Fatal oxidative haemolysis and methaemoglobinaemia in a patient with alkaptonuria and acute kidney injury

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Alkaptonuria (AKU) is a rare inherited disorder of tyrosine metabolism, which leads to an accumulation of homogentisic acid (HGA) and is associated with a progressive arthropathy. Fatal complications are unusual and usually result from cardiac disease or progressive renal impairment; rapidly fatal haematological complications are exceptionally rare and described in only a handful of case reports. This case involves a 63-year-old male with AKU and modest chronic kidney disease who developed rapidly fatal haemolysis and methaemoglobinuria following an episode of acute kidney injury triggered by an obstructing ureteric calculus and urosepsis. The patient succumbed despite aggressive antioxidant therapy with ascorbic acid and n-acetyl cysteine. A rapid build-up of HGA due to reduced renal clearance, triggering oxidative haemolysis and methaemoglobinuria is proposed as the mechanism. Alternative strategies to consider when conventional antioxidants fail are discussed including the potent inhibitor of HGA production, nitisonone.

Related collections

Most cited references 15

Record: found
Abstract: found
Article: not found

Natural history of alkaptonuria.

Lynn Gerber, Marjan Huizing, A L Fitzpatrick … (2002)

Alkaptonuria, caused by mutations in the HGO gene and a deficiency of homogentisate 1,2-dioxygenase, results in an accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue. There is no effective therapy for this disorder, although nitisinone inhibits the enzyme that produces HGA. We performed a study to delineate the natural history of alkaptonuria. We evaluated 58 patients with alkaptonuria (age range, 4 to 80 years), using clinical, radiographic, biochemical, and molecular methods. A radiographic scoring system was devised to assess the severity of spinal and joint damage. Two patients were treated with nitisinone for 10 and 9 days, respectively. Life-table analyses showed that joint replacement was performed at a mean age of 55 years and that renal stones developed at 64 years, cardiac-valve involvement at 54 years, and coronary-artery calcification at 59 years. Linear regression analysis indicated that the radiographic score for the severity of disease began increasing after the age of 30 years, with a more rapid increase in men than in women. Twenty-three new HGO mutations were identified. In a 51-year-old woman, urinary HGA excretion fell from 2.9 to 0.13 g per day after a 10-day course of nitisinone (7 days at a dose of 0.7 mg per day and 3 days at 2.8 mg per day). In a 59-year-old woman, urinary HGA fell from 6.4 g to 1.7 g per day after nine days of treatment with nitisinone (0.7 mg per day). Plasma tyrosine levels in these patients rose from approximately 1.1 mg per deciliter (60 micromol per liter) in both to approximately 12.8 mg per deciliter (700 micromol per liter) and 23.6 mg per deciliter (1300 micromol per liter), respectively, with no clinical signs or symptoms. The reported data on the natural history of alkaptonuria provide a basis for the evaluation of long-term therapies. Although nitisinone can reduce HGA production in humans with homogentisate 1,2-dioxygenase deficiency, the long-term safety and efficacy of this treatment require further evaluation. Copyright 2002 Massachusetts Medical Society

0 comments Cited 109 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

A 3-year randomized therapeutic trial of nitisinone in alkaptonuria.

W Introne, William Gahl, Vandana Sachdev … (2011)

Alkaptonuria is a rare, autosomal recessive disorder of tyrosine degradation due to deficiency of the third enzyme in the catabolic pathway. As a result, homogentisic acid (HGA) accumulates and is excreted in gram quantities in the urine, which turns dark upon alkalization. The first symptoms, occurring in early adulthood, involve a painful, progressively debilitating arthritis of the spine and large joints. Cardiac valvular disease and renal and prostate stones occur later. Previously suggested therapies have failed to show benefit, and management remains symptomatic. Nitisinone, a potent inhibitor of the second enzyme in the tyrosine catabolic pathway, is considered a potential therapy; proof-of-principle studies showed 95% reduction in urinary HGA. Based on those findings, a prospective, randomized clinical trial was initiated in 2005 to evaluate 40 patients over a 36-month period. The primary outcome parameter was hip total range of motion with measures of musculoskeletal function serving as secondary parameters. Biochemically, this study consistently demonstrated 95% reduction of HGA in urine and plasma over the course of 3 years. Clinically, primary and secondary parameters did not prove benefit from the medication. Side effects were infrequent. This trial illustrates the remarkable tolerability of nitisinone, its biochemical efficacy, and the need to investigate its use in younger individuals prior to development of debilitating arthritis. Published by Elsevier Inc.

0 comments Cited 49 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Drug-induced methaemoglobinaemia. Treatment issues.

Bianca Coleman, N Coleman (1996)

In normal erythrocytes, small quantities of methaemoglobin are formed constantly and are continuously reduced, almost entirely by the reduced nicotine adenine dinucleotide (NADH) diaphorase system, rather than the reduced nicotine adenine dinucleotide phosphate (NADPH) diaphorase system. Methaemoglobinaemias are usually the result of xenobiotics, either those that may directly oxidise haemoglobin or those that require metabolic activation to an oxidising species. The most clinically relevant direct methaemoglobin formers include local anaesthetics (such as benzocaine and, to a much lesser extent, prilocaine) as well as amyl nitrite and isobutyl nitrite, which have become drugs of abuse. Indirect, or metabolically activated, methaemoglobin formation by dapsone and primaquine may cause adverse reactions. The clinical consequences of methaemoglobinaemia are related to the blood level of methaemoglobin; dyspnoea, nausea and tachycardia occur at methaemoglobin levels of > or = 30%, while lethargy, stupor and deteriorating consciousness occur as methaemoglobin levels approach 55%. Higher levels may cause cardiac arrhythmias, circulatory failure and neurological depression, while levels of 70% are usually fatal. Cyanosis accompanied by a lack of responsiveness to 100% oxygen indicates a diagnosis of methaemoglobinaemia, which should be confirmed using a CO-oximeter. Pulse oximeters do not detect methaemoglobin and may give a misleading impression of patient oxygenation. Methaemoglobinaemia is treated with intravenous methylene blue (methyl-thioninium chloride; ;1 to 2 mg/kg of a 1% solution). If the patient does not respond, perhaps because of glucose-6-phosphate dehydrogenase (G6PD) deficiency or continued presence of toxin, admission to an intensive care unit and exchange transfusion may be required. Dapsone-mediated chronic methaemoglobin formation can be reduced by coadministration of cimetidine to aid patient tolerance. Increasing knowledge and awareness of drug-mediated acute methaemoglobinaemia among physicians should lead to prompt diagnosis and treatment of this potentially life-threatening condition.

0 comments Cited 44 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-ta): Clin Kidney J

Journal ID (iso-abbrev): Clin Kidney J

Journal ID (publisher-id): ckj

Journal ID (hwp): ndtplus

Title: Clinical Kidney Journal

Publisher: Oxford University Press

ISSN (Print): 2048-8505

ISSN (Electronic): 2048-8513

Publication date (Print): February 2015

Publication date (Electronic): 17 November 2014

Publication date PMC-release: 17 November 2014

Volume: 8

Issue: 1

Pages: 109-112

Affiliations

[1 ]Renal Unit, Aberdeen Royal Infirmary , Aberdeen, UK

[2 ]Royal Liverpool University Hospital , Liverpool, UK

[3 ]Department of Haematology, Aberdeen Royal Infirmary , Aberdeen, UK

[4 ]Department of Clinical Biochemistry and Metabolic Medicine, Royal Liverpool Hospital , Liverpool, UK

Author notes

Correspondence to: Adam Mullan; E-mail: a.mullan@ 123456nhs.net

Article

Publisher ID: sfu121

DOI: 10.1093/ckj/sfu121

PMC ID: 4310424

PubMed ID: 25713720

SO-VID: 92be9270-2249-4870-819a-1f3eaba59464

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Date received : 23 September 2014

Date accepted : 22 October 2014

Comments

Comment on this article

scite_

Cited by 2

See all cited by

Most referenced authors 131

See all reference authors

- Version 1
- Version 1

Fatal oxidative haemolysis and methaemoglobinaemia in a patient with alkaptonuria and acute kidney injury

Read this article at

Abstract

Related collections

Karger: Nephrology

Most cited references 15

Natural history of alkaptonuria.

A 3-year randomized therapeutic trial of nitisinone in alkaptonuria.

Drug-induced methaemoglobinaemia. Treatment issues.

Author and article information

Journal

Affiliations

Author notes

Article

History

Categories

Comments

Comment on this article

Similar content 233

Cited by 2

Most referenced authors 131