Scientists have reported the first clear evidence that the kidney is actively involved in its own maintenance, a discovery likely to alter our perception of the kidney as merely a passive mechanical filtering system.
Most significantly, identification of this self-cleaning process has disclosed a novel route to kidney disease patho-genesis; breakdown of this clearance mechanism and subsequent clogging of the filtration system could impair kidney function, leading to kidney damage and disease.
The colossal filtering capacity of the kidneys is well-documented; each one filters, through a series of increasingly more selective screens, 150–200 l of blood every day. Until now, it has not been understood why, with such a large amount of protein passing through them, the fine filters do not frequently become clogged with large plasma proteins.
Scientists from the Washington University School of Medicine in St Louis (MO, USA) have recently shed some light upon this mystery, reporting the first evidence that the kidney itself is actively involved in the maintenance of its most selective filter – the glomerular filtration barrier. This, the finest filter of the kidney, is comprised of specialized epithelial cells called podocytes and forms the final barrier to the passage of serum proteins into the urine. Scientists have identified a protein expressed within these podocyes, FcRn, with the capacity to bind both albumin and IgG, the two most abundant proteins in the blood and, therefore, prime candidates for blocking the filters. FcRn is thought to take hold of these common serum proteins and remove them from the filter, thus preventing them clogging up the system and ensuring proper kidney function.
This theory is supported by studies in mice engineered to lack FcRn; such animals have a reduced ability to clear protein from the kidney in the short-term and, over time, show evidence of protein accumulation within the kidneys. The build-up of proteins on the filter not only impairs the proper functioning of the kidney, such trapped proteins could also potentially be nephrotoxic.
Kidney disease and renal failure are among the top ten causes of death in the USA and a clear understanding of kidney functioning is key to identifying new therapeutic targets. As well as revealing one way the kidneys avoid becoming blocked with serum proteins, this study has crucially disclosed a novel route through which individuals can succumb to glomerular disease. Now it has been discovered that certain forms of kidney damage and disease may be a consequence of genetic or acquired defects in this system, there emerges the potential to develop novel treatments aimed at tackling these underlying causes.
Source: Akilesh S, Huber TB, Wu H et al. Podocytes use FcRn to clear IgG from the glomerular basement membrane. Proc. Natl Acad. Sci. USA 105(3), 967–972 (2008)
Successful completion of Rhitol™ Phase II clinical trial
Drug: Rhitol™
Manufacturer: Kiadis Pharma, The Netherlands
Indication: Treatment option for patients with chronic GVHD resistant or intolerant to immunosuppressive agents
Kiadis Pharma (The Netherlands) has announced the successful completion of its Rhitol™ Phase II clinical trial. This marks a promising step forward in the treatment of chronic graft-versus-host disease (GVHD) in cases where standard immunosuppressive therapies are either ineffective or not well tolerated.
GVHD is a complication that can arise following allogeneic bone marrow transplantation, whereby immune cells from the donor graft attack the patient’s cells. The condition resembles an autoimmune disease and, in general, GVHD is treated using immuno-suppressive drugs. However, some patients do not respond to this treatment and others develop severe side effects. In these instances, GVHD can become a life-threatening condition. As such, it is imperative that alternative agents are found that can be used to treat those patients who are resistant or intolerant to standard immunosuppressive agents. Rhitol is one such agent under development for the treatment of chronic GVHD for use in these individuals.
The recently completed Rhitol Phase II trial demonstrated excellent safety results as well as efficacy in reducing the symptoms of GVHD. “We are very pleased with the positive outcome of this study and the potential shown by Rhitol”, Manja Bouman, CEO of Kiadis Pharma commented. Now that their Phase II trial has been successfully completed, Kiadis Pharma plans to undertake a Phase III multicenter clinical trial in the USA and Canada.
Source: Kiadis Pharma (The Netherlands): www.kiadis.com
Kidney cancer drug also targets leukemia cells
A drug currently used to treat kidney cancer is also effective against certain types of leukemia cells, according to researchers at the University of Texas MD Anderson Cancer Center (TX, USA).
In a Phase I clinical trial, sorafenib, currently only US FDA approved for advanced renal cell carcinoma and inoperable liver cancer, reduced the average percentage of circulating leukemia cells in the blood by over 70% – from 81 to 7.5% – in patients whose leukemia involves the FLT3 gene internal tandem duplication (ITD) mutation. The promising results of this initial trial could signify a significant step forward in the treatment of leukemia.
Acute myeloid leukemia (AML) is the most common and most lethal form of adult leukemia. Each year in the USA, approximately 14,000 new cases of AML are diagnosed and AML causes approximately 9000 deaths annually. Sorafenib, known commercially as Nexavar®, targets a genetic mutation, FLT3-ITD, active in approximately a third of AML sufferers. AML patients with this mutation have a -particularly poor prognosis so the apparent discovery of a drug that is highly targeted to this specific mutation is particularly encouraging.
The drug appears to have little or no effect on cells with normal copies of the gene and no major side effects were reported from the clinical trial. Significantly, sorafenib appears to have enhanced anticancer effects compared with previously tested leukemia therapies that target the FLT3 gene.
A Phase I/II trial incorporating sorafenib, in combination with standard chemotherapy drugs, is already open for relapsed patients and those newly diagnosed with high-risk leukemia. Once further research has been conducted into drug safety and maximum tolerated dose data have been obtained, it is predicted that sorafenib will be made available to more patients and will begin to play a role in frontline combination AML therapy.
Source: The University of Texas, MD Anderson Cancer Center, TX, USA: www.mdanderson.org
Rheumatic diseases appear to be on the increase in China
The prevalence rates of common rheumatic diseases in China are rising, according to a new survey. Although generally thought to be primarily an affliction of the Western world, there is now evidence that rheumatism is also common in China.
In this new and comprehensive survey, data were compiled from 38 previously published studies, covering over 240,000 individuals across 25 different provinces and cities. Although the prevalence of different rheumatic complaints varied with locality, the research shows that incidence rates of certain conditions within the Chinese population bear a close resemblance to those found in Western populations. Notably, the prevalence of osteoarthritis (OA) was comparable to that in Western countries although, interestingly, the sites of complaint varied; Caucasians tend to suffer from OA of the hips and hands whereas the Chinese suffer more from OA of the lumbar spine, knee joint and cervical spine.
Compared with the Western world, the prevalence of rheumatoid arthritis (RA) in China was similar to most Asian and South American countries but was lower than in Caucasian populations. The exception to this was in Taiwan where, in urban and suburban parts, the incidence of RA was close to Caucasian populations. This finding supports the idea that, although there is undoubtedly a strong genetic basis for RA, other contributing risk factors also play an important role. “These areas are more developed than mainland China. Apart from genetic factors, it looks as if environmental and socioeconomic factors might be important risk factors for RA,” said Qing Yu Zeng who led the study.
Further research is required to tease apart the relative importance of the different interplaying factors. “That’s something we’d certainly like to investigate further,” Zeng commented.
Sources: Zeng QY, Chen R, Darmarwan J et al. Rheumatic diseases in China. Arthritis Res. Ther. 10(1) R17 (2008); Arthritis Research Campaign: www.arc.org.uk
Positive results found in Phase IIa asthma trial
Drug: Nadolol
Tradename: Corgard®
Manufacturer: Inverseon, Inc., CA, USA
Current indication: Used alone or in combination to treat high blood pressure and angina
Inverseon Inc. (CA, USA) has announced the encouraging results of a Phase IIa study that trialed the use of a β-blocker to ameliorate the symptoms of asthma.
At present, β-blockers are contraindicated for use in asthmatics, as their acute administration has been associated with exacerbating bronchospasm. Paradoxically, a new trial has shown that a β-blocker, nadolol, may be safe and effective in the treatment of chronic asthma. Escalating doses of nadolol, currently licensed for the treatment of high blood pressure and angina, were administered to ten patients with mild asthma over a 9-week period. All subjects tolerated the drug and a clinically meaningful, dose-dependent decline in airway hyper-responsiveness was observed in eight of the ten patients.
Over 20 million Americans suffer from asthma, and morbidity and mortality rates continue to increase, meaning all avenues of therapy should be considered. Now that a positive Phase IIa proof-of-concept trial in asthma patients has been completed, further trials need to be conducted to ascertain whether the drug offers real promise to asthma sufferers.
The authors conclude that their findings justify the initiation of large-scale nadolol clinical trials for the treatment of chronic asthma.
Sources: Hanania NA, Singh S, El-Wali R et al. The safety and effects of the beta-blocker, nadolol, in mild asthma: An open-label pilot study. Pulm. Pharmacol. Ther. 21(1) 134–141 (2008); Inverseon Inc., CA, USA: www.inverseon.com
Potential new treatment target identified for asthma and other respiratory diseases
Mast cells residing in lung tissue could be a new therapeutic target for treating asthma and other respiratory diseases, according to a team at Weill Cornell Medical College (NY, USA).
It seems as if an enzyme released by mast cells in the lungs kick-starts a localized biochemical cascade of events which leads to the tightening of airways, a hallmark of asthma. By targeting drugs against this biological cascade, it should be possible to inhibit bronchoconstriction and relieve the symptoms associated with this risky physiological reaction.
Small numbers of mast cells reside in all organs of the body where they serve an immunologically protective role. The Weill Cornell team found that, during an immune response, these mast cells secrete renin, an enzyme that in turn produces angiotensin, a potent smooth muscle constrictor. In the lung, angiotensin acts locally on the smooth muscle lining of the airw.ays to trigger bronchoconstriction. Although antihypertensive medicines are currently available, these all tackle angiotensin in a systemic manner. The discovery of a pathway of ‘localized’ angiotensin production has revealed a potential new treatment opportunity; targeting agents against localized renin production could prove an effective way of relieving asthma and other respiratory diseases where bronchoconstriction is involved.
“These types of ‘renin inhibitors’ are, in fact, currently being developed by the pharmaceutical industry right now,” said Arul Veerappan, the study’s lead author. Furthermore, drugs developed to target this localized biochemical cascade may also prove effective against diseases involving vasoconstriction and fibrosis since local renin/angiotensin production appears to be associated with these features as well.
Source: Weill Cornell Medical College (NY, USA): www.med.cornell.edu