renal tubular acidosis

Summary

Summary: A group of genetic disorders of the KIDNEY TUBULES characterized by the accumulation of metabolically produced acids with elevated plasma chloride, hyperchloremic metabolic ACIDOSIS. Defective renal acidification of URINE (proximal tubules) or low renal acid excretion (distal tubules) can lead to complications such as HYPOKALEMIA, hypercalcinuria with NEPHROLITHIASIS and NEPHROCALCINOSIS, and RICKETS.

Top Publications

  1. Karet F, Finberg K, Nelson R, Nayir A, Mocan H, Sanjad S, et al. Mutations in the gene encoding B1 subunit of H+-ATPase cause renal tubular acidosis with sensorineural deafness. Nat Genet. 1999;21:84-90 pubmed
    ..encoding the B-subunit of the apical proton pump mediating distal nephron acid secretion, cause distal renal tubular acidosis, a condition characterized by impaired renal acid secretion resulting in metabolic acidosis...
  2. Sly W, Whyte M, Sundaram V, Tashian R, Hewett Emmett D, Guibaud P, et al. Carbonic anhydrase II deficiency in 12 families with the autosomal recessive syndrome of osteopetrosis with renal tubular acidosis and cerebral calcification. N Engl J Med. 1985;313:139-45 pubmed
    Osteopetrosis with renal tubular acidosis and cerebral calcification was identified as a recessively inherited syndrome in 1972...
  3. Bruce L, Unwin R, Wrong O, Tanner M. The association between familial distal renal tubular acidosis and mutations in the red cell anion exchanger (band 3, AE1) gene. Biochem Cell Biol. 1998;76:723-8 pubmed
    In distal renal tubular acidosis (dRTA) the tubular secretion of hydrogen ion in the distal nephron is impaired, leading to the development of metabolic acidosis, frequently accompanied by hypokalemia, nephrocalcinosis, and metabolic bone ..
  4. Ruf R, Rensing C, Topaloglu R, Guay Woodford L, Klein C, Vollmer M, et al. Confirmation of the ATP6B1 gene as responsible for distal renal tubular acidosis. Pediatr Nephrol. 2003;18:105-9 pubmed
    Primary distal renal tubular acidosis (dRTA) type I is a hereditary renal tubular disorder, which is characterized by impaired renal acid secretion resulting in metabolic acidosis...
  5. Comer D, Droogan A, Young I, Maxwell A. Hypokalaemic paralysis precipitated by distal renal tubular acidosis secondary to Sjögren's syndrome. Ann Clin Biochem. 2008;45:221-5 pubmed publisher
    ..Subsequent biochemical and clinical assessments established a diagnosis of distal renal tubular acidosis (RTA) in association with underlying Sjögren's syndrome as the aetiology of her profound hypokalaemia...
  6. Shayakul C, Alper S. Defects in processing and trafficking of the AE1 Cl-/HCO3- exchanger associated with inherited distal renal tubular acidosis. Clin Exp Nephrol. 2004;8:1-11 pubmed
    Distal renal tubular acidosis (dRTA) results from impaired urinary acidification by the renal collecting duct...
  7. Yenchitsomanus P. Human anion exchanger1 mutations and distal renal tubular acidosis. Southeast Asian J Trop Med Public Health. 2003;34:651-8 pubmed
    ..effects resulting in two distinct and seemingly unrelated defects, an erythrocyte abnormality and distal renal tubular acidosis (dRTA)...
  8. Demirci F, Chang M, Mah T, Romero M, Gorin M. Proximal renal tubular acidosis and ocular pathology: a novel missense mutation in the gene (SLC4A4) for sodium bicarbonate cotransporter protein (NBCe1). Mol Vis. 2006;12:324-30 pubmed
    ..Though rare, recessive SLC4A4 mutations have been reported in patients with proximal renal tubular acidosis, short stature, and ocular pathology. A 27-year-old male presented with these findings...
  9. Igarashi T, Sekine T, Inatomi J, Seki G. Unraveling the molecular pathogenesis of isolated proximal renal tubular acidosis. J Am Soc Nephrol. 2002;13:2171-7 pubmed
    Proximal renal tubular acidosis (pRTA) results from an impairment of bicarbonate (HCO(3)(-)) reabsorption in the renal proximal tubules and is characterized by a decreased renal HCO(3)(-) threshold...

More Information

Publications62

  1. Tanner M. Band 3 anion exchanger and its involvement in erythrocyte and kidney disorders. Curr Opin Hematol. 2002;9:133-9 pubmed
    ..developments in the structure of erythrocyte band 3 and its role in hereditary spherocytosis and distal renal tubular acidosis are described...
  2. Batlle D, Moorthi K, Schlueter W, Kurtzman N. Distal renal tubular acidosis and the potassium enigma. Semin Nephrol. 2006;26:471-8 pubmed
    Severe hypokalemia is a central feature of the classic type of distal renal tubular acidosis (RTA), both in hereditary and acquired forms...
  3. Usui T, Hara M, Satoh H, Moriyama N, Kagaya H, Amano S, et al. Molecular basis of ocular abnormalities associated with proximal renal tubular acidosis. J Clin Invest. 2001;108:107-15 pubmed
    Proximal renal tubular acidosis associated with ocular abnormalities such as band keratopathy, glaucoma, and cataracts is caused by mutations in the Na(+)-HCO(3)(-) cotransporter (NBC-1)...
  4. Watanabe T. Proximal renal tubular dysfunction in primary distal renal tubular acidosis. Pediatr Nephrol. 2005;20:86-8 pubmed
    Low-molecular-weight (LMW) proteinuria has been described in patients with primary distal renal tubular acidosis (dRTA). However, other proximal renal tubular dysfunctions have rarely been reported...
  5. Tasic V, Korneti P, Gucev Z, Hoppe B, Blau N, Cheong H. Atypical presentation of distal renal tubular acidosis in two siblings. Pediatr Nephrol. 2008;23:1177-81 pubmed publisher
    Primary distal renal tubular acidosis (dRTA) is an inherited disease characterized by the inability of the distal tubule to lower urine pH <5.50 during systemic acidosis...
  6. Inatomi J, Horita S, Braverman N, Sekine T, Yamada H, Suzuki Y, et al. Mutational and functional analysis of SLC4A4 in a patient with proximal renal tubular acidosis. Pflugers Arch. 2004;448:438-44 pubmed
    Permanent isolated proximal renal tubular acidosis (pRTA) with ocular abnormalities is a systemic disease with isolated pRTA, short stature and ocular abnormalities...
  7. Bruce L, Wrong O, Toye A, Young M, Ogle G, Ismail Z, et al. Band 3 mutations, renal tubular acidosis and South-East Asian ovalocytosis in Malaysia and Papua New Guinea: loss of up to 95% band 3 transport in red cells. Biochem J. 2000;350 Pt 1:41-51 pubmed
  8. Rungroj N, Devonald M, Cuthbert A, Reimann F, Akkarapatumwong V, Yenchitsomanus P, et al. A novel missense mutation in AE1 causing autosomal dominant distal renal tubular acidosis retains normal transport function but is mistargeted in polarized epithelial cells. J Biol Chem. 2004;279:13833-8 pubmed
    Mutations in SLC4A1, encoding the chloride-bicarbonate exchanger AE1, cause distal renal tubular acidosis (dRTA), a disease of defective urinary acidification by the distal nephron...
  9. Yang Q, Li G, Singh S, Alexander E, Schwartz J. Vacuolar H+ -ATPase B1 subunit mutations that cause inherited distal renal tubular acidosis affect proton pump assembly and trafficking in inner medullary collecting duct cells. J Am Soc Nephrol. 2006;17:1858-66 pubmed
    ..of vacuolar H+ -ATPase are associated with impaired ability of the distal nephron to secrete acid (distal renal tubular acidosis)...
  10. Devonald M, Smith A, Poon J, Ihrke G, Karet F. Non-polarized targeting of AE1 causes autosomal dominant distal renal tubular acidosis. Nat Genet. 2003;33:125-7 pubmed
    Autosomal dominant distal renal tubular acidosis (ddRTA) is caused by mutations in SLC4A1, which encodes the polytopic chloride-bicarbonate exchanger AE1 that is normally expressed at the basolateral surface of alpha-intercalated cells in ..
  11. Rodriguez Soriano J. Renal tubular acidosis: the clinical entity. J Am Soc Nephrol. 2002;13:2160-70 pubmed
  12. Kittanakom S, Cordat E, Reithmeier R. Dominant-negative effect of Southeast Asian ovalocytosis anion exchanger 1 in compound heterozygous distal renal tubular acidosis. Biochem J. 2008;410:271-81 pubmed
    ..Mutations in AE1 can cause SAO (Southeast Asian ovalocytosis) or dRTA (distal renal tubular acidosis), an inherited kidney disease resulting in impaired acid secretion...
  13. Karet F. Mechanisms in hyperkalemic renal tubular acidosis. J Am Soc Nephrol. 2009;20:251-4 pubmed publisher
    The form of renal tubular acidosis associated with hyperkalemia is usually attributable to real or apparent hypoaldosteronism...
  14. Oduwole A, Giwa O, Arogundade R. Relationship between rickets and incomplete distal renal tubular acidosis in children. Ital J Pediatr. 2010;36:54 pubmed publisher
    ..The recently reported high prevalence of Incomplete Distal Renal Tubular Acidosis (idRTA) in adults with osteoporosis as brought to fore the possibility of this being a possible cause of ..
  15. Kasap B, Soylu A, Oren O, Turkmen M, Kavukcu S. Medullary sponge kidney associated with distal renal tubular acidosis in a 5-year-old girl. Eur J Pediatr. 2006;165:648-51 pubmed
    ..Medullary sponge kidney (MSK) is characterized by cystic dilatation of the inner medullary collecting ducts, which causes the kidneys to resemble a sponge...
  16. Tang H, Chu K, Cheuk A, Tsang W, Chan H, Tong K. Renal tubular acidosis and severe hypophosphataemia due to toluene inhalation. Hong Kong Med J. 2005;11:50-3 pubmed
    ..revealed severe hypokalaemia and a normal anion gap hyperchloraemic metabolic acidosis secondary to renal tubular acidosis. Her initial presentation mimicked hypokalaemic periodic paralysis, but toxicology screening of her blood ..
  17. Kim S, Lee J, Park J, Na K, Joo K, Ahn C, et al. The urine-blood PCO gradient as a diagnostic index of H(+)-ATPase defect distal renal tubular acidosis. Kidney Int. 2004;66:761-7 pubmed
    ..We have previously demonstrated that the lack of normal H(+)-ATPase may underlie secretory defect distal renal tubular acidosis (dRTA)...
  18. Joshua B, Kaplan D, Raveh E, Lotan D, Anikster Y. Audiometric and imaging characteristics of distal renal tubular acidosis and deafness. J Laryngol Otol. 2008;122:193-8 pubmed
    Primary distal renal tubular acidosis with sensorineural hearing loss is a rare autosomal recessive disease, usually caused by mutations in the ATP6V1B1 gene...
  19. Im E, Lee J, Kim J, Chang S, Moon S, Ahn Y, et al. Hypokalemic periodic paralysis associated with thyrotoxicosis, renal tubular acidosis and nephrogenic diabetes insipidus. Endocr J. 2010;57:347-50 pubmed
    ..to acidify urine during spontaneous metabolic acidosis was confirmed by detection of coexisting distal renal tubular acidosis (RTA)...
  20. Igarashi T, Inatomi J, Sekine T, Seki G, Shimadzu M, Tozawa F, et al. Novel nonsense mutation in the Na+/HCO3- cotransporter gene (SLC4A4) in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma. J Am Soc Nephrol. 2001;12:713-8 pubmed
    Permanent isolated proximal renal tubular acidosis (pRTA) with ocular abnormalities is a systemic disease involving short stature, isolated pRTA, mental retardation, and ocular abnormalities...
  21. Hemstreet B. Antimicrobial-associated renal tubular acidosis. Ann Pharmacother. 2004;38:1031-8 pubmed
    To review the literature documenting the association of various antimicrobial medications with the development of renal tubular acidosis (RTA).
  22. Yenchitsomanus P, Sawasdee N, Paemanee A, Keskanokwong T, Vasuvattakul S, Bejrachandra S, et al. Anion exchanger 1 mutations associated with distal renal tubular acidosis in the Thai population. J Hum Genet. 2003;48:451-6 pubmed
    ..anion exchanger 1 (AE1) gene, encoding erythroid and kidney AE1 proteins, cause autosomal recessive distal renal tubular acidosis (AR dRTA) in Thai patients...
  23. Igarashi T, Sekine T, Watanabe H. Molecular basis of proximal renal tubular acidosis. J Nephrol. 2002;15 Suppl 5:S135-41 pubmed
    Proximal renal tubular acidosis (pRTA) results from an impairment of bicarbonate (HCO3-) reabsorption in the renal proximal tubules, characterized by a decreased HCO3- threshold...
  24. Smith A, Borthwick K, Karet F. Molecular cloning and characterization of novel tissue-specific isoforms of the human vacuolar H(+)-ATPase C, G and d subunits, and their evaluation in autosomal recessive distal renal tubular acidosis. Gene. 2002;297:169-77 pubmed
    ..genes, ATP6V1B1 and ATP6V0A4, encoding the H(+)-ATPase B1 and a4 subunit isoforms, cause recessive distal renal tubular acidosis (dRTA)...
  25. Muthukrishnan J, Hari Kumar K, Jha R, Jha S, Modi K. Distal renal tubular acidosis due to primary hyperparathyroidism. Endocr Pract. 2008;14:1133-6 pubmed
    To present 4 cases of distal renal tubular acidosis (RTA) in patients with primary hyperparathyroidism (PHPT) and discuss their possible etiopathogenetic correlation.
  26. Batlle D, Ghanekar H, Jain S, Mitra A. Hereditary distal renal tubular acidosis: new understandings. Annu Rev Med. 2001;52:471-84 pubmed
    The primary or hereditary form of distal renal tubular acidosis (dRTA), although rare, has received increased attention recently because of dramatic advances in the understanding of its genetic basis...
  27. Hoshino Y, Odaka M, Hirata K. [Pontine hemorrhage in a patient with type 1 renal tubular acidosis associated with osmotic demyelination syndrome]. Brain Nerve. 2008;60:1061-5 pubmed
    Here, we report the case of a 23-year-old man with type 1 renal tubular acidosis (RTA) associated with osmotic demyelination syndrome (ODS) who developed pontine hemorrhage...
  28. Berrettini S, Neri E, Forli F, Panconi M, Massimetti M, Ravecca F, et al. Large vestibular aqueduct in distal renal tubular acidosis. High-resolution MR in three cases. Acta Radiol. 2001;42:320-2 pubmed
    High-resolution MR of the inner ear performed in 3 consecutive pediatric patients affected by distal renal tubular acidosis (dRTA) and progressive sensorineural hearing loss (SNHL) revealed enlarged vestibular aqueducts (LVA) (bilateral ..
  29. Toye A, Bruce L, Unwin R, Wrong O, Tanner M. Band 3 Walton, a C-terminal deletion associated with distal renal tubular acidosis, is expressed in the red cell membrane but retained internally in kidney cells. Blood. 2002;99:342-7 pubmed
    ..in the deletion of the 11 COOH-terminal amino acids of the protein and is associated with dominant distal renal tubular acidosis. The properties of band 3 Walton expressed with normal band 3 in the heterozygous mutant erythrocytes and ..
  30. Hahn H, Kang H, Ha I, Cheong H, Choi Y. ATP6B1 gene mutations associated with distal renal tubular acidosis and deafness in a child. Am J Kidney Dis. 2003;41:238-43 pubmed
    A large proportion of autosomal recessive distal renal tubular acidosis (RTA) is associated with mutations in the ATP6B1 gene encoding the B1 subunit of H+-ATPase...
  31. Carboni I, Andreucci E, Caruso M, Ciccone R, Zuffardi O, Genuardi M, et al. Medullary sponge kidney associated with primary distal renal tubular acidosis and mutations of the H+-ATPase genes. Nephrol Dial Transplant. 2009;24:2734-8 pubmed publisher
    ..These are considered to be secondary to morphological changes of collecting tubules. Primary distal renal tubular acidosis (dRTA) is a rare genetic disease caused by mutations in different genes involved in the secretion of H(+) ..
  32. Chang Y, Shaw C, Jian S, Hsieh K, Chiou Y, Lu P. Compound mutations in human anion exchanger 1 are associated with complete distal renal tubular acidosis and hereditary spherocytosis. Kidney Int. 2009;76:774-83 pubmed publisher
    ..and frameshift mutations in the human anion exchanger 1 have been associated with inherited distal renal tubular acidosis and hereditary spherocytosis. These two disorders, however, are almost always mutually exclusive...
  33. Fracchia M, Galatola G, Corradi F, Dall Omo A, Rovera L, Pera A, et al. Coeliac disease associated with Sjögren's syndrome, renal tubular acidosis, primary biliary cirrhosis and autoimmune hyperthyroidism. Dig Liver Dis. 2004;36:489-91 pubmed
    ..weight loss, who had already received a diagnosis of primary biliary cirrhosis, Sjögren's syndrome and renal tubular acidosis. Following the development of diarrhoea we established the diagnosis of coeliac disease, based on the ..
  34. Lee C, Wu M, Lu K, Hsu K. Renal tubular acidosis, hypokalemic paralysis, rhabdomyolysis, and acute renal failure--a rare presentation of Chinese herbal nephropathy. Ren Fail. 1999;21:227-30 pubmed
    ..Proximal renal tubular acidosis and selective glucosuria were the main tubular dysfunctions...
  35. Tanphaichitr V, Sumboonnanonda A, Ideguchi H, Shayakul C, Brugnara C, Takao M, et al. Novel AE1 mutations in recessive distal renal tubular acidosis. Loss-of-function is rescued by glycophorin A. J Clin Invest. 1998;102:2173-9 pubmed
    ..Several AE1 mutations cosegregate with dominantly transmitted nonsyndromic renal tubular acidosis (dRTA)...
  36. Pessler F, Emery H, Dai L, Wu Y, Monash B, Cron R, et al. The spectrum of renal tubular acidosis in paediatric Sjögren syndrome. Rheumatology (Oxford). 2006;45:85-91 pubmed
    b>Renal tubular acidosis (RTA) is a well-recognized extraglandular complication of adult Sjögren syndrome (SS) but has been reported only rarely in paediatric SS. We wished to describe the natural history of RTA in paediatric SS.
  37. Li H, Szigligeti P, Worrell R, Matthews J, Conforti L, Soleimani M. Missense mutations in Na+:HCO3- cotransporter NBC1 show abnormal trafficking in polarized kidney cells: a basis of proximal renal tubular acidosis. Am J Physiol Renal Physiol. 2005;289:F61-71 pubmed
    ..Two well-described missense mutations in NBC1, R510H and S427L, are associated with renal tubular acidosis (RTA)...
  38. Walsh S, Turner C, Toye A, Wagner C, Jaeger P, Laing C, et al. Immunohistochemical comparison of a case of inherited distal renal tubular acidosis (with a unique AE1 mutation) with an acquired case secondary to autoimmune disease. Nephrol Dial Transplant. 2007;22:807-12 pubmed
  39. Baburaj P, Khanna L. Secondary Sjogren's syndrome and scleroderma presenting as renal tubular acidosis. J Assoc Physicians India. 2007;55:78-9 pubmed
    We report a case of distal renal tubular acidosis in a twenty year old female patient of scleroderma and secondary Sjogren's syndrome...
  40. Suzuki M, Vaisbich M, Yamada H, Horita S, Li Y, Sekine T, et al. Functional analysis of a novel missense NBC1 mutation and of other mutations causing proximal renal tubular acidosis. Pflugers Arch. 2008;455:583-93 pubmed
    ..Multiple experimental approaches would be required to elucidate potential disease mechanism by NBC1 mutations...
  41. Katzir Z, Dinour D, Reznik Wolf H, Nissenkorn A, Holtzman E. Familial pure proximal renal tubular acidosis--a clinical and genetic study. Nephrol Dial Transplant. 2008;23:1211-5 pubmed
    Inherited proximal renal tubular acidosis (pRTA) is commonly associated with more generalized proximal tubular dysfunctions and occasionally with other organ system defects...
  42. Ungsupravate D, Sawasdee N, Khositseth S, Udomchaiprasertkul W, Khoprasert S, Li J, et al. Impaired trafficking and intracellular retention of mutant kidney anion exchanger 1 proteins (G701D and A858D) associated with distal renal tubular acidosis. Mol Membr Biol. 2010;27:92-103 pubmed publisher
    ..carrier family 4, anion exchanger, member 1 (SLC4A1) were identified in two pediatric patients with distal renal tubular acidosis (dRTA)...
  43. Stehberger P, Shmukler B, Stuart Tilley A, Peters L, Alper S, Wagner C. Distal renal tubular acidosis in mice lacking the AE1 (band3) Cl-/HCO3- exchanger (slc4a1). J Am Soc Nephrol. 2007;18:1408-18 pubmed
    ..encodes the AE1 Cl(-)/HCO(3)(-) exchanger (SLC4A1) cause autosomal recessive and dominant forms of distal renal tubular acidosis (dRTA)...
  44. Ribeiro M, Alloisio N, Almeida H, Gomes C, Texier P, Lemos C, et al. Severe hereditary spherocytosis and distal renal tubular acidosis associated with the total absence of band 3. Blood. 2000;96:1602-4 pubmed
    ..Band 3 and protein 4.2 were absent; spectrin, ankyrin, and glycophorin A were significantly reduced. Renal tubular acidosis was detected by the age of 3 months. Nephrocalcinosis appeared soon thereafter...
  45. Smith A, Skaug J, Choate K, Nayir A, Bakkaloglu A, Ozen S, et al. Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing. Nat Genet. 2000;26:71-5 pubmed
  46. Dymot J, McKay G. Type 1 (distal) renal tubular acidosis in a patient with Type 1 diabetes mellitus--not all cases of metabolic acidosis in Type 1 diabetes mellitus are due to diabetic ketoacidosis. Diabet Med. 2008;25:114-5 pubmed publisher
  47. Vargas Poussou R, Houillier P, Le Pottier N, Strompf L, Loirat C, Baudouin V, et al. Genetic investigation of autosomal recessive distal renal tubular acidosis: evidence for early sensorineural hearing loss associated with mutations in the ATP6V0A4 gene. J Am Soc Nephrol. 2006;17:1437-43 pubmed
    ..and ATP6V0A4 genes, encoding subunits B1 and 4 of apical H(+) ATPase, cause recessive forms of distal renal tubular acidosis (dRTA)...
  48. Li S, Liou L, Fang J, Tsai W. Symptomatic renal tubular acidosis (RTA) in patients with systemic lupus erythematosus: an analysis of six cases with new association of type 4 RTA. Rheumatology (Oxford). 2005;44:1176-80 pubmed
    We have analysed the association between different parameters of renal tubular acidosis (RTA) with clinical and laboratory parameters in patients with systemic lupus erythematosus (SLE).
  49. Izzedine H, Launay Vacher V, Deray G. Topiramate-induced renal tubular acidosis. Am J Med. 2004;116:281-2 pubmed
  50. Fulop M, Mackay M. Renal tubular acidosis, Sjögren syndrome, and bone disease. Arch Intern Med. 2004;164:905-9 pubmed
    ..There has been disagreement about whether osteomalacia (adult rickets) occurs in adults with type 1 (distal) renal tubular acidosis (RTA1)...
  51. Warth R, Barriere H, Meneton P, Bloch M, Thomas J, Tauc M, et al. Proximal renal tubular acidosis in TASK2 K+ channel-deficient mice reveals a mechanism for stabilizing bicarbonate transport. Proc Natl Acad Sci U S A. 2004;101:8215-20 pubmed
    ..The consequences of the task2 gene inactivation in mice are reminiscent of the clinical manifestations seen in human proximal renal tubular acidosis syndrome.
  52. Soy M, Pamuk O, Gerenli M, Celik Y. A primary Sjögren's syndrome patient with distal renal tubular acidosis, who presented with symptoms of hypokalemic periodic paralysis: Report of a case study and review of the literature. Rheumatol Int. 2005;26:86-9 pubmed
    Although renal tubular acidosis (RTA), secondary to autoimmune interstitial nephritis, develops in a large proportion of patients with Sjögren's syndrome (SS), most of the subjects are asymptomatic...
  53. Hostutler R, DiBartola S, Eaton K. Transient proximal renal tubular acidosis and Fanconi syndrome in a dog. J Am Vet Med Assoc. 2004;224:1611-4, 1605 pubmed
    ..These laboratory abnormalities were diagnostic of proximal renal tubular acidosis and Fanconi syndrome. Results of initial and convalescent serologic tests for leptospirosis were negative...