management of the nephrotic syndrome - bmj

Personal Practice*

Arch. Dis. Childh., 1968, 43, 257.

Management of the Nephrotic SyndromeGAVIN C. ARNEIL

From the Department of Child Health, University of Glasgow

The nephrotic syndrome may be defined as grossproteinuria, predominantly albuminuria, with con-sequent selective hypoproteinaemia; usually accom-panied by oedema, ascites, and hyperlipaemia, andsometimes by systemic hypertension, azotaemia, orexcessive erythrocyturia.

Grouping of Nephrotic SyndromeThe syndrome falls into three groups.

(1) Congenital nephrosis. A group of dis-orders present at and presenting soon after birth,which are familial and may be acquired or inherited.Persistent oedema attracts attention in the firstweeks of life. The disease may be rapidly lethal,but occasionally the patient will survive for a yearor more without fatal infection or lethal azotaemia.The disease pattern tends to run true within afamily. It does not respond to steroid treatment,and palliation alone is possible. Death frominfection is usual before renal failure proves lethal.This group has been well described by Hallman,Hjelt, and Ahvenainen (1956) and Lange et al.(1963), and will not be considered further.

(2) Secondary nephrosis. In this group ofconditions a known primary disorder precedes orcoexists with the nephrotic syndrome. Causesmay be summarized as follows.

(a) Collagen disease: e.g. anaphylactoid purpura,disseminated lupus erythematosus, polyarteritisnodosa.

(b) Quartan malaria: as described from Nigeria(Gilles and Hendrickse, 1963).

(c) Post-nephritic state: a rare form followingacute haemorrhagic glomerulonephritis.

(d) Heavy metal poisoning: due to lead or mercury.(e) Renal vein thrombosis.(f) Diverse rare causes: amyloidosis, diabetic

glomerulosclerosis, neoplastic infiltration, snake bite,and many others.

* In the 'Personal Practice' series of articles an author is invitedto set out his personal views on the handling of some currentpaediatric problem.

(3) Idiopathic nephrosis. This may be re-garded either as a primary disease, or as a secondarydisorder, with the primary cause or causes stillunknown. It is the common form of nephrosis inchildhood, but the less common in adult patients.Unless otherwise specified, the present discussionconcerns idiopathic nephrosis.

Assessment of the CaseFull history and examination helps to exclude

many secondary forms of the disease. Bloodpressure is recorded employing as broad a cuff aspracticable, and the width of the cuff used isrecorded as of importance in comparative estima-tions. A careful search for concomitant infectionis made, particularly to exclude pneumococcalperitonitis or low grade cellulitis. In a patientpreviously treated elsewhere, evidence of steroidtherapy such as Cushingoid obesity, hirsutism, orstriae is sought, and osteoporosis is then assessedradiologically. Oliguria is the rule in the oedema-tous phase, with marked hyposaluria (sodiumexcretion may be less than 1 mEq daily). Urineosmolality and specific gravity should be withinnormal limits. Haematuria, when present, con-sists of intact erythrocytes rather than the smokyquality produced by lysis in the urine of acutehaemorrhagic nephritis (Heymann et al., 1958).The amount of protein in the urine fluctuates

widely from patient to patient and from day to dayin the same patient, and though arbitrary limits areof little practical use, an attempt must be made todefine quantity per unit volume of urine, per unittime, or even per unit surface area in relation tounit time. Proteinuria usually exceeds 50 mg./hourand 1 g./litre at onset. The Esbach test is used forrough quantitation, but the turbidimetric salicylsul-phonic method is simple and useful for quantitation.The precise but laborious biuret method is not hereemployed for this measurement.Microscopy of the urine gives diverse results.

Casts vary in frequency and cellularity. Whiteblood cells are rarely present in excess, save on thenot rare occasions when pyuria is superimposed on

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Gavin C. Arneilthe nephrotic syndrome. Red blood cells arepresent to gross excess in 10% of children and tomicroscopical excess in a further 15%. Techniquesof measuring haematuria vary, but our practice isto use quantitation per unit volume, employing asimple method such as that of McGeachie andKennedy (1963) or Stansfeld and Webb (1953).The latter test is simpler and is recommended.These simple quantitations may be complicated byexpression in terms of unit time and/or surface areaas desired. Initial haematuria carries a bad prog-nosis, and in a recent series the mortality after 5-10years was 17% and continuing illness 29% whenthere was initial haematuria, compared with 7% and18%, respectively, when there was not (Arneil andLam, 1966).

Renal function tests. These are of limitedvalue and this particularly applies to urea-clearancetests. The urea concentration and the endogenouscreatinine-clearance tests are usually normal.Selectivity of proteinuria, if the estimation isavailable, is probably the most useful test of renalfunction applicable to this situation.

Renal biopsy. Percutaneous renal biopsy ofthe child is easy to essay but difficult to apply wiselyor with consistent success. Such acupuncture iscarried out by a trained person where there iscertainty that two kidneys exist, and where there isno gross hypertension, hydronephrosis, or bleedingdiathesis. With local anaesthesia it is technicallyeasier, and probably more often successful thanwith general anaesthesia, which is nevertheless lesstraumatic physically and psychologically. Localanaesthesia for older children and general anaes-thesia for younger children is probably a reasonablecompromise. Of several simple marker techniquesavailable, we prefer to take a straight postero-anterior film of the prone patient with a markerfixed on the skin at the proposed site of puncture;intravenous urography is then performed to checkthe correct placing of the marker, which is left insitu until the actual operation.The necessarily limited amount of material

provided often reduces the value of needle biopsy,so that there is something to be said for the viewthat if biopsy is vital for the patient a small openbiopsy is justified. A good surgical biopsy isprobably no more hazardous and is more informativethan unskilled percutaneous needle biopsy. Althoughsome specimens are disappointing in glomerularyield (i.e. less than 10 glomeruli), the practica-bility of repeated percutaneous biopsies in thesame patient has made possible the serial study

of individual diseased kidneys; this is a greatadvantage. The success rate of the procedure inour unit is about 85%.

Electron microscopy, though yielding fascinatingdata on the pedicels of the epithelial cells, has so farcontributed little to the practical management ofthe disease. Simple light microscopy of serialsections, cut at 2-4 ,u, yields valuable data if arange of stains (H. and E., P.A.S., silver, etc.) areemployed to reveal the underlying tissue changes.Study of tubules, vessels, and interstitial tissue is ofinterest, but it is the glomeruli that yield the crucialdata. A simple classification is:

(a) Light microscopy negative: no significantdetectable lesion.

(b) Light microscopy positive: (i) Membranous:showing significant thickening of basement mem-brane; (ii) Proliferative: proliferative changes withor without membranous change.(More detailed classifications demand an expertrenal pathologist, and if unanimity of opinion issought only one should be consulted!)A further sophistication is the application of

immunofluorescent techniques. The presence orabsence of 'bumps' of immunoglobulin is estab-lished with specific antisera, whose delightfulshimmer on microscopy beckons like will-o'-the-wisp, and deludes the unwary employer of insuffi-ciently specific agents just as successfully. Thework of Drummond et al. (1966) in this respect isworthy of study.

Study of immune protein levels in serum.Investigation of various fractions such as comple-ment and P3 I c-globulin are now well established,but confined to a few centres. P3I c-globulin (acomponent of complement) is low in level in theplasma when complement is being used, and indi-cates immunological activity (West, Northway, andDavis, 1964; Gotoffet al., 1965). These techniquesare of little help in idiopathic nephrosis. Thesimple plate tests for IgG are a much more practicalproposition, but not yet of proven use.

Selectivity of proteinuria. Various tech-niques have been used to differentiate cases wheresmall protein molecules mainly constitute theproteinuria from those where larger molecules alsoleak through the glomerular membrane. Immuno-logical techniques for quantitative assay of thevarious components of protein in plasma and urine,and comparison of the relative proportions of eachleaking out, have been developed by Blainey et al.(1960), Soothill (1962), Cameron and White (1965),and Cameron and Blandford (1966). Here,

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Management of the Nephrotic SyndromeCameron's method is used, the immunological testsbeing available as a 'prefabricated kit' readily usedin any laboratory. Cameron found that the patientwith a highly selective small-molecular leak tendedto retain this pattern throughout the course of theillness, responded well to steroid, and had anexcellent prognosis. Cases in which a greaterproportion of larger protein molecules penetratedto the urine along with the albumin and smallmolecular y-globulins had a much less goodprognosis; the selectivity of proteinuria againremained constant throughout the illness. Thissimple test (which is mercifully independent ofrenal biopsy) seems the one most likely to predictthe cases where steroid treatment will succeed, andthose in which steroid resistance, poor response, orfrequent relapse may be expected. Such data inthe future may spare the patient excessive anduseless steroid therapy in high dosage, and indicatethe need for cytostatic and low dosage steroidtherapy. Many clinicians may prefer to reservebiopsy for those whose protein clearance is nothighly selective, unless a scientific trial is in progress.

TreatmentThis is best considered under the headings of

dietetic, antibiotic, diuretic, steroid, cytostatic, andterminal.

Dietetic. In the oedematous phase sodiumintake is restricted to 0 5-2 g. daily, with a fluidintake of 0 *5-1 litre. Such restriction rarelyprovokes diuresis, since the urinary sodium excretionmay be as low as 1 mEq/day, but it does help toslow the rate of oedema formation. A generousintake of protein is indicated to help minimize thekatabolic loss (unless the level of blood urea beraised). Calorie restriction, with a high-proteincontent in the diet, accompanies intensive steroidtherapy in an effort to reduce the development ofCushingoid obesity, moon face, and permanentcutaneous striae. A high-protein diet is continuedas long as proteinuria with or without oedemapersists, and until the onset of renal failure.

Dietetic treatment of chronic renal failure isbeset with problems of personality. There wasmuch to be said for allowing the patient free choiceand little restriction when therapeutic nihilism wasthe rule. It behoves one to remember that to thechild (who is about to die) food is a great comfort,and such essentials as mince, bread, and sausages pro-bably justify their protein content on humanitariangrounds. All forms of dietetic restriction-alkalineash diet, rice diet, Giovanetti diet-are but pallia-tive, and may be an unwarranted imposition unless

some positive action such as renal transplant isbeing considered in the future.

Antibiotic therapy. It is not our practice togive prophylactic antibiotic treatment when apatient is adequately supervised, though the use ofcytostatic treatment may alter this practice in thefuture. Long-term use of antibiotics does noteliminate the hazard of infection by an organismresistant to the specific antibiotic employed.Immediate intensive antibiotic therapy is mandatoryif infection arises. Pyelonephritis excluded, theantibiotic of choice in pyrexia of unknown origin, orinfection, is penicillin. The reduction in themortality of idiopathic nephrosis is certainly asmuch due to efficient antibiotics as to specific effectof steroid therapy.

Care is taken not to overlook concomitantbacterial pyelonephritis, which is by no means rare,and should be treated vigorously for not less thansix months.

Diuretic therapy. Impressive diuresis is pro-voked by steroid therapy in over 90% of childrenwith primary nephrosis. This, together withmemories of the inefficacy of the older diureticagents, such as plasma expanders and mercurials,has tended to obscure the usefulness ofmore moderndiuretics. Steroid is the best form of diuretic formost cases, but other diuretics must be consideredin the following circumstances.

Infection. When infection such as peritonitis,cellulitis, pneumonia, or pyelonephritis coexistswith nephrotic oedema, steroid therapy may bebetter delayed until the infection is cleared.

Steroid 'resistance'. This is only accepted hereafter adequate steroid therapy has failed. Elsewhere,the demonstration of proliferative nephritis onrenal biopsy may be accepted as proof of un-suitability for treatment. We do not considerthe presence of non-selective proteinuria, or ofazotaemia, systemic hypertension, or gross haema-turia as absolute but rather as relative contra-indications to the use of steroid therapy.

Steroid toxicity. Acute hypertension, severeseizures, osteoporosis with potential vertebralcollapse, and papilloedema, in relation to previoussteroid therapy, are contraindications. Diabetesmellitus, gross cutaneous striation, and severedwarfing are also usually considered contraindica-tions.

Percutaneous renal biopsy. If histology is essentialbefore steroid therapy is begun, this is easier tocarry out on a patient who has been rendered free ofgross oedema and ascites.

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Miscellaneous. Periods such as that followingexposure to chicken-pox are not considered a

suitable time to begin intensive steroid therapy, andpalliative diuretic treatment complements the use

of y-globulin.Diuretic treatment is employed in association

with a sodium-restricted diet (20-80 mEq daily) andpossibly water restriction to 1 1. daily. It involvesthree drugs, (i) chlorothiazide: the dosage initially is1-2 g. daily depending on the size of the child.If this fails, dosage is increased to 2-4 g. daily,irrespective of the size of the patient. If this failsthen, (ii) spironolactone-A is added, 100 mg. dailyin divided doses, together with, (iii) potassiumsupplements, best given as effervescent tablets ofpotassium bicarbonate, 0 5 g. (6-5 mEq), 2 to 4tablets daily; alternatively potassium chloride may

be given up to 4 g./day (= 54 mEq) but the enteric-coated tablet must not be used.There is no shortage of alternative diuretics, but

while some (e.g. frusemide) may be as effective,none seems to produce a more reliable or saferdiuresis or with less risk of hypokalaemia than theproven system outlined above.

Steroid TreatmentShort vs. prolonged steroid course. In 1950, when

treatment with ACTH and cortisone first began,steroid treatment was given for a few days only andthen stopped abruptly. Diuresis followed suchshort-term steroid on occasions, and 2 of ourpatients given 200 mg. cortisone daily for 5 days in1952 promptly recovered and remain well 15 yearslater. Results improved considerably when inten-sive steroid therapy with prednisolone becameavailable in 1955. Two principal methods oftreatment evolved. The first consisted of an

intensive course of treatment which was tailed offand then stopped, as shown in the Table (Arneil,1956). The second consisted of intensive therapy

TABLEDosage of Steroid Therapy Employed (irrespective of

size)

Intensive Therapy60 mg. prednisolone orally daily for 10 days (15 mg. x 4)40 mg. prednisolone orally daily for 10 days (10 mg. x 4)20 mg. prednisolone orally daily for 10 days (5 mg. x 4)10 mg. prednisolone orally for not less than 10 days (5 mg. X 2),

depending on absence of proteinuria.

Intermittent Therapy20-40 mg. prednisolone orally daily for 3 consecutive days of each

week, e.g. on Monday, Tuesday, and Wednesday, for minimumperiod of 3 months.

Immediate Short-term 5-yearResults Follow-up Follow-up

70/o Steroid 70/o Steroid 5°/o WellResistant Resistant 20/o Dead

I 400/o Remain 400/o WellWell

930/o SteroidResponsive ,240/o Well

530/o Relapse 220/0 Unwell

70/o Dead

FIG. 1.-Immediate, short-term, and long-term results ofintensive steroid therapy.

followed by some form of intermittent (e.g. threedays every week) treatment over a period of years.The best known system of this type employedACTH and cortisone (Lange, Wasserman, andSlobody, 1958); our own is shown in the Table. Itis clear that any one of many different systems maybe successful with a steroid-sensitive patient.Our own results with patients followed for aminimum of 5 years are shown in Fig. 1. Intensivesteroid therapy has evoked diuresis in 93% of our45 children with idiopathic nephrosis, with completeor considerable loss of proteinuria: 40% have notrelapsed, 53% have relapsed, of whom 22% haverecovered and 31% have remained unwell or havedied (Arneil and Lam, 1966). These results shouldbe interpreted against the results before steroidtreatment, when 48% of children recovered, 20%died of infection within 2 years, and 18% died ofrenal failure within 10 years (Arneil, 1961).When initial success has been achieved, the risk

of giving prolonged intermittent therapy to the40% of patients who would not relapse without it,must be balanced against the theoretical risk ofincreasing liability to one relapse by not givingintermittent therapy following the first response tosteroid therapy. It is to be hoped that sophisticatedtechniques such as differential protein clearances,renal biopsy, immunoglobulin (Soothill, 1962),[-I c-globulin estimations (Gotoff et al., 1965), orimmunofluorescent techniques may prove helpfulhere. If they could indicate which patients wereunlikely to relapse, one could avoid intermittentsteroid prophylaxis for children who do not requireit, and so avoid the Scylla of long-term unnecessarysteroids for 40%, and the Charybdis of delay in thestart of long-term steroid treatment for the 53%

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Management of the Nephrotic Syndromewho require it. It is our practice to give oneintensive course, to stop, and, if relapse occurs, togive a second intensive course followed by inter-mittent treatment for a minimum of six months(Table).The most vexatious problem arising from steroids

relates not to the 40% who respond and recover,but to the 53% who, having responded in whole orin part, then relapse. A wide range exists, from thechild who relapses once or twice in the first yearafter steroid treatment is begun, but not subsequent-ly, to the child who relapses frequently withcomplete or incomplete clearance of proteinuriabetween successive episodes for five or more years.This group with recurrent relapses amounts to some40% of all children with primary nephrosis. Somecases will have presented with initial haematuria,will have shown membranous and/or proliferativechanges on light microscopy, and will have non-selective proteinuria, and it is amongst this groupthat the problems of prolonged steroid administra-tion are most clamant.

Complications. These are similar to those seenin the natural disease of hypercorticism. The mostcommon effect, Cushingoid obesity, may be reducedin part by the use of a high-protein and low-carbo-hydrate diet. Centripetal obesity, with buffalohump and 'moon' or 'tomato' face, contributes tothe stretching and striae of skin over certain areassuch as the thighs, abdomen, and on occasions thepubescent mammae. The combination of obesityand oedema with underlying ascites may produceenough tension to cause rupture of striae withsubcutaneous oedema leaking out and soaking theskin, a situation vulnerable to infection.The second problem is that of osteoporosis. We

record an osteoporotic index (relation of bicorticaldiameter to transverse diameter of three bones)initially, and every 3-6 months on steroid thereafter,depending on the intensity of steroid treatment.This gives some indication of the progression orotherwise of osteoporosis. Between intensivesteroid courses or on intermittent therapy weencourage a high calcium (milk) intake and givesupplements of vitamin D.The third problem is that of stunting of growth.

In any patient this is difficult to assess because ofthe variation in individual growth pattern, and thetendency to stunting in all chronic renal disease.It is to the latter group that the most steroid islikely to be given for the longest period.

It is because of this danger of growth retardationthat various forms of intermittent therapy have beendevised. Several theories have been advanced to

justify the use of such intermittent therapy. Itremains in doubt whether growth suppression is dueto steroids competing with or suppressing produc-tion of pituitary growth hormone, or to the suppres-sion of so-far unidentified growth-promotingsubstances in the adrenals.

It has been known for some time that a compensa-tory growth spurt often occurs after stopping a nottoo prolonged course of steroids (Blodgett et al.,1956); hence the observation of Friedman andStrang (1966), that oral steroids may cause moreshort-term growth retardation than ACTH intra-muscularly, is less worrying.Our own cases have recently been analysed, and

indicate that intensive steroid therapy for up to 6months has had no effect on height 5-12 years later.Dwarfism was found in those who had chronicrenal disease of long duration and who had had manycourses of steroid in high dosage, continuous lowdosage, or intermittent dosage. Even in this grouponly some are seriously dwarfed, and a proportionof this stunting may be due to the renal disease,rather than to steroids.

Cytostatic (immunosuppressant) therapy.Several recent publications concem the use ofdrugs formerly called 'immunosuppressants', butnot now thought to be so (White, Cameron, andTrounce, 1966; Shearn, 1965; Grupe and Heymann,1966). The place for these drugs is obviously notin treating the 50% who recover within one year ofonset on intensive steroid therapy alone, but (ifanywhere) in the steroid-resistant, in the frequentrelapser, and perhaps in those patients intolerant ofhigh doses of steroid.The theoretical reasons for the use of such cyto-

toxic agents as cyclophosphamide and azothioprineare tenuous, and there is at present no convincingtrial of their efficiency. The best data are those ofMichael et al. (1967) who showed that azothioprinehad no worth-while effects on steroid-resistantidiopathic nephrotic syndrome, thus agreeing withGoodman et al. (1963), but not with Milliez, Lagrue,and Bariety (1965). A large international trial ofazothioprine plus steroid is under way.

Indications for considering cytostatic agents are:(a) unsatisfactory response to steroid courses; (b)proliferative glomerulonephritis on renal biopsy;(c) steroid toxicity in a responsive patient; (d) non-selective proteinuria; (e) anaphylactoid (Schonlein-Henoch syndrome) glomerulonephritis persistingfor more than 6 weeks.A reasonable therapy would consist of azothio-

prine 2 5 mg./kg. per day, plus 10-20 mg. pred-nisolone daily for 60 days. If no response is

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262 Gavin C. Arneil

Assessed as Idiopathic Nephrosis

Intensive Steroid Therapy No response to SteroidGood response or

l Steroid not indicated

Relapse,.repeat intensive Thiazidee Steroid +Potassium supplement

o -I-~~~~~~~~~~~Aldactone -A

0 Lonq termz iintermittent

Steroid (6months)

|Well,with no Occasional relapse; Frequent relapse Low dose SteroidProteinuria repeat intensive* despite +

and intermittent intermittent Azothioprine orSteroid Steroid Cyclophosphamide

FIG. 2.-Proposed scheme for luse of therapeutic agents in nephrosis. *For definition of intensive and intermittentsteroid therapy, see Table.

obtained, treatment should probably then be dis-continued. Throughout the period the whiteblood count and platelet count must be monitoredseveral times weekly. Severe leucopenia and/orthrombocytopenia is an indication to discontinueazothioprine therapy and not to restart, sincesubsequent sensitivity is common.

Haemodialysis and renal transplant. Inhandling the hypertensive and chronic nephrotic inprogressive renal failure, one must take stock of theprobability of effective renal transplantation becom-ing available in the near future. Most paediatricianswill feel that the physical, emotional, and economiccomplications of chronic haemodialysis do notjustify the use of this technique in young children,unless leading up to renal transplant.

SummaryFig. 2 summarizes the views set out in this

article.REFERENCES

Ameil, G. C. (1956). Treatment of nephrosis with prednisolone.Lancer, 1, 409.(1961). 164 children with nephrosis. ibid., 2, 1103.

-, and Lam, C. N. (1966). Long-term assessment of steroidtherapy in childhood nephrosis. ibid., 2, 819.

Blainey, J. D., Brewer, D. B., Hardwicke, J., and Soothill, J. F.(1960). The nephrotic syndrome. Diagnosis by renal biopsyand biochemical and immunological analyses related to theresponse to steroid therapy. Quart. J. Med., 29, 235.

Blodgett, F. M., Burgin, L., Iezzoni, D., Gribetz, D., and Talbot,N. B. (1956). Effects of prolonged cortisone therapy on thestatural growth, skeletal maturation and metabolic status ofchildren. New Engl. J. Med., 254, 636.

Cameron, J. S., and Blandford, G. (1966). The simple assessmentof selectivity in heavy proteinuria. Lancet, 2, 242.

-, and White, R. H. R. (1965). Selectivity of proteinuria inchildren with the nephrotic syndrome. ibid., 1, 463.

Drummond, K. N., Michael, A. F., Good, R. A., and Vernier, R. L.(1966). The nephrotic syndrome of childhood. J. clin.Invest., 45, 620.

Friedman, M., and Strang, L. B. (1966). Effect of long-termcorticosteroids and corticotrophin on the growth of children.Lancer, 2, 569.

Gilles, H. M., and Hendrickse, R. G. (1963). Nephrosis inNigerian children. Role of plasmodium malariae, and effect ofantimalarial treatment. Brit. med. J., 2, 27.

Goodman, H. C., Wolff, S. M., Carpenter, R. R., Andersen, B. R.,and Brandriss, M. W. (1963). Current studies on the effect ofantimetabolites in nephrosis, other non-neoplastic diseases,and experimental animals. Ann. intern. Med., 59, 388.

Gotoff, S. P., Fellers, F. X., Vawter, G. F., Janeway, C. A., andRosen, F. S. (1965). The ,.-.c-globulin in childhoodnephrotic syndrome. New Engl. J. Med., 273, 524.

Grupe, W. E., and Heymann, W. (1966). Cytotoxic drugs insteroid-resistant renal disease. Amer. J7. Dis. Child., 112, 448.

Hallman, N., Hjelt, L., and Ahvenainen, E. K. (1956). Nephroticsyndrome in newborn and young infants. Ann. Paediat. Fenn.,2, 227.

Heymann, W., Rothenberg, M. B., Gilkey, C., and Lewis, M. (1958).Difference in color of hematuria in the nephrotic syndrome andglomerulonephritis. Pediatrics, 21, 375.

Lange, K., Wachstein, M., Wasserman, E., Alptekin, F., andSlobody, L. B. (1963). The congenital nephrotic syndrome.Amer. J. Dis. Child., 105, 338.

-, Wasserman, E., and Slobody, L. B. (1958). Prolongedintermittent steroid therapy for nephrosis in children andadults. J. Amer. med. Ass., 168, 377.

McGeachie, J., and Kennedy, A. C. (1963). Simplified quantitativemethod for bacteriuria and pyuria. J. clin. Path., 16, 32.

Michael, A. F., Vernier, R. L., Drummond, K. N., Levitt, J. I.,Herdman, R. C., Fish, A. J., and Good, R. A. (1967). Immuno-suppressive therapy of chronic renal disease. New Engl. J.Med., 276, 817.

Milliez, P., Lagrue, G., and Bariety, J. (1965). La chimioth6rapieimmunosuppressive des syndromes nephrotiques et de certainesglomerulonephrites. Bull. Acad. nat. Mid. (Paris), 149, 259.

Shearn, M. A. (1965). Mercaptopurine in the treatment of steroid-resistant nephrotic syndrome. New Engl. J7. Med., 273, 943.

Soothill, J. F. (1962). Estimation of eight serum proteins by a geldiffusion precipitin technique. J. Lab. clin. Med., 59, 859.

Stansfeld, J. M., and Webb, J. K. G. (1953). Observations inpyuria in children. Arch. Dis. Childh., 28, 386.

West, C. D., Northway, J. D., and Davis, N. C. (1964). Serumlevels of ,.-sc-globulin, a complement component, in thenephritides, lipoid nephrosis, and other conditions. J. clin.Invest., 43, 1507.

White, R. H. R., Cameron, J. S., and Trounce, J. R. (1966).Immunosuppressive therapy in steroid-resistant proliferativeglomerulonephritis accompanied by the nephrotic syndrome.Brit. med. 3., 2, 853.



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