Efectos adversos de la acumulación renal de hemoproteínas. Nuevas herramientas terapéuticas / Adverse effects of the renal accumulation of haem proteins. Novel therapeutic approaches

La hemoglobina y la mioglobina son hemoproteínas que juegan un papel fundamental en el organismo ya que participan en el transporte de oxígeno. Sin embargo, debido a su estructura química, estas moléculas pueden ejercer efectos deletéreos cuando se liberan al torrente sanguíneo de forma masiva, como sucede en determinadas condiciones patológicas asociadas a rabdomiólisis o hemólisis intravascular. Una vez en el plasma, estas hemoproteínas se pueden filtrar y acumular en el riñón, donde resultan citotóxicas, principalmente para el epitelio tubular, e inducen fracaso renal agudo y enfermedad renal crónica. En la presente revisión analizaremos los distintos contextos patológicos que provocan la acumulación renal de estas hemoproteínas, su relación con la pérdida de función renal a corto y largo plazo, los mecanismos fisiopatólogicos responsables de sus efectos adversos y los sistemas de defensa que contrarrestan tales acciones. Por último, describiremos los distintos tratamientos utilizados actualmente y mostraremos nuevas opciones terapéuticas basadas en la identificación de nuevas dianas celulares y moleculares, prestando especial atención a los diversos ensayos clínicos que se encuentran en marcha en la actualidad (AU)

Haemoglobin and myoglobin are haem proteins that play a key role as they help transport oxygen around the body. However, because of their chemical structure, these molecules can exert harmful effects when they are released massively into the bloodstream, as reported in certain pathological conditions associated with rhabdomyolysis or intravascular haemolysis. Once in the plasma, these haem proteins can be filtered and can accumulate in the kidney, where they become cytotoxic, particularly for the tubular epithelium, inducing acute kidney failure and chronic kidney disease. In this review, we will analyse the different pathological contexts that lead to the renal accumulation of these haem proteins, their relation to both acute and chronic loss of renal function, the pathophysiological mechanisms that cause adverse effects and the defence systems that counteract such actions. Finally, we will describe the different treatments currently used and present new therapeutic options based on the identification of new cellular and molecular targets, with particular emphasis on the numerous clinical trials that are currently ongoing (AU)

Can hemozoin alone cause host anaemia?

Both schistosomes and malaria parasites produce hemozoin and cause host anaemia. However, the relationship between anaemia and hemozoin is unclear. Although some studies have proposed that hemozoin is related to anaemia in malaria patients, whether hemozoin alone can cause anaemia in patients infected by malaria parasites or schistosomes is uncertain. To investigate the effect of hemozoin on hosts, ß-haematin was injected intravenously to normal mice. Then, liver and spleen tissues were observed. Mouse blood was examined. Red blood cells (RBCs), white blood cells (WBCs) and haemoglobin were analysed. Macrophage changes in the spleens and marrow cells were compared using immunofluorescence and H&E or Giemsa stain, respectively. We found that after 15 injections of ß-haematin, a large amount of ß-haematin was observed to deposit in the livers and spleens. Splenomegaly and bone marrow mild hyperplasia were detected. The average number of RBCs, average number of WBCs and average concentration of haemoglobin decreased significantly from 9.36 × 1012 cells/L to 8.7 × 1012 cells/L, 3.8 × 109 cells/L to 1.7 × 109 cells/L and 142.8 g/L to 131.8 g/L, respectively. In specific, the number of macrophages in the spleens greatly increased after ß-haematin infection. The results showed that injections of ß-haematin alone can cause anaemia possibly through hypersplenism.

Malaria theranostics using hemozoin-generated vapor nanobubbles.

Malaria remains a widespread and deadly infectious human disease, with increasing diagnostic and therapeutic challenges due to the drug resistance and aggressiveness of malaria infection. Early detection and innovative approaches for parasite destruction are needed. The high optical absorbance and nano-size of hemozoin crystals have been exploited to detect and mechanically destroy the malaria parasite in a single theranostic procedure. Transient vapor nanobubbles are generated around hemozoin crystals in malaria parasites in infected erythrocytes in response to a single short laser pulse. Optical scattering signals of the nanobubble report the presence of the malaria parasite. The mechanical impact of the same nanobubble physically destroys the parasite in nanoseconds in a drug-free manner. Laser-induced nanobubble treatment of human blood in vitro results in destruction of up to 95% of parasites after a single procedure, and delivers an 8-fold better parasiticidal efficacy compared to standard chloroquine drug treatment. The mechanism of destruction is highly selective for malaria infected red cells and does not harm neighboring, uninfected erythrocytes. Thus, laser pulse-induced vapor nanobubble generation around hemozoin supports both rapid and highly specific detection and destruction of malaria parasites in one theranostic procedure.

TLR9 adjuvants enhance immunogenicity and protective efficacy of the SE36/AHG malaria vaccine in nonhuman primate models.

The SE36 antigen, derived from serine repeat antigen 5 (SERA5) of Plasmodium falciparum, is a promising blood stage malaria vaccine candidate. Ongoing clinical trials suggest the efficacy of the SE36 vaccine could be increased by the incorporation of more effective adjuvants into the vaccine formulation. In this study, we assessed the safety, immunogenicity and protective efficacy of SE36/AHG formulated with TLR9 ligand adjuvants K3 CpG oligodeoxyribonucleotides (CpG ODNs) (K3 ODN), D3 ODN or synthetic hemozoin, in two non-human primate models. SE36/AHG with or without each adjuvant was administrated to cynomolgus monkeys. A combination of TLR9 ligand adjuvant with SE36/AHG induced higher humoral and cellular immune response compared with SE36/AHG alone. Administration of a crude extract of P. falciparum parasite resulted in the induction of more SE36-specific IgG antibodies in monkeys vaccinated with a combination of SE36/AHG and adjuvant, as opposed to vaccination with SE36/AHG alone. The most effective TLR9 ligand, K3 ODN, was chosen for further vaccine trials in squirrel monkeys, in combination with SE36/AHG. All monkeys immunized with the combined SE36/AHG and K3 ODN formulation effectively suppressed parasitemia and symptoms of malaria following challenge infections. Furthermore, no serious adverse events were observed. Our results show that the novel vaccine formulation of K3 ODN with SE36/AHG demonstrates safety, potent immunogenicity and efficacy in nonhuman primates, and this vaccine formulation may form the basis of a more effective malaria vaccine.

Age sensitizes the kidney to heme protein-induced acute kidney injury.

Age increases the risk for ischemic acute kidney injury (AKI). We questioned whether a similar age-dependent injury occurs following exposure to hemoglobin, a known nephrotoxin. Old mice (~16 mo old), but not young mice (~6 mo old), when administered hemoglobin, exhibited marked elevation in blood urea nitrogen (BUN) and serum creatinine, and acute tubular necrosis with prominent tubular cast formation. The aged kidney exhibited induction of heme oxygenase-1 (HO-1) and other genes/proteins that may protect against heme-mediated renal injury, including ferritin, ferroportin, haptoglobin, and hemopexin. Old mice did not evince induction of HO-2 mRNA by hemoglobin, whereas a modest induction of HO-2 mRNA was observed in young mice. To determine the functional significance of HO-2 in heme protein-induced AKI, we administered hemoglobin to relatively young HO-2(+/+) and HO-2(-/-) mice: HO-2(-/-) mice, compared with HO-2(+/+) mice, exhibited greater renal dysfunction and histologic injury when administered hemoglobin. In addition to failing to elicit a protective system such as HO-2 in response to hemoglobin, old mice exhibited an exaggerated maladaptive response typified by markedly greater induction of the nephrotoxic cytokine IL-6 (130-fold increase vs. 10-fold increase in mRNA in young mice). We conclude that aged mice, unlike relatively younger mice, are exquisitely sensitive to the nephrotoxicity of hemoglobin, an effect attended by a failure to induce HO-2 mRNA and a fulminant upregulation of IL-6. Age thus markedly augments the sensitivity of the kidney to heme proteins, and HO-2 confers resistance to such insults.

A prospective study of intakes of zinc and heme iron and colorectal cancer risk in men and women.

Although laboratory studies linked zinc and heme iron to colorectal cancer, epidemiologic evidence is limited. We prospectively examined these associations in the Nurses' Health Study and Health Professionals Follow-up Study. We used Cox proportional hazards regression analyses to calculate cohort-specific relative risks (RRs) and pooled results using a fixed-effects model. We documented 2,114 incident colorectal cancer cases during up to 22 years of follow-up. Compared highest to lowest quintile of dietary zinc intake, the pooled multivariable RRs (95% CIs) were 0.86 (0.73, 1.02) for colorectal cancer, 0.92 (0.76, 1.11) for colon cancer, and 0.68 (0.47, 0.99) for rectal cancer. The significant inverse association between dietary zinc intake and risk of rectal cancer was mainly driven by data in women, although the difference in the sex-specific results was not statistically significant. For the same comparison, the pooled multivariable RRs (95% CIs) for heme iron were 1.10 (0.93, 1.30) for colorectal cancer, 1.06 (0.88, 1.29) for colon cancer, and 1.20 (0.83, 1.75) for rectal cancer. These associations were not significantly modified by alcohol consumption, body mass index, physical activity, menopausal status, or postmenopausal hormone use. Total zinc intake, total iron intake, dietary iron intake, and zinc or iron supplement uses were largely not associated with colorectal cancer risk. Our study does not support strong roles of zinc and heme iron intake in colorectal cancer risk; however, a suggestive inverse association of dietary zinc intake with rectal cancer risk in women requires further study.

Rationale and design of the oral HEMe iron polypeptide Against Treatment with Oral Controlled Release Iron Tablets trial for the correction of anaemia in peritoneal dialysis patients (HEMATOCRIT trial).

BACKGROUND: The main hypothesis of this study is that oral heme iron polypeptide (HIP; Proferrin ES) administration will more effectively augment iron stores in erythropoietic stimulatory agent (ESA)-treated peritoneal dialysis (PD) patients than conventional oral iron supplementation (Ferrogradumet). METHODS: Inclusion criteria are peritoneal dialysis patients treated with darbepoietin alpha (DPO; Aranesp(R), Amgen) for >or= 1 month. Patients will be randomized 1:1 to receive either slow-release ferrous sulphate (1 tablet twice daily; control) or HIP (1 tablet twice daily) for a period of 6 months. The study will follow an open-label design but outcome assessors will be blinded to study treatment. During the 6-month study period, haemoglobin levels will be measured monthly and iron studies (including transferring saturation [TSAT] measurements) will be performed bi-monthly. The primary outcome measure will be the difference in TSAT levels between the 2 groups at the end of the 6 month study period, adjusted for baseline values using analysis of covariance (ANCOVA). Secondary outcome measures will include serum ferritin concentration, haemoglobin level, DPO dosage, Key's index (DPO dosage divided by haemoglobin concentration), and occurrence of adverse events (especially gastrointestinal adverse events). DISCUSSION: This investigator-initiated multicentre study has been designed to provide evidence to help nephrologists and their peritoneal dialysis patients determine whether HIP administration more effectively augments iron stores in ESP-treated PD patients than conventional oral iron supplementation. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry number ACTRN12609000432213.