Sposobnosti koncentriranja bubrega sisavaca: povijesni pregled

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The first description of the renal tubules is attributed to Lorenzo Bellini in 1662 and four 

years later Marcello Malpighi described the glomerulus. In 1842 Sir William Bowman de-

scribed the capsule that surrounds the Malpighian body and its connection with the renal 

tubule and introduced the “excretory” hypothesis of urine formation. In the same year, Carl 

Ludwig introduced the “filtration-reabsorption” hypothesis of urine formation. Bowman’s 

hypothesis was accepted by the so-called “vitalists” and Ludwig’s hypothesis by the so-called 

“mechanists”. In the middle of this confliction, Jacob Henle described in 1862 the homony-

mous “U” shaped loop but his discovery has neglected. In 1942 Werner Kuhn, a physical 

chemist, proposed that the loop of Henle may be the natural analog of the hairpin countercur-

rent multiplication system which concentrates urine in mammalian kidneys. In 1951 Kuhn, 

Hargitay and Wirz showed experimentally that the loop of Henle was the most important 

part of the countercurrent multiplication system of urine-concentrating mechanism in mam-

malian kidneys. The new theory was accepted by English-speaking scientists later, in 1958, 

when Carl Gottschalk and Margaret Mylle published their experimental work and proved 

that Kuhn’s theory was correct. Gottschalk summarized the evidence of the accumulated 


Nephrology Department, General Hospital of Corfu. Greece.


St. Elizabeth’s Medical Center, Boston. USA. 

Corresponding author: Efstathios Koulouridis, MD. Nephrology Department. General 

Hospital of Corfu. Greece. Spirou Rath 41. TK 49100. Corfu, Greece. Tel. 0030-2661-

360-562. Fax: 0030-26610-22660. Electronic address: koulef@otenet.gr

Pregledni rad 

Acta med-hist Adriat 2014; 12(2);413-428

Review article 

UDK: 61(091):001.894

knowledge in 1962, three centuries after the first description of renal tubules and one century 

after description of Henle’s loop. 

: Loop of Henle, urine formation mechanism, vitalists, mechanists, countercur-

rent multiplication system.


At the end of the Mesozoic era, about 66 million years ago, mammals 

migrated from the water to terrestrial life. As a consequence, they were de-

prived from free access to water and sodium. In order to survive in the new 

environment, they had to develop an excretory organ with the capacity to 

independently conserve salt and water. This organ was no other than the 



We know now that lower vertebrates are capable to produce isotonic or 

hypotonic urine. Nevertheless, only mammals and some birds are capable 

to produce hypertonic urine. This capability is essential to conserve water 

under conditions of environmental dryness and limited access to water




The mechanism by which the mammalian kidney concentrates urine 

is complex and relies upon the specialized architecture and sophisticated 

function  of  certain  nephron  segments  as  well  as  accompanying  blood  ves-

sels. The fundamental structure of urine concentration is the “U” shaped 

loop of Henle accompanied with the collecting duct and the vasa recta in 

an obligatory manner unique only among species with the capacity of urine 



The loop of Henle was first described by the German pathologist 

Friedrich Gustav Jacob Henle in 1862, and presented with excellent accuracy 

in his monograph with the title: “Zur Anatomie der Niere” Von J. Henle. 

Gottingen. Verlag der Dieterichscen Buehhandlung. 1862. The monograph 

is accompanied with marvelous hand made illustrations showing the thin 

descending limb, the thick ascending limb and the transition from the thin 

ascending to the thick ascending limb. (Figure: 1). It took almost a century 

to recognize the importance of this structure in urine concentrating mech-

anism, for many years it was thought that loop of Henle has no functional 

significance and was considered only as an “incidence of organogenesis” 


The reason that Henle’s discovery remained buried for a long time before 

physiologists recognize its importance in urine concentration is the lack of 

knowledge upon the structure and function of the elemental kidney unit, 

the nephron, as well as the lack of proper instruments for experimental work 

upon renal function and proper estimation of plasma and urine constituents. 

The first description of renal tubule is attributed to the Italian anatomist 

Lorenzo Bellini who in 1662 described the papillary ducts which took his 

name. Four years later in 1666 the Italian physician and anatomist Marcello 

Malpighi described the glomerulus in the renal cortex, which took the name 

“Malpighian body”, and its connection with the efferent and afferent arter-

ies. He proposed also the possible connection with renal tubules but did not 

prove it 


The debate between “Vitalists” and “Mechanists”.

After the above mentioned preliminary discoveries, it took about two 

centuries until the English surgeon, histologist and anatomist Sir William 

Bowman in 1842 described the capsule which surrounds the “Malpighian 

body” and its connection with the kidney tubules. (Figure: 2). Bowman in-

vestigated also the epithelium of uriniferous tubules and he was impressed 

with the similarities between this epithelium and the epithelium of excreto-

ry tubules of digestive glands and he arbitrarily inferred that tubular cells 

Figure 1: Left: Friedrich Gustav Jacob Henle (1809-1885). German 

physician, pathologist and anatomist. Right: Hand made drawings of the 

homonymous loop showing with accuracy the thin descending limb, the 

thick ascending limb and the transition from the thin ascending to the 

thick ascending limb. (“Zur Anatomie der Niere”, 1862).

Slika 1. Lijevo: Friedrich Gustav Jacob Henle (1809.-1885.). Njemački liječnik, 

patolog i anatom. Desno: Ručno rađeni crteži homonimne petlje, koji točno 

pokazuju tanku silaznu granu, debelu uzlaznu granu i prelazak od tanke uzlazne 

ka debeloj uzlaznoj grani. (“Zur Anatomie der Niere”, 1862.).

excrete the urine constituents and glomerulus produce only a stream of wa-

ter which washes out the excreted solutes from tubules 


In his seminal paper “On the structure and use of the Malpighian bodies 

of the kidney, with observations on the circulation through that gland”, pre-

sented to the Royal Society of London, 17 February 1842, http://www.jstor.

org/stable/108143, he wrote: 

 “These tubes consists of an external tunic of transparent homogeneous tissue 

(which I have termed the basement membrane), lined by epithelium. The Malpighian 

bodies I saw to be rounded mass of minute vessels invested by a cyst or capsule of pre-

cisely similar appearance to the basement membrane of the tubes”.

“… I injected some kidneys through the artery, by this method, in order to notice 

the nature of the vascular ramifications in the Malpighian bodies. I not only found 

what I sought, but the clearest evidence that the capsule which invest them is, in 

Figure 2: Left: Sir William Bowman, 1st Baronet, (1816 - 1892). English 

surgeon, histologist and anatomist. Right: Hand made drawings showing 

the glomerulus the surrounding capsule and the uriniferous tubules 

from many species including humans. (“On the structure and use of the 

Malpighian bodies of the kidney”, 1842).

Slika 2. Lijevo: Sir William Bowman, I. Baron (1816. - 1892.). Engleski kirurg, 

histolog i anatom. Desno: Ručno rađeni crteži koji pokazuju glomerus, okružujuću 

kapsulu i urinoferusne tubule mnogih vrsta, uključujući i ljude. (“On the structure 

and use of the Malpighian bodies of the kidney”, 1842.).

truth, the basement membrane of the uriniferous tube expanded over the tuft of 


“It occurred to me that as the tubes and their plexus of capillaries were probably, 

for reasons presently to be stated, the parts concerned in the secretion of that portion 

of the urine to which its characteristic properties are due (the urea, lithic acid &c.), 

the Malpighian bodies might be an apparatus destined to separate from the blood 

the watery portion”. 

“This abundance of water is apparently intended to serve chiefly as a menstruum 

for the proximate principles and salts which this secretion contains, and which, 

speaking generally, are far less soluble than those of any other animal product”. 

This arbitrary explanation was reinforced later, in 1874, when Rudolf 

Heidenhain of Breslau established the “excretory” hypothesis in urine for-

mation which is known as the “Bowman-Heidenhain” hypothesis of “vital-



In 1842, the same year that Bowman published his work, another brilliant 

mind in Germany, Carl Ludwig, a young physiologist in the University of 

Marburg, published his thesis in order to gain a senior degree. Carl Ludwing’s 

thesis was a scientific work of 24 pages written in Latin “De viribus physics 

secretionem urinae adjuvantibus” (On the physical forces that promote the 

secretion of urine). Based upon his own experimental observations and lit-

erature available at that time, he introduced the hypothesis that glomerulus 

acts as a sieving filter which produces an ultra filtrate of blood free of cells 

and proteins and contains all the other constituents of the blood in the same 

concentration without any modification by the glomerulus itself. He contin-

ued that the volume of the filtrate is influenced by blood pressure variation 

in the renal artery and that, as it passes through the renal tubules, it under-

goes reabsorption or secretion which alter the final concentration of certain 

substances in urine in relation to the blood 


. (Figure: 3). 

Somme details of his paper are as follow:

 “… the membranes of the vessels in the glomeruli are subjected to high pressure, 

resulting in a copious secretion from the delicate glomeruli. When kidneys were in-

jected with wax, I detected discharge of the wax from the glomeruli.

“The second physical process occurring in the kidney is an endosmotic action 

between the solution of salts secreted and the partly altered blood retained in the 

vessels. The first and best proof of endosmosis is the fact that, given the same com-

position of the blood, the concentration of the urine depends on the urine flow rate. 

It is clear that the process of expulsion of the urine is as follows: “When the blood 

vascular system is filled with fluid, pressure is exerted against the walls of the glom-

eruli, and the water in the blood leaves the glomeruli and is taken up by the urinifer-

ous ducts. It is here that endosmosis can occur as described above. The quantity of 

urine secretion is accelerated when the blood vascular system is filled with fluid, in 

which case the pressure against the walls of the glomeruli is increased”.

In this work Ludwig introduced the hypothesis that the phenomena 

of living organisms are influenced from the laws of physics and chemis-

try and can be “the consequence of simple attractions and repulsions between a 

limited numbers of chemical atoms”. With this revolutionary concept for his 

era, Ludwig introduced the hypothesis of “filtration-reabsorption” in urine 

formation which was accepted only from the so called “mechanists” and it 

Figure 3: Left: Carl Friedrich Wilhelm Ludwig, (1816-1895). German 

physician and physiologist. Right: Hand made drawings showing in 

the upper panel a schematic representation of the glomerulus and the 

uriniferous tubule with its blood supply and in the lower panel blood 

hydrostatic pressure changes during its passage through the glomerular 

capillaries. (“De viribus physics secretionem urinae adjuvantibus”, 1842).

Slika 3. Lijevo: Carl Friedrich Wilhelm Ludwig, (1816.-1895.). Njemački liječnik 

i fiziolog. Desno: Rukom rađeni crteži koji pokazuju u gornjem dijelu shematski 

prikaz glomerusa i urinoferusne tubule sa pripadajućim sustavom opskrbe krvlju 

te u donjem dijelu promjene hidrostatskog krvnog tlaka tijekom prolaska kroz 

glomerualne kapilare. (“De viribus physics secretionem urinae adjuvantibus”, 1842.).

would be a matter of controversy between them and “vitalists” for the fol-

lowing 80 years 


At the middle of this conflict, and with a lot of items of renal function un-

resolved, it was expected that Henle’s discovery would be neglected. At the 

beginning of the 20


 century, in 1922, Alfred Richards and his colleagues in-

troduced a new method in the experimental investigation of renal function 

which is known as the “micropuncture technique” and proved that Ludwig 

was quite right in his pioneer concept regarding the mechanism of urine for-



. Somme details of his paper are as follow 



“… it was possible to insert sharply pointed tubes into the space within Bowman’s 

capsule and to abstract the fluid which issues from the blood of the glomerular cap-

illaries ..”. 

“The results showed that the glomerular fluid is free from protein but contains 

chloride and glucose, both of these being absent from the bladder urine. It is alka-

line, contains urea, and indeed every diffusible constituent of plasma for which we 

were able to make a test …” 

“These results seem to me to leave little room for doubt that, in amphibia, the 

glomerular urine actually has the same composition of a protein-free filtrate from 

plasma, precisely as Ludwig had imagined ninety-three years ago”. 

 Thereafter the use of micropuncture technique and the measurement of 

Glomerular Filtration Rate (GFR) with the use of the polysaccharide inulin 

in animals as well as in man by Homer Smith and his colleagues in 1932 at 

the New York University Medical College provided the scientific commu-

nity with a rapid increasing bulk of knowledge upon renal physiology and 

the interest of researchers turned mainly to the filtration, reabsorption and 

excretion of solutes along the nephron 


The countercurrent hypothesis

During 1940-1944 Europe was almost devastated by the 2


 World War 

but Switzerland’s neutrality allowed some brilliant minds to continue their 

experimental work and produce knowledge, one of them was Werner Kuhn, 

Professor of Physical Chemistry in University of Basel, who worked upon 

the enrichment of sugar in water using semi-permeable membranes and phe-

nol as an auxiliary liquid in a hairpin countercurrent system without any 

other  external  force.  He  showed  that  at  each  bend  of  the  hairpin  counter-

current system solute concentration increased by a factor n which equals to 

the length of the system divided by its width (n=L/W). Based upon these 

observations Kuhn and his colleague Kaspar Ryffel published, in 1942, a pa-

per in German and proposed that the “U” shaped loop of Henle may be the 

natural analog of a countercurrent multiplication system capable to produce 

urine concentration in mammalian kidney but the paper overlooked by renal 



Although countercurrent exchangers and countercurrent multipliers 

were known among engineers and utilized in many applications in indus-

try, mainly in heat exchange and solute concentration, the first description 

of the importance of heat exchange between arteries and veins in mammals 

is attributed to Claude Bernard in 1876. Many years later in 1940’s Bazett 

and his colleagues showed experimentally the heat exchange between deep 

arteries and veins in the arms and the legs which prevents heat loss to the 

environment and achieves blood warming before entrance to the central cir-



In 1950’s extensive experimental work showed that Arctic mammals and 

birds utilizes a countercurrent heat exchange system between deep arter-

ies and veins in their legs in order to prevent freezing while standing on icy 

ground or wading in icy water. It was also showed that some species utilizes 

a specialized network of arteries and veins bundles capable to exchange heat 

and gazes, known as “rete mirabile” which help them to regulate body tem-

perature, to exchange oxygen in fish gills and in the case of deep ocean fishes 

to store oxygen in swim bladder in high pressures exceeding in some cases a 

hundred time the partial oxygen pressure of surrounding see water



In early 1900’s Karl Peter in his book “Untersuchungen uber Bau und 

Entwickelung der Niere” (Jena Fisher 1909, editor) first pointed to the rela-

tion between length of Henle’s loop and urine concentrating ability among 

some species. Later in 1944 Sperber pointed again to the relation between 

length of Henle’s loop and urine concentration because animals with long 

Henle’s loops exhibited the greater urine concentrating ability


Meanwhile in 1946 Bart Hargitay, a young graduate of chemistry at the 

University of Budapest, received a fellowship offered by the University of 

Basel where he joined Werner Kuhn. As the Iron Curtail closed this year 

he decided to stay in Switzerland and asked Professor Kuhn to accept him 

as a graduate student to work in a thesis. Kuhn assigned Hargitay to prove 

the hypothesis of countercurrent multiplication system of urine concentra-

tion in the kidney 


. Hargitay contacted Dr Heinrich Wirz at the Physiology 

Institute in order to obtain some knowledge about renal physiology and help 

him in experiments with animals. Wirz enthused with the idea and started 

promptly experiments with rat kidneys and later with Syrian hamster be-

cause the solitary papilla of this rodent protrudes in to the renal pelvis and 

it is easier for micropuncture and collect urine sample from renal tubules. 

Soon thereafter the two researchers encountered a serious problem: the 

estimation of the chemical constituents had to be performed in a very scant 

sample of urine, about 10


 ml, obtained by micropuncture. Hargitay decided 

to determine only the osmotic pressure of the samples by cryoscopic method 

according to the formula:

Relative freezing point depression = 100 



 – Δ


 / Δ


 – Δ





: the freezing point depression in x position in the kidney


In order to perform their calculations they needed a cryo-chamber with 

temperature lower than -20


 C. They used the cold room of the Burgerspital 

hospital in Basel. The procedure needed to be carried out in the room, under 

heavy clothes and furs in the middle of the summer, bringing with the mi-

cropipette urine samples and observing under polarized microscope the bi-

refringence of ice formed at the melting point of each sample. They gathered 

multiple urine samples along the axis from the renal cortex to the papilla and 

found that in all samples the osmotic pressure was equal at the same level but 

it was gradually increasing at each deferent level from the renal cortex to the 

papilla. The lowest pressure was observed in the renal cortex and estimated 

to be 25 Atm while the greatest was observed in the papilla and was estimat-

ed to be 58 Atm 


. (Figure: 4) 

These findings as well as experimental findings from a mechanical hair-

pin model constructed by Hargitay and colleagues in his laboratory, prompt-

ed Hargitay and Wirz to consider that the “U” shaped loop of Henle is the 

natural analog of a hairpin countercurrent multiplication system in the kid-

ney which by the antiparallel circulation of urine in the descending and as-

cending limb of the loop produces the maximum concentration of solutes at 

the bending point of the loop in the deep renal medulla.

 Although they were ignorant of the specialized properties of the descend-

ing and ascending limb of Henle’s loop concerning its water permeability 

and active sodium chloride transport, they realized that the single effect, by 

means of the leading process, in urine concentration mechanism could not 

be a component of hydrostatic pressure difference but an “electroosmosis” 

phenomenon which they de-

scribed as follows: “It seems 

much more likely that, in epitheli-

al cells, energy from metabolism 

is used to establish a potential 

field  and  that  in  this  potential 

field electroosmosis takes place” 



In order to explain the se-

quence of events in urine con-

centration, they considered it 

mainly as a process of water 

absorption. They hypothe-

sized that the electroosmosis 

phenomenon produces water 

transport from the lumen of 

descending limb to the inter-

stitial space and then to the 

lumen of the ascending limb. 

They said that the latter de-

livers diluted urine to the 

distal convoluted tubule from 

which water is transferred 

to the blood. Hence, a final 

concentration of urine takes 

place in the collecting duct as 

it passes through the hypertonic medulla




As we know now water permeability of the thin descending limb of 

Henle’s loop is owing to the expression of aquaporin-1 (AQP-1) in its epithe-

lium. Thorough investigation of this nephron segment showed that short 

looped nephrons do not express AQP-1 in their descending thin limb and 

they are practically impermeable to water. Conversely AQP-1 is expressed in 

the thin descending limb of long looped nephrons especially those extend-

ing deep in the medulla but AQP-1 expression is limited to the first 40% of 

their length and never beyond the last 2-2,5 mm before bending in the inner 

medulla. The remainder 60% of their length is devoid of AQPs and hence 

impermeable to water but it is permeable to urea and chloride ions because 

of the expression of urea transporters and chloride channels. The thick 

Figure 4: The original findings from 

experiments conducted by Bart Hargitay 

and Heinrich Wirz showing the increase of 

osmotic pressure from the renal cortex to 

the tip of the renal papilla. 

Slika 4. Izvorni nalazi iz opita Barta 

Hargitaya i Heinricha Wirza koji pokazuju 

povećanje osmotskog tlaka od bubrežnog 

korteksa do vrha bubrežne papile.

ascending limb of Henle’s loop is impermeable to water but posses the capac-

ity of active transport of sodium, potassium and chloride via the Na







cotransporter which transfer sodium chloride to the interstitium and con-

tributes significantly to the hypertonicity of the renal medulla 


The work was first presented in May 1951 by Hargitay to the Bunsen 

Gesellschaft at the meeting for physical chemists in Gottingen and a few 

weeks later by Wirz at the International Conference for Physiology in 

Copenhagen. The physical chemists accepted the findings by Hargitay and 

Wirz with enthusiasm but the physiologists expressed their skepticism and 

reluctance to accept the new theory. The work was published in German 

in the same year and thereafter it became a mater of investigation among 

German speaking scientists but not among English for at least the follow-

ing 7 years. Wirz continued his experiments by micropuncture but he never 

managed to puncture with accuracy the lumen of Henle’s loop especially at 

the tip of renal medulla 


During this period a considerable work upon urine concentration and 

dilution was conducted by Karl Julius Ullrich and was published mainly in 

German.  Although  during  his  contribution  to  Gottschalk’s  laboratory  in 

Chapel Hill he published also some articles in English. Ullrich examined the 

composition of interstitial fluid in renal cortex and medulla and proved that 

except electrolyte accumulation other osmolytes especially urea contributes 

to the medullary hypertonicity of mammalian kidney



 He showed also 

that glycerophosphocholine and inositol accumulate in the renal medulla 

and act as osmolytes and that medullary collecting duct participates in urea 




 The reluctance of English speaking scientists to accept the new theory 

is in part attributed to the fact that the first half of 20


 century was predom-

inated by Homer Smith’s proposals in renal physiology. In his book “The 

kidney: Structure and Function in Health and Disease”, published in 1951, 

by drawing the nephron he omitted the loop of Henle and included only 

a part of the descending limp as short straight tubule. Smith believed that 

the urine concentration is accomplished at least by two mechanisms one at-

tributed to passive reabsorption of water in the proximal tubule and another 

one attributed to active reabsorption of water in some parts of distal tubule 

although no evidence of active water reabsorption mechanism had been 

proved in any biological system. (Figure: 5).

He wrote exactly: 

“… the reabsorption of water by the renal tubules involves at least two more or 

less independent processes: 1. passive water reabsorption in the proximal tubule and 

thin segment (proximal system), and, under appropriate circumstances, in the distal 

tubule; and 2. active water reabsorption that is presumably confined to the distal 

system, i.e., in the distal tubule and possibly in the collecting ducts also”.

When he asked by Carl Gottschalk what he believes about the counter-

current hypothesis he said: “The smart boys don’t believe in it” 


Meanwhile USA entered the 2


 World War in 1941 and Alfred Richard’s 

laboratory stopped the experiments with micropuncture for almost a decade. 

After the war Carl Gottschalk expressed the intention to revive renal micro-

puncture and asked Richard’s advice upon restarting kidney micropuncture 

but for unknown reasons he discouraged him 


In 1952 Gottschalk joined the Department of Medicine at the University 

of North Carolina and established in Chapel Hill his “Micropuncture 

Laboratory” which was equipped with the Ramsey/Brown micro-osmome-

ter built especially for the Chapel Hill laboratory



. Gottschalk recruited 

in his laboratory Margaret Mylle who was considered as “one of the most 

Figure 5: Left: The rectilinear model of the nephron omitting the loop 

of Henle proposed by Homer Smith in his book “The kidney: Structure 

and Function in Health and Disease”. (London, Oxford University Press, 

1951). Right: The countercurrent multiplication system with gradually 

increasing osmolality from the cortex to the renal medulla proposed by 

Kuhn, Hargitay and Wirz. (Das Multiplikationsprinzip als Grundlage der 

Harnkonzentrierung in der Niere, 1951).

Slika 5. Lijevo: Rektilinearni model nefrona bez Henleove petlje predložen od 

strane Homera Smitha u knjizi “The kidney: Structure and Function in Health 

and Disease”. (London, Oxford University Press, 1951.). Desno: Protustrujni 

multiplikacijski sustav sa postupno povećavajućom osmolarnošću od korteksa do 

bubrežne medule po Kuhnu, Hargitayu i Wirzu. (Das Multiplikationsprinzip als 

Grundlage der Harnkonzentrierung in der Niere, 1951.).

skilled micropuncturists in the word”. Gottschalk’s intention was to check 

the hypothesis proposed by Robert Berliner that the urine at the tip of the 

loop of Henle should be hypotonic 


After performing a series of brilliant experiments with Wistar rats, gold-

en hamsters, one kangaroo rat and Psammomys obesus, they collected urine 

samples in nanoliter specimens from short looped nephrons, from the thin 

limb  and  the  bend  of  loop  of  Henle,  collecting  ducts  as  well  as  vasa  recta. 

They showed that fluid from the bend of loops of Henle, collecting ducts and 

vasa recta at the same level in the papilla were hyperosmotic and exhibited 

almost equal osmotic pressure 


After that Gottschalk published a brief report of his findings in an article 

less than one page in Science in September 1958 with the title: “Evidence 

that the mammalian nephron functions as a countercurrent multiplier sys-

tem” establishing by this way the validity of “the new theory” proposed by 

Kuhn, Hargitay and Wirz 


. According to Francois Morel’s declaration, 

after personal communication with Gottschalk, he sent the data to Homer 

Smith before full publication. Homer Smith was so impressed by these find-

ings that he asked from Gottschalk to postpone the full publication until he 

will make known his new opinion. After that Smith delivered a lecture with 

the title “The fate of sodium and water in the renal tubules”, in October 17, 

1958 at the Annual Postgraduate Week organized by the New York Academy 

of Medicine and he recognized the importance of the “new theory” with re-

markable accuracy and humour 


. In advance Gottschalk and Mylle pub-

lished their findings in American Journal of Physiology the next year 


By extending their experiments they showed, by micropuncture in ham-

sters, that the water permeability of thin descending limb of Henle’s loop 

greatly exceeded that of the thin ascending limb. Experiments in hamsters 

with diabetes insipidus showed that the fluid collected from the loop of 

Henle and blood from the vasa recta, at the tip of the papilla, were hyperos-

motic in contrast to the fluid of the adjacent collecting ducts which was hy-

po-osmotic. These experiments showed that water permeability and urine 

concentration in the thin descending limb of Henle’s loop is independent of 

the presence of ADH and that the final concentration of urine takes place in 

the medullary collecting duct 


Gottschalk summarized the evidence of the accumulated knowledge 

upon the countercurrent hypothesis in a lecture with the title “Renal tubular 

function: lessons from micropuncture” presented in “The Harvey Lectures” 

(series 58) in 1962 three centuries after the firs description of renal tubules 

and a century after Jacob Henle’s description of the homonymous loop in 

mammalian kidney. 

The above mentioned fundamental work was simply the beginning fol-

lowed by an enormous experimental investigation of renal physiology based 

first upon micropuncture and later upon microperfusion and patch clamp 

technique which expanded our knowledge upon ion channels properties. 

Genetic analysis of specific ion and solute transporters upon molecular level 

as well as the use of specific gene knockout animals enabled researchers to 

unravel step by step the mysteries of renal function 


Any further detailed analysis of the ongoing research upon this very in-

teresting topic is beyond the scope of this historical review but the adventure 

is still in progress because “we have to go miles before sleep”. 


1.  Smith HW. The fate of sodium and water in the renal tubules. Bull N Y Acad 

Med 1959; 35: 293-316. 

2.  Soper Ch. The paradoxical urinary concentrating mechanism. Jurnal of 

Creation 2005; 19: 91-95

3.  Morel F. The loop of Henle, a turning-point in the history of kidney physiology. 

Nephrol Dial Transplant 1999; 14: 2510-2515. 

4.  Richards AN. Physiology of the kidney. Bull N Y Acad. Med. 1938; 14: 5-20. 

5.  Davis JM, Thurau K, Haberle D. Carl Ludwig: the discoverer of glomerular fil-

tration. Nephrol Dial Transplant 1996; 11: 717-20. 

6.  Smith HW, Goldring W, Chasis H. The measurement of the tubular excretory 

mass, effective blood flow and filtration rate in the normal human kidney. J Clin 

Invest 1938; 17: 263-78.

7.  Gottschalk CW. History of the urinary concentrating mechanism. Kidney Int 

1982; 31: 507-11.

8.  Kuhn W, Ryffel K. Herstellung konzentrienter Losungen aus verdunnten durch 

blosse Membranwirkung. Ein Modellversuch zur Funktion der Niere. Hoppe-

Seyler’s Zeit Physiol Chem 1942; 276: 145-78.


Irving L, Krog J. Temperature of skin in the Arctic as a regulator of Heat. J Appl 

Physiol 1955; 7: 355-64. 

10.  Scholander PF, Krog J. Countercurrent heat exchange and vascular bundles in 

sloths. J Appl Physiol 1957; 3: 405-11. 

11.  Hargitay B, Kuhn W. The multiplication principle as the basis for concentrating 

urine in the kidney. J Am Soc Nephrol 2001; 12: 1566-86. 

12.  Zhai X-Y, Fenton RA, Andreasen A, Thomsen JS, Christensen EI. Aquaporin-1 

is not expressed in descending thin limbs of short-loop nephrons. J Am Soc 

Nephrol 2007; 18: 2937-44.

13.  Pannabecker TL, Dantzler WH, Layton HE, Layton AT. Role of three-dimensi-

onal architecture in the urine concentrating mechanism of the rat renal medu-

lla. Am J Physiol Renal Physiol 2008; 295: F1271-F1285. 

14. Hargitay B, Kuhn W. Das Multiplikationsprinzip als Grundlage der 

Harnkonzentrierung in der Niere. Z Electrochem Angew Phys Chem 1951; 55: 


15.  Wirz H, Hargitay B, Kuhn W. Lokalisation des Konzentreirungsprozesses in der 

Niere durch direkte Kryoscopie. Helv Physiol Pharmacol Acta 1951; 9: 196-207.

16.  Jarausch KH, Ullrich KJ. Studies on the problem of urine concentration and 

dilution; osmotic behavior of renal cells and accompanying electrolyte accu-

mulation in renal tissue in various diuretic conditions. Pflugers Arch. 1956; 


17.  Murer H, Burckhardt G. Professor Karl Julius Ullrich – in memoriam. Kidney 

Int. 2010; 78: 827-8. 

18.  Valtin H. Carl W Gottschalk’s contribution to elucidating the urinary concen-

trating mechanism. J Am Soc Nephrol 1999; 10: 620-7. 

19.  Schafer JA. Experimental validation of the countercurrent model of urinary 

concentration. Am J Physiol Renal Physiol 2004; 287: F861-F863. 

20.  Gottschalk CW, Mylle M. Evidence that the mammalian nephron functions as 

a countercurrent multiplier system. Science 1958; 128: 594. 

21.  Gottschalk CW, Mylle M. Micropuncture study of the mammalian urinary 

concentrating mechanism: evidence for the countercurrent hypothesis. Am J 

Physiol 1959; 196: 927-36. 

22.  Agree P, Preston GM, Smith BL, Jung JS, Raina S, Moon C et al. Aquaporin 

CHIP: the archetypal molecular water channel. Am J Physiol Renal Physiol 

1993; 265: F463-F476.

23.  Fenton RA, Knepper MA. Mouse models and the urinary concentrating mecha-

nism in the new millennium. Physiol Rev 2007; 87: 1083-1112. 


Prvi se opis bubrežnih tubula iz 1662. pripisuje Lorenzu Belliniju, a četiri je godine kasnije 

Marcello Malpighi opisao glomerul. Godine 1842. je Sir William Bowman opisao kapsulu 

koja okružuje malpigijevo tjelešce i njegovu vezu s bubrežnim tubulima te uveo “ekskretornu” 

hipotezu  o  stvaranju  urina.  Iste  je  godine  Carl  Ludwig  uveo  je  “filtracijsko-reasorpcijsku” 

hipotezu stvaranja urina. Bowmanova je hipoteza bila prihvaćena od strane tzv. “vitalista”, 

a Ludwigova hipoteza od strane tzv. “mehanicista”. U jeku tog sukoba Jakob Henle opisao je 

1862. homonimne petlje u obliku slova “U”, ali njegovo je otkriće zanemareno. Godine 1942. 

je Werner Kuhn, fizikalni kemičar, predložio ideju da je Henleova petlja možda prirodni 

analogon kopče protustrujnog multiplikacijskog sustava koji koncentrira urin u bubrezi-

ma sisavaca. Godine su 1951. Kuhn, Hargitay i Wirz eksperimentalno pokazali da da je 

Henleova petlja najvažniji dio protustrujnog multiplikacijskog sustava mehanizma za kon-

centriranje urina u bubrezima sisavaca. Nova je teorija prihvaćena od strane anglofonih 

znanstvenika kasnije, 1958. godine, kada su Carl Gottschalk i Margaret Mylle objavili svoj 

eksperimentalni rad i dokazali da je Kuhnova teorija bila točna. Gottschalk je sažeo dokaze 

sakupljenog znanja 1962., tri stoljeća nakon prvog opisa bubrežnih tubula i jednog stoljeća 

nakon opisa Henleove petlje.

: Henleova petlja, mehanizam formiranja urina, vitalisti, mehanicisti, protu-

strujni multiplikacijski sustav.

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