Test papers to dipsticks in 72 years 

The SSA test came first. From Cornell Vet School, with permission*

For urinary protein detection the basic chemistry was established in the late 1700s, and until the late 1950s the standard test was still based on acidification and/or heating of urine to precipitate protein.

Carrying bottles of acid about was not very physician-friendly, but this was standard for physicians until after 1900.  Efforts to develop dry chemistry that could achieve the same ends were beginning to be productive by 1850. Maumené described a method using sheeps wool impregnated with stannous chloride, then heated with a candle, to detect glucose.  In 1883 physician George Oliver, working in London and Yorkshire, described tests for glucose and protein using paper or linen.  He is best known for describing the effect of adrenaline (he injected his son with extracts of glands obtained from a local butcher), but also did extensive work leading to a Lancet paper in 1883 and a book Bedside Urine Testing in 1884 which went through several editions. These described test papers for urine which were marketed (and copied) in the UK and particularly in Europe into the early part of the 20th century. 

Figures show Oliver’s test papers and their predecessor, a urine testing kit that includes bottles of acid and a spirit lamp, from Arnold and Sons 1895 Catalogue of Surgical Instruments and Appliances (University of Edinburgh Library)

At about the same time London physician William Pavy developed tablets (‘Pavy’s pellets’) which could be dropped into a tube of urine to test for glucose.  His 1880 test was based on copper and so was the antecedent of ‘Clinitest’ tablets which were introduced in 1941, but he also had a test for protein based on citrate-ferricyanide. In the 1920s and 30s a variety of competing dry chemistry approaches were available, but Fritz Feigl (1891-1971) working in Vienna developed the tetrabromophenol blue spot test that we still use in dipsticks.  He worked extensively on the concept of spot tests, and exploited the prior observation that protein inhibited the effect of acid on the colour of the compound, so in an acid buffer its colour changes from yellow to blue as protein concentration increases. This had been termed ‘protein error’.  His development of these tests was curtailed by his forced flight from the Nazi regime to Brazil, where he later became a successful chemist.

Ames/Bayer urine tests, with permission*

The final commercialisation of these inventions can be attributed to the husband-wife team of Helen Murray and Alfred Free working in the Miles (originally Ames; later Bayer) labs in Indiana.  The company had developed Clinitest for glucose, based on its experience in producing the fizzy soluble antacid/aspirin preparation Alka-Seltzer.  They worked on a similar method for protein, but guided by the Frees moved to the idea of dry chemistry.  Picking up the newer and more specific glucose oxidase method they developed Clinistix for glucose, first marketed in 1956.  The following year Albustix were released for detection of urinary protein.  Albustix applied the principles of Feigl’s chemistry.  Over the following 20 years the group added methods for detecting ketones, blood, biliubin, urobilinogen, nitrite, leukocytes and pH to make multi-analyte dipsticks.  In parallel they developed methods for blood glucose and for machine reading of sticks. 

In 1958 de Wardener still described the salicyl sulphonic acid (SSA) test as standard for urinary protein.  It was graded from trace to ++++ (see image at top), a grading scale we still use on dipsticks today. 

Further info
Proteinuria – a bad thing since 400 BC (this blog)
Voswinckel P 1994  A marvel of colors and ingredients.  The story of urine test strips.  Kidney Int 46 (Suppl47) S3-7.  Outstanding review.
Cameron JS, Neil GH. 2013. Oliver and Feigl: two forgotten fathers of stick testing of urine for albumin.  J Nephrol 26 (Supl 22) S77-81
American Chemical Society 2010.   National Historic Chemical Landmarks. Development of Diagnostic Test Strips.  http://bit.ly/MiXthn
de Wardener HJ 1958 The Kidney (1st edition). Churchill: London
Wikipedia on Urine test strips is a very good account.

Images – Thanks to Cornell Vet School for permission to use the image of the SSA test for urinary protein from their excellent eClinPath website.  The image of Ames historic urine testing products is used with kind permission of Bern Harrison (Bayer Sensor Technology).  More info on this and the Frees from the American Chemical Society.