Historical Aspects of Protein

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Historical aspects in the investigation, evaluation, andmanagement of patients with proteinuria, in large part, as they relate to

patientswith glomerulonephritis, are reviewed. This evaluation has been a long and complex processwithmany divergent and

cross pathways. Although the history covers more than 2000 years, it is only in the past 2 centuries, with the more advanced

experimental methods that have developed in science, that the growth has been exponential. With these advances, the knowl-

edge between kidney structure and function evolved, and the subsequent links determined between physiology and pathology

of kidney disease, and the clinical phenotypes of glomerular disease have revealed the overwhelming importance of proteinuria

as both an indicator of kidney involvement and a marker of disease progression.

Q 2011 by the National Kidney Foundation, Inc. All rights reserved.Key Words: Proteinuria, Kidney disease, Glomerulonephritis, Pathology, History

Ancient History

The relationship between kidney disease and protein-uria has been extraordinarily long and filled with

many stops, detours, and cul-de-sacs since the originaland still valid observation of Hippocrates.1 His commentthat ‘‘when bubbles settle on the surface of the urine, it in-dicates disease of the kidneys and that the complaint willbe protracted’’ remains a touchstone for nephrologistseven today. This observation, based on the alteration ofthe surface tension of urine by protein, remains a commonquestion still asked by physicians during a systems re-view in an effort to determine the starting point of the pro-teinuric process. However, it was some time before thedirect relationship between urine formation and itssource, the kidney, was defined by physicians in ancientAlexandria.2

The Middle Ages

An even longer hiatus elapsed before further elucidationof this process occurred. It was not until the 15th centurythat the first description of the clinical features that wenow associate with generalized edema was outlined byCornelius Roelans.3 Cameron in his article4 noted thatone of Roelans’ disorders in children was described as‘‘a generalized swelling of the body,’’ although therewas no further evaluation of the patient’s illness.This in retrospect was not surprising, given the prevail-ing view at that time that virtually all disorders were re-lated to abnormalities or dysregulation of the ‘‘bodyhumours.’’

m Toronto General Hospital, Toronto, Ontario, Canada.

translations of Dekkers6 and of Cotugno8 and the quotations fromll10 are given in Dock W. Early observers of albuminuria. Ann Med922;4:287-290.

dress correspondence to Daniel C. Cattran, MD, Suite 1256 11th CSB,

o General Hospital, 585 University Avenue, Toronto, Ontario, CanadaN2. E-mail: daniel.cattran@uhn.on.ca

011 by the National Kidney Foundation, Inc. All rights reserved.

8-5595/$36.00:10.1053/j.ackd.2011.06.008

Advances in Chronic Kidney Disease, Vo

There is a further lapse in time of more than 2 centu-ries in the medical literature before new insights con-nected the clinical features of edema (referred to asdropsy) and proteinuria to kidney-specific disease. Aninteresting aside and perhaps one of the incentives forrenewed interest in the evaluation of the urine was thework of the alchemist Hennig Brandt. He believed thaturine contained a substance that could change basemetal into gold, the so-called philosopher’s stone.5 Dur-ing his experiments in the mid-1600s, he noted that afterextreme heating of urine residues, glowing fumes wereproduced that could burst into flames. This discoverywas not of the elusive ‘‘philosopher’s stone’’ but the el-ement phosphorus and perhaps the golden glowbrought this fascinating biologic material, urine, intoa new light.

In the late 17th century, the next advance occurred asdescribed by Dekkers of the Netherlands.6 He theorizedthat ‘‘the wasting diseases’’ might be because of thebodily substances leaking away in the urine. After exam-ining the urine from such patients, he reported that ‘‘thespecimens tasted sweet and when boiled after added ace-tic acid, a coagulum settled out and an oily layer rose tothe surface.’’ However, the renowned Dutch doctor madeno similar tests of urine from other patients, and so thepotential relationship between proteinuria, glycosuria,and the wasting state of such patients was not deter-mined. It was left to Theador Zwinger III of Basel inthe early 18th century to describe the clinical picture ofthe nephrotic syndrome.7 It is difficult to improve his de-scription of the syndrome even today, and it bears repeat-ing. He described it as follows: ‘‘the edema whengeneralized, as hydrops involves swelling of the wholebody. From head to foot, the skin is a pale dirty yellow;the swelling is oedematous and characterised by inflationof the whole periphery with persistent collections oflymph. The swelling is not hard or tense, but such thatthe print of a finger remains behind. Commonly, thirstis very great, the bowel action not as free as usual, andthe urine is scanty because of obstruction and compres-sion of the tubules of the kidney. The breathing is diffi-cult, often accompanied by anxiety because of the

l 18, No 4 (July), 2011: pp 224-232

History of Proteinuria 225

compromised function of chest muscles and diaphragmfrom the swelling of the skin. There may be soon a strongdesire to sleep because the brain is overfull with serum;sleep is poor because of disturbance of the spiritus ani-malis. Additionally, there may be a dry cough from irrita-tion of the nerves to the lung by the liquid, salty lymph.At the beginning, the swelling may be small, but later itincreases steadily if the remedies used do not have theirexpected effects, so that legs, abdomen and even the faceare blown up with a bluish colour, and one must fear at-tacks of suffocation. We have seen children of either sexin whom the eyelids were so swollen they could notopen their eyes, and also the genitalia were so swollenand full of serum, that they looked almost transparent.In boys, the virile member was so swollen that they couldmake water only with difficulty.’’ However, despite thisquite precise description of the clinical evolution of pa-tients with severe proteinuria, the author makes no refer-ence to the kidneys. It was Cotugno in Naples, almost 50years later, connected the presence of proteinuria toedema.8 He also introduced diuretic treatment for themanagement of edema. He performed the heat and acetic

CLINICAL SUMMARY

� Proteinuria and its relation to the kidney was described byastute clinicians centuries ago.

� Over the middle ages, further clinical descriptions of whatis now knownas nephrotic syndromeand uremia emerged.

� Over the past 2 centuries, and more so the last one, therehas been increasing study of proteinuria and itsrelationship to kidney and cardiovascular disease, and asa potential target for intervention.

acid test on the urine of anedematous patient aftertreating the patient with thediuretic, potassium bitar-trate. A significant precipi-tate occurred when heperformed this test not onlyon the urine but also on thepatient’s blood and edemafluid. However, his interpre-tation of the sequence ofevents was somewhatflawed. He interpreted the

findings as indicating that the diuretic had moved edemafluid into the urine, because under normal conditions it (apositive acetic acid test) was not present in the urine. Heconcluded that the patient’s sciatica (the subject of hisstudy) was therefore because of edema in the patient’snerves sheath, and the response to diuretic therapy wasmovement of this fluid (protein) into the urine. An inter-esting recent publication has suggested that the presenceof a now recognized specific type of kidney disease, cur-rently known to be associated with edema and protein-uria, was present around that time. Mozart, accordingto eyewitness, died in 1791, shortly after developing mas-sive edema. A review of the case has suggested that thecause of his death was kidney failure.9 Death recordskept in Vienna at that time indicated edema was the thirdmost common cause of death. Around the same period ofMozart’s demise, these authors also found a marked in-crease in the death rate after severe pharyngitis amongyounger men compared with the previous and followingyears. The authors’ interpretation was that Mozart’s lastillness and subsequent death could well have been

caused by a throat infection followed by acute (poststrep-tococcal) glomerulonephritis.

The 19th Century and the Introduction of theScientific Method

It was in the early 19th century that the association be-tween proteinuria, kidney disease, and the clinical fea-tures of the nephrotic syndrome became a recognizedentity. John Blackall was the first to make a systematicstudy of albuminuria.10 He noted that ‘‘the coagulationof the urine takes place long before the boiling heat andthat this is not part of the relief of the process but a contin-ued symptom of dropsy through their whole course.’’ Hequoted Cotugno’s work but noted that if more observa-tions had been made he would have learned that ‘‘the cu-rative effort of Nature is not urine loaded with serum, butalmost devoid of it,’’ thereby indicating to the reader thatnormal urine should not contain protein. Blackall wasalso the first to comment on the lipemic nature of theserum in patients with severe edema.

It remained, however, for Richard Bright in his classic

1827 article to describe thetriad of proteinuria, edema,and diseased kidneys.11

The clinical scenariosand re-nal pathology from his orig-inal cases have beendescribed several timessince his original report.The most recentre-examination of the origi-nal pathology was done in1972.12 Weller and Nesterwere able to determine,

based on the re-examination of the 150-year-old pathologyspecimens, that the cases represented 2 ofmembranoproli-ferative glomerulonephritis (MPGN) and 1 of amyloid-osis.12

Bright’s colleague, John Bostock (1773-1846), first as-sociated proteinuria with a decrease in the quantity ofprotein in the blood.11 Bostock, a chemist and physicianfrom Liverpool, quantified the urine and serum pro-teins by methods that relied on changes in specificgravity and noted that the greater the amount of pro-tein in the urine, the lower the level of protein in theblood. However, how the edema formed in relationshipto the loss of protein in the urine was not clarified. Thesequence of events that holds the largest sway even to-day in regard to its formation was originally suggestedby the Parisian physician, Sabatier, in 1834.13 He pro-posed that ‘‘as the serum of the blood becamedepleted (sic albumin), the serum becomes more fluid,(sic thinner), and by this mechanism is more easilyable to penetrate the walls of the arterial capillaries.’’He also supposed that ‘‘following this modification of

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the blood, venous (re)absorption is less active, and insuch cases effusions may develop in the serous cavitiesand infiltrations of the tissue may arise.’’

The 20th Century

The rest of the 19th century was relatively stagnant interms of advances in the evaluation and interpretationof proteinuria, but this all changed rapidly in the nextcentury. The focus on animal models and clinical patho-logical correlations in humans initiated this expansionand began the focus on potential mechanisms of the dis-ease processes and the cause-and-effect sequence ratherthan just cross-sectional observations. One of the earlydetailed pathological descriptions of diseased kidney tis-sue was given by M€ueller,14 whose work was subse-quently expanded by Volhard and Fahr.15 This was thebeginning of the 50-year debate between nephritis, a con-dition associated with inflammation within the kidneystructure, and nephrosis, a condition associated with de-generative changes of the kidney tubules. This distinctionwas further emphasized byMunk in 1913 who during hisstudy of lipiduria (in a syphilitic population with high-grade proteinuria) found that the tubular degenerativechanges in the kidney were associated with fatty depositsand coined the term lipoid nephrosis.16 He was also thefirst to indicate that there were no pathological changesobserved in the glomeruli of these patients. This debateof the primary anatomical site of injury leading to pro-teinuria (glomerular, tubular, or both) raged throughthe next half-century. A unique set of experiments carriedout in this same period by Randerath, a German, has re-cently been reviewed, and clearly illustrates new insightthat unfortunately received little credit at the time.17 Hisexperimental studies in the salamander used theirunique kidney structure in which some tubules con-nected directly to the peritoneal cavity (no interveningglomerulus), whereas others had a typical nephron struc-ture (with a glomerulus at the head of each nephron).After injecting a variety of different protein species intothe peritoneal cavity, he found that nephrons withouta glomerulus had significant tubular damage versusthose with the classic nephron structure had none. Heconcluded that in those cases of nephrosis described byMunk and M€ueller, glomerular damage must be present,despite the apparent lack of morphologic glomerularinjury.

An insightful lecture by Shore in 1929 attempted tocollate the morbid anatomist’s viewpoint with the clini-cian’s nomenclature in the classification of kidney disor-ders associated with proteinuria.18 Shore began byseparating the pathology into 4 structural components:glomerular, tubular, arterial, and interstitial. He empha-sized that in nephrosis (note that although Randerath’swork had already been completed, it was not publisheduntil much later because of World War II), the injury

was confined to the tubules, and that the glomeruli andinterstitial are not injured. Thus, from a clinical perspec-tive, he concluded that the renal efficiency (function) isnot impaired and fibrosis does not occur. He describedthe tubular epithelial cells being foamy with a special af-finity for fatty stains and that these bodies could also befound on examination of the urine (oval fat bodies). Healso described elevated lipid levels in the serum of thesepatients. Further, he noted that the gross pathology inthese conditions revealed kidneys that were swollenand pale. His error came in the interpretation of the infor-mation, suggesting that the kidney is the agent for theremoval of this excessive lipid, and that this fat subse-quently causes tubular damage as it passes down the tu-bules. In this condition, he concluded that the kidney is‘‘more sinned against than sinning.’’ He went on to de-scribe the associated clinical spectrum of lipoid nephro-sis. In its most modest form, he indicated there were noclinical features beyond albuminuria, but in the more se-vere cases, edema formation could be profound. He alsonoted that urinary casts were uncommon, blood in theurine was usually absent, blood urea, the index of nitro-gen retention (and renal failure) was normal, and that se-vere glomerular involvement was not present in thiscondition. These were excellent clinical descriptionsthat relate to the histologic variants, which we nowmost commonly associate with the nephrotic syndromein children (minimal change disease) and adults (mem-branous nephropathy).

Nephritis was the next category in his classification.The pathologists had previously agreed that there was in-flammation of the various kidney structures and that theclinical features and prognosis depended in large part onthe amount of injury and the degree to which such injurycould be repaired and function restored in nephritis.Shore labeled the first major subdivision of this groupas glomerulotubal nephritis. He noted that to a greateror lesser degree, all of the substructures, including theglomeruli, tubules, and interstitial, were affected in thiscategory. He also suggested that the inciting injury couldbe continuous and progressive because all stages of glo-merular injury can be seen in the same tissue section.He described in the acute phase both blood cells and castsin the urine and clinically, if the blood pressure was ele-vated or urea retention was present, this was probablyan acute phase on top of a chronic kidney process. Healso described the outcome indicating that althoughsome cases appeared to have a complete clinical recovery,this did not necessarily mean recovery at a structurallevel. His observations included the comment that the re-nal reserve is considerable and that the blood urea maynot be increased above normal level until approximatelytwo-thirds of the total kidney tissue has been rendered‘‘hors de combat.’’ This continues to be a difficult areaeven today because of our limited ability to measure re-nal reserve, and the specific amount of chronic versus

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reversible structural damage present despite our moresophisticated methods of estimating glomerular filtrationrate. He was also quite astute in his observation that ‘‘it ispossible for a person to be going about with a largeamount of his kidney tissue functionless and in completeignorance of his condition and that this could also bequite unknown to his physician as well unless there is oc-casion to test his urine’’ (for protein). This remains amajorproblem even today where the asymptomatic patientwith proteinuria appears in the emergency room ‘‘de-novo’’ with end stage kidney disease. His classificationcontinued with the description of the most common clin-ical scenarios of nephritis with and without edema. Theedematous type of nephritis, he stated, consists of abun-dant albuminuria, normal blood urea, and no cardiovas-cular involvement, an identical description of nephrosisby Shore, but with the addition of casts in the urine; a de-scription that is compatible with the present histologicvariants of MPGN, focal and segmental glomerulosclero-sis, and other primary nephrotic glomerular diseases. Inhis second category of nephritis with scanty albuminuria,Shore described a tendency for the blood urea to be in-creased and cardiovascular symptoms (hypertension) todevelop. However, rather than perpetuating the separa-tion of these 2 major clinical scenarios (nephritis and ne-phrosis), Shore states that although these 2 types mayseem at first sight to be different diseases, all degrees ofassociation between the 2 occur, and ‘‘the hydraemic(nephrotic) type’’ tends, if life continues, to pass on tothe ‘‘azotaemic type’’ and that ‘‘uremia may supervene’’in either case of severe renal failure. He emphasizedthat in the ‘‘azotemic type it is the natural terminationof the disease.’’ In his summary, he indicated that the sim-ilarity between hydremic and nephrosis types wouldsuggest similar pathological lesions, and this, in his opin-ion, was often the case.

The pace of evaluating proteinuria, including both theclinical scenarios and pathology, accelerated quickly be-yond this point. This paralleled the rapid growth of ex-perimental medicine in general. It is worth recallingthat throughout this time, cause-and-effect studies thatincluded pathology were significantly hindered by thelimited kidney tissue available for examination. This tis-sue was only available from patients who had either suc-cumbed to kidney failure or to the even more rarecircumstance, from proteinuric patients dying from unre-lated causes.

Despite this limitation, 2 articles from the late 1930sprovided important new concepts in the managementof patients with proteinuric kidney disease. The first byBennett in 193719 provided a well-characterized templatethat encompasses much of our thinking today in regardto classifying primary kidney disease associated withproteinuria. The first category included patients withpersistent albuminuria but no blood or epithelial castsin the urine. Other characteristics of this group included

a normal blood pressure, no increase in heart size orchanges in fundi, and usually persistent edema of theface, lower limbs, lumbar area, and in male children,the scrotal area. If severe, patients could also have pleuraland peritoneal fluid accumulation (anasarca). Laboratorytests demonstrated reduced serum protein levels, with al-bumin more diminished than the globulin fraction anda normal blood urea. Bennett went further than Shorein describing their prognosis as good, with the main un-derlying threat of infection in either the subcutaneous orbody cavities fluid (edema). He also noted that some ofthese cases could also have a complete recovery sponta-neously. This was an even better description of the clini-cal and laboratory features that are associated even todaywith patients who have minimal change disease or mem-branous nephropathy. However, the controversy contin-ued regarding whether there were any specific lesionsin the glomeruli with these specific conditions. In an ex-pansion of earlier work, it was demonstrated that pro-teins in the urine were not qualitatively different fromthose in the serum. Bennett proposed that in cases of ne-phrosis, the impossibility of this amount of protein pass-ing directly through the tubular epithelium. Therefore, heconcluded that the glomerular filter must be abnormal.Bennett’s treatment discussion is also worth discussing.He suggested that a high-protein diet was warranted toreplace protein loss, whereas before this discussion, ithad been customary to recommend that all cases withedema from kidney disease should bemaintained on a di-etary regimen containing the lowest possible amount ofprotein. In addition, Bennett stressed the need to elimi-nate or reduce dietary salt in all cases of edema, particu-larly when in the nephrotic range, and added that thiswas an even more important need than restriction of di-etary protein intake. Additionally, he commented on anissue, existing even today, related to the divergence be-tween advertisements in the popular press touting thereadily available tasty (salty) food versus his (and otherphysicians) recommendations for salt restriction, particu-larly in patients with proteinuria and edema. Osman in1938 provided further insight into the care of patients suf-fering from Bright’s disease.20 Osman emphasized therarity of these conditions, and that successful manage-ment and treatment was tied very closely to the informa-tion derived from specialized clinics such as his, whichallowed the study of both the natural history and treat-ment outcomes in a large cohort of such patients. Manyof these issues remain today, where despite their best in-tent, internists and even nephrologists are managingthese cases, despite their lack of experience due to theirlimited exposure to such patients. He indicated that their(sic doctors) attitude of disappointment and pessimismin connection with the treatment of Bright’s disease areoften attributed to their sense of a lack of specific reme-dies, which was attributed in his words, by ‘‘a neglectto use to the fullest possible advantage, quite simple

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measures for management already at hand.’’ Further,he stated that this attitude often resulted from notunderstanding the true prognosis in this group ofdiseases. He further discussed his approach to the man-agement of these conditions under the rubric of a seriesof questions:

1. Why or for what purpose is treatment required?2. What is to be treated?3. How is treatment to be effected?4. When is treatment to be instituted?5. Where is treatment to be carried out?

Each question was followed by a narrative addressingthe specific areas, with practical and very prescient ad-vice. He emphasized the need for long-term observationof these subjects clearly paralleling our current manage-ment of patients with proteinuria. Specifically, he be-lieved that there were 2 items much neglected but ofoutstanding importance in relationship to the treatmentand outcome of Bright’s disease. The first was the neces-sity of formulating a definite plan before commencingtreatment, and the second was choosing and applyingsuitable standards of reference with which to assess theefficacy (the elements we call today a treatment planand appropriate outcomemeasures). He stated that ‘‘hap-hazard dabbling with this and that remedy or method ismuch too prevalent and is a frequent cause of failure anddisappointment.’’ Osman illustrated the need for carefullongitudinal study of these conditions and in particularfocused on protein restriction, especially when azotemiawas present. Protein restriction in the diet was indicatedat this point, but at an earlier stage when there was signif-icant proteinuria and edema (but no azotemia), proteinsupplementation may be required. He indicated thatsuch extreme variations in terms of management arethe rule and not the exception in the treatment of patientswith Bright’s disease.

The second point, which also resonates today, was thatinsufficient attention was being paid to appropriatemethods for either assessing progress or the results oftreatment of the disease. He emphasized that there wouldbe long periods in many patients with no clinical signs orsymptoms, except presence of low-grade albumin in theurine. In such cases, he indicated the need for appropri-ate laboratory monitoring that would ‘‘reveal the truestate of affairs.’’ He further stated that disappearance ofclinical features as a result of treatment, ‘‘though a matterfor congratulation is by no means evidence of completerecovery.’’ To justify the latter conclusion, he indicatedthat much more rigid standards must be satisfied thancan be supplied by clinical observation alone. Further,he noted that the interval between clinical and biochem-ical recovery may be months or years, and regardless ofits duration, this period is one of potential danger tothe patient and requires ongoing and assiduous supervi-

sion. He emphasized that the only method of properlymonitoring these conditions was by regular clinical andbiochemical assessments and by charting and graphingthese data. He argued that such a graphic representationhad proved particularly helpful in reducing the complexand diverse phenomena to a form which could be readilycomprehended by the attending physician (a flowchart intoday’s parlance). He further suggested that this monitor-ing needed to be continued during convalescence but atdecreasing intervals and for as long as any abnormalitieswere found (in the blood or urine). He concluded that inpatients with these proteinuric disorders, such investiga-tions are indispensable for correct treatment, and in thosewho no longer show clinical evidence of the disease,real recovery is not assured until these occult signshave also disappeared. These remain important elementsin today’s management of patients with proteinuria.

In the 1940s, the 50-year old quest for the location ofthe primary defect in proteinuric kidney conditions con-tinued. Addis, a prominent physician of the time, resur-rected the concept of specific lesions within the kidneystructural compartments producing distinct clinical phe-notypes. In a 1948 lecture, entitled ‘‘the mechanism ofproteinuria,’’ he outlined the current belief that patientswith proteinuria had a damaged glomerular membraneallowing increased permeability to protein.21 This theorywas based on earlier observation that the urine of healthypeople was protein-free as a result of which the normalmembrane was impermeable to protein. This conceptwas based on the classical experimental work of Wearnand Richards in 1924, which indicated that the glomeru-lus was a filter. In their classic experiment, they obtainedminute quantity of fluid from Bowman’s space and deter-mined that the solute concentrations in it were identicalto the plasma (a filtrate). This filtrate was ‘‘protein-free’’using the best measurement tools of the day that mea-sured protein down to a concentration of approximately30 mg/dL. Addis noted that although this provideda sound foundation for the notion of proteinuria andmight even be regarded as beyond assail—if it were notfor the subsequent observation that the filtered volumeper day was approximately 180,000 cc—even a filtrateprotein concentration as low as 10 mg/dl could poten-tially produce 18 g of proteinuria through a ‘‘normal fil-ter’’ everyday. He supported this theoretical calculationby a series of experiments in which he injected increasingamounts of rat serum into the peritoneal cavity of normalrats and showed that they did develop significantproteinuria. This indicated to him that the glomerularmembrane (capillary wall, basement membrane, and ep-ithelial membrane) was not absolutely impermeable toprotein and that all clinical meaningful proteinuria doesarise because of damage to the membrane. This, however,did not resolve the question of the location of the lesionsbecause the experiments were hindered by limited accessto human tissue and lack of technological advances at the

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microscopic level. His call following these experimentswas for more collaborative research given the complexityof the mechanism of proteinuria. He suggested that thisprocess likely involved all 3 kidney elements: filtration,reabsorption, and intracellular digestion. He admittedthat this was only a working hypothesis given the afore-mentioned limitations but that the more complex viewprovided the opportunity for experimental validation,correction, and extension that would require thecoordinated efforts of experts in physical chemistry, his-tochemistry, and enzyme chemistry. This provided thetemplate of a collaborative team approach to the studyof the structure and function of the nephron. This multi-disciplinary approach to the evaluation of proteinuriahas become the norm and has produced in large partour current understanding of the mechanisms of protein-uria formation.

It was the advent of the percutaneous biopsy in the1950s by Iversen and then Kark that provided a criticalkey to understanding the glomerular disease because itallowed access to kidney tissue at a much earlier timepoint in the pathophysiology of the process. Thischanged our approach from a purely descriptive and inlarge part, post hoc clinicopathological correlation toa more real-time corollary between histology and the pa-tient’s clinical state. It is interesting that this technicalprocess was believed to largely vantage the medical stu-dent who would no longer be the victim of the divergentopinions of the clinicians, based on the patients signs,symptoms, and laboratory findings, versus the opinionsof morbid pathologists’ based on the description of thekidney appearance at end-stage disease. Its applicationwas slow, but by the late 1950s, studies were publishedof real-time correlation by Ross and colleagues betweenthe renal histology and clinical findings.22 The first cate-gory in Ross’s classification was nephrotic syndrome.This was a term introduced by Leiter in 1930 to differen-tiate the association of massive proteinuria, edema, hypo-proteinemia, and hypercholesterolemia in patients withglomerulonephritis often associated with hypertension,urea retention, and excess red blood cells in the urinefrom lipoid nephrosis, a condition having the same first4 features only and no identifiable morphologic glomeru-lar lesions. The differential diagnosis of nephrotic syn-drome had already been considerably expanded byKark and colleagues who had already described 31 possi-ble causes of the condition; until then, all such glomeru-lonephritis cases were lumped under Ellis type IInephritis.23 The new pathology features found on renalbiopsy were dramatically different despite the very sim-ilar clinical phenotype. The interpretation of these strik-ing morphologic differences was particularly relevantgiven their apparent influence on prognosis. For instance,Ross intimated that generalized basement membranethickening or intercapillary hyalinization of the glomer-uli represented irreversible change and presaged inevita-

ble progression to renal failure, even though it may bedelayed for years. The capacity to prognosticate wasbased on the presence or absence of certain lesions andwas further advanced with the advent of electron micros-copy. This level of microscopic examination led to thefirst description of effacement of foot processes in the ep-ithelial cell. Folli et al were the first to describe this lesion,its potential reversibility, and its relevance to an excellentprognosis.24 This lesion became the sine qua non of lipoidnephrosis and the major distinction between patientswith the same clinical features and histologic effacementprocess, but who had, in addition, the subepithelial de-posits classically seen in membranous nephropathy.

Ross’s second category in this real-time approach toclinicopathological correlations was the acute variant ofglomerulonephritis classified until that time as Ellistype I. Ross indicated that kidney biopsies taken shortlyafter the onset of symptoms of hematuria and/or protein-uria in general showed inflammatory infiltrates and evennecrotic lesions. Surprisingly, these patients often hadchronic irreversible lesions as well and Ross interpretedthese lesions as either previous renal disease or lesions,which could develop much more rapidly than previouslythought to be possible (a question still unanswered to-day). Electron microscopy confirmed that the hypercellu-larity was usually restricted to the endothelial cells andonly mild to moderate foot process effacement that waslimited to the severely affected areas of the glomerulioccurred in these cases.

The third category in Ross’s classificationwas focal glo-merulonephritis. This entity, first described by Bates andcolleagues in 1957, was of 9 patients with mild nephriticsigns and symptoms associated with acute pharyngitis,but no history of recent streptococcal infection. In thesecases, gross hematuria was the predominant clinical fea-ture in the expanded clinical description. Ross addedthat this scenario was usually confined to the youngerage group, who had repeated attacks of gross hematuriabut without edema, hypertension, or nitrogen retention.Further, there were often multiple attacks, initiated bya variety of infections and that the proteinuria couldpersist between attacks. Renal function usually remainednormal, even after many years of these episodes. On his-tology, the glomerular lesions were focal and consistedof small areas in the tufts containing increased numbersof cells and intercapillary (matrix) material with associ-ated adhesions to Bowman’s capsule. He also indicatedthat after repeated courses of disease, structural damagecould become quite severe, and that long-term treatmentwith penicillin and short courses of steroids did not pre-vent or shorten the attacks of hematuria. This is a clearand convincing description of the presentation and courseof what we today call IgA nephropathy.

The introduction of ‘‘specific’’ therapies for glomerulo-nephritis (GN) and proteinuria also began in the 1950swith the introduction of corticosteroids and long-acting

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adrenocorticotropic hormone (ACTH) preparations. Al-though treatment was initially focused on all patientswith nephrotic range proteinuria, the introduction of per-cutaneous biopsy allowed a more targeted approach topatients with kidney disease. Smart was one of the firstto introduce the concept of specific treatment determinedby a combination of clinical and comorbid features (al-though the results of kidney biopsy pathology, a processonly recently initiated, played little part in his decision-making).25 A major area of controversy that still re-mained was regarding how to differentiate the nephroticsyndrome secondary to classic Ellis type II glomerulone-phritis from lipoid nephrosis. This was not possible at theclinical level and although themethodology as well as therisks and benefits of percutaneous biopsies were knownby this time, access to the procedure was very limited.Histologic examination with the more advanced electronmicroscopy (regardless of the uncertainty about its inter-pretation) was even more restricted. This mandated thatthe decision-making regarding the use of these specifictherapies was based on the clinical setting. This resultedin patients being ruled out for treatments rather thanruled in. Smart indicated, for instance, in his experience,patients with the nephrotic syndrome in association withdisseminated lupus erythematosus, amyloidosis, orKimmelstiel–Wilson disease never showed a satisfactoryresponse to these treatments and therefore should notbe treated. In addition, he indicated that patients withdefinite evidence of prolonged and constant nitrogen re-tention (sic renal failure) were also unlikely to be respon-sive and that a significant elevation of systolic or diastolicpressure would further reduce the likelihood of a re-sponse. There still remained the major question of whatto dowith patients with apparent primary kidney diseaseand significant proteinuria. This issue was further com-plicated by the recent recognition that part of the varia-tion in the natural history of apparent primary GN wasrelated to infectious triggers. Nephrotic patients wereknown to undergo remissions and relapses spontane-ously, but they also appeared to remit or relapse as a re-sult of infections. Smart’s summary statement alluded tothis issue and indicated that relapses appeared morecommonly after upper respiratory infections, whereasmore serious infections tended to be followed by remis-sions. He also indicated that although these remissionsusually consisted of a diuresis and consequent loss ofedema, they could at times be associated with a completecessation of proteinuria and an apparent cure. An impor-tant clue to the underlying issue was illustrated by the re-ported much higher spontaneous remission rate inchildren versus adults. In a study by Ellis in 1942, only5 of his 145 adult cases recovered spontaneously, butcompletely, whereas Fanconi and colleagues (1951) andBarness and colleagues (1950) reported a cure rate ofonly approximately 30% in their studies that containeda significant proportion of children. This predated our

recognition that minimal change disease was the histol-ogy most commonly underlying the nephrotic syndromein childhood (with its high spontaneous remission rate)versus a membranous, MPGN pattern or other histologicvariants in adults (with a much lower spontaneousremission rate). Smart summarized his opinion of howlong to wait by noting that it was currently impossibleto determine how often this (spontaneous remission)happens, because no one could differentiate ‘‘pure ne-phrosis from subacute nephritis in the nephrotic stage.’’However, his report did provide some interesting in-sights into the effects of treatment of proteinuric patientstreated with long-acting ACTH preparations includingissues of dosage and duration of therapy. His sage adviceincluded the need to maintain a low-sodium dietthroughout the course of therapy and that, when embark-ing on treatment with cortisone or ACTH, a close eyeshould be kept on the potassium level. An interesting el-ement of this approach, in contrast to today, was his com-ment that periodic electrocardiogram monitoring couldbe used to detect inordinately high levels of potassiumif biochemical measures were not readily available. Interms of treatment protocols, he recommended thelong-acting ACTH gel in a dosage of 80 IU/d, and for60 mg/d of prednisone, the latter similar to today’s initi-ation of therapy, for instance, in lupus nephritis. He didsuggest the duration of therapy to be only 2 to 3 weekswhich by current standard is perhaps a bit short, buthis statement that continuation of low-dose prednisoneor its equivalent in terms of preventing relapses strikesa familiar chord in today’s guidelines for managing re-lapsing minimal change disease. A table from his articleis interesting to review considering the current renewedinterest in ACTH therapy. He reported a case series of37 patients treated with long-acting ACTH: 17 patientshad a complete remission and at follow-up 15 remainedprotein-free, 2 had relapsed, but there were no cases of re-nal failure or death; 14 patients had a partial remission(undefined), and at follow-up, 1 was in complete remis-sion, 7 remain with proteinuria but without renal failure,3 had renal failure, and 3 had died. In the 6 patients withno response, 2 remained with proteinuria, 3 had renalfailure, and 1 had died. These results in terms of protein-uria are not dissimilar to the outcome in a case series us-ing a similar product reported at the 2010 AmericanSociety of nephrology meeting26!

Little was known about the mechanism of action ofthese specific therapies. Lange and colleagues had con-sidered that the nephrotic syndrome might result fromantigen-antibody reactions involving the glomerularbasement membrane similar to the experimental modelof Masugi nephritis. Smart wondered whether the actionof these hormones might be through interference withantigen-antibody formation, although he admitted thatthere was no evidence of such complexes and no evi-dence of circulating antibodies to human glomeruli in

History of Proteinuria 231

the plasma of nephrotic patients. This possible mecha-nism of disease remained only a theory in patients withidiopathic nephrotic syndrome until the very recent dis-covery of an antibody to a component of the human po-docyte in the circulation of 75% of patients withidiopathic membranous nephropathy.27

Surprisingly, it was not until the late 1960s, an entiredecade later, before the seminal work of Pollack andcolleagues brought more clarity to the distinction be-tween lipoid nephrosis and the other major cause ofthe nephrotic syndrome, membranous nephropathy.28

Their classic review focused not only on the clinical andtherapeutic elements of these 2 diseases but also on thehistopathologic patterns. This article used not only per-cutaneous kidney biopsy tissue but also the best stainingmethods of the day combined with years of longitudinalobservations that documented both the natural historyand response to therapy in these conditions. The conclu-sions of Pollack and colleagues, in large part, remainvalid today. They indicated that patients with minimalchange disease had a high response rate to corticoste-roids, an excellent prognosis, but a high relapse ratethat decreased as the patient aged. They combined thiswith a description of the specific histologic changes inMCD. In their patients with membranous nephropathy,they described a significant component that had a sponta-neous remission rate, another segment with persistentbut subnephrotic proteinuria, and a third group that pro-gressed to ESRD. This article set a new standard for howto study proteinuria in patients with glomerulonephritis.Of particular interest is how closely it aligned with therecommendations of Shore from half a century earlier.It reiterated the absolute need for careful ongoing obser-vation of these patients not only in those with the clinicalfeatures of high grade proteinuria but perhaps even moreimportantly in those without symptoms recognizing thatmany of these cases will have progressive disease. Thisarticle ushered in the new era of management and treat-ment of patients with proteinuric kidney conditions.

Historically, the recognition of protein in the urine asan indicator of kidney of disease and its reduction a targetof therapies to prevent progression of disease had beena hallmark of glomerular disease. With the advent of sci-entific technology, there have been significant major ad-vances in glomerulonephritis and its sine qua nonproteinuria with the discovery of novel genes, proteins,and a better understanding of the cellular basis of dis-ease. The recognition that proteinuria can damage thekidney directly and is not just a marker of disease hasalso revolutionized our thinking about the process. Thequalitative and quantitative effect on the outcome relatedto differences in histology, the quantitative relevance ofpartial remission in proteinuria, and numerous random-ized controlled trials involving newer agents have all ad-vanced our understanding of the critical importance ofproteinuria in both primary kidney disease and in the

general health of our patients. Some of the other aspectsof proteinuria screening, evaluation, and managementare illustrated in the subsequent articles in this editionof the Journal. The connections between the clinical pat-terns of GN and our current understanding of the patho-physiology have also expanded greatly and now includethe application of the most sophisticated technology, in-cluding tissue expression patterns, genomics, urinaryproteomics and metabolomics, messenger ribonucleicacids, and so forth. This exponential growth in ourknowledge of the relationship between proteinuria, kid-ney disease, and patient outcome has come a long waysince Hippocrates’ observation, and it is noteworthythat his comment still remains true today and remainsthe best (and often the only) clue to the time of onset ofsignificant proteinuria, ie, ‘‘when bubbles settle on thesurface of the urine, it indicates disease of the kidneysand that the complaint will be protracted.’’1

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