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Longevity Library · Lab reference

Written by Daniel Tagge, MD
Updated October 10, 2026
Reviewed October 12, 2026
27 sources · Measured in mg/g

System: Metabolism & Metabolomics

Urine albumin-to-creatinine ratioUACR · Microalbumin · Albuminuria

The urine albumin-to-creatinine ratio measures how much albumin, the main blood protein, is leaking into the urine, and in pooled cohorts of more than 100,000 adults mortality rose continuously from the lowest values, 1.20 times at about 10 mg/g and 1.63 times at about 30 compared with about 5, with no threshold at the 30 mg/g line that reports print as normal. A single value is noisy: a first-morning sample, repeated, is what counts.

UACR is the albumin in a spot urine sample divided by its creatinine, which corrects for how dilute the urine is. Laboratories print under 30 mg/g as normal, the guideline's A1 category. In the large cohorts, risk of death, heart disease and kidney failure rose without a threshold from about 5 mg/g upward, and albuminuria within the printed normal range predicted cardiovascular events in people without diabetes or hypertension. Exercise, fever, menstruation, posture and the day itself move the number, so one value settles little.

01 · The scale

Where the laboratory range and the evidence sit.

In pooled general-population cohorts, mortality rose continuously with the albumin-to-creatinine ratio with no threshold: compared with about 5 mg/g, 1.20 times at about 10, 1.63 at about 30 and 2.22 at about 300, and kidney failure 5 times at 30. In single cohorts of people without diabetes or hypertension, values well under 30 still predicted cardiovascular events. The lowest-risk stratum in the 2024 heat maps was under 10 mg/g.

0102030405060

  1. Printed as normal, A1: under 30

    0 to 29 mg/g · KDIGO 2024

  2. A2 moderately increased: 30 to 300; A3 above 300. Both categories run beyond this scale

    30 and above mg/g · KDIGO 2024

  3. Reference point of the pooled cohorts, about 5 mg/g; under 10 was the lowest-risk stratum in the 2024 heat maps

    0 to 9 mg/g · CKD Prognosis Consortium 2010, 105,872 people; KDIGO 2024

  4. Mortality 1.20 times at about 10 and 1.63 times at about 30, compared with 5

    10 to 29 mg/g · CKD Prognosis Consortium 2010

  5. Kidney failure 5 times at 30 and 13 times at 300 versus 5; mortality 2.22 times at 300

    30 and above mg/g · CKD Prognosis Consortium 2010 and 2011

  • Laboratory range
  • Evidence supports
  • Guideline goal or unstudied
  • Higher risk in studies
Scale in mg/g. Milligrams of albumin per gram of creatinine in a single urine sample. Some reports print mg/mmol: multiply by about 8.8 to get mg/g (3 mg/mmol is about 30 mg/g). Because an average adult excretes roughly a gram of creatinine a day, the ratio in mg/g approximates the albumin excreted in milligrams per day. Bands show where studies found something, not a recommendation for any one person.

02 · What it is

What Urine albumin-to-creatinine ratio measures.

Albumin is the most abundant protein in the blood. A healthy kidney filters very little of it and reabsorbs most of what gets through, so the urine of a healthy adult carries only a trace. The guideline's test for that trace is the albumin-to-creatinine ratio on an untimed urine sample, with a first void in the morning, midstream, preferred in adults and children. Albumin is measured rather than total protein because it is the single most important protein lost in most kidney diseases and because the reagent strips that measure total protein are insufficiently sensitive, do not adjust for concentration and are only semiquantitative.1,2Grade A

The ratio exists because a 24-hour collection, the reference method, is hard to do correctly. Creatinine leaves the body at a fairly constant rate through the day, so dividing albumin by creatinine corrects for how concentrated or dilute a single sample happens to be and reduces within-person variability. The equivalence of mg/g to approximately grams per day rests on the simple assumption that a person excretes about 1 gram (10 mmol) of creatinine a day; in someone whose creatinine production is far from average, a timed collection or an equation that estimates creatinine excretion gives a truer figure.1,3Grade A

Chronic kidney disease is defined as abnormalities of kidney structure or function present for a minimum of 3 months with implications for health, and albuminuria is one of its markers. The guideline's categories are A1, under 30 mg/g (normal to mildly increased); A2, 30 to 300 (moderately increased); and A3, over 300 (severely increased), set beside the GFR categories in a two-axis grid. The 2009 consensus conference that fixed these lines reviewed 45 cohorts with 1,555,332 participants and chose to keep 30 mg/g as the diagnostic threshold while adding the albuminuria categories to the staging, so the 30 on a report is a staging convention, not the point where risk begins.1,4Grade A

03 · Origins

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

Albumin belongs to a four-gene family that also includes alpha-fetoprotein, afamin and the vitamin D-binding protein, all of them liver-made carriers that let fat-soluble molecules travel in a watery blood. The four genes sit in a row on one chromosome and descend from a single ancestor by three duplications: the first split off the vitamin D-binding protein, the second gave albumin, and the last, dated to about 250 million years ago, before the earliest mammals diverged, separated alpha-fetoprotein from afamin. Albumin's concentration in plasma, around 0.6 millimolar, makes it the main source of the colloid osmotic pressure that holds water inside the vessels, and the residues that have been under positive selection in mammals cluster in its binding sites for fatty acids and thyroxine, which is to say the protein has been shaped as a transport vehicle.5Grade C

The machinery that keeps albumin out of the urine is older than the kidney. Excretory organs appeared early in animal evolution, and across the animal kingdom primary urine is made by ultrafiltration through a filtration slit bridged by a slit diaphragm, a structure so conserved that the fruit fly's nephrocyte builds its diaphragm from the same proteins as the human podocyte, nephrin, NEPH1, CD2AP, ZO-1 and podocin, and loses it, with the same loss of filtration, when nephrin or NEPH1 is removed. What vertebrates added was the glomerulus: capillary loops lined by fenestrated endothelium pressed against the podocytes' basement membrane, with mesangial cells holding the tuft open. Birds and mammals then raised blood pressure, and a mammalian glomerular capillary runs at about 50 mm Hg, roughly 5 to 10 times the aortic pressure of lower vertebrates, which is what lets a human kidney filter so much plasma and also what makes the barrier vulnerable to pressure.6,7Grade C

In the network, albumin in the urine reads the condition of the endothelium everywhere, not only in the kidney. The glomerular barrier is size- and charge-selective at three layers, the endothelium with its surface gel, the basement membrane and the podocyte slits, and the little albumin that passes is taken back by the megalin-cubilin receptors of the proximal tubule and degraded. The endothelial surface layer, the glycocalyx, lines every vessel in the body and is degraded by the same insults that drive cardiovascular disease, which is the current framework for why a protein leak in the kidney tracks with heart attack and stroke: the kidney is simply the one organ whose endothelium can be sampled in a cup.2,8Grade C

04 · The laboratory range

What a laboratory calls normal.

Under 30 mg/g printed as normal (KDIGO A1); 30 to 300 flagged as moderately increased (A2); above 300 severely increased (A3). Many laboratories print a value only when it is 30 or more and otherwise report "under 30".

The 30 mg/g line is not a statistical reference interval drawn from healthy people. It is the guideline's boundary between the A1 and A2 categories, and the NKDEP-IFCC working group on urine albumin stated plainly that the recommended reference intervals for the ratio take account neither of the large intergroup differences in creatinine excretion related to age, sex and ethnicity nor of the continuous increase in risk with albumin excretion. The same group found considerable between-method differences for both albumin and creatinine, with no reference measurement procedure for albumin in urine; the 2024 guideline notes results may vary by greater than 40 percent between laboratories depending on method.3,1Grade A

Albumin excretion is one of the noisiest numbers in the laboratory. The guideline puts the biological variation of urine albumin at more than 60 percent and sets the analytical target at about 15 percent accordingly. In 241 adults who each gave three 24-hour collections, a first-morning void and a random spot sample, the within-person coefficient of variation of the first-morning ratio was 19 percent, the same as the 24-hour collection, and all other measures varied more; spot samples labeled 22.4 percent of participants as having microalbuminuria against 10.0 percent by 24-hour collection and 7.5 percent by first-morning void. The guideline therefore prefers a first-morning sample and asks that a ratio of 30 mg/g or more on a random sample be confirmed on a subsequent first-morning midstream sample.1,9Grade A

In 157 stable clinic patients who gave spot samples at 9 a.m. on consecutive days, day-to-day variability was substantial. For someone with a normal ratio (under about 27 mg/g), a change of more than 467 percent was needed to be 95 percent certain the albuminuria had really changed; in the 27 to 265 mg/g range the figure was 170 percent and above 265 it was 83 percent. The guideline's monitoring rule follows: for people with kidney disease, a doubling of the ratio on a subsequent test exceeds laboratory variability and warrants evaluation, and small fluctuations may not indicate progression. The diabetes standard asks that two of three specimens collected within a 3- to 6-month period be abnormal before a person is considered to have moderately or severely elevated albuminuria, citing biological variability of more than 20 percent between measurements.10,1,11Grade A

05 · The evidence

What the studies support.

The CKD Prognosis Consortium pooled 14 general-population cohorts with 105,872 participants and 730,577 person-years who had an albumin-to-creatinine ratio at baseline. The ratio was associated with mortality linearly on the log-log scale without threshold effects: compared with 0.6 mg/mmol (about 5 mg/g), adjusted hazard ratios for all-cause death were 1.20 at 1.1 mg/mmol (10 mg/g), 1.63 at 3.4 mg/mmol (about 30) and 2.22 at 33.9 mg/mmol (about 300). The authors' own conclusion names 10 mg/g or more, not 30, as an independent predictor of mortality in the general population. Cardiovascular mortality behaved the same way, and the ratio multiplied the risk from a low eGFR without interaction. These are associations after adjustment, not a trial.12Grade A

For the kidney itself the gradient is steeper. In 9 general-population cohorts with 845,125 participants, log albuminuria was linearly associated with log risk of end-stage renal disease without thresholds: adjusted hazard ratios at ratios of 30, 300 and 1,000 mg/g were 5, 13 and 28 compared with 5 mg/g, independent of eGFR and of cardiovascular risk factors, with similar associations for acute kidney injury and progressive disease. The 2024 guideline's updated heat maps, drawn from up to 27,503,140 people, treat under 10 mg/g as the lowest albuminuria stratum and note that even at an eGFR of 45 to 59 this stratum carried 3 times the adjusted risk of acute kidney injury and 13 times the risk of kidney failure of the reference group.13,1Grade A

The signal below 30 was seen before the consortium pooled it. In the Dutch PREVEND study, 40,548 inhabitants of one city aged 28 to 75 gave an early-morning urine sample and were followed a median of 961 days, during which 516 deaths with known cause occurred. Each doubling of urinary albumin concentration carried a relative risk of 1.29 for cardiovascular death and 1.12 for non-cardiovascular death after adjustment, and the authors wrote that the relationship was already apparent at levels of albuminuria currently considered to be normal. A single population and a short follow-up, but a dose-response from the bottom of the range.14Grade B

In the Framingham Offspring Study, 1,568 participants with neither hypertension nor diabetes nor prior cardiovascular disease (mean age 55) were followed a median of 6 years, in which 54 had a first cardiovascular event. Those with a ratio at or above the sex-specific median, 3.9 mg/g in men and 7.5 mg/g in women, had 2.92 times the adjusted risk of a cardiovascular event, and the association held when the analysis was restricted to the 1,470 people without microalbuminuria. In the Copenhagen City Heart Study, 2,762 adults aged 30 to 70 gave a timed overnight sample; an albumin excretion above the upper quartile, 4.8 micrograms per minute (about 7 mg a day), carried 2.0 times the risk of coronary heart disease and 1.9 times the risk of death independently of creatinine clearance, diabetes, hypertension and lipids, and the authors proposed redefining microalbuminuria at that level. Small numbers of events in both; the direction is consistent.15,16Grade B

In the HOPE cohort of 9,043 adults aged 55 and over with cardiovascular disease or diabetes plus a risk factor, followed a median of 4.5 years, the risk of a major cardiovascular event rose quartile by quartile of the ratio: compared with under 0.22 mg/mmol (about 2 mg/g), the relative risk was 1.11 at 0.22 to 0.57 mg/mmol (about 2 to 5), 1.38 at 0.58 to 1.62 (about 5 to 14) and 1.97 above 1.62 mg/mmol (about 14 mg/g), with the trend holding after everyone with microalbuminuria was excluded. For every 0.4 mg/mmol (about 3.5 mg/g) increase, the adjusted hazard of a major event rose 5.9 percent. High-risk people, not a healthy population, but the finest-grained look at the range below 30.17Grade B

Why a kidney leak should predict heart attacks is still a hypothesis. The Steno hypothesis of 1989 proposed that albuminuria in type 1 diabetes marks generalized vascular dysfunction rather than kidney disease alone, with damage to the anionic matrix of vessel walls as the common cause. A supporting observation came from 75 people with type 1 diabetes: the rate at which albumin escaped from the circulation into the tissues was 5.0 percent an hour in controls and 5.2 percent in those with normal albumin excretion, and 8.1 percent in those with microalbuminuria, a body-wide leak measured in the blood rather than the urine. A 2006 review found no strong evidence that microalbuminuria causes atherothrombosis or the reverse, or that one shared risk factor explains the link, and concluded that a common process such as endothelial dysfunction, low-grade inflammation or increased transvascular leakage of macromolecules is the most likely explanation. The glycocalyx, the sugar-protein gel lining every vessel, is the current candidate for that process.18,19,20,8Grade 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.

  • Lowering blood pressure and protein leak with medication

    lowers it; in trials, the fall in albuminuria tracked the fall in kidney risk

    Across 41 treatment comparisons from randomized trials with 29,979 participants (71 percent with diabetes) followed a median of 3.4 years, each 30 percent reduction in geometric mean albuminuria produced by a treatment was associated with an average 27 percent lower hazard of kidney failure, an eGFR under 15 or a doubling of creatinine. The association was stronger in people whose baseline ratio was above 30 mg/g and, in the authors' words, less certain for patients with low baseline levels. The trials used blood-pressure and kidney-protective drug classes; which agent, and whether any is warranted at a given level, is a decision for the physician.21Grade A

  • Weight loss

    lowers it in proportion to the weight lost; cut the incidence of high-risk kidney disease in one trial

    Across 13 trials and 522 overweight or obese adults, intentional weight loss by diet, exercise, medication or surgery lowered microalbuminuria by 14 mg, and each kilogram lost was associated with a 1.1 mg fall in microalbuminuria independent of the fall in blood pressure; the authors found no data on whether the effect lasts. In the Look AHEAD trial, 5,145 overweight or obese adults with type 2 diabetes aged 45 to 76 were randomized to an intensive lifestyle intervention or to support and education; over a median of 8 years the incidence of very-high-risk chronic kidney disease, defined from albuminuria and eGFR, was 0.63 against 0.91 cases per 100 person-years (hazard ratio 0.69), an effect partly attributable to reductions in weight, hemoglobin A1c and systolic blood pressure. Diabetes populations in both; no trial in healthy adults.22,23Grade B

  • Salt reduction

    lowers it modestly along with blood pressure

    In a randomized double-blind crossover trial, 169 adults with untreated mildly raised blood pressure (71 white, 69 Black, 29 Asian) took slow-release sodium or placebo for 6 weeks each on a reduced-salt diet. Cutting salt from 9.7 to 6.5 g a day, about the amount public health guidance asks for, lowered blood pressure from 146/91 to 141/88 mm Hg, urinary albumin from 10.2 to 9.1 mg a day, and the albumin-to-creatinine ratio from 0.81 to 0.66 mg/mmol (about 7 to 6 mg/g), with the albumin reduction significant in all three groups. A small effect at a low starting level, in one trial of people with mild hypertension.24Grade B

  • Smoking

    raises it, dose-dependently; former smokers sat closer to never-smokers

    Among 7,476 PREVEND participants without diabetes, current smokers had a higher median albumin excretion than nonsmokers. After adjustment, smoking 20 or fewer cigarettes a day carried 1.33 times the risk of high-normal albuminuria (15 to 30 mg a day) and 1.92 times the risk of microalbuminuria, and more than 20 a day 1.98 and 2.15 times, with both an abnormally high and an abnormally low filtration rate more common in smokers. Former smokers showed the association only for microalbuminuria and less strongly. Cross-sectional data; no trial has measured what quitting does to the ratio.25Grade C

07 · Reading it well

Caveats, and what belongs with a physician.

The day moves it. The diabetes standard lists exercise within 24 hours, infection, fever, congestive heart failure, marked hyperglycemia, menstruation and marked hypertension as things that may elevate the ratio independently of kidney damage, and the kidney guideline's own table adds hematuria and symptomatic urinary infection to menstruation and exercise. Strenuous exercise in particular raises urine protein in proportion to its intensity rather than its duration, through a mixed increase in glomerular permeability and a partial block on tubular reabsorption. A sample taken the morning after a hard workout, during a cold or during a period is not a baseline.11,1,26Grade A

Posture matters, which is one reason for the first-morning sample. The guideline prefers it because it correlates well with 24-hour excretion, has relatively low within-person variability and is required to exclude orthostatic (postural) proteinuria, in which protein appears in the urine only after time upright; the condition is estimated to affect 2 to 5 percent of adolescents. A random sample is acceptable when a first-morning void is not available, and a borderline positive on a concentrated random sample in a low-risk person is a reason to repeat on a first-morning void, not a diagnosis.1Grade A

The denominator is muscle. Because creatinine excretion depends on muscle mass, the same albumin loss produces a lower ratio in a muscular person and a higher one in a slight person. In a nationally representative US sample, urine albumin concentrations did not differ between men and women but urine creatinine was significantly higher in men, so a single 30 mg/g cutoff found microalbuminuria in 6.0 percent of men and 9.2 percent of women; with sex-specific cutoffs (17 mg/g in men, 25 in women) the difference disappeared. Urine creatinine was also higher in non-Hispanic Black and Mexican American participants than in non-Hispanic white participants. The guideline's table says the same: women's lower creatinine excretion raises the ratio, men's lowers it, and low body weight pushes it up while high protein intake pushes it down. The ratio has never carried a race term, and the eGFR equations dropped theirs in 2021; the muscle effect is handled by reading the ratio against the person, or by a timed collection when the number would change a decision.27,1Grade B

A ratio of 30 or more on one sample is a prompt, not a diagnosis. Chronic kidney disease requires the abnormality to persist for a minimum of 3 months; the diabetes standard asks for two of three specimens within 3 to 6 months to be abnormal; the kidney guideline asks for a positive random sample to be confirmed on a first-morning void and for positive tests to be confirmed especially in people without risk factors, since every factor in its table can lead to false detection of kidney disease or of its progression. Between the day-to-day noise and the laboratory differences of more than 40 percent between methods, a trend across several first-morning samples from the same laboratory is the only form in which small changes mean anything.1,11,10Grade A

The cohort curves describe populations, not a target. The hazard ratios run from a reference of about 5 mg/g, and the consortium's own threshold statement names 10 mg/g, but these are the values at which a pooled curve begins to climb, not levels anyone has been treated to. The trial evidence that lowering albuminuria lowers kidney risk is strongest above 30 mg/g and, by its authors' account, less certain below it. A healthy adult with a ratio of 12 is on the shallow part of a gradient, and the right response is to know the number, know what moved it, and watch it, not to medicate it.12,21Grade B

See a physician

  • A ratio of 30 mg/g or more on two of three first-morning samples within 3 to 6 months, which meets the definition of albuminuria whatever the eGFR and is the point at which the guidelines move from watching to evaluating.
  • Any value above 300 mg/g, even once, or any value above 30 together with blood in the urine, since the combination is one of the guideline's listed reasons for specialist referral.
  • A ratio that has doubled from a previous value, after allowing for exercise, fever, infection, menstruation or a random rather than first-morning sample, which the guideline treats as exceeding laboratory variability and warranting evaluation.
  • A rising trend in someone with diabetes or high blood pressure, where the ratio is the earliest kidney signal and where medication decisions depend on it; the diabetes standard asks for the test at least once a year in these groups.
  • Visible blood in the urine, swelling of the legs or around the eyes, or foamy urine, with any ratio, since these point to a cause that needs to be found rather than a number to be tracked.

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.

  • No trial has treated healthy adults to a UACR target. The 10 mg/g figure is where the pooled cohort curves begin to climb and where the consortium drew its line for prediction; it has never been tested as a goal, and the trial meta-analysis that links a fall in albuminuria to a fall in kidney risk is explicit that the link is less certain below 30 mg/g.
  • Whether the thresholds should differ by sex is unresolved. The sex-specific cutoffs that equalize prevalence (about 17 mg/g in men, 25 in women) have been proposed since 2002, the NKDEP-IFCC group called for reference intervals that respect creatinine excretion, and the 2024 guideline kept a single 30 mg/g line while listing sex and weight as sources of variation.
  • The mechanism is still a hypothesis. Endothelial dysfunction, the glycocalyx and transvascular leakage are consistent with the data and with the Steno hypothesis, but prospective studies that tie a measured endothelial defect to later albuminuria and later events in healthy people are few.
  • Measurement is not yet standardized. There is no reference measurement procedure for albumin in urine, between-laboratory differences can exceed 40 percent, and the biological variation of urine albumin is above 60 percent; the thresholds in use were set before either problem was quantified.
  • Whether the levers that lower albuminuria in people with diabetes, hypertension or obesity do anything useful for a healthy adult with a ratio under 30 has not been studied; the Look AHEAD, salt and weight-loss data all come from people who already had a condition.

10

Questions

11 · Sources

27 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.

    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 a minimum of 3 months; albuminuria categories A1 under 30 mg/g, A2 30 to 300, A3 over 300; first-morning midstream ACR preferred and a random ACR of 30 or more confirmed on a first-morning void (practice points 1.3.1.1 and 1.3.1.2); Table 16 lists hematuria, menstruation, exercise, infection, sex, weight and protein intake as sources of variation; biological variation of urine albumin exceeds 60 percent and between-laboratory differences exceed 40 percent; a doubling of ACR warrants evaluation (2.1.5); the updated heat maps from up to 27,503,140 people use under 10 mg/g as the lowest stratum.

  2. 2.

    Haraldsson B, Nyström J, Deen WM. Properties of the glomerular barrier and mechanisms of proteinuria. Physiological Reviews. 2008. PMID 18391170. DOI 10.1152/physrev.00055.2006.

    Review · The glomerular barrier, endothelium with its surface layer, basement membrane and podocytes, is highly size- and charge-selective; the small amounts of albumin filtered are reabsorbed by the megalin-cubilin complex and degraded by proximal tubular cells, and proteinuria follows disease of any layer.

  3. 3.

    Miller WG, Bruns DE, Hortin GL, et al.; National Kidney Disease Education Program-IFCC Working Group on Standardization of Albumin in Urine. Current issues in measurement and reporting of urinary albumin excretion. Clinical Chemistry. 2009. PMID 19028824. DOI 10.1373/clinchem.2008.106567.

    Consensus statement · ACR is recommended as a surrogate for error-prone timed collections but is affected by patient preparation and time of day; there are considerable intermethod differences and no reference measurement procedure for urine albumin; the recommended reference intervals ignore large intergroup differences in creatinine excretion by age, sex and ethnicity and the continuous increase in risk with albumin excretion.

  4. 4.

    Levey AS, de Jong PE, Coresh J, El Nahas M, Astor BC, Matsushita K, Gansevoort RT, Kasiske BL, Eckardt KU. The definition, classification, and prognosis of chronic kidney disease: a KDIGO Controversies Conference report. Kidney International. 2011. PMID 21150873. DOI 10.1038/ki.2010.483.

    Consensus statement · On analyses in 45 cohorts with 1,555,332 participants, the 2009 conference agreed to retain the CKD definition of GFR under 60 or an albumin-to-creatinine ratio over 30 mg/g, and to add albuminuria stages to the classification.

  5. 5.

    Mozzi A, Forni D, Cagliani R, Pozzoli U, Vertemara J, Bresolin N, Sironi M. Albuminoid genes: evolving at the interface of dispensability and selection. Genome Biology and Evolution. 2014. PMID 25349266. DOI 10.1093/gbe/evu235.

    Review · The albuminoid family (vitamin D-binding protein, albumin, alpha-fetoprotein, afamin) arose by successive duplications of one ancestral gene, the last dated to about 250 million years ago; albumin, at around 0.6 mM in plasma, is the most abundant serum protein, and positively selected sites in mammals cluster in its fatty-acid and thyroxine binding sites.

  6. 6.

    Ichimura K, Sakai T. Evolutionary morphology of podocytes and primary urine-producing apparatus. Anatomical Science International. 2017. PMID 26627098. DOI 10.1007/s12565-015-0317-7.

    Review · Excretory organs arose early in metazoan evolution; filtration slits and slit diaphragms are highly conserved across animals; the vertebrate glomerulus adds fenestrated endothelial capillary loops and mesangial cells; birds and mammals run glomerular capillary pressure at about 50 mm Hg, 5 to 10 times the aortic pressure of lower vertebrates.

  7. 7.

    Weavers H, Prieto-Sánchez S, Grawe F, et al.. The insect nephrocyte is a podocyte-like cell with a filtration slit diaphragm. Nature. 2009. PMID 18971929. DOI 10.1038/nature07526.

    Laboratory method study · Fruit-fly orthologues of nephrin, NEPH1, CD2AP, ZO-1 and podocin form a nephrocyte diaphragm mirroring the vertebrate slit diaphragm complex, lost with impaired filtration when nephrin or NEPH1 is absent, evidence that nephrocytes and podocytes are evolutionarily related.

  8. 8.

    Rabelink TJ, de Zeeuw D. The glycocalyx--linking albuminuria with renal and cardiovascular disease. Nature Reviews Nephrology. 2015. PMID 26460356. DOI 10.1038/nrneph.2015.162.

    Review · Loss of the glycocalyx, the polysaccharide gel lining the luminal endothelial surface that normally acts as a barrier against albumin filtration, follows endothelial activation and can lead to albuminuria and to renal and vascular inflammation, a framework for the association of albuminuria with kidney and cardiovascular disease.

  9. 9.

    Witte EC, Lambers Heerspink HJ, de Zeeuw D, Bakker SJ, de Jong PE, Gansevoort R. First morning voids are more reliable than spot urine samples to assess microalbuminuria. Journal of the American Society of Nephrology. 2009. PMID 19092125. DOI 10.1681/ASN.2008030292.

    Laboratory method study · In 241 cohort participants with three 24-hour collections, a first-morning void and a spot sample, the first-morning ACR agreed best with 24-hour excretion, with a within-person coefficient of variation of 19 percent equal to the 24-hour collection; microalbuminuria prevalence was 7.5 percent by first-morning void, 10.0 percent by 24-hour collection and 22.4 percent by spot ACR.

  10. 10.

    Naresh CN, Hayen A, Weening A, Craig JC, Chadban SJ. Day-to-day variability in spot urine albumin-creatinine ratio. American Journal of Kidney Diseases. 2013. PMID 23958401. DOI 10.1053/j.ajkd.2013.06.016.

    Laboratory method study · In 157 stable outpatients with spot samples on consecutive mornings, a change of more than 467 percent was needed to show a real change with 95 percent certainty at ACR under 27 mg/g, 170 percent at 27 to 265 mg/g and 83 percent above 265 mg/g.

  11. 11.

    American Diabetes Association Professional Practice Committee. 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes-2024. Diabetes Care. 2024. PMID 38078574. DOI 10.2337/dc24-S011.

    Guideline · Assess urinary albumin at least annually in type 1 diabetes of 5 or more years and in all type 2 diabetes (11.1a, grade B); normal under 30 mg/g, moderately elevated 30 to 300, severely elevated 300 or more; because of biological variability above 20 percent, two of three specimens within a 3- to 6-month period should be abnormal before albuminuria is diagnosed; exercise within 24 hours, infection, fever, congestive heart failure, marked hyperglycemia, menstruation and marked hypertension may elevate UACR independently of kidney damage.

  12. 12.

    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 (730,577 person-years) from 14 cohorts with ACR measurements, ACR was associated with mortality linearly on the log-log scale without threshold: versus 0.6 mg/mmol, hazard ratios 1.20 at 1.1 mg/mmol (10 mg/g), 1.63 at 3.4 and 2.22 at 33.9; the authors name ACR of 10 mg/g or more as an independent predictor of mortality.

  13. 13.

    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, log albuminuria was linearly associated with log risk of end-stage renal disease without thresholds; adjusted hazard ratios at ACR 30, 300 and 1,000 mg/g were 5, 13 and 28 versus 5 mg/g, independent of eGFR and cardiovascular risk factors.

  14. 14.

    Hillege HL, Fidler V, Diercks GF, et al.; Prevention of Renal and Vascular End Stage Disease (PREVEND) Study Group. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation. 2002. PMID 12356629. DOI 10.1161/01.cir.0000031732.78052.81.

    Prospective cohort · Among 40,548 Groningen residents aged 28 to 75 followed a median of 961 days (516 deaths), a doubling of early-morning urinary albumin concentration carried a relative risk of 1.29 for cardiovascular and 1.12 for non-cardiovascular death, with the relationship already apparent at levels considered normal.

  15. 15.

    Arnlöv J, Evans JC, Meigs JB, Wang TJ, Fox CS, Levy D, Benjamin EJ, D'Agostino RB, Vasan RS. Low-grade albuminuria and incidence of cardiovascular disease events in nonhypertensive and nondiabetic individuals: the Framingham Heart Study. Circulation. 2005. PMID 16087792. DOI 10.1161/CIRCULATIONAHA.105.538132.

    Prospective cohort · In 1,568 nonhypertensive, nondiabetic Framingham Offspring participants followed a median of 6 years (54 events), a UACR at or above the sex-specific median (3.9 mg/g men, 7.5 women) carried an adjusted hazard of 2.92 for cardiovascular disease, robust in the 1,470 without microalbuminuria.

  16. 16.

    Klausen K, Borch-Johnsen K, Feldt-Rasmussen B, Jensen G, Clausen P, Scharling H, Appleyard M, Jensen JS. Very low levels of microalbuminuria are associated with increased risk of coronary heart disease and death independently of renal function, hypertension, and diabetes. Circulation. 2004. PMID 15210602. DOI 10.1161/01.CIR.0000133312.96477.48.

    Prospective cohort · In 2,762 Copenhagen adults aged 30 to 70 with a timed overnight sample, albumin excretion above the upper quartile (4.8 micrograms per minute) carried relative risks of 2.0 for coronary heart disease and 1.9 for death independently of creatinine clearance, diabetes, hypertension and lipids.

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    Gerstein HC, Mann JF, Yi Q, et al.; HOPE Study Investigators. Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals. JAMA. 2001. PMID 11466120. DOI 10.1001/jama.286.4.421.

    Prospective cohort · In 9,043 high-risk adults aged 55 and over followed a median of 4.5 years, relative risks of major cardiovascular events by ACR quartile were 1.11, 1.38 and 1.97 (quartile bounds 0.22, 0.57 and 1.62 mg/mmol) versus the lowest, with the trend persisting after excluding microalbuminuria; each 0.4 mg/mmol increase raised the hazard 5.9 percent.

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    Deckert T, Feldt-Rasmussen B, Borch-Johnsen K, Jensen T, Kofoed-Enevoldsen A. Albuminuria reflects widespread vascular damage. The Steno hypothesis. Diabetologia. 1989. PMID 2668076. DOI 10.1007/BF00285287.

    Review · Albuminuria in type 1 diabetes is proposed as a marker of generalized vascular dysfunction, with damage to anionic extracellular-matrix components such as heparan sulfate proteoglycan as the common cause of albuminuria and of the renal and extrarenal complications associated with it.

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    Feldt-Rasmussen B. Increased transcapillary escape rate of albumin in type 1 (insulin-dependent) diabetic patients with microalbuminuria. Diabetologia. 1986. PMID 3522326. DOI 10.1007/BF00452063.

    Cross-sectional study · In 75 people with type 1 diabetes and 15 controls, the transcapillary escape rate of albumin was 5.0 percent in controls and 5.2 percent with normal albumin excretion, and 8.1 percent with microalbuminuria and with nephropathy, a universal vascular leak present by the microalbuminuric stage.

  20. 20.

    Stehouwer CD, Smulders YM. Microalbuminuria and risk for cardiovascular disease: Analysis of potential mechanisms. Journal of the American Society of Nephrology. 2006. PMID 16825333. DOI 10.1681/ASN.2005121288.

    Review · No strong evidence that microalbuminuria causes atherothrombosis, that atherothrombosis causes microalbuminuria, or that a common risk factor explains the link; the most likely possibility is a common process such as endothelial dysfunction, chronic low-grade inflammation or increased transvascular leakage of macromolecules.

  21. 21.

    Heerspink HJL, Greene T, Tighiouart H, et al.; Chronic Kidney Disease Epidemiology Collaboration. Change in albuminuria as a surrogate endpoint for progression of kidney disease: a meta-analysis of treatment effects in randomised clinical trials. Lancet Diabetes and Endocrinology. 2019. PMID 30635226. DOI 10.1016/S2213-8587(18)30314-0.

    Systematic review and meta-analysis · Across 41 randomized treatment comparisons with 29,979 participants (71 percent with diabetes) over a median 3.4 years, each 30 percent treatment-induced decrease in geometric mean albuminuria was associated with an average 27 percent lower hazard of the kidney composite, stronger above a baseline of 30 mg/g and less certain at low baseline albuminuria.

  22. 22.

    Afshinnia F, Wilt TJ, Duval S, Esmaeili A, Ibrahim HN. Weight loss and proteinuria: systematic review of clinical trials and comparative cohorts. Nephrology Dialysis Transplantation. 2010. PMID 19945950. DOI 10.1093/ndt/gfp640.

    Systematic review and meta-analysis · Across 5 controlled and 8 uncontrolled trials with 522 overweight or obese adults, weight-loss interventions lowered microalbuminuria by 14 mg and proteinuria by 1.7 g, with each kilogram lost associated with a 1.1 mg fall in microalbuminuria independent of blood pressure; no data on durability.

  23. 23.

    Look AHEAD Research Group. Effect of a long-term behavioural weight loss intervention on nephropathy in overweight or obese adults with type 2 diabetes: a secondary analysis of the Look AHEAD randomised clinical trial. Lancet Diabetes and Endocrinology. 2014. PMID 25127483. DOI 10.1016/S2213-8587(14)70156-1.

    Randomized trial · Among 5,145 overweight or obese adults with type 2 diabetes randomized to intensive lifestyle intervention or support and education, very-high-risk CKD over a median 8 years occurred at 0.63 versus 0.91 cases per 100 person-years (hazard ratio 0.69), partly attributable to lower weight, A1c and systolic blood pressure.

  24. 24.

    He FJ, Marciniak M, Visagie E, Markandu ND, Anand V, Dalton RN, MacGregor GA. Effect of modest salt reduction on blood pressure, urinary albumin, and pulse wave velocity in white, black, and Asian mild hypertensives. Hypertension. 2009. PMID 19620514. DOI 10.1161/HYPERTENSIONAHA.109.133223.

    Randomized trial · In a randomized double-blind crossover trial of 71 white, 69 Black and 29 Asian adults with untreated mild hypertension, reducing salt from 9.7 to 6.5 g a day lowered blood pressure from 146/91 to 141/88 mm Hg, urinary albumin from 10.2 to 9.1 mg a day and ACR from 0.81 to 0.66 mg/mmol, significant in all three groups.

  25. 25.

    Pinto-Sietsma SJ, Mulder J, Janssen WM, Hillege HL, de Zeeuw D, de Jong PE. Smoking is related to albuminuria and abnormal renal function in nondiabetic persons. Annals of Internal Medicine. 2000. PMID 11033585. DOI 10.7326/0003-4819-133-8-200010170-00008.

    Cross-sectional study · Among 7,476 nondiabetic PREVEND participants, smoking 20 or fewer and more than 20 cigarettes a day carried adjusted relative risks of 1.33 and 1.98 for high-normal albuminuria (15 to 30 mg a day) and 1.92 and 2.15 for microalbuminuria; associations were less pronounced or absent in former smokers.

  26. 26.

    Poortmans JR. Postexercise proteinuria in humans. Facts and mechanisms. JAMA. 1985. PMID 3965775.

    Review · Postexercise proteinuria relates to the intensity of exercise rather than its duration and is of mixed glomerular-tubular type after heavy exercise, reflecting increased glomerular permeability and partial inhibition of tubular reabsorption.

  27. 27.

    Mattix HJ, Hsu CY, Shaykevich S, Curhan G. Use of the albumin/creatinine ratio to detect microalbuminuria: implications of sex and race. Journal of the American Society of Nephrology. 2002. PMID 11912263. DOI 10.1681/ASN.V1341034.

    Cross-sectional study · In a nationally representative US sample, urine albumin did not differ by sex but urine creatinine was higher in men, so a single 30 mg/g cutoff found microalbuminuria in 6.0 percent of men and 9.2 percent of women; sex-specific cutoffs of 17 mg/g (men) and 25 mg/g (women) removed the difference; urine creatinine was also higher in non-Hispanic Black and Mexican American participants.

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