significant. The authors note the trial may have been underpowered, but the observational link between water intake and kidney function did not survive the test.22Grade B

07 · Reading it well

Caveats, and what belongs with a physician.

Muscle moves creatinine without moving the kidney. The guideline lists body builders and people doing extreme exercise, eating disorders, amputation and spinal cord injury among the situations in which creatinine eGFR misleads and cystatin C is more appropriate; a lifter with a lot of muscle reads low, and a frail person reads deceptively high. In the pooled cohorts the very lowest creatinine values marked poor health, which is why the creatinine curve bends up again at high eGFR.2,14Grade A

Diet moves it too. The guideline names high-protein diets, creatine supplements, ketogenic diets, vegetarian diets and low-protein diets as non-GFR determinants of creatinine. In the one meta-analysis of creatine supplementation (6 trials pooled), creatinine was higher on creatine by a standardized mean difference of 0.48 and urea by 1.10, with no sign of kidney damage at the amounts and durations studied; a creatine user's eGFR can read a few points low for a reason that has nothing to do with filtration.2,23Grade B

Some drugs raise creatinine by blocking its secretion in the kidney tubule rather than by harming the kidney. Trimethoprim, at ordinary doses, inhibits tubular creatinine secretion and produces a rapid, reversible rise in creatinine and a falsely low eGFR without any change in true filtration; the guideline lists decreases in tubular secretion and some broad-spectrum antibiotics among the medication effects for which cystatin C-based eGFR is more appropriate. A fall in eGFR that coincides with a new prescription deserves a question before a diagnosis.24,2Grade B

Cystatin C has confounders of its own. In 3,418 people with measured GFR, after adjusting for filtration, cystatin C was 8.5 percent higher with diabetes, 9.2 percent lower in women, 4.3 percent lower per 20 years of age, and higher with higher C-reactive protein and white cell count and lower albumin. Thyroid status moves it the opposite way from creatinine: in 22 patients, cystatin C rose from 0.84 to 1.10 mg/L as hypothyroidism was corrected and fell from 1.32 to 0.95 mg/L as hyperthyroidism was treated. The guideline adds adiposity, smoking, glucocorticoid excess and chronic inflammation to the list. Because the two markers fail in different ways, the combined equation is more accurate than either alone.25,26,2Grade B

A disagreement between the creatinine and cystatin C estimates is information, not noise. The guideline notes that 25 to 30 percent of people have a discordance of 15 mL/min/1.73 m² or 20 percent or more between the two; when they agree, either is about 87 to 91 percent accurate within 30 percent of measured GFR, and when they disagree the combined estimate is the more accurate. Higher creatinine eGFR than cystatin C eGFR went with older age, female sex, higher body mass index, weight loss and current smoking.2Grade A

Kidney filtration falls with age in healthy people. In 254 Baltimore Longitudinal Study volunteers with no kidney or urinary disease and no diuretic or blood pressure treatment, followed with serial creatinine clearances between 1958 and 1981, the mean decline was 0.75 mL/min per year, the slopes were normally distributed around that mean, and one third of all subjects followed had no decline at all. A group of nephrologists has argued from this and from the consortium data that the threshold for disease should be age-adapted, 75 for younger adults and 45 for the elderly; the guideline considered the proposal and kept 60 for all ages, on the grounds that the absolute risk from a low eGFR is higher, not lower, in older people.27,28,2Grade B

See a physician

  • An eGFR under 60 on two tests at least 3 months apart, which is the definition of chronic kidney disease whatever the cause, or under 45 on any single test.
  • An eGFR that has fallen by more than about 20 percent from a previous value, after allowing for a meat meal, hard exercise, a new creatine supplement or a new medication.
  • Albumin in the urine (an albumin-to-creatinine ratio of 30 mg/g or more) or blood in the urine on more than one test, at any eGFR, since kidney damage is defined by these as much as by filtration.
  • A low eGFR together with diabetes, high blood pressure, a family history of kidney disease, or regular use of anti-inflammatory pain relievers or any supplement, where the cause and the trend matter more than the single number.
  • A creatinine eGFR and a cystatin C eGFR that disagree by 15 points or more, which is a reason for a physician to sort out muscle, thyroid, inflammation and medication before either number is believed.

This page is education, not individual medical advice, and reading it creates no physician-patient relationship.

08 · Open questions

What the literature does not settle.

  • Whether the threshold for kidney disease should depend on age is unresolved: the nephrologists proposing age-adapted limits read the same consortium data as the guideline committee that kept 60 for everyone, and the disagreement is about whether relative or absolute risk should decide.
  • The consortium curves come from creatinine estimated with an older equation; the 2021 equations shift individual values by a few points, and the cystatin C curves are steeper and more linear. Where risk begins to rise on a creatinine-cystatin C estimate in healthy adults has not been mapped as finely.
  • Hyperfiltration, an eGFR well above what age predicts in someone with obesity or diabetes, tracked higher mortality in one cohort and is a recognized early stage of diabetic kidney disease, but there is no agreed definition, no agreed number, and no trial showing that bringing it down changes outcomes.
  • Cystatin C is more accurate and the guideline now recommends it for staging, but it costs more, is not run by every laboratory, and its own confounders (thyroid, steroids, adiposity, inflammation) are less well characterized than creatinine's.
  • Every protective intervention with trial evidence was tested in people who already had kidney disease, diabetes or hypertension. Whether blood pressure, weight, protein intake or anything else changes the trajectory of a healthy kidney reading above 90 has not been tested.

10

Questions

11 · Sources

28 sources, read in full.

Numbered in the order they appear. Each line says what this page relies on from the paper; the link opens the record at PubMed or the publisher.

  1. 1.

    Inker LA, Eneanya ND, Coresh J, et al.; Chronic Kidney Disease Epidemiology Collaboration. New Creatinine- and Cystatin C-Based Equations to Estimate GFR without Race. New England Journal of Medicine. 2021. PMID 34554658. DOI 10.1056/NEJMoa2102953.

    Laboratory method study · In a validation set of 4,050 participants the race-based creatinine equation overestimated measured GFR in Black participants by a median 3.7 mL/min/1.73 m²; 85 percent or more of estimates fell within 30 percent of measured GFR for every equation; the race-free creatinine-cystatin C equations were more accurate than creatinine alone.

  2. 2.

    Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney International. 2024. PMID 38490803. DOI 10.1016/j.kint.2023.10.018.

    Guideline · CKD is abnormality of kidney structure or function for at least 3 months; GFR categories G1 (90 and above) to G5 (under 15) with albuminuria A1 to A3; creatinine eGFR first and the creatinine-cystatin C combination for staging where available (1B); laboratories flag under 60; a change over 20 percent exceeds expected variability; systolic target under 120 when tolerated (2B); diet, muscle, tubular secretion, thyroid, steroids and inflammation listed as non-GFR determinants.

  3. 3.

    Chevalier RL. Evolution, kidney development, and chronic kidney disease. Seminars in Cell & Developmental Biology. 2019. PMID 29857053. DOI 10.1016/j.semcdb.2018.05.024.

    Review · Homer Smith's account of the high-filtration nephron as an adaptation to fresh water, with reabsorbing tubule segments added for land; human kidneys are 1 percent of body weight and 10 percent of oxygen consumption, spent reabsorbing 99 percent of the filtrate; nephron number varies tenfold at birth and falls about 50 percent in the last decades of life; adult mammals, unlike ectotherms, form no new nephrons.

  4. 4.

    Wallimann T, Tokarska-Schlattner M, Schlattner U. The creatine kinase system and pleiotropic effects of creatine. Amino Acids. 2011. PMID 21448658. DOI 10.1007/s00726-011-0877-3.

    Review · The creatine kinase and phosphocreatine system is an immediately available temporal energy buffer, with a cytosolic phosphocreatine pool of up to 30 mM; creatinine is the cyclic degradation product of creatine formed by non-enzymatic conversion toward a roughly 2 to 1 equilibrium, measured as a kidney marker because it is prominent and easy to assay, and a modest rise with creatine supplementation reflects that chemistry, not kidney injury.

  5. 5.

    Kordis D, Turk V. Phylogenomic analysis of the cystatin superfamily in eukaryotes and prokaryotes. BMC Evolutionary Biology. 2009. PMID 19919722. DOI 10.1186/1471-2148-9-266.

    Laboratory method study · Across more than 2,100 genomes the cystatin superfamily arose in the ancestor of eukaryotes; the cystatin lineage gained a signal peptide and became extracellular inhibitors; the first vertebrate cystatin families, including the progenitor of cystatin C, are about 650 million years old, cystatin C itself originated in the ancestor of bony vertebrates, and it retains the ancestral inhibitory function.

  6. 6.

    Chronic Kidney Disease Prognosis Consortium; Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, Coresh J, Gansevoort RT. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010. PMID 20483451. DOI 10.1016/S0140-6736(10)60674-5.

    Systematic review and meta-analysis · In 105,872 participants with albumin-to-creatinine ratios and 1,128,310 with dipstick protein, mortality was unrelated to eGFR between 75 and 105 and rose below: hazard ratios 1.18 at 60, 1.57 at 45 and 3.14 at 15 versus 95; albuminuria was linearly associated on the log-log scale without threshold (1.20 at 10 mg/g, 1.63 at 30, 2.22 at 300).

  7. 7.

    Gansevoort RT, Matsushita K, van der Velde M, et al.; Chronic Kidney Disease Prognosis Consortium. Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney International. 2011. PMID 21289597. DOI 10.1038/ki.2010.531.

    Systematic review and meta-analysis · In 9 general-population cohorts with 845,125 participants, end-stage renal disease risk was unrelated to eGFR between 75 and 105 and rose exponentially below, with hazard ratios of 4, 29 and 454 at eGFR 60, 45 and 15 versus 95; albumin-to-creatinine ratios of 30, 300 and 1,000 mg/g carried 5, 13 and 28 times the risk of 5 mg/g.

  8. 8.

    Johnson RJ, Nakagawa T, Jalal D, et al.. Uric acid and chronic kidney disease: which is chasing which?. Nephrology Dialysis Transplantation. 2013. PMID 23543594. DOI 10.1093/ndt/gft029.

    Review · Serum uric acid is retained as GFR falls, and separately most studies find that an elevated level predicts the development of CKD; raising urate in rats induces glomerular hypertension, arteriolosclerosis and fibrosis, and disease progressed in hyperuricemic animals without crystals; pilot studies suggest lowering urate may slow progression, with further trials necessary.

  9. 9.

    Hommos MS, Glassock RJ, Rule AD. Structural and Functional Changes in Human Kidneys with Healthy Aging. Journal of the American Society of Nephrology. 2017. PMID 28790143. DOI 10.1681/ASN.2017040421.

    Review · With healthy aging nephron number declines and whole-kidney measured GFR falls by a comparable amount while single-nephron GFR and glomerular volume stay about constant; without albuminuria, an age-related eGFR under 60 is associated with very modest to no increase in age-standardized mortality or end-stage kidney disease, which raises the question of whether disease labeling is appropriate.

  10. 10.

    Carobene A, Marino I, Coşkun A, et al.; European Biological Variation Study of the EFLM Working Group on Biological Variation. The EuBIVAS Project: Within- and Between-Subject Biological Variation Data for Serum Creatinine Using Enzymatic and Alkaline Picrate Methods and Implications for Monitoring. Clinical Chemistry. 2017. PMID 28720681. DOI 10.1373/clinchem.2017.275115.

    Laboratory method study · In 91 healthy adults bled weekly for 10 weeks, within-subject variation of creatinine was 4.4 percent (enzymatic) and 4.7 percent (alkaline picrate), below the 5.9 percent previously listed; analytical imprecision was 1.1 versus 4.4 percent.

  11. 11.

    Preiss DJ, Godber IM, Lamb EJ, Dalton RN, Gunn IR. The influence of a cooked-meat meal on estimated glomerular filtration rate. Annals of Clinical Biochemistry. 2007. PMID 17270090. DOI 10.1258/000456307779595995.

    Laboratory method study · In 32 adults, a cooked-meat meal raised median creatinine from 80.5 to 101.0 micromol/L and lowered median eGFR from 84 to 59.5 at one to two hours and 64 at three to four hours; a meat-free meal had little effect and cystatin C was generally uninfluenced.

  12. 12.

    Hallan SI, Matsushita K, Sang Y, et al.; Chronic Kidney Disease Prognosis Consortium. Age and association of kidney measures with mortality and end-stage renal disease. JAMA. 2012. PMID 23111824. DOI 10.1001/jama.2012.16817.

    Systematic review and meta-analysis · In 2,051,244 participants from 46 cohorts, the hazard of death at eGFR 45 versus 80 was 3.50, 2.21, 1.59 and 1.35 at ages 18 to 54, 55 to 64, 65 to 74 and 75 and over, while absolute excess deaths rose from 9.0 to 27.2 per 1,000 person-years; low eGFR and high albuminuria carried risk in every age group.

  13. 13.

    Shlipak MG, Sarnak MJ, Katz R, et al.. Cystatin C and the risk of death and cardiovascular events among elderly persons. New England Journal of Medicine. 2005. PMID 15901858. DOI 10.1056/NEJMoa043161.

    Prospective cohort · In 4,637 Cardiovascular Health Study participants, death rose dose-dependently with cystatin C (hazard ratios 1.08 to 2.58 across fifths) while creatinine was J-shaped; the top fifth of cystatin C (1.29 mg/L or more) versus the lowest two fifths (0.99 or less) carried 2.27 times the cardiovascular mortality.

  14. 14.

    Shlipak MG, Matsushita K, Ärnlöv J, et al.; CKD Prognosis Consortium. Cystatin C versus creatinine in determining risk based on kidney function. New England Journal of Medicine. 2013. PMID 24004120. DOI 10.1056/NEJMoa1214234.

    Systematic review and meta-analysis · Across 11 general-population cohorts (90,750 participants), cystatin C eGFR called 13.7 percent under 60 versus 9.7 percent by creatinine; reclassification by cystatin C tracked risk of death, cardiovascular death and kidney failure, with a net reclassification improvement of 0.23 for death.

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    Park M, Yoon E, Lim YH, Kim H, Choi J, Yoon HJ. Renal hyperfiltration as a novel marker of all-cause mortality. Journal of the American Society of Nephrology. 2015. PMID 25343954. DOI 10.1681/ASN.2014010115.

    Prospective cohort · Among 43,503 Korean adults with baseline eGFR of 60 or more followed a median 12.4 years, hyperfiltration (eGFR above the 95th percentile adjusted for age, sex, muscle mass, diabetes and antihypertensive use) carried a hazard of 1.37 for all-cause death and was more common in the highest muscle-mass quartile (odds ratio 1.31).

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    Cheung AK, Rahman M, Reboussin DM, et al.; SPRINT Research Group. Effects of Intensive BP Control in CKD. Journal of the American Society of Nephrology. 2017. PMID 28642330. DOI 10.1681/ASN.2017020148.

    Randomized trial · In 2,646 SPRINT participants with CKD, a systolic target under 120 versus under 140 gave hazards of 0.81 for the cardiovascular composite and 0.72 for all-cause death over 3.3 years; the kidney composite occurred in 15 versus 16, and eGFR fell 0.47 versus 0.32 mL/min/1.73 m² per year after 6 months.

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    Zoungas S, Arima H, Gerstein HC, et al.; Collaborators on Trials of Lowering Glucose (CONTROL) group. Effects of intensive glucose control on microvascular outcomes in patients with type 2 diabetes: a meta-analysis of individual participant data from randomised controlled trials. Lancet Diabetes and Endocrinology. 2017. PMID 28365411. DOI 10.1016/S2213-8587(17)30104-3.

    Systematic review and meta-analysis · Across ACCORD, ADVANCE, UKPDS and VADT (27,049 participants, median 5 years), intensive glucose control lowered A1c by 0.90 points and reduced kidney events by 20 percent (hazard ratio 0.80) and eye events by 13 percent, with no effect on nerve events.

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    Navaneethan SD, Yehnert H, Moustarah F, Schreiber MJ, Schauer PR, Beddhu S. Weight loss interventions in chronic kidney disease: a systematic review and meta-analysis. Clinical Journal of the American Society of Nephrology. 2009. PMID 19808241. DOI 10.2215/CJN.02250409.

    Systematic review and meta-analysis · Across 13 studies, nonsurgical weight loss (BMI down 3.67 kg/m²) reduced proteinuria by 1.31 g/24 h and systolic blood pressure with no further GFR decline over 7.4 months; in severe obesity with hyperfiltration (GFR over 125), surgery lowered GFR by 25.56 mL/min with lower albuminuria and blood pressure.

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    Xia J, Wang L, Ma Z, et al.. Cigarette smoking and chronic kidney disease in the general population: a systematic review and meta-analysis of prospective cohort studies. Nephrology Dialysis Transplantation. 2017. PMID 28339863. DOI 10.1093/ndt/gfw452.

    Systematic review and meta-analysis · Across 15 prospective cohorts with 65,064 incident cases, summary relative risks of new CKD were 1.34 for current and 1.15 for former smokers versus never-smokers, and 1.91 and 1.44 for end-stage renal disease.

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    Nderitu P, Doos L, Jones PW, Davies SJ, Kadam UT. Non-steroidal anti-inflammatory drugs and chronic kidney disease progression: a systematic review. Family Practice. 2013. PMID 23302818. DOI 10.1093/fampra/cms086.

    Systematic review and meta-analysis · In observational studies of adults 45 and over, regular-dose NSAID use did not change the odds of accelerated CKD progression (an eGFR fall of 15 or more; pooled odds ratio 0.96) while high-dose use raised them (odds ratio 1.26).

  21. 21.

    Hahn D, Hodson EM, Fouque D. Low protein diets for non-diabetic adults with chronic kidney disease. Cochrane Database of Systematic Reviews. 2020. PMID 33118160. DOI 10.1002/14651858.CD001892.pub5.

    Systematic review and meta-analysis · Across 17 trials and 2,996 adults with nondiabetic CKD stages 3 to 5, a low-protein diet made little or no difference to death or kidney failure versus normal intake (risk ratio 1.05), while a very low-protein diet probably reduced progression to kidney failure (risk ratio 0.65, 165 fewer per 1,000) without changing death.

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    Clark WF, Sontrop JM, Huang SH, et al.. Effect of Coaching to Increase Water Intake on Kidney Function Decline in Adults With Chronic Kidney Disease: The CKD WIT Randomized Clinical Trial. JAMA. 2018. PMID 29801012. DOI 10.1001/jama.2018.4930.

    Randomized trial · In 631 adults with stage 3 CKD, coaching to drink more water raised urine volume by 0.6 L/day but eGFR fell 2.2 versus 1.9 mL/min/1.73 m² over one year (difference 0.3, not significant).

  23. 23.

    de Souza E Silva A, Pertille A, Reis Barbosa CG, et al.. Effects of Creatine Supplementation on Renal Function: A Systematic Review and Meta-Analysis. Journal of Renal Nutrition. 2019. PMID 31375416. DOI 10.1053/j.jrn.2019.05.004.

    Systematic review and meta-analysis · Across 6 pooled trials, serum creatinine on creatine supplementation differed by a standardized mean difference of 0.48 (confidence interval 0.24 to 0.73) and urea by 1.10, with no evidence of renal damage at the amounts and durations studied.

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    Delanaye P, Mariat C, Cavalier E, Maillard N, Krzesinski JM, White CA. Trimethoprim, creatinine and creatinine-based equations. Nephron Clinical Practice. 2011. PMID 21832843. DOI 10.1159/000328911.

    Review · Trimethoprim at recommended doses inhibits tubular creatinine secretion, producing a rapid, reversible rise in creatinine independent of GFR and a falsely low eGFR from creatinine-based equations.

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    Stevens LA, Schmid CH, Greene T, et al.. Factors other than glomerular filtration rate affect serum cystatin C levels. Kidney International. 2009. PMID 19119287. DOI 10.1038/ki.2008.638.

    Cross-sectional study · In 3,418 people with measured GFR, cystatin C after adjustment for GFR was 4.3 percent lower per 20 years of age, 9.2 percent lower in women, 8.5 percent higher with diabetes, and higher with higher C-reactive protein and white cell count and lower albumin.

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    Fricker M, Wiesli P, Brändle M, Schwegler B, Schmid C. Impact of thyroid dysfunction on serum cystatin C. Kidney International. 2003. PMID 12675875. DOI 10.1046/j.1523-1755.2003.00925.x.

    Prospective cohort · In a prospective series of 22 patients, cystatin C rose from 0.84 to 1.10 mg/L as hypothyroidism was corrected and fell from 1.32 to 0.95 mg/L as hyperthyroidism was treated, the opposite direction from creatinine.

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    Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. Journal of the American Geriatrics Society. 1985. PMID 3989190. DOI 10.1111/j.1532-5415.1985.tb07117.x.

    Prospective cohort · Among 254 Baltimore Longitudinal Study of Aging volunteers free of kidney disease and of diuretics or antihypertensives, serial creatinine clearances fell a mean 0.75 mL/min per year, with a normal distribution of slopes and one third of all subjects showing no decline.

  28. 28.

    Delanaye P, Jager KJ, Bökenkamp A, et al.. CKD: A Call for an Age-Adapted Definition. Journal of the American Society of Nephrology. 2019. PMID 31506289. DOI 10.1681/ASN.2019030238.

    Review · GFR declines with healthy aging without signs of compensation or damage; the consortium data show mortality rising below 75 in younger people and below 45 in the elderly, so the authors propose age-specific GFR thresholds for defining CKD.

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