Hemoglobinuria

Intravascular hemolysis can result in hemoglobinuria with acute kidney injury. In this study we systematically explored two in vivo animal models and a related cell culture system to identify hemoglobinuria-triggered damage pathways. In models of stored blood transfusion and hemoglobin (Hb) exposure in guinea pigs and beagle dogs we found that hemoglobinuria led to intrarenal conversion of ferrous Hb(Fe(2+)) to ferric Hb(Fe(3+)), accumulation of free heme and Hb-cross-linking products, enhanced 4-hydroxynonenal reactivity in renal tissue, and acute tubule injury. These changes were associated in guinea pigs with activation of a renal cortex gene expression signature indicative of oxidative stress and activation of the unfolded protein response (UPR). Tubule cells of hemolytic animals demonstrated enhanced protein expression of heme oxygenase and heat shock protein and enhanced expression of acute kidney injury-related neutrophil gelatinase-associated lipocalin. These adverse changes were completely prevented by haptoglobin treatment. The in vivo findings were extrapolated to a MS-based proteome analysis of SILAC-labeled renal epithelial cells that were exposed to free heme within a concentration range estimate of renal tubule heme exposure. These experiments confirmed that free heme is a likely trigger of tubule barrier deregulation and oxidative cell damage and reinforced the hypothesis that uncontrolled free heme could trigger the UPR as an important pathway of renal injury during hemoglobinuria.

BackgroundChanges in the geographical distribution of genetic disorders are often thought to happen slowly, especially when compared with infectious diseases. Whereas mutations, genetic drift, and natural selection take place over many generations, epidemics can spread through large populations within a few days or weeks. Nevertheless, population movements can interfere with these processes, and few studies have been done of their eff ect on genetic disorders. We aimed to investigate the eff ect of global migration on the distribution of the sickle-cell gene-the most common and clinically significant haemoglobin structural variant.MethodsFor each country, we extracted data from the World Bank’s Global Bilateral Migration Database about international human migrations between 1960 and 2000. We combined this information with evidence-based estimates of national HbS allele frequencies, generated within a Bayesian geostatistical framework, to analyse temporal changes in the net numbers of migrants, and classified countries with an index summarising these temporal trends.FindingsThe number of international migrants increased from 92.6 million in 1960, to 165.2 million in 2000. The estimated global number of migrants with HbS increased from about 1.6 million in 1960, to 3.6 million in 2000. This increase was largely due to an increase in the number of migrants from countries with HbS allele frequencies higher than 10%, from 3.1 million in 1960, to 14.2 million in 2000. Additionally, the mean number of countries of origin for each destination country increased from 70 (SE 46) in 1960, to 98 (48) in 2000, showing an increasing diversity in the network of international migrations between countries. Our index of change map shows a patchy distribution of the magnitude of temporal changes, with the highest positive and negative values scattered across all continents.InterpretationGlobal human population movements have had a substantial eff ect on the distribution of the HbS gene. Population movements can create a long-term burden on health-care systems. Our findings, which emphasise countries in which migration fluxes are changing the most, should increase awareness about the global burden of haemoglobinopathies and encourage policy makers to implement specific public health interventions, such as screening programmes and genetic counselling.FundingWellcome Trust, European Research Council, Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases-National Institutes of Health, the Research and Policy for Infectious Disease Dynamics program, Fogarty International Center.

BackgroundHaemoglobinuria is one of the manifestations of severe malaria and results from severe intravascular haemolysis. Glucose-6-phosphate dehydrogenase (G6PD) deficiency has been implicated in its aetiology. Haemoglobinuria may be associated with severe anaemia and, less frequently, acute renal failure.MethodsA prospective case-control study was carried out to determine the incidence of haemoglobinuria as confirmed by dipstick urinalysis, microscopy and spectrophotometric measurement, among children with severe malaria. A total of 251 children presenting at the Children's Emergency Ward with severe malaria were recruited over a period of 21 months. The G6PD status and the outcomes of severe malaria in children with and without haemoglobinuria was studied with respect to renal failure, the recurrence of haemoglobinuria and blood pressure changes over a three-month follow-up period.ResultsIt was found that the incidence of haemoglobinuria among children with severe malaria is 19.1%. Children ConclusionsHaemoglobinuria was a prominent feature of severe malaria and it was significantly associated with jaundice at presentation. Haemoglobinuria was commoner in older children than younger children but not related to sex. G6PD deficiency was not an independent predictor of the occurrence or outcome of haemoglobinuria. Blood pressure was not affected by haemoglobinuria on admission nor during follow-up.

In a dairy herd in the state of Goiás, Central-West Brazil, a cow died following an acute illness characterized by jaundice and hemoglobinuria. Necropsy revealed jaundice, dark-red urine and dark-red discoloration of the kidneys, and a diffusely copper-colored liver with two extensive, firm lesions surrounded by hyperemic halos in the right and left lobes. Histopathological analysis showed multifocal coagulative necrosis in the liver, accompanied by abundant intralesional bacillary structures and multifocal thrombosis. Renal lesions included tubular cell degeneration and necrosis, intracellular hyaline droplet accumulation, and occasional proteinaceous casts within the tubular lumen. PCR and sequencing confirmed the presence of Clostridium haemolyticum DNA in the liver lesions. Based on the characteristic clinical presentation and pathological findings, the diagnosis of bacillary hemoglobinuria was established, with further molecular evidence of the clostridial agent. To our knowledge, this is the first reported case of bacillary hemoglobinuria in the Central-West region of Brazil, and an unusual report in the Tropical Zone in the country, especially in dairy cattle.