ORIGINAL ARTICLE
JNEPHROL 2013; 26 ( Suppl 22): S77-S81
DOI: 10.5301/jn.5000344
Oliver and Feigl: 2 forgotten fathers of “stick”
testing of urine for albumin
J. Stewart Cameron 1, Guy Hume Neild 2
1
Guy’s Campus, King’s College, London - UK
UCL Centre for Nephrology, University College,
London - UK
2
Introduction
It is surprising, given the central importance of urine testing in nephrology that so little is known among practitioners
about the background and history of the commonest method used today: “stix” testing. The only major discussion we
know of is the superb work of the Lűbeck historian Peter
Voswinckel which, although published in Kidney International, was in a supplement for a symposium on new urinary
markers (1) and has rarely been cited (Google 23 citations,
Scopus 13).
We focus here particularly on 2 pioneers in the area whose
role has been overlooked: the Englishman George Oliver
(1841-1915) and the Viennese/Brazilian Friedrich (Fritz) Feigl
(1891-1971). The first was a family physician, the second
a chemist, and their roles in the 19th and 20th centuries,
respectively, epitomize the shift in innovation within medical
chemistry from clinician–scientists to professional laboratory-based full-time scientists. We shall also focus principally
on the testing of urine for protein, as this is the single most
important urine test, at least for nephrology.
Urine testing before 1880
Ignoring the millennium of uroscopy, we can say that urine
testing began in the late 18th century. William Cruickshank
(2) showed in 1798 that what came to be called “albuminous” urine would coagulate, using a number of reagents including nitric acid. Cotugno had shown already in 1774 that
urine in dropsy could coagulate on heating, an observation
emphasised and correlated by John Bostock and Richard
Bright in 1827 (2).
In British hospitals, coagulation of acidified urine by heat
remained the standard. But for family physicians, riding on
their horses or in their carriages to see their patients in their
homes, it was a problem to carry in their medical bags a
spirit lamp and test tubes.
On the Continent in contrast, many physicians preferred
the nitric acid test of the Czech Florian Heller (1813-1845)
(3), which used careful layering of the acid below the urine,
poured slowly down the side of a vessel, and the white ring
formed at the junction of the 2 layers. This involved carrying
concentrated acid either in the bag or in the waistcoat, but
according to an editorial at the time: “It is no joke, to have a
bottle of this burst in the pocket” (4).
“Wet” chemistry involving bottles of dangerous reagents
and/or heat was clearly unsatisfactory, and many general
practitioners must have dismissed these tests as something
only for hospitals. In fact “dry” chemistry already had quite
a long history. Voswinckel (1) mentions a test for iron adulteration of bronze coinage of Pliny the Elder (ad 1st century),
using papyrus strips impregnated with gallae (oak gall extract). The invention of litmus paper is attributed to Robert
Boyle in the 17th century, which was possibly the original
urine “stick” test and is still in use today. But dry testing for
urine constituents really began with Edme Jules Maumené
(1818-1898), an agricultural chemist expert in wine and
sugars. In 1850 he introduced a test for glucose involving
strands of merino sheep’s wool, impregnated with tin protochloride (stannous chloride, ZnCl2), which, when urine was
added and heated, turned black (5). Although not a clinician,
he was clearly aware of the utility of this test in clinical practice: “With the aid of this chloride-impregnated merino wool
the doctor could, without any difficulty, determine whether
the urine of patient shows appreciable traces of sugar” (5).
It appears that Maumené’s test, although used in France
and Germany (1) was unknown to the English George
Oliver (1841-1915), family physician, chemist and physiologist, who stated: “About a year ago (1883) the idea occurred
to me to run test solutions into chemically inert filtering
paper, linen or other fabric, and after drying, to use the
product cut up into test papers” (6). Unlike Maumené, Oliver
could use paper or linen as a base, because he did not
employ heat in his tests.
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Cameron and Neild: Origins of urine “stick” testing: Oliver and Feigl
George Oliver: the biography
George Oliver (Fig. 1) (7-9) was the second son of
Walter Oliver, a surgeon practising in Middleton-in-Teesdale.
Schooled in Yorkshire then in medicine at London’s University College, George Oliver qualified in 1863, then took his
MD (London) in 1873, winning the gold medal for the year.
He settled into family practice in Harrogate in 1876, and
specialised in caring for the wealthy summer visitors to the
spa there. This not only assured him an of an income but
allowed him to spend the winter around London to pursue
his many research interests. Elected a fellow of the Royal
College of Physicians of London in 1887, he gave their
prestigious Croonian lectures in 1896 (10). He stayed in
Harrogate until 1908, when he retired further south. He died
in 1915 aged 73, at his country house in Farnham, Surrey.
Oliver was also an inventor of clinical instruments, including
one for measuring the diameter of blood vessels, the details
of which are not now clear. He studied the effect of extracts
prepared with water or glycerol from brain and glands such
as thyroid and adrenal on the vessels, often using members
of his family as subjects (11). He injected his young son with
extracts of adrenal gland from his local butcher, which led to
scientific papers on “adrenaline” with Schäfer, for which he
is best known (12).
Oliver’s “test papers”
In contrast, his copious work on bedside urine testing is
usually ignored. Oliver launched his paper test strips in a
2-part article in the Lancet in 1883 (13), followed by his book
On Bedside Urine Testing: Qualitative Albumen and Sugar,
published the next year (6).
Oliver’s idea was that papers with reagents dried onto them
could be used with the urine as the aqueous medium for
the test reaction. Testing for albumin, he first acidified the
urine using a strip impregnated with citric acid. He was able
also to make single compound strips, bound to rubber, one
side containing citrate, the other side containing the reagent
of interest. For protein he studied picrate, tungstate and
(potassium) ferricyanide, then finally, following a suggestion
in 1872 from Tanret in France, potassio-mercuric iodide,
which he preferred as being the most sensitive, although
praising also ferricyanide.
The second half of Oliver’s book On Bedside Urine Testing
deals with glucose using papers impregnated with indigo
carmine, which we will not consider further here.
Both book and strips met with success – the former sold
beyond 1900 in 4 editions, and the test papers were sold
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Fig. 1 - Photograph of George Oliver (1841-1915) in 1895 (photographer unknown).
by Arnold and Sons of London, at 1 shilling for the protein
strips, and 1s 6d for the glucose strips. In the United Kingdom, it seems that their use did not survive the World War I,
however, perhaps because their author and promoter died
in 1915. Voswinckel (1) relates that Oliver’s strips were first
exported to, then pirated in, Germany in 1895 by Geissler of
Dresden. At first they were referred to as Olivers Reagenspapiere, but then became Geisslerische Reagenspapiere, sold
by Chemische Fabrik Helfenberg AG, and were still in use in
Germany during the 1920s. During this decade also a number
of urine test strips were created by Hans Lipp (1876-1944), a
bacteriologist in Munich, one being Albucit (later Albumacit),
based on molybdic and sulphosalicylic acids. These were still
in use, in veterinary practice at least, until World War II.
Oliver’s work was paralleled by the physician William Pavy
(1829-1911) of Guy’s Hospital in London, who achieved
a “dry” reaction for urine testing in 1880 using reagents in
© 2013 Società Italiana di Nefrologia - ISSN 1121-8428
JNEPHROL 2013; 26 ( Suppl 22): S77-S81
tablet form – called Pavy’s pellets – which could be dropped
into a tube full of urine. Although his solid system for
glucose is quite well-known (14) because they were antecedent to the famous Clinitest tablets (introduced in 1941),
Pavy also described in 1885 a less well-known citrateferricyanide pellet for albumin (15). This appears not to
have caught on much even in England, and again did not
survive long after their inventor’s demise (in 1911).
Enter the chemists:
fritz feigl (1891-1971)
The World War II destroyed German science and manufacture, and the Hitler regime depleted Germany of huge
numbers of talented people of Jewish background. One
of these was Friedrich (Fritz) Feigl, also known as Efraim
ben Shemuel HaKohen (16-18) (Fig. 2).
Feigl was born in Vienna in 1891. He served with distinction as an officer in World War I in the Austro-Hungarian
army on the Russian front, and was wounded in action.
Returning to his studies, he completed his doctoral thesis
in science in 1920 with work on Tűpfelreaktionen (spot
tests) – which became his life’s work (16, 18).
His spot tests were microchemical analyses of amazing
sensitivity, depending on specific reactions of often complex molecules, using surfaces to concentrate and bring the
reagents together – usually absorbent filter paper, although
many surfaces were suitable. They were particularly useful for screening purposes outside the laboratory, even if
not quantitative. On the basis of this work he was, by
1928, professor in the Vienna Polytechnic and by 1937
a full university professor, respected and admired internationally, with a number of already classic texts to his
name.
In 1937 Feigl and associate Vincenz Anger described the
exact principles of the reaction upon which stick tests to
detect albuminuria depend today (19). His search for a spot
test for albumin was stimulated by Viennese physician
Otto von Fűrth’s review of his 1931 book (20), and his and
Anger’s paper was dedicated to Fűrth’s 70th birthday
(19).
The principle of Feigl’s test for albumin is now well-known,
and was based on observations of Søren P.L. Sørensen
(1868-1939) at the Carlsberg laboratory in Copenhagen
in 1909-1912, on the interaction of proteins with hydrogen ions – work which led Sørensen to introduce
the pH scale. In the course of measuring pH using coloured chemical indicators, he noticed that in the pres-
Fig. 2 - Photograph of Friedrich (Fritz) Feigl (1891-1971) in
about 1960 (courtesy of Conselho Regional de Química, IV
Região (photographer unknown).
ence of amphoteric protein, particularly albumins, several indicator dyes had the pH at which their colour
changed shifted, which interfered with the measurement. This effect was therefore called by Sørensen
(21) Proteinfehler, usually translated as “protein error.”
Feigl cited the observations of his old mentor, Nobel Prize
winner Peter Karrer, involving the dye tetra brom(o)phenol
(phthalein) blue in designing his spot test. This compound
when acidified is yellow, turning blue with alkali. When an
acid-buffered fluid added to the spot test on filter paper
(“bibulous paper”) contains albumin, a blue colour appears. Despite the simplicity of this test in principle and
practice, it remained buried in the chemical literature, unused by and unknown to clinicians for 20 years.
But there was another factor leading to this albumin test
being lost and forgotten. Feigl’s days of hard, successful
work in Vienna finished abruptly shortly after the paper
on albumin was published, with the Anschluss in 1938.
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Cameron and Neild: Origins of urine “stick” testing: Oliver and Feigl
As a prominent Jew, he and his family had to leave, first
for Switzerland, then Belgium where he managed to work
until its invasion in 1940 by the Nazis. His escape to Britain was being planned, when he was arrested (while his
wife Regine and their son were away) and sent to a camp
in Vichy France, near Perpignan. Regine managed to persuade the Brazilian consul at the Vichy government to
prepare papers which allowed their escape to Brazil via
Andorra and Portugal.
Feigl was welcomed as an experienced scientist, and settled in quickly in Rio in the Laboratório da Produçâo Mineral, now walking as he loved to do, along Copacabana
beach, rather than through the Wienerwald. He published
another 300 papers on chemistry from 1941 onwards, and
several more books. He worked mainly on extraction of
natural resources (coffee and phosphate) and agriculture
(e.g., lead contamination of water and fish), retiring nominally in 1961. He received many honours in Brazil and
internationally after the war for his work, and a Chemistry
prize was created in his name. But clinicians know nothing of Feigl, despite using his method every day.
Ames –
and
Lilly:
the
“stix”
era
arrives
The small laboratory of Ames in Elkhart, Indiana, run by
chemist Walter Ames Compton, had merged in 1938 with
the much larger Miles Laboratories, founded in 1884.
Miles manufactured the famous fizzing stomach remedy
Alka Seltzer, which led to their producing the equally successful Clinitest tablet test for urine sugar in 1941, a direct descendant of Pavy’s pellets to detect glucose in the
1880s.
Chemist Alfred Free (1913-2000) (22, 23) from Cleveland,
Ohio, joined Miles in 1946; he is often, but erroneously,
credited with “inventing” stick tests. The following year
he recruited and then married Helen Murray (born 1923)
(23, 24), also trained in Ohio. Together they worked to
improve Clinitest and produce another tablet, Acetest in
1950.
Now the Frees and their colleagues had albuminuria in their
sights. They evolved a tablet test for albumin – Albutest. This
was the first really “dry” urine test, in that urine and water
were placed on the tablet on a tile or bench, and no test tube
was needed. The methodology was exactly that of Feigl,
using tetrabromophenol blue buffered in its yellow acid
form, and employing the “protein error” to detect albumin.
But in the meantime, the Frees exploited the ideas and
technology of Albert H. Keston of the New York University School of Medicine (25), to transfer a test for urine
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glucose onto the surface of a paper stick. Keston also
used entirely novel methodology – the recently described
glucose oxidase. Thus Dextrostix were born; the “-stix”
ending was a novelty which has stuck. Meanwhile, identical chemistry was developed at Eli Lilly Laboratories by
J.P. Comer (25) leading to the paper Tes-tape, for which a
similar patent had been filed as early as 1954.
So Albutest tablets (26) had scarcely been introduced
when, again using the same Feigl methodology but now
on filter paper, the Frees designed Albustix in 1957 (27).
But nowhere had they cited Feigl’s crucial work – or Keston’s - although they were certainly aware of Feigl since
both the 1957 clinical evaluation paper for Albutest (26),
and the patent filed in 1957 (28) by Galen F. Collins for
Miles Laboratories (accepted in 1962) do cite Feigl. Despite this, published material from Miles Laboratories
(now part of Bayer Labs) implies that the idea of using
Sørensen’s colour change to detect protein, and the use
of paper, were both the Frees’ discovery. However, by
1956 at least 2 other groups had used the Sørensen/Feigl
technology to estimate albumin concentrations (29, 30)
both citing Feigl’s priority.
Today, stick tests for albuminuria – and now microalbuminuria – are ubiquitous, and a billion or more urine
tests a year must depend upon stick technology and
“dry” chemistry. Oliver did not see this, but although
Feigl lived to see the beginning, we do not know if
he was aware of the success of his ideas. We imagine he would have been delighted to see the ubiquity
of micro-tests depending on Sorensen’s colour reaction on “bibulous paper” in the form of a “stick” to appose the reagents. What he thought of the vast profits
derived from his work we will never know – he himself
led a modest life, and took out very few patents from his
thousands of new reactions.
Financial support: The authors report no financial support.
Conflict of interest: The authors report no conflicts of interest.
Address for correspondence:
Emeritus Professor J.S. Cameron
Elm Bank
Melmerby, Cumbria CA10 1HB, UK
jstewart.cameron2@btopenworld.com
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JNEPHROL 2013; 26 ( Suppl 22): S77-S81
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