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Acute Renal Failure and the MELAS Syndrome, a Mitochondrial Encephalomyopathy1 Fred Hsieh, Reginald Gohh, and Lance Dworkin2

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Acute Renal Failure and the MELAS Syndrome, a Mitochondrial Encephalomyopathy1 Fred Hsieh, Reginald Gohh, and Lance Dworkin2 EDITORIAL COMMIT1’EE Tomas Berl, EdItor William Henrich Mark Paller Fred Silva Denver, CO Toledo, OH Minneapolis, MN Oklahoma CIty, OK BROWN UNIVERSITY DIVISION OF RENAL DISEASES Initiated in 1966, the nephrology training program at Brown University consists of a first year of clinical training followed by a second year primarily devoted to research. The program is designed to prepare fellows for careers in academic medicine and/or primary nephrology care. Trainees interested in additional training may apply for a third year of laboratory research or for a combined clinical/research year in critical care and nephrology that confers eligibility in both subspecialties. The Renal Division includes seven full-time and nine voluntary faculty members and recruits three fellows each year. The clinical experience covers all aspects of clinical nephrology, including patient consultation, outpatient nephrol- ogy. hemodialysis, peritoneal dialysis, hemofiltratlon, vascular access, hypertension, fluid and electrolyte disorders, and renal transplantation. Trainees rotate at The Rhode Island and Miriam hospitals and also see patients in outpatient dialysis facilities. The Division has an extensive didactic program for trainees that includes four to five conferences per week in which the fellows take an active role. Fellows also teach and direct the activities of Brown residents and students taking nephrology electives. Major areas of research include the progression of renal disease, glomerular hemodynamics. experimental hypertension, diabetic nephropathy, molecular control of renal growth and injury repair, growth factors and receptors, renal effects of diet and antihypertensive agents, molecular determinants of cardiac hypertrophy, cell volume regulation. ion exchange and transport properties along the nephron. and the regulation of intracellular pH. The laboratories are equipped for a wide range of techniques, Including whole-animal physiology; ultrasonic blood flow determination; micropuncture; isolated perfused tubule; intracellular Ion fluorescence; morphometric image analysis; ELISA; radloimmunoassays, and receptor assays; cell culture; Northern, Southern, and Western analysis; RNase protection assay; PCR; and gel-shift assay. There is also a clinical research program in hypertension and renal disease with a dedicated research clinic and full-time research coordinator. The director of the division is Lance D. Dworkin, MD, and the fellowship program director is J. Gary Abuelo, MD. Acute Renal Failure and the MELAS Syndrome, a Mitochondrial Encephalomyopathy1 Fred Hsieh, Reginald Gohh, and Lance Dworkin2 MELAS syndrome who subsequently developed acute F. Hsieh, P. Gohh, L. Dworkin, Division of Renal Diseases, renal failure is reported. Although no clear renal insult Department of Medicine, The Rhode Island Hospital was evident at the time, the clinical picture was and Brown University School of Medicine, Providence, consistent with the diagnosis of acute tubular necro- RI sis. The patient’s renal function subsequently returned (J. Am. Soc. Nephrol. 1996; 7:647-652) to baseline. This article reviews the literature concern- ing renal Involvement in the mitochondrial encepha- lomyopathies, including MELAS, and proposes a ABSTRACT mechanism by which patients suffering from mito- MELAS (mitochondrial encephalomyopathy with lac- chondrial disorders may be more susceptible to renal tic acidosls and stroke-like episodes) is one of a hypoxic Injury and acute renal failure. group of heterogeneous yet clinically distinct syn- Key Words: MELAS, acute renal failure, mitochondrial en- dromes ascribed to a defect in mitochondrial func- cephalomyopathies tion. Here, the case of a patient diagnosed with the O ver the past decade, defects in mitochondrial 1 Received November 21, 1994. Accepted October 19. 1995. function have increasingly been associated with 2 Correspondence to Dr. L Dworkin, Division of Renal Diseases, The Rhode Island human disease. Many of these diseases have now Hospital, 593 Eddy Street, Providence, RI 02806. been ascribed to specific mutations in the mitochon- 1046.6673/0705.0647$03.00/0 drial genome and share a maternal pattern of inheri- Journal of the American society of Nephrology Copyright C 1996 by the American society of Nephrology tance. Diseases related to lesions of mitochondrial Journal of the American Society of Nephrology 647 Acute Penal Failure and the MELAS Syndrome DNA (mtDNA) can be divided into two groups: pure hancement. This was felt to be consistent with en- encephalopathies with no gross morphological muscle cephalitis. A lumbar puncture revealed clear cerebro- abnormalities, and mitochondrial encephalomyopa- spinal fluid with no nucleated cells, no red blood cells, thies that are associated with ragged-red muscle fi- 65 mg/dL ofprotein, and 153 mg/dL ofglucose. Rapid bers. The latter group of mitochondrial encephalo- plasma reagin, Lyme, and viral antibody titers were myopathies encompasses a diverse group of distinct negative. During this time, the patient remained clinical syndromes with characteristic signs and awake, alert, agitated, and vocal but noncommunica- symptoms. These include myoclonic epilepsy with tive. ragged-red fibers (MERRF), Kearns-Sayre Syndrome (KSS), and mitochondrial encephalomyopathy with The Hospital Course lactic acidosis and stroke-like episodes (MELAS) (1). The patient underwent a brain biopsy of her cortical Renal involvement in patients with mitochondrial lesion. A detailed morphologic description of the brain encephalomyopathies has been demonstrated by din- biopsy has been presented elsewhere (E. Stopa, ical symptomatology, biopsy, and molecular genetic manuscript submitted). Electron microscopy revealed studies. In this paper, we report a case of acute bizarre, enlarged mitochondria with irregular abnor- nonoliguric renal failure in a patient with the MELAS ma! cristae-findings consistent with but not specific syndrome. We review the literature concerning renal for a mitochondrial disorder (Figure 1 ). However, mo- involvement in patients with biopsy-proven mitochon- lecular analysis of the brain biopsy revealed that 80% drial disorders and propose a mechanism by which of the mitochondria had the typical genetic mutation these patients may be more susceptible to renal fail- associated with MELAS. (J. Gilchrist, personal corn- ure as a result of their mitochondrial disease. munication; see Discussion). The serum lactate level ranged between 3. 1 and 4.8 mEq/L on repeated mea- CASE REPORT surements and a diagnosis of MELAS syndrome (mi- The patient is a 46-yr-old white female admitted to the hospital for an acute deterioration in mental sta- tus. Nine months before admission, she had two tonic-clonic seizures. Work-up at that time included a magnetic-resonance imaging study of the brain with gadolinium which showed a nonenhancing right tem- poral lobe lesion consistent with a cerebrovascular accident. The patient did well until 1 wk before admis- sion, when she developed hallucinations and garbled speech. On the day of admission, she was unable to obey commands or answer questions. She had a past medical history of type II diabetes mellitus since age 29, and was now insulin-depen- dent, with peripheral neuropathy and enteropathy. There was a history of cognitive delays, mild mental retardation, cardiac dysrhythmias, and bilateral sen- sorineural deafness. Her medications included pheny- toin and insulin. On examination, the patient was a thin white woman with short stature. She was alert but would not interact with the examiner. Her blood pressure was 150/90 mm Hg, pulse 96 beats/min, respiratory rate 18 breaths/mm, and temperature 99#{176}F.Abnor- mal findings were limited to the neurological exam. She had increased motor tone throughout and an asymmetric Achilles tendon reflex, 2+ on the right and trace on the left. She moved all four extremities without difficulty and withdrew all four extremities to pain. Laboratory studies on admission included a BUN concentration of 1 1 mg/dL, creatinine concen- tration of 0.9 mg/dL, and glucose level of 386 mg/dL. Further workup included an electroencephalogram that was negative for epileptiform activity. A magnetic Figure 1 . Ultrastructural findings on brain biopsy. This pho- resonance imaging study with gadolinium showed a tomicrograph Is remarkable for bizarre, enlarged mitochon- cortical lesion involving the left temporal, parietal, and dna with Irregular, abnormal concentric cristae (original occipital lobes, with patchy, ill-defined contrast en- magnification, x55,000). 648 Volume 7 ‘ Number 5 ‘ 1996 Hsieh et al tochondrial myopathy, encephalopathy, lactic acido- system. The liver, endocrine glands, and kidney are sis, and stroke-like episodes) was made. less often affected. Clinical distinctions between three During the next month, the patient underwent an of the major syndromes are listed in Table 1 . Diagno- exploratory laparotomy for a suspected perforated sis can now be made at a genetic level as well; an A to viscus, experienced fluctuating glucose values, had G point mutation in the tRNALeu gene at nucleo- intermittent vomiting and poor food intake by mouth tide 3243 has been described in patients with MELAS. (eventually requiring percutaneous endoscopic gas- Approximately 80% of MELAS patients have been trostomy tube placement for enteral feedings), and found to have this mutation (3). MELAS mutations developed an Escherichta colt urinary tract infection, can now be detected by molecular analysis of periph- which
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