7773

Saturday 19 August 1972

RECURRENCE OF IDIOPATHIC

NEPHROTIC SYNDROME AFTER

RENAL TRANSPLANTATION

JOHN R. HOYER LEOPOLDO RAIJROBERT L. VERNIER RICHARD L. SIMMONS

JOHN S. NAJARIAN ALFRED F. MICHAEL

Departments of Pediatrics, Internal Medicine, and Surgery,University of Minnesota Medical School,Minneapolis, Minnesota 55455, U.S.A.

Summary Three patients with steroid-resistant

idiopathic nephrotic syndrome were

studied at onset and during recurrent nephrotic syn-drome after renal transplantation. Renal biopsies at theonset of the nephrotic syndrome showed typicalfeatures of the idiopathic nephrotic syndrome; no orminimal focal glomerular abnormalities were presentby light microscopy and glomerular-basement-orienteddeposits were not demonstrated by immunofluorescentor electron microscopy. Progression to renal failureoccurred in 2, 2, and 6 years. Recurrence of

nephrotic syndrome was noted 1, 1½, and 5 months aftertransplantation. Renal biopsies done 1½, 5, and 7months after transplantation when proteinuria was12·8, 7·6, and 8·5 g. per 24 hours, respectively, showedminimal or no glomerular abnormalities by lightmicroscopy. Immunofluorescent and electron micro-

scopic studies revealed no evidence suggesting immuno-logical injury. Subsequent kidney specimens after

transplantation obtained from two of these patientswith recurrent nephrotic syndrome showed focal

segmental glomerulosclerosis limited primarily to thejuxtamedullary glomeruli—a feature further suggestingrecurrence of the original disease in the transplantedkidney. These observations suggest that the patho-genesis of the steroid-resistant idiopathic nephroticsyndrome may involve systemic circulating factors; thishypothesis would account for development of a

recurrent nephrotic syndrome in the transplantedkidney.

Introduction

THE morphology of the idiopathic nephrotic syn-drome is characterised by minimal or no abnormalitieson light microscopy and lack of immune deposits on theglomerular basement membrane (G.B.M.) by immuno-fluorescent and electron microscopy.1-4 Althoughmost patients with this disease respond to adrenalsteroid therapy, in a small percentage of patients the

urine does not clear of protein and these patients pro-gress to renal failure. We have studied four such

patients at the onset of their disease and after renaltransplantation. The nephrotic syndrome recurred inthree of them shortly after renal transplantation.

Case-reportsFIRST CASE

This boy developed intermittent periorbital oedema atn- years of age. 6 months later the nephrotic syndrome wasdiagnosed (fig. 1). Prednisone 80 mg. per day for 21 daysdid not decrease proteinuria. 6 weeks later anasarca was

present and laboratory studies demonstrated a nephroticsyndrome (table I). 7 months later, laboratory studies wereunchanged and prednisone 60 mg. per day was given for 20days without decrease in proteinuria. 10 months later,when renal function was decreasing, azathioprine (’ Imu-ran’) 50 mg. per day and prednisone 50 mg. on alternatedays were given without improvement. In January, 1971,he had become severely ursemic and was referred to theUniversity of Minnesota Hospitals for renal transplantation.There was no family history of renal disease and audiogramwas normal. Hsemodialysis was performed for one month.Bilateral nephrectomy and splenectomy were performed andon March 11, 1971, he received a Terasaki C-match kidneytransplant from his father and was given standard immuno-suppressive therapy including azathioprine, prednisone, andantilymphoblast globulin. 20 days after transplantation theserum-creatinine was 0-9 mg. per 100 ml. and urinary pro-tein was 5-1 g. per 24 hours. 10 days later, he showed signs of

Fig. I-Clinical course of case 1.Proteinuria in excess of 3 g. per 24 hours was always present

after transplantation. Renal function was normal at the time ofthe kidney biopsies.

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TABLE I-CLINICAL AND LABORATORY FEATURES

upper-respiratory-tract infection. The serum-creatininewas 2-4 mg. per 100 ml. and delayed excretion was seen onan isotopic renogram. He was treated for homograftrejection with local irradiation of the kidney and intravenousmethylprednisolone 500 mg. per day for 3 days. Dailytemperature elevation to 102°F (38-8°C) or higher occurredfor 15 days. The liver became tender and enlarged to8-10 cm. below the costal margin. Serological tests forAustralian antigen and antibody were negative. A liverbiopsy showed periportal inflammation; viral inclusionswere not seen. Signs of hepatic injury receded withoutfurther therapy. Recurrent nephrotic syndrome was

diagnosed 6 weeks after transplantation (table l).5 months after transplantation physical examination

showed trace oedema. Urinary protein excretion was 7-6 g.per 24 hours. The blood-urea-nitrogen was 18 mg., serum-creatinine 0-6 mg., albumin 2-2 g., and cholesterol was520 mg. per 100 ml. The creatinine clearance was 82 ml.per minute per 1-73 sq.m. and urinary lysozyme was 0.2 mg.

per ml. Serum-&bgr;IC (C3) was 136 mg. per 100 ml. (normal164J=40). A renal venogram was normal. There was nochange during the next 5 months.

SECOND CASE

This boy developed periorbital and ankle cedema onseveral occasions between 2 and 4 years of age, the oedemaclearing spontaneously without therapy. Family historyrevealed no renal disease. At 4 years of age he was admittedto hospital because of anasarca and the nephrotic syndromewas diagnosed (table i). An intravenous pyelogram wasnormal.

Prednisone 45 mg. daily for 4 weeks and on alternatedays for 2 months was given. Cyclophosphamide (’ Cy-toxan’) 50 mg. per day (2-5 mg. per kg.) was added duringthe later two-month period. Prednisone 45 mg. per day wasgiven for an additional 4 weeks, followed by corticotrophin100 units per day for 16 days. There was no decrease in

proteinuria (fig. 2). During the next 2 years, the serum-creatinine and B.U.N. rose to 7-5 and 123 mg. per 100 ml.respectively.

Peritoneal and hxmodialysis were performed for 5months and a renal homograft was received from a cadaverdonor on Aug. 25, 1967. He was treated with standardimmunosuppressive therapy including prednisone and

azathioprine. Urinary protein excretion was 11-7 g. per 24hours on the first day after transplantation. After a briskimmediate diuresis (6700 ml. in the first 20 hours), hebecame temporarily dehydrated and was oliguric (volumeless than 100 ml. per day) for the next 16 days. Haemo-dialysis was performed. As renal function returned, thenephrotic syndrome became apparent. 6 weeks after trans-plantation, the creatinine clearance was 60 ml. per minute persq.m. and urinary protein excretion was 12-8 g. per 24hours. A renal venogram at this time showed patency ofthe main renal vein with filling defects in small venousradicals. Urinary protein excretion remained greater than5 g. per 24 hours except at the time of severe rejectionreactions.

In June, 1969, he developed a cough, fever, cyanosis, anddyspncea, and died of progressive Pneumocystis cariniipneumonia. A calcified thrombus in the inferior vena cavaextending from the renal vein to above the diaphragm wasdemonstrated at necropsy.

Fig. 2-Clinical course of case 2.

Except for the period of oliguria shortly after transplantation and during rejection episodesproteinuria always exceeded 5 g. per 24 hours.

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TABLE II-LIGHT MICROSCOPY* OF KIDNEY, AT TIME OF NEPHROTIC SYNDROME BEFORE AND AFTER TRANSPLANTATION

* Grading of abnormalities from 0 to + + + as follows: 0= normal; ± = mild, rare; + = minimal in severity and extent; + + = moderate in severityand extent; + + + = severe in severity and extent; F = focal; s = segmental; JM= juxtamedullary glomeruli primarily involved; T=fibrin thrombi.

t Necropsy.

THIRD CASE

This woman developed periorbital and peripheral oedemaafter an upper-respiratory-tract infection at 22 years of age.Her past and family history were unremarkable. Laboratorystudies demonstrated a nephrotic syndrome (table I). AnL.E. clot test was negative. She was treated with predni-sone 20-40 mg. per day for 2 years without decrease ofproteinuria. 2 years after onset, the serum-creatinine hadrisen to 1-5 mg. per 100 ml. The serum-albumin was 0-6 g.per 100 ml. and urinary protein excretion was 10-1 g. per 24hours. Treatment with prednisone 50-100 mg. on alternatedays and azathioprine 50-200 mg. daily for 38 monthscaused no decrease in proteinuria or improvement in renalfunction. 6 years after onset, although in severe renalfailure with a serum-creatinine of 10-2 mg. per 100 ml.,

(a) Typical glomerulus from biopsy no. 6 obtained 7 monthsafter transplantation demonstrating normal G.B.M. and minimalsegmental increase in mesangial matrix. (Silver-methenamine;x 400.)

urinary protein excretion was 6-9 g. per 24 hours. Haemo-dialysis was performed for 21 months.

After bilateral nephrectomy and splenectomy the patientwas given a renal homograft from a cadaver donor. 3 weeksafter transplantation the serum-creatinine was 1-0 mg. per100 ml. and urinary protein was 2+ qualitatively. 2months later urinary protein excretion was 2-0 g. per 24hours. 7 months after transplantation, urinary proteinexcretion was 8-5 g. per 24 hours. The serum-albumin was1-2 g. and creatinine 1-5 mg. per 100 ml. Antinuclearantibodies were not detected in the serum. Selectivevenography showed a patent renal vein.

2 months later she suddenly became febrile and died ofoverwhelming pneumococcal pneumonia and septicxmia 3hours after admission to hospital. This case is describedelsewhere.5

(b) Typical juxtamedullary glomeruli seen at necropsy 9months after transplantation, demonstrating segmental sclerosis.(Azocarmine; x 160.)

Fig. 3-Glomeruli in specimens from allograft of case 3 during recurrent nephrotic syndrome.

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MicroscopyMethods

Portions of kidney were fixed in formalin,embedded in paraffin, sectioned at 4 (J." and stainedwith hasmatoxylin-eosin, periodic-acid/Schiff, azocar-mine, and silver methenamine. Part of the tissue was

rapidly frozen in isopentane prechilled in liquidnitrogen, sectioned in a Lipshaw cryostat, and stainedwith monospecific fluorescein-conjugated antisera tohuman IgG, IgM, IgA, IgE, fibrinogen, and albuminusing methods previously described. Other portionsof tissue were fixed in glutaraldehyde and osmicacid, embedded in ’Vestopal’ or methacrylate andstained with uranyl acetate and lead citrate. e

Light MicroscopyThe findings on light microscopy are summarised

in table 11. Biopsy findings showing similar pro-gression of changes are grouped together.

Early biopsy specimens before and after (fig. 3a)transplantation showed minimal or no focal glomerularabnormalities. Segmental sclerosis was seen in oneglomerulus in biopsy 1 of case 1 and in one glomerulusof biopsy 6 of case 3. G.B.M. thickening and endo-capillary proliferation were not present in any of theearly biopsies.

Focal segmental glomerulosclerosis was a prominentfeature of later biopsy specimens of each patientbefore and after (fig. 3b) transplantation. Theselesions were much more common in the deeper,juxtamedullary nephrons. For example, segmentalsclerosis was present in more than 80% of juxta-medullary glomeruli in biopsy specimen 7 from thetransplanted kidney of case 3; such lesions were seenin less than 10% of superficial glomeruli.

All other renal specimens obtained at the time oftransplant nephrectomy or at necropsy 3-30 monthsafter transplantation during the period 1966-71 at

the University of Minnesota were studied concurrently.Twenty specimens were judged adequate for evaluatingdistribution of focal glomerulosclerosis. None ofthese twenty otherwise unselected specimens showedglomerulosclerosis predominantly within the juxta-medullary region.

Extensive fresh glomerular capillary loop andarteriolar thrombi were present post mortem in thetransplanted kidney of case 3. Large numbers ofgram-positive diplococci were present within eacharea of thrombosis-a pattern typical of pneumono-coccal septicmmia.7

Immunofluorescent MicroscopyThe earliest available specimens from the original

kidneys and the transplanted kidneys of each patientwere studied.

All glomeruli in specimens of case 1 were negativewhen stained for human IgG, IgM, IgA, IgE, piC,fibrinogen, and albumin except for 10 of 30 glomeruliin the transplanted kidney which showed trace to 1 +mesangial deposition of IgM.

Glomeruli in the specimens of case 2 obtainedbefore and after transplantation were negative whenstained for IgG and &bgr;IC,Most glomeruli in the specimen of case 3, obtained

2 years after onset of the nephrotic syndrome, were

negative when stained for IgG and &bgr;IC; others showedtrace to 3+ mesangial and axial deposits. The

glomeruli in the specimen after transplantation werenegative for IgG, IgE, IgM, and fibrinogen andshowed focal 1 + axial deposition of PiC. The trans-planted kidney at necropsy showed extensive inter-capillary deposition of fibrinogen.Electron MicroscopyThin sections of three or more glomeruli and

associated tubules were studied from biopsy specimensobtained early in the course of the disease process incases 2 and 3. Similar numbers of glomeruli frombiopsy specimens of the transplanted kidneys of cases1 and 2 were evaluated.The ultrastructural features of the glomeruli in

the specimens obtained early in the original kidneys ofthe two patients were very similar. The most prominentabnormality was a diffuse loss of epithelial-cell footprocesses (fusion) and replacement of these structuresby long expanses of uninterrupted direct contract ofthe epithelial cytoplasm with the G.B.M. The epithelialcells also contained numerous large low-density

Fig. 4-Electron micrograph of a glomerular capillary loopfrom the kidney allograft of case 1.

Fusion and broadening of epithelial-cell (EP) foot processesare present in this specimen obtained during recurrence of thenephrotic syndrome 5 months after transplantation. BM=base-ment membrane, us == urinary space, cL=capillary lumen.( x 9300.)

347

vacuoles and many dense droplets. There was exten-sive microvillus formation over the free surface of the

epithelial cells. The G.B.M. was entirely normal exceptfor focal areas of scalloping and low-density wideningof the subendothelial cell space. No electron-dense

subendothelial, intramembranous, or subepithelialdeposits were seen. Although mesangial cells were notincreased in number, mesangial matrix appearedminimally increased in some lobules.

Glomeruli from specimens of the transplantedkidneys were very similar but showed less extensiveepithelial-cell foot-process fusion in case 1 than incase 2 and more extensive focal subendothelial spacethickening than seen in the original kidneys (fig. 4).Again dense deposits were not observed along thecapillary walls, and the G.B.M. lamina densa was ofnormal thickness. Definite focal increase in mesangial-cell nuclei and mesangial matrix was apparent in bothspecimens; the changes were more prominent in thespecimen of case 2 obtained 14 months after

transplantation.

Discussion

We have described the progression of idiopathicnephrotic syndrome to renal failure and recurrenceof the nephrotic syndrome after renal transplantationin three cases. Terms used to describe this clinicalentity include idiopathic nephrotic syndrome, I, aminimal-lesion nephrotic syndrome,8 nephrotic syn-drome with focal glomerulosclerosis,4,9 and lipoidnephrosis.10-11 Rich 10 established that patients withlipoid nephrosis may rarely progress to renal failure.He called attention to the fact that juxtamedullaryglomeruli were the first to show focal and segmentalsclerosis; progressive sclerosis developed with minimalor no proliferative changes. Progression of the

idiopathic nephrotic syndrome to renal failure hasbeen described by several other groups. 4,9,11-13These patients can be separated clinically from themajority of patients with the idiopathic nephroticsyndrome, since those in this subgroup do not respondto high-dose adrenal steroid therapy and have per-sistent proteinuria. Although focal and segmentalglomerulosclerosis may not be demonstrated early inthis disease, subsequent specimens may show thisfeature 9,11,12 and a characteristic interstitial fibro-sis.11,12 Differences in sampling probably accountfor variability in histological appearance within thissubgroup early in the disease course.Previous studies of renal tissue in the idiopathic

nephrotic syndrome have demonstrated either no

significant deposition of immunoglobulins and comple-ment or irregular deposition in the mesangium andaxial poles of glomeruli. The significance of mesangialand axial deposits in the idiopathic nephrotic syndromeis unknown, although such deposits have also beenobserved in two presumably non-immunologicalforms of the nephrotic syndrome, in aminonucleosidenephrosis in rats,14,15 and in the congenital nephroticsyndrome after long-standing proteinuria.16Each of the three patients described here have

demonstrated these features and was steroid resistant.When first studied, kidney tissue from case 1 showedsegmental sclerosis in one glomerulus, while that of

the other two patients had no or minimal mesangialabnormalities. Focal glomerulosclerosis was seen insubsequent renal-biopsy specimens. Immuno-fluorescent studies early in the disease demonstratedno or minimal mesangial and axial deposition ofimmunoglobulins and complement. Electron micro-scopy demonstrated the typical ultrastructural featuresof the idiopathic nephrotic syndrome without evidencesuggestive of glomerulonephritis.

It seems that the nephrotic syndrome which

developed shortly after renal transplantation reflectsrecurrence of the original disease in these patients.No major G.B.M. abnormalities were demonstrated bylight or immunofluorescent microscopy and onlyminimal abnormalities were observed in the

mesangium. The major morphological glomerularchange observed by electron microscopy was fusionof epithelial-cell foot processes-the characteristicultrastructural abnormality of the idiopathic nephroticsyndrome. 2, 3

Although focal segmental glomerulosclerosis wasnot seen in initial biopsies after transplantation,subsequent specimens showed this feature. Renaltissue of case 3 obtained at necropsy 9 months aftertransplantation provided strong evidence for recurrenceof the initial disease. Although nearly every glomerulusin the juxtamedullary region showed segmentalsclerosis, glomeruli in the superficial cortex rarelyshowed this change. Renal tissue of case 2 obtainedat necropsy showed a similar but less extreme contrastbetween deep and superficial cortex. This distributionof focal glomerulosclerosis in the nephrotic syndromeoriginally described by Rich 10 has not been previouslydescribed in renal homografts and was not observedin twenty homografts evaluated specifically far thisfeature as part of the present study. It may be specificfor recurrence of the idiopathic nephrotic syndrome.

Other possible explanations for recurrence of thenephrotic syndrome after transplantation includedevelopment of recurrent glomerulonephritis mediatedby anti-G.B.M. antibody z18 or immune-complexinjury. 18 11 Recurrence of glomerulonephritis was

documented in eleven of seventeen renal isografts byGlassock et all, five of these identical twins had anephrotic syndrome after transplantation. Renalspecimens obtained after transplantation of the

patients described here did not show G.B.M.-orientedimmunoglobulin deposition of the type seen in anti-G.B.M. antibody or immune-complex glomerulo-nephritis ; electron-dense deposits were not seen alongthe G.B.M. by electron microscopy.

Proteinuria after renal transplantation has alsobeen linked to homograft rejection. Hamburger et al,called attention to glomerular changes secondary torejection. 20 The studies of Harlan et aI.21 and Porteret al. 22 demonstrated a strong correlation between the

degree of histoincompatibility and the development ofprogressive renal insufficiency, proteinuria, and G.B.M.thickening. At the first biopsy after transplantation,each of our patients had normal renal function.G.B.M. changes suggestive of homograft rejection werelacking by light microscopy. The minimal wideningof the subendothelial space noted by electron micro-scopy of glomeruli from the transplanted kidney may

348

reflect a minimal rejection reaction, but similar

changes were also observed in the original kidney oftwo patients studied by electron microscopy.

Partial renal venous thrombosis was demonstrated

radiographically 6 weeks after transplantation of case 2.Renal venograms of cases 1 and 3 showed no evidenceof thrombosis. Although the coexistence of renal-vein thrombosis and the nephrotic syndrome is a

well-recognised clinical association, the precise patho-genetic relationship has not been established. Con-siderable clinical and experimental evidence, however,indicates that renal-vein thrombosis may be a conse-quence of the nephrotic syndrome. This evidenceincludes the occurrence of renal-vein thrombosis inthe nephrotic syndrome secondary to such diversediseases as diabetes mellitus,23 amyloidosis,24 systemiclupus erythematosus, 23, 25 and most frequently inmembranous glomerulopathy.23,26 Renal venous

thrombosis has also been described in minimal-lesion

idiopathic nephrotic syndrome. 2 8 The abnormalitiesof coagulation 25 and fibrinolysis 27 demonstrated inpatients with the nephrotic syndrome may predisposeto development of thrombotic complications. Renal-vein thrombosis has also been observed as a frequentcomplication of an experimental model of glomerulo-nephritis in rats (Heymann nephritis), having morpho-logical features similar to those observed in humanmembranous glomerulopathy.29 However, morpho-logical features of membranous glomerulopathy werenot observed in the transplanted kidney of case 2and have not been produced in the laboratory bypartial renal venous occlusion. 26 6 Furthermore,massive proteinuria after transplantation preceded theperiod of dehydration that presumably led to renalvenous thrombosis.

Frequency of recurrence of nephrotic syndromeafter renal transplantation is also of interest. Oneadditional patient with biopsy-documented idiopathicnephrotic syndrome received a renal transplant at theUniversity of Minnesota during the period 1963-71.Onset of the nephrotic syndrome was at 3 years ofage, with progression to renal failure in 11 years.Proteinuria was not observed during the first 2 yearsafter transplantation. Thus, in three out of four

patients with the nephrotic syndrome the syndromerecurred after renal transplantation.

In the absence of evidence that the recurrent

nephrotic syndrome of these patients resulted fromrecurrent glomerulonephritis or homograft rejection,an alternate aetiology must be considered. An appealinghypothesis is that a circulating humoral substance inthese patients injures glomerular membranes, causingincreased permeability to protein. The nature of such afactor(s) is not known. Careful clinical studies ofpatients with the idiopathic nephrotic syndrome afterrenal transplantation may throw light on the patho-genesis of this disorder.

J. R. H. is a National Institutes of Health special postdoctoralfellow AM 50447. This work is supported by grants from theKational Institutes of Health (AM 12375, AM 05671, AM 13756,HE 06314) and the American Heart Association.

Requests for reprints should be addressed to J. R. H., Depart-ment of Pediatrics, University of Minnesota Hospitals, Min-neapolis, Minnesota 55455, U.S.A.

DR. HOYER AND OTHERS: REFERENCES

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INFLUENCE OF A PARTOGRAPH ON

THE ACTIVE MANAGEMENT OF LABOUR

JOHN M. BEAZLEY ASIM KURJAKInstitute of Obstetrics and Gynæcology,Queen Charlotte’s Maternity Hospital,

Goldhawk Road, London W.6

The plotting of partographs to monitorSummary the progress of cervical dilatation

during labour was introduced into regular hospitalpractice in December, 1971. It enabled labour to bemore actively managed by methods such as amniotomy,’Syntocinon’ (oxytocin) acceleration, and epiduralanalgesia. Acceleration of labour reduced the frequencyof protracted labour. In primigravidæ, accelerationwas associated with a reduced frequency of babieswith respiratory depression at birth. In multiparouswomen there was an increase in the frequency ofdepressed babies at birth. Forceps deliveries in

multiparæ increased significantly. Extreme cautionand careful partograph monitoring of the progressof labour is advised whenever uterine activity isaccelerated in multiparæ.