Chronic kidney disease, severe arterial and arteriolar sclerosis and kidney neoplasia: on the spectrum of kidney involvement in MELAS syndrome

BMC Nephrology

Gabriella Restagno⁴  Francesco Porpiglia⁶  Isabelle Brocheriou²  Federica Fassio⁵  Martina Ferraresi⁵  Federica Neve Vigotti⁵  Paola Campisi³  Laura Davico Bonino¹  Giorgina Barbara Piccoli⁶ 

[1] Anatomia Patologica ASOU Molinette, Torino, Italy;Assistance Publique- Hôpitaux de Paris, Hôpital Tenon, Department of Pathology, Université Pierre et Marie Curie Univ Paris 06, Paris, France;Department of Pathology, Laboratory of Pathology, Molinette Hospital, Turin, Italy;Genetica Medica, ASOU OIRM sant'Anna, Torino, Italy;SS Nephrology ASOU san Luigi, Orbassano, Torino, Italy;Department of Medical and Biological Sciences. SS Nephrology, ASOU san Luigi Gonzaga, Regione Gonzole, Orbassano, Torino, Italy

关键词: Kidney cancer;    Disease;    Renal vascular;    Chronic kidney disease;    MELAS syndrome;   

Others  :  1083204
DOI  :  10.1186/1471-2369-13-9

 received in 2011-07-18, accepted in 2012-02-21,  发布年份 2012

【 摘 要 】

Background

MELAS syndrome (MIM ID#540000), an acronym for Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like episodes, is a genetically heterogeneous mitochondrial disorder with protean manifestations and occasional kidney involvement. Interest in the latter is rising due to the identification of cases with predominant kidney involvement and to the hypothesis of a link between mitochondrial DNA and kidney neoplasia.

Case presentation

We report the case of a 41-year-old male with full blown MELAS syndrome, with lactic acidosis and neurological impairment, affected by the "classic" 3243A > G mutation of mitochondrial DNA, with kidney cancer. After unilateral nephrectomy, he rapidly developed severe kidney functional impairment, with nephrotic proteinuria. Analysis of the kidney tissue at a distance from the two tumor lesions, sampled at the time of nephrectomy was performed in the context of normal blood pressure, recent onset of diabetes and before the appearance of proteinuria. The morphological examination revealed a widespread interstitial fibrosis with dense inflammatory infiltrate and tubular atrophy, mostly with thyroidization pattern. Vascular lesions were prominent: large vessels displayed marked intimal fibrosis and arterioles had hyaline deposits typical of hyaline arteriolosclerosis. These severe vascular lesions explained the different glomerular alterations including ischemic and obsolescent glomeruli, as is commonly observed in the so-called "benign" arteriolonephrosclerosis. Some rare glomeruli showed focal segmental glomerulosclerosis; as the patient subsequently developed nephrotic syndrome, these lesions suggest that silent ischemic changes may result in the development of focal segmental glomerulosclerosis secondary to nephron loss.

Conclusions

Nephron loss may trigger glomerular sclerosis, at least in some cases of MELAS-related nephropathy. Thus the incidence of kidney disease in the "survivors" of MELAS syndrome may increase as the support therapy of these patients improves.

【 授权许可】

   
2012 Piccoli et al; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]DiMauro S, Hirano M: MELAS: Mitochondrial Encephalomyopathy, Lactic Acidosis and Stroke-like Episodes. In Gene Reviews. Edited by Pagon RA, Bird TD, Dolan CR, Stephens K. University of Washington, Seattle; 1993. NCBI Bookshelf. PMID 20301411 (updated Oct14)
• [2]Jansen JJ, Maassen JA, van der Woude FJ, Lemmink HA, van den Ouweland JM, t'Hart LM, Smeets HJ, Bruijn JA, Lemkes HH: Mutation in mitochondrial tRNA(Leu(UUR)) gene associated with progressive kidney disease. J Am Soc Nephrol 1997, 8(7):1118-1124.
• [3]Hirano M, Konishi K, Arata N, Iyori M, Saruta T, Kuramochi S, Akizuki M: Renal, complications in a patient with A-to-G mutation of mitochondrial DNA at the 3243 position of leucine tRNA. Intern Med 2002, 41(2):113-118.
• [4]Lau KK, Yang SP, Haddad MN, Butani L, Makker SP: Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes syndrome with hypothyroidism and focal segmental glomerulosclerosis in a paediatric patient. Int Urol Nephrol 2007, 39(3):941-946. Epub 2007 Feb 10.
• [5]Koszka C: Friedrich Nietzsche (1844-1900): a classical case of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome? J Med Biography 2009, 17:161-164.
• [6]Ringelstein EB, Kleffner I, Khulenbaumer G, Ritter MA: Hereditary and non-hereditary microangiopathies in the young. An up-date. J Neurol Sci 2010, 299:81-85.
• [7]Sproule DM, Kaufmann P: Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes: basic concepts, clinical phenotype, and therapeutic management of MELAS syndrome. Ann N Y Acad Sci 2008, 1142:133-158.
• [8]Sangkhathat S, Kusafuka T, Yoneda A, Kuroda S, Tanaka Y, Sakai N, Fukuzawa M: Renal cell carcinoma in a pediatric patient with an inherited mitochondrial mutation. Pediatr Surg Int 2005, 21(9):745-748. Epub 2005 Oct 20.
• [9]Bárcena C, Martínez MA, Ortega MP, Muñoz HG, Sárraga GU: Mitochondria with tubulovesicular cristae in renal oncocytomas. Ultrastruct Pathol 2010, 34(6):315-320.
• [10]Windpessl M, Wallner M: M3243A > G: many faces of one single point mutation. Wien Klin Wochenschr 2010, 122(19-20):601. author reply 601-2.
• [11]Lederer SR, Klopstock T, Schiffl H: MELAS: a mitochondrial disorder in an adult patient with a renal transplant. Wien Klin Wochenschr 2010, 122:363-365.
• [12]Yanagihara C, Oyama A, Tanaka M, Nakaji K, Nishimura Y: An autopsy case of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes syndrome with chronic renal failure. Intern Med 2001, 40(7):662-665.
• [13]Manouvrier S, Rötig A, Hannebique G, Gheerbrandt JD, Royer-Legrain G, Munnich A, Parent M, Grünfeld JP, Largilliere C, Lombes A, et al.: Point mutation of the mitochondrial tRNA(Leu) gene (A 3243 G) in maternally inherited hypertrophic cardiomyopathy, diabetes mellitus, renal failure, and sensorineural deafness. J Med Genet 1995, 32(8):654-656.
• [14]Kubota H, Tanabe Y, Takanashi J, Kohno Y: Episodic hyponatremia in mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS). J Child Neurol 2005, 20(2):116-120.
• [15]Nakamura S, Yoshinari M, Doi Y, Yoshizumi H, Katafuchi R, Yokomizo Y, Nishiyama K, Wakisaka M, Fujishima M: Renal complications in patients with diabetes mellitus associated with an A to G mutation of mitochondrial DNA at the 3243 position of leucine tRNA. Diabetes Res Clin Pract 1999, 44(3):183-189.
• [16]Kurogouchi F, Oguchi T, Mawatari E, Yamaura S, Hora K, Takei M, Sekijima Y, Ikeda S, Kiyosawa K: A case of mitochondrial cytopathy with a typical point mutation for MELAS, presenting with severe focal-segmental glomerulosclerosis as main clinical manifestation. Am J Nephrol 1998, 18(6):551-556.
• [17]Cheong HI, Chae JH, Kim JS, Park HW, Ha IS, Hwang YS, Lee HS, Choi Y: Hereditary glomerulopathy associated with a mitochondrial tRNA(Leu) gene mutation. Pediatr Nephrol 1999, 13(6):477-480.
• [18]Mima A, Shiota F, Matsubara T, Iehara N, Akagi T, Abe H, Nagai K, Matsuura M, Murakami T, Kishi S, Araoka T, Kishi F, Kondo N, Shigeta R, Yoshikawa K, Kita T, Doi T, Fukatsu A: An autopsy case of mitochondrial myopathy, encepalopathy, lactic acidosis and stroke-like episodes (MELAS) with intestinal bleeding in chronic renal failure. Ren fail 2011, 33(6):622-625.
• [19]Mochizuki H, Joh K, Kawame H, Imadachi A, Nozaki H, Ohashi T, Usui N, Eto Y, Kanetsuna Y, Aizawa S: Mitochondrial encephalomyopathies preceded by de-Toni-Debré- Fanconi syndrome or focal segmental glomerulosclerosis. Clin Nephrol 1996, 46(5):347-352.
• [20]Thambisetty M, Newman NJ: Diagnosis and management of MELAS. Expert Rev Mol Diagn 2004, 4:631-644.
• [21]Iwasaki N, Babazono T, Tsuchiya K, Tomonaga O, Suzuki A, Togashi M, Ujihara N, Sakka Y, Yokokawa H, Ogata M, Nihei H, Iwamoto Y: Prevalence of A-to-G mutation at nucleotide 3243 of the mitochondrial tRNA(Leu(UUR)) gene in Japanese patients with diabetes mellitus and end stage renal disease. J Hum Genet 2001, 46(6):330-334.
• [22]Maxwell SD, Hertel A, Seibel P, Reichmann H, Bachmann G, Shachenmayr W, Hoer G, Dorndorf W: Follow-up in carriers of the 'MELAS' mutation without strokes. Eur Neurol 1998, 39:9-15.
• [23]Kaufman KR, Zuber N, Rueda-Lara MA, Tobia A: MELAS with recurrent partial seizures, non convulsive status epilepticus, psychosis and behavioural disturbances: case analysis with literature review. Epilepsy Behav 2010, 18:494-497.
• [24]Nguyen MT, Maynard SE, Kimmel PL: Misapplications of commonly used kidney equations: renal physiology in practice. Clin J Am Soc Nephrol 2009, 4:528-534.
• [25]Hostetter TH, Olson JL, Rennke HG, Venkatachalam MA, Brenner BM: Hyperfiltration in remnant nephrons: a potentially adverse response to renal ablation. J Am Soc Nephrol 2001, 12:1315-1325.
• [26]Remuzzi G, Benigni A, Remuzzi A: Mechanisms of progression and regression of renal lesions of chronic nephropathies and diabetes. J Clin Invest 2006, 116:288-296.
• [27]An WS, Kim HJ, Cho KH, Vaziri ND: Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney. Am J Physiol Renal Physiol 2009, 297(4):F895-F903. Epub 2009 Aug 5.
• [28]Zhang ZQ, Niu ST, Liang XH, Jian F, Wang Y: Vascular involvement in the pathogenesis of mitochondrial encephalomyopathies. Neurol Res 2010, 32(4):403-408.
• [29]Gilchrist JM, Sikirica M, Stopa E, Shanske S: Adult-onset MELAS. Evidence for involvement of neurons as well as cerebral vasculature in strokelike episodes. Stroke 1996, 27(8):1420-1423.
• [30]Guéry B, Choukroun G, Noël LH, Clavel P, Rötig A, Lebon S, Rustin P, Bellané-Chantelot C, Mougenot B, Grünfeld JP, Chauveau D: The spectrum of systemic involvement in adults presenting with renal lesion and mitochondrial tRNA(Leu) gene mutation. J Am Soc Nephrol 2003, 14(8):2099-2108.
• [31]Hotta O, Inoue Chiyoko N, Miyabayashi S, Furuta T, Takeuchi A, Taguma Y: Clinical and pathologic features of focal segmental glomerulosclerosis with mitochondrial tRNALeu(UUR) gene mutation. Kidney Int 2001, 59:1236-1243.
• [32]Löwik MM, Hol FA, Steenbergen EJ, Wetzels JF, van den Heuvel LP: Mitochondrial tRNALeu(UUR) mutation in a patient with steroid-resistant nephrotic syndrome and focal segmental glomerulosclerosis. Nephrol Dial Transplant 2005, 20(2):336-341. Epub 2004 Dec 7.ì.
• [33]Lu J, Sharma LK, Bai Y: Implications of mitochondrial DNA mutations and mitochondrial dysfunction in tumorigenesis. Cell Research 2009, 19:802-815. published online 16 June 2009.
• [34]Abu-Amero K, Zou M, Shi Y: Mitochondrial A135149 mutation without MELAS but in association with papillary thyroid carcinoma. Clin Genet 2004, 66(6):569-570.
• [35]Lorenc A, Bryk J, Golik P, Kupryjańczyk J, Ostrowski J, Pronicki M, Semczuk A, Szołkowska M, Bartnik E: Homoplasmic MELAS A3243G mtDNA mutation in a colon cancer sample. Mitochondrion 2003, 3(2):119-124.
• [36]Ohno A, Mori A, Doi R, Yonenaga Y, Asano N, Uemoto S: Successful left hemihepatectomy and perioperative management of a patient with biliary cystadenocarcinoma, complicated with MELAS syndrome: report of a case. Surg Today 2010, 40(9):878-882. Epub 2010 Aug 26.
• [37]Trpkov K, Yilmaz A, Uzer D, Dishongh KM, Quick CM, Bismar TA, Gokden N: Renal oncocytoma revisited: a clinicopathological study of 109 cases with emphasis on problematic diagnostic features. Histopathology 2010, 57(6):893-906. 1.
• [38]Erlandson RA, Shek TW, Reuter VE: Diagnostic significance of mitochondria in four types of renal epithelial neoplasms: an ultrastructural study of 60 tumors. Ultrastruct Pathol 1997, 21(5):409-417.
• [39]Tickoo SK, Lee MW, Eble JN, Amin M, Christopherson T, Zarbo RJ, Amin MB: Ultrastructural observations on mitochondria and microvesicles in renal oncocytoma, chromophobe renal cell carcinoma, and eosinophilic variant of conventional (clear cell) renal cell carcinoma. Am J Surg Pathol 2000, 24(9):1247-1256.
• [40]Yusenko MV, Ruppert T, Kovacs G: Analysis of differentially expressed mitochondrial proteins in chromophobe renal cell carcinomas and renal oncocytomas by 2-D gel electrophoresis. Int J Biol Sci 2010, 6(3):213-224.
• [41]Gasparre G, Hervouet E, de Laplanche E, Demont J, Pennisi LF, Colombel M, Mège-Lechevallier F, Scoazec JY, Bonora E, Smeets R, Smeitink J, Lazar V, Lespinasse J, Giraud S, Godinot C, Romeo G, Simonnet H: Clonal expansion of mutated mitochondrial DNA is associated with tumor formation and complex I deficiency in the benign renal oncocytoma. Hum Mol Genet 2008, 17(7):986-995.
• [42]Nagy A, Wilhelm M, Sükösd F, Ljungberg B, Kovacs G: Somatic mitochondrial DNA mutations in human chromophobe renal cell carcinomas. Genes Chromosomes Cancer 2002, 35(3):256-260.
• [43]Tickoo SK, Amin MB: Discriminant nuclear features of renal oncocytoma and chromophobe renal cell carcinoma. Analysis of their potential utility in the differential diagnosis. Am J Clin Pathol 1998, 110:782-787.
• [44]Gobbo S, Eble JN, Delahunt B, Grignon DJ, Samaratung H, Martignoni G, Zhang S, Wang M, Brunelli M, Cossu-Rocca P, Cheng L: Renal cell neoplasms of oncocytosis have distinct morphologic, immunohistochemical and cytogentic profiles. Am J Surg Path 2010, 34:620-626.