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 -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 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- 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 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 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 . 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 , , 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 was treated with iv ampicillin for 10 days. eral blood samples (4). During this time period, however, her renal function Patients affected by mitochondrial encephalo- remained stable. myopathies have both normal and mutant mitochon- On hospital Day 66, the patient was noted to have a drial DNA coexisting in all tissues. This is termed heart rate of 100 bpm, a blood pressure of 92 I 62 mm , and explains how mitochondrial dis- Hg, BUN concentration of 37 mg/dL, a creatinine ease can variably affect many organ systems. If a concentration of 1 .6 mg/dL and an elevated anion gap mitochondrial DNA mutation occurs early in develop- of 22 mEq/L (from 13 mEq/L 1 day previously). The ment, then mitochondria with mutated will patient had a baseline blood pressure of 120/70 mm assort randomly among daughter cells during mitosis. Hg. She was believed to be volume-depleted and was In the process of development, different cells acquire given iv fluid therapy with normal saline. Despite this varying numbers of mutated and wild-type mtDNA. treatment, she became oliguric (200 mL urine output Cells containing a higher ratio of mutant-to-wild-type over 24 h) and her serum creatinmne concentration mitochondrial genomes will be more likely to show progressively rose to a value of 4.0 mg/dL after 48 h. significant clinical dysfunction, particularly in those Urinalysis showed a specific gravity of 1 .005, pH of tissues with high demands for oxidative energy (5). 6.0, trace protein, and no blood by dipstick, with 0 to In addition, it has been proposed that tissues with a 2 red blood cells, 0 to 5 white blood cells, no red blood high mitotic index, such as hematopoietic cells, are cell casts, and occasional tubular epithelial cells by able to select against heteroplasmic cells over the microscopic examination. Repeat urinalysis was un- course of many generations of cell division, so that the changed. Urine electrolyte studies revealed a urine ratio of mutant to normal mitochondria decreases sodium level of 1 13 mEq/L, urine chloride level of 99 with age. This explains the spontaneous resolution of mEq/L, and urine osmolality of 264 mosmol. The anemia seen in patients with long-standing mitochon- serum osmolality was 293 mosmol. drial disease (6). On the other hand, in tissues with As the patient’s creatinine level continued to rise, little mitotic activity, including brain and muscle, the she developed a progressive metabolic acidosis. On ratio of mutant to normal mitochondria will increase hospital Day 69, her BUN concentration was 62 mgI with age, which accounts for the later onset of pro- dL, her creatinine concentration was 4.7 mg/dL, and gressive neuromuscular dysfunction (7). The mecha- serum CO2 level was 15 mEq/L, which eventually fell nism for selection favoring mtDNA with deletion is to 1 1 mEq/L. The serum lactate level was 3.9 mEq/L. unclear, but might be related to an increased mito- Therapy with iv bicarbonate was initiated. chondrial proliferation in response to deficient energy The patient’s serum creatinine concentration production (8). UltImately, the clinical involvement of peaked at 5.4 mg/dL 4 days after the initial increase any given organ will depend on at least two factors: the was noted, with a BUN concentration of 71 mg/dL. percentage ofabnonnal mitochondria and the require- Additional studies revealed a serum eosinophil per- ment of that organ for functioning mitochondria (I.e., centage of4%, no urine eosinophils, and no skin rash. the relative demand on oxidative metabolism) (5). For Subsequently, the patient’s urine output increased to each individual patient, different organ systems will 4.3 L over a 24-h period and then diminished to 1 to 2 be affected to varying degrees. L I day. The acidosis improved once renal function Another interesting feature of these diseases is that returned to normal and bicarbonate therapy was both mitochondrial division and mtDNA replication stopped. The patient’s creatinine concentration had are random processes unconnected to the cell cycle, fallen to 1 . 1 mgldL by the time she was discharged. resulting in mitotic segregation of mtDNA (9). It is for this reason that the proportion of mutant mtDNA can DISCUSSION vary both in space (e.g. , different tissues) and in time in heteroplasmic patients. As such, patients may each Great heterogeneity exists in the presentation of present with entirely different constellations of symp- mitochondrial diseases, but they can be classified into toms over their lifetimes. distinct syndromes. Mitochondrial diseases are mul- Kidney involvement in mitochondrial encephalo- tisystemic and most commonly affect the brain and myopathies, although infrequent and usually late in the muscle, hence the term encephalomyopathy. Nev- the course of disease, has been well-documented. The ertheless, other organs can be affected as well, most most commonly observed abnormality is renal tubular commonly the heart, pancreas, and hematopoietic dysfunction, which has been associated with a wide

Journal of the American Society of Nephroiogy 649 Acute Penal Failure and the MELAS Syndrome

TABLE 1 . Mitochondrial encephalomyopathiesa

Previous Reports of Renal Involvement Disorder DistInguIshing Symptoms

Kearns-Sayre Syndrome (KSS) Onset before age 20 ChronIc renal failure (4), Fanconl’s Opthalmoplegia syndrome (4,5,6), renal Tubular acldosls Retinal degeneration (7), Bartter’s syndrome (8), Acute Heart block nonollgurlc renal failure (6) CSF protein >100 mg/dl Myoclonic Epilepsy with Myoclonus None reported Ragged-red Fibers (MERRF) Ataxla Weakness Seizures Mitochondrial Encephalomyopathy, Seizures Proteinurla (9,10,11) Lactic Acidosis, and Stroke-like Repeated stroke-like episodes with Episodes (MELAS) neuralogic deficits Hemlparesls, hemlanopsia Cognitive regression Episodic vomiting Cortical blindness Symptoms Common to All Sensorlneural hearing loss Dementia Short stature Weakness Lactic acidosis Ragged-red muscle fibers on biopsy Spongy degeneration of the brain a Data modified from Reference 1. variety of mitochondrial disorders. These include the Our patient had the MELAS syndrome and a corn- Kearns-Sayre syndrome ( 10, 1 1), mitochondrial myop- plex hospitalization complicated by acute renal fail- athy (12), and Pearson’s syndrome (13), all of which ure. She developed transient oliguria that was unre- usually present in early childhood. Occasionally, pa- sponsive to the administration of fluids, and a tients may first present with renal abnormalities, progressive increase in serum creatinine concentra- including the de Toni-Fanconi-Debre syndrome tion that peaked after 4 days, followed by a vigorous (12, 13), renal tubular acidosis (10), and defects mim- diuresis. Within 10 days, her creatinine level had icking Bartter’s syndrome (1 2). Details of the biopsy- almost returned almost to baseline. Her clinical proven renal findings in patients with mitochondrial course and laboratory studies are most consistent encephalomyopathies are found in Table 2. with a diagnosis ofacute tubular necrosis. Notably, no Kidney involvement has also been reported in pa- obvious inciting event was identified. tients with the MELAS syndrome. Nephrotic-range Hypoxic injury results when energy supply and proteinuria has been noted in three cases (14-16). substrate provision are inadequate to serve a tissue’s Postmortem study of one patient revealed global gb- metabolic demands (1 9). Although renal blood flow is merubosclerosis and interstitial fibrosis consistent extremely high, the unique countercurrent anatomi- with an end-stage kidney (14). Biopsy-proven focal cal structure of the renal medulla makes it particu- gb omeruboscierosis was found in the other two pa- larly susceptible to ischemic injury. Previous studies tients (15, 16). A pedigree study of three generations have delineated the thick ascending limbs and, to a carrying the MELAS mutation demonstrated hetero- lesser extent, the 53 portion of the proximal tubules plasmic mitochondria in the kidney. Polymerase chain as areas of the medulla in which structural factors reaction amplification and Southern analysis of DNA limit the availability ofoxygen (20). On the other hand, retrieved from the kidney of the deceased proband and the principal determinant of medullary oxygen re- from the proband’s deceased son revealed 60 to 63% quirement is the rate of active reabsorption along the of the mitochondria to be mutant ( 1 7). Acute nonoli- thick ascending limb, and oxygen consumption is, guric renal failure has been observed in a patient with predictably, ten times higher in this region than in the Kearns-Sayre syndrome, who also had stroke-like ep- rest of the kidney (2 1). Thus, the combination of low isodes as seen in MELAS. Muscle biopsy of this pa- oxygen delivery and high metabolic rate serves to tient, however, did not yield evidence of the MELAS make the renal tubules unusually susceptible to hy- tRNA point mutation (18). poxic damage. In fact, renal tubular involvement has

650 Volume 7 . Number 5 ‘ 1996 Hsieh et al

TABLE 2. Patients with mitochondrial disorders who underwent renal biopsy

Disorder Renal Symptoms Renal Biopsy Findings Ultrastructural Findings

Kearns-Sayre Syndrome Renal tubular acidosis, Extensive glomerulosclerosis with Enlarged mitochondria in (5,7,8) hypocalcemla tubular atrophy; thick-walled epithellum of convoluted vessels with intimal fibrous tissue tubules with abnormal proliferation and mononuclear peripherally oriented Infiltrate crlstae Fanconi’s syndrome Hyaline casts In distal tubules; Increased numbers of Interstitial fibrosis and abnormal mitochondria inflammatory cell infiltrate; in proximal and distal periglomerular fibrosis tubular cells Banter’s syndrome Not reported Increased number of mitochondria but no structural changes in proximal tubules; increased numbers of giant mitochondria with abnormal cristae in distal tubules Kearns-Sayre/Pearson’s Partial Fanconi’s syndrome, Irregular retraction of the Increased number of Syndrome (4) chronIc nonoliguric renal glomerular tuft with dilatation of pleomorphic failure Bowman’s space; stripe-like mitochondria with atrophy of the medullary ray with disoriented crlstae in interstitial fibrosis; PAS-positive proximal tubules fibrillar casts In atrophic tubules, immunofluorescence negative for immunoglobulins or complementa Pearson’s Syndrome (4) Polyuria, metabolic Tubular dilation with degenerative Giant mitochondria in acidosls, Fanconi’s changes In tubular epithelium; proximal tubules syndrome Immunofluorescence negative for immunoglobulins, complement, or fibrin a PAS, periodic acid-Schlff.

been demonstrated by both pathologic analysis and chondrion to undergo oxidative decarboxylation to by molecular genetic studies in mitochondrial en- acetyl coenzyine A (C0A) by pyruvate dehydrogenase cephalomyopathies (6, 10, 13,22). Pathologic studies (Figure 2) Acetyl CoA is then shutfied into the Krebs have demonstrated dilated tubules in patients with cycle, which then contributes electrons to the electron MELAS (14, 15) and DNA studies of patients with transfer chain. Defects in complex I (NADH coenzyme MELAS have demonstrated the presence of mutated Q reductase), complex III (reduced coenzyme Q-cyto- mitochondria genomes as well (17). chrome c reductase), and complex IV (cytochrome c In our case, we presume that the kidneys of our oxidase) of the mitochondrial respiratory chain have patient were heteroplasmic for mutant mitochondrial been documented in patients with MELAS (23). genomes. The mild hypotension seen in our patient Because of the impaired utilization of pyruvate in might not result in an ischemic injury in a healthy the Krebs cycle, excess NADH accumulates in the host; however, it seems likely that this factor, com- cytosol. Under anaerobic conditions, pyruvate is then bined with her mitochondrial disease, was sufficient reduced to lactate by lactate dehydrogenase and one to produce acute tubular necrosis. A kidney biopsy stoichiometric equivalent of ATP is produced. The might have provided more definitive information, but hydrolysis of ATP yields one equivalent of hydrogen this procedure did not seem clinically indicated for ion, which then must be buffered by extracellular this patient. bicarbonate. Bicarbonate is consumed, lactate accu- Lactic acidosis, commonly seen in patients with mulates, and lactic acidosis develops (24). mitochondrial encephalomyopathies and also noted in In summary, the mitochondrial encephalomyopa- this patient, is a consequence of impairment in oxida- thies are a diverse group of clinical syndromes that tive metabolism because of defective mitochondria. present with multiple organ-system involvement, in- During normal metabolism, pyruvate is transported cluding the kidney. In some cases, kidney dysfunction across the mitochondrial membrane into the mito- can be the predominant symptom and patients with

Journal of the American Society of Nephrology 651 Acute Renal Failure and the MELAS Syndrome

ius M: Progressive increase of the mutated mitochondrial Cytosol DNA fraction in Kearns-Sayre syndrome. Pediatr Res glucose 1990;28: 131-136. NAD’ NADH+H’ Glycolysis aerobic 8. Larsson NG, Holme E, Kristiansson B, Oldfors A, Tulin- conditions ius M: Progressive increase of the mutated mitochondrial 2 pyruvate -p- 2 pyruvateh.. 2 acetyl C0A PDH DNA fraction in Kearns-Sayre syndrome. Pediatr Res NADH + H’ 1990;28: 131-136. 9. Schon EA, DiMauro 5: Mitochondrial diseases. Karger anaerobic Lactate conditions Dehydrogenase Gazette 1994;58:2-4. 10. Eviatar L, Shanske 5, Gauthier B, et at.: Kearns-Sayre NAD’ syndrome presenting as renal tubular acidosis. Neurol- ogy 1990;40:1761-1763. 3 NADH + H’ and FADH, 2 lactate’ + 2ATP + 2HOH 1 1 . Goto Y, Itami N, Kajii N, Tochimaru H, Endo M, Horal 5: Renal tubular involvement mimicking Bartter syndrome ATP hydrolysis in a patient with Kearns-Sayre syndrome. J Pediatr 2 lactate’ + 2W 1990;1 16:904-9 10. 12. Van Bierviiet JBGM, Bruinvis L, Ketting D, deBrec PK, Figure 2. Pathway for lactate production in mitochondrial Van der Heiden C, Wadman 5K: Hereditary mitochon- disease. If pyruvate utilization by the mitochondrion is Im- drial myopathy with lactic aciduria, a de Toni-Fanconi- Debre syndrome, and a defective respiratory chain in paired at the level of the electron transfer chain NADH + H voluntary striated muscles. Pedlatr Res 1977; 11:1088- will accumulate. NADH + H generated by pyruvate dehy- 1090. drogenase (PDH) and by the Krebs Cycle cannot be oxi- 13. Majander A, Suomalainen A, Vettenranta K, Sariola H, dized properly to generate ATP. As a result, acetyl-CoA and Perkkio M, Holmberg C, Pihko H: Congenital hypoplas- tic anemia, diabetes, and severe renal tubular dysfunc- the NADH/NAD ratio will increase, downregulating PDH. tion associated with a mitochondrial DNA deletion. Pe- Any Increased demand for AlP will drive the formation of diatr Res 1991;30:327-331. lactate, precipitating a lactic acidosis (24). 14. Ban SI, Mon N, Saito K, Mizukami K, Suzuki T, Shi- mislil H: An autopsy case of mitochondrial encephalo- myopathy (MELAS) with special reference to extra- renal tubular acidosis, Bartter’s syndrome, or Fanco- neuromuscular abnormalities. Acta Pathol Jpn 1992;42: ni’s syndrome have been described. Lactic acidosis 818-824. 15. Yoneda M, Tanaka M, Nishikimi M: Pleotropic molecular may result from mitochondrial dysfunction. Because defects in energy-transducing complexes in mitochon- of the unique susceptibility of the renal medulla to drial encephalomyopathy (MELAS). J Neurol Sci 1989; hypoxia, the mitochondrial syndromes may also pre- 92:143-158. 16. Matsushita T, Sano T, Nakano 5, Matsuda H, Okada 5: dispose patients to tubular necrosis and the syn- Successful mitral valve replacement for MELAS. Pediatr drome of acute renal failure. Neurol 1993;9:391-393. 17. Remes AM, Majamaa K, Herva R, Hassinen I: Adult- ACKNOWLEDGMENTS onset diabetes mellitus and neurosensory hearing loss in maternal relatives of MELAS patients in a family with We are grateful to Drs. Edward Stopa and Michael Sikirica for the tRNA Leu(UUR) mutation. Neurology 1993;43: 10 15- providing and Interpreting the electron micrograph used in this 1020. article. 18. Zupanc ML, Moraes CT, Shanske 5, Langman CB, Ciafa- loni E, DiMauro 5: Deletion of mitochondrial DNA in REFERENCES patients with combined features of Kearns-Sayre and MELAS syndromes. Ann Neurol 1991;29:680-683.

1 . DiMauro 5, Moraes CT: Mitochondrial encephalomyopa- 19. Gronow GHJ, Cohen JJ: Substrate support for renal thies. Arch Neurol 1993;50: 1197-1208. function during hypoxia in the perfused rat kidney. Am J 2. Deleted in proof. Physiol 1984;247:F6 18-F63 1. 3. Goto Yl, Nonaka I, Horai 5: A mutation in the RNA 20. Brezis M, Rosen 5: Hypoxia of the renal medulla-its gene associated with the MELAS subgroup of mitochon- implications for disease. N Engi J Med 1995;332:647- dual encephalomyopathies. Nature 1990348:651-653. 655. 4. Hamman SR, Sweeny MC, Brickington M, Morgan- 2 1 . Brezis M, Rosen 5, Silva P, Epstein FH: Renal ischemia: Hughes JA, Harding AZ: Mitochondrial encephalomy- A new perspective. Kidney mt 1984;26:375-383. opathy: Molecular genetic diagnosis from blood samples. 22. Mon K, Narahara K, Ninomiya 5, Goto Y, Nonaka I: Lancet 1991;337:1311-1313. Renal and skin involvement in a patient with complete 5. Munnich A, Rustin P, Rotig A, et at.: Clinical aspects of Kearns-Sayre syndrome. Am J Med Genet 199 1;28:583- mitochondrial disorders. J Inherited Metab Dis 1992; 15: 587. 448-55 1. 23. Koo B, Becker LE, Chuang 5, et at.: Mitochondrial 6. Szabolcs MJ, Seigle R, Shanske 5, Bonila E, DiMauro encephalomyopathy, lactic acidosis, stroke-like episodes 5, D’Agati V: Mitochondrial DNA deletion: A cause of (MELAS): Clinical, radiological, pathological, and genetic chronic tubulointerstitial nephropathy. Kidney Int 1994; observations. Ann Neurol 1993;34:25-32. 45:1388-1396. 24. Stacpoole PW: Lactic acidosis. Endocrinol Metab Chin 7. Larsson NG, Holme E, Kristianson B, Oldfors A, Tulin- North Am 1993;22:221-245.

652 Volume 7 ‘ Number 5 - 1996