Bock, H. A.

Gudat, F.

Mihatsch, M. J.

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Nephrol Dial Transplant (1995) 10: 2368-2370Teaching Point(Section Editor: K. Ktihn)NephrologyDialysisTransplantationA patient with microhematuria and proteinuria: Do we still needelectronmicroscopy?M. J. Mihatsch, H. A. Bock1 and F. GudatInstitut for Pathology, University Basel and 'Division of Nephrology, Cantonal Hospital, Basel, SwitzerlandA 47-year-old white male was referred to the medicalservice for newly discovered hypercholesterolemia. Hepreviously had been seen by the ENT service forprogressive bilateral hearing loss for four years, whichwas determined to be of the inner ear type.There was no relevant family history: specificallytwo sisters and his 79-year-old father were reported tobe in good health. His 78-year-old mother had ahistory of gout but was otherwise well.His personal history included an infectious mono-nucleosis at the age of 19 which apparently had beenaccompanied by 'nephritis'. There was again an episodeof 'nephritis' including macrohaematuria at the age of22, possibly related to a respiratory infection for whichhe had been prophylactically treated with penicillin for4 years. An occupational health screening at the ageof 34 had revealed proteinuria which was not furtherinvestigated at that time. His physical examination wasunremarkable except for elevated blood pressure(150/100 mmHg); in particular, there was no oedema.He took no medication or drugs, did not smoke anddrank approximately 4 dl of wine per day.Routine work-up showed a serum sodium of142 mmol/1, potassium 4.0 mmol/1, creatinine103 umol/1, urea 7.0 mmol/1, cholesterol 7.94 mmol/1,triglycerides 1.68 mmol/1, albumin 36 g/1 and protein59 g/1. His haemoglobin was 16.4 g/dl, leukocytes9170/mm3, platelets 269000/mm3. Liver enzymes, bili-rubin and blood sugar profile were normal, as wereserum electrophoresis, serum complement and anti-streptolysin titre. Antinuclear antibodies were negative.The urinary sediment showed + + + proteinuria,>40 dysmorphic erythrocytes/HPF, 0,3 leukocytes/HPF, hyaline and a few granular casts as well as lipiddroplets and some oval fat bodies. 24-h proteinuriawas 5.0 g/d and creatinine clearance 86 ml/min. Bence-Jones protein in urine was negative. Abdominal ultra-sound showed two normal sized kidneys and wasotherwise normal.Fig. 1. Segmental glomerular sclerosis,foam cells.Correspondence and offprint requests to: M. J. Mihatsch, Institutefor Pathology, University Basel, Basel, Switzerland.Fig. 2. Peripheral glomerular capillary loop: the basement membraneshows thinning and splitting of the lamina densa.11995 European Dialysis and Transplant Association-European Renal Association2369Fig. 3. Peripheral glomerular capillary loop: the basement showsfocal thinning and pronounced irregular thickening. The laminadensa is split and fragmented.Morphology of kidney biopsyBy light microscopy eleven glomeruli were found ofwhich three showed segmental sclerosis (Figure 1). Thearterioles exhibited medium severe arteriolar hylinosis.In the interstitial space groups of foam cells werepresent (Figure 1). Also some of the tubular cellsexhibited a foam transformation. A minimal interstitialfibrosis with tubular atrophy was present. Foetal-likeglomeruli were not found.Immunohistological investigation (IgG, IgM, IgA,C3, C4, fibrin) showed minimal segmental deposits ofIgG, IgA and C3 in glomeruli with segmental sclerosis.Two glomeruli investigated by electron microscopyexhibited thinning and thickening of the basementmembrane with a lamellation and fragmentation of thelamina densa in all loops (Figures 2 and 3).The EM findings were interpreted as characteristicof Alport's syndrome.This case is of interest for several reasons (teachingpoint):Is electron microscopy still necessary in so-called clear-cut diagnostic situations? In the present case, lightmicroscopy showed segmental sclerosis, immunohist-ology was compatible with this finding. So, the dia-gnosis of segmental glomerular sclerosis could beaccepted as sufficiently documented. However, electronmicroscopy showed lesions typical of Alport's syn-drome. Therefore, we still believe that electron micro-scopy is essential for the definite diagnosis of renalbiopsies of native kidneys. Our studies of hundredconsecutive renal biopsies have shown that electronmicroscopy contributes clinically relevant additionalinformation in about 30% of cases [1]. The mostimportant point is that the combined use of lightmicroscopy, immunohistology and electron microscopyresults in nearly all cases in an unequivocal diagnosiswhich forms a sound basis for the further managementof the patient.Interstitial foam cells are usually thought to be onlypresent in cases of long standing nephrotic syndrome.The primary clinical information: 'glomerular hematu-ria and proteinuria without nephrotic syndrome' raisedour suspicion of Alport's syndrome due to the presenceof foam cells. Foam cells are commonly found in casesBMsplitting in the presence of intramembranous depositsBM lamellation and fragmentation in Alport's syndrome\\Unspecific BM splittingFig. 4. Differential diagnosis of basement membrane splitting [4].2370of nephrotic syndrome and in Alport's syndrome. InAlport's syndrome foam cells are present withoutnephrotic syndrome and are far more common thanin glomerulonephritis [1,4]. About 40% of cases ofAlport's syndrome are accompanied by foam cellswhereas only 6% of biopsies with glomerulonephritis.Thus, the presence of foam cells without long standingnephrotic syndrome should always prompt electronmicroscopic investigation. In our patients severeproteinuria (>5g/day) with hypercholesterinemia(~8 mmol/1) and lipiduria could, however, explain thepresence of foam cells even in the absence of full blownnephrotic syndrome or Alport's syndrome.Since the publication of Spear and Slusser [2] elec-tron microscopic findings were considered the goldenstandard for the diagnosis of Alport's syndrome. Thecharacteristic features are basement membrane thin-ning and thickening accompanied by a lamellation,reticulation and fragmentation of the lamina densa asfound in the present case.Since the beginning, it was, however, clear that alsoin other diseases basement changes may be foundwhich may be confused with Alport's basement mem-brane changes (Figure 4). Recent studies have shownthat patients with Alport's syndrome have a mutationof the Alpha 5 chain of collagen 4 (COL 4 A5) whichis located on the long arm of the X chromosome [3].Therefore, all cases with so-called typical Alportlesions by electron microscopy should be confirmed inthe future by chromosomal studies. This time consum-ing and expensive study is justified since the diagnosisof Alport's syndrome has extensive implications forthe patient e.g. life insurance, family planning etc.Is the trias of deafness, hematuria and proteinuriaproof of Alport's syndrome?References1. Mihatsch MJ, Zollinger HU. 1st eine elektronenmikroskopischeUntersuchung von Nierenbiopsien klinisch notig, wiinschenswert,unnotig? Med Klin (1978); 73: 389-3942. Spear GS, Slusser RJ. Alport's syndrome: Emphasizing electronmicroscopic studies of the glomerulus. Am J Pathol 1972; 69:213-2223. Hostikka SL, Eddy RL, Byers MG, Hoyhtya M, Shows TB,Tryggvason K. Identification of a distinct type IV collagen alphachain with restricted kidney distribution and assignment of itsgene to the locus of X chromosome—linked Alport syndrome.Proc Nail Acad Sci USA 1990; 87: 1606-16104. Zollinger HU, Mihatsch MJ. Renal pathology in biopsy. SpringerVerlag, Berlin, Heidelberg, New York: 1978

A patient with microhematuria and proteinuria: Do we still need electronmicroscopy?

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