Hereditary tubulointerstitial disease approach to biopsy diagnosis

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1 Hereditary tubulointerstitial disease approach to biopsy diagnosis Kerstin Amann Nephropathology, University of Erlangen-Nürnberg Krankenhausstr. 12 D Erlangen Kerstin.amann@uk-erlangen.de

2 maternally transmitted disease Mitochondrially Inherited Tubulointerstitial Kidney Disease (MITKD) (Connor et al., 2017)

3 Results of morphology and Sanger sequencing in MITKD Focal tubular atrophy Normal mitochondria homoplasmic m.547a>t substitution unspecific morphology (Connor et al., 2017)

4 Interesting case

5 PAS 30 glomeruli, 11 globally sclerosed

6 PAS Other glomeruli normal.

7 Acute tubular damage (ATN), % IF/TA. PAS

8 Thickened and lamellated tubular basement membranes PAS PAS

9 Electron microscopy: Mild thickening and wrinkling of glomerular and tubular basement membranes, lamellation of tubular basement membranes. No osmiophilic deposits, no fibrils.

10 Electron microscopy: Mild thickening and lamellation of tubular basement membranes. No osmiophilic deposits, no fibrils.

11 Diagnosis Global glomerulosclerosis (11/30) Ischemic glomerular damage and moderate arteriosclerosis (hypertension?) % IF/TA with thickened and lamellated tubular basement membranes In view of the positive family history highly suggestive for an autosomal dominant tubulointerstitial kidney disease (i.e. ADTKD-UMOD). Genetic testing: Mutation in Uromodulin (Umod) was confirmed.

12 more specific name for the large group (or wastebasket) of medullocystic kidney disease 17

13 Clinical findings in ADTKD + specific findings in each of the 4 different types of ADTKD (i.e. hyperuricemia / gout in ADTKD-UMOD) 17

14 Additional findings in each of the 4 different types of ADTKD more or less specific histology does not help that much.

15 Typical histology in ADTKD? untypical and unspecific - Interstitial fibrosis - Tubular atrophy - Thickening and lamellation of tubular basement membranes ( EM) - (cystic) tubular degeneration - negative IH/- IF unspecific findings family history and genetic testing 000

16 Immunohistochemical analysis of uromodulin expression in the kidney does it help? normal diffuse cytoplasmatic staining with maximum on apical membranes FJHN (ADTKD - Umod) modified staining without characteristic apical reactivity (Liu et al. 2013)

17 Disturbances of ER homeostasis in ADTKD-UMOD (Kemter et al., Scientific Reports 2016)

18 (Autosomal Dominant Tubulointerstitial Kidney Disease, MUC1-Related. Bleyer AJ, Kmoch S: In: Pagon RA et al., editors, GeneReviews [Internet]. Seattle (WA): ). Kidney imaging and histology in ADTKD-MUC Renal ultrasound examination is usually normal or shows small kidneys. As with other patients with chronic kidney disease, occasional cysts may be seen. Kidney biopsy reveals focal tubular atrophy, secondary glomerular scarring, and interstitial fibrosis. biopsy findings are nonspecific and usually do NOT lead to the diagnosis of ADTKD-MUC1.

19 Renal disease in ADTKD-REN (Clissold et al., BMC Nephrology 2017)

20 Histology in ADTKD-REN (courtesy of M. Mihatsch) In addition to the unspecific usual findings marked cystic and glomerulocystic changes can be seen! 000

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22 ADTKD-HNF1beta - Complex and heterogenous kidney phenotype with atrophy, cysts, dysplasia and tubulopathies - Hyperuricemia and hypomagnesia Chronic interstitial disease that is usually slowly progressing - Atrophy of pancreas, post-transplant diabetes - Elevated liver enzymes - Diabetes (young, MODY5) - Dominantly inherited and de novo 000

23 And now another interesting case

24 24 glomeruli, 17 sclerosed 2 Nierenstanzzylinder mit 38 Glomeruli, davon 1 global vernarbt. PAS

25 approx. 20% IFTA

26 Arterien und Arteriolen mit schwerer Fibrose bei teils myxoider Aufquellung und amorphen Ablagerungen. PAS

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28 < 5% IF/TA, kein nennenswertes Entzündungszellinfiltrat. Tubuli strukturell unauffällig, keine Casts. PAS

29 Diagnosis Advanced global glomerulosclerosis (17/24) Ca. 20 % IF/TA Mild arterio-arteriolosclerosis Moderate tubular damage Mild focal interstitial inflammation Suspicous for autosomal dominant tubulointerstitial kidney disease (ADTKD) Genetic testing Counseling of pediatric nephrologist: history of polydipsia Genetic testing for nephronophthisis positive for NPHP1 nephronophthisis

30 >90 genes Monogenic genes of nephronophthisis-related ciliopathies (NPHP-RC) (Braun and Hildebrandt 2017)

31 3 major phenotypes of NPH most important cause of ESRD in children Infantile NPH 3 years oligohydramnios sequence Juvenile NPH (most common form) 13 years polydipsia and poly-uria, growth retarda-tion, chronic iron-re-sistant anemia, or other findings of CKD Adolescent / adult NPH 19 years See above Histologic findings: again quite unspecific! tubulointerstitial fibrosis thickened and disrupted tubular basement membrane sporadic corticomedullary cysts normal or reduced kidney size

32 A very last case

33 13 Glomeruli / 5 sclerosed

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37 Karyomegalic tubulointerstitial nephritis (first officially described by Mihatsch et al. 1979) FAN = Fanconi Anemia associated nuclease (Zhou et al., Nature Genetics 2012) role in DNA-reparation (DDR - DNAdamage response pathway) 9 families around the world similarities to nephronophthisis (and possibly also other chronic kidney diseases) (Zhou et al., Nature Genetics 2012)

38 Summary - Morphological and genetic approach to hereditary tubulointerstitial disease Diseases with characteristic morphology that are easy to diagnose (if you know them) There are others, where morphological information (although of great importance) is limited, most likely due to limited reaction patterns of the body (i.e. the kidney) molecular biology and genetics may help to better classify and treat renal diseases It is the pleasure and duty of the renal pathologist to ask for additional genetic tests where appropriate!