New Treatments For FSGS -ASN Conference

FSGS 

Nephron
Idiopathic focal and segmental glomerular sclerosis or FSGS is one of the most common causes of non diabetic kidney disease in the world and also one of the least satisfying to treat due to the difficulty with initiating and maintaining a durable remission. For decades the standard of treatment has been steroid therapy in high doses given either daily or every other day. This results in significant toxicity which includes the development of diabetes mellitus, osteoporosis, personality changes, weight gain, easy bruising etc. Yet these negative effects of steroid therapy are outweighed significantly by the result of not treating FSGS as the disease will usually progress to end stage renal disease (with a requirement for dialysis and transplantation). Even after transplantation there is a risk of recurrence of the disease within hours after surgery in some patients.

If ever there was a nephropathy in need of new treatment options it would be FSGS.

NEW OPTIONS

• Oral dexamethasone for FSGS

Oral dexamethasone was found to be as effective as steroid therapy, not superior however. The side effect profile is very similar. It is unlikely that further studies will change the outlook for dexamethasone as an alternative therapy

• Rituximab

Rituximab in FSGS has had a stormy course with the safety of rituximab as a therapeutic option under scrutiny due to deaths from a rare condition known as plemorphic multifocal leucoencephalopathy. The first cases were seen in patients with lupus treated with rituximab. Response rates to rituximab have varied in different studies implying that perhaps there are certain patient specific factors which predispose for response to rituximab. The key for the future of rituximab will be identifying patients with FSGS who are likely to respond.

• Rosiglitazone

This drug is primarily used in the treatment of type 2 diabetes where it acts to reduce insulin resistance and enhance glucose uptake into skeletal muscle. The drug however has an antifibrotic effect which may be useful in FSGS this drug is currently undergoing phase I trials.

• Adalimumab

This drug is an inhibitor of tumour necrosis factor one of the major cytokines (hormone produced by cells that affect other cells ) that induces inflammation. Inhibition of TNF is a possible pathway for treating FSGS. The FONT II study will look at the efficacy of adalimumab in patients with FSGS.

• Retinoids

Wikipedia defines retinoids as " A class of chemical compounds that are related chemically to vitamin A. Retinoids are used in medicine, primarily due to the way they regulate epithelial cell growth. Retinoids have many important and diverse functions throughout the body including roles in vision, regulation of cell proliferation and differentiation, growth of bone tissue, immune function, and activation of tumor suppressor genes."

What that essential translates to is that retinoids are a group of molecules that alter the expression of a variety of genes some of these genes are important to the proliferation of cells within the kidney and may play a role in the mechanism of FSGS. Trials with accutane (a retinoid currently used for treatment of acne) are currently at phase II.

• Perfinidone

Which has been shown to be helpful in diabetic nephrosclerosis has shown some efficacy in FSGS as well. The drug is capable of altering the rate of decline of kidney function in FSGS however it does not induce remission. It also does not alter proteinuria.

So some hope exists for improving the treatment of FSGS but it is still early days for almost all of the above.

ASN conference day 2

 Some rights reserved by Michael in San Diego, California 

The conference has been extremely crowded so far with some talks having to close doors due to inability to accommodate any more people after all sitting and standing room has been exhausted. So I have turned to the poster sessions in attempt to connect with some of the breaking research which is yet to be published. When they are eventually published the data presented in posters may be the source of the next oversubscribed big session at ASN next year.

Dr. Mita M shah et. al. sought to answer the question as to whether the immune system in older patients becomes less responsive. If this is true then older patients who receive transplants will need less medication. This would be an important finding because immunosuppressive medications have side effects which worsen lipid profile and may place a group already at risk for cardiovascular disease at further risk of increased events.

In the study that is yet to be published 158 stable patients were followed for roughly 6.5 years post transplant. The end result was that there was no basis for discontinuing or decreasing immunosuppressives  in older patients. In fact doing so may decrease graft survival.

Dr. Abdelaziz En-Nia presented a poster on polymorphism within the HLA-DR gene promoter and the predictive effect on post transplant kidney rejection and cardiovascular events. This is novel research that suggests that the HLA-DR locus that is routinely tested for prior to transplantation may be involved in the cardiovascular outcome post transplant. Cardiovascular disease mortality being one of the major causes of death after transplantation. Being able to isolate a subset of patients on a genetic basis who are more prone to cardiovascular disease will allow more aggressive therapy for the patients that need it most post transplantation which may translate into survival.

Dr. G Dreyer et. al presented a poster on the variation of Vitamin D levels in a multi ethnic renal transplantation population. The basis of the study was the fact that vitamin D deficiency is highly prevalent in patients after renal transplantation. This being important because of the risk of increased infections in patients with vitamin D deficiency and immunosuppression.

The unpublished results suggest that vitamin D levels vary considerably by ethnic group post transplant when other factors are controlled or accounted for. South Asians and Black patients having the lowest levels of vitamin D.

Research of Gudrun E Norby and others from Oslo in Norway have shown that SLE transplanted patients have equal survival of the transplanted kidney as other patients. However patients with SLE are at higher risk of death after tranplantation most likely from cardiovascular disease. This increased risk of cardiovascular disease in patients with SLE has been described before in the SLE patients with and without cardiovascular disease.

Highlights of the American Society of Nephrology Conference Day 1.

 Some rights reserved by Michael in San Diego, California 

After a whirlwind 12 hours of connecting flights I have finally arrived in San Diego to attend this years American Society of Nephrology conference.

The opening session of the 42nd annual conference was kicked off with an engrossing lecture by Nobel Prize winner Dr. Roger Tsien MD.

Dr Tsien gave an overview of his prize winning research on labeling of molecules with photo-labile elements and fluorescent techniques which allow direct visualization of processes which could only previously be imagined. The highlight of his presentation was his novel use of color as a tool and guide for surgeons. By injecting molecules that bind to cancer cells or their products, cancer cells can be made to glow any color that he chooses. This allows the operating surgeon to see the extent of the tumor in realtime allowing the possibility of more complete resection of tumors and thus increasing the chances of cure.

The possibilities opened by this research are amazing, almost any molecule can be tagged by his method and then linked to a marker of his choosing. Gadolinium for instance can be applied as a marker instead of a light emitting compound if the true extent of the tumor needed to be visualized on MRI.

Also of note........

The John P Peters Award was awarded to William E Mith MD, FASN for a lifetime of work in renal nutrition, muscle protein catabolism and acidemia induced muscle protein metabolism.

The Outcome of three major studies are expected to be revealed this year.

FAVORIT - The purpose of this randomized clinical trial is to determine if lowering homocysteine levels in renal transplant recipients with a multivitamin will reduce the occurrence of cardiovascular disease outcomes.

ROADMAP - ROADMAP is a randomized, double-blind, placebo-controlled, parallel-group, multi-center Phase III study being conducted at 262 collaborating centers in 19 European countries. The primary goal of the study is to test the hypothesis that treatment of T2DM patients with 40 mg of olmesartan medoxomil will prevent or delay the occurrence of microalbuminuria in comparison to a regimen that excludes agents that directly block the RAS. The secondary objective is to test the hypothesis that treatment with olmesartan medoxomil has a positive effect on cardiovascular and renal morbidity and mortality.

TREAT - Will evaluate whether treatment of anemia with Aranesp (darbopoietin) reduces cardiovascular events in patients with chronic kidney disease and with type 2 diabetes.

One of the most interesting papers mentioned today in the presidents opening address was the localization of increased risk of non-diabetic kidney disease in African Americans to the Myh9 gene locus. This finding may finally explain why African Americans are at increased risk of kidney disease and ultimately lead to understanding the mechanism of this increased risk thus guiding more specific therapy for patients with the gene.

Stay tuned the conference has only just begun....

Insulin Resistance and Kidney Disease, some thoughts.

Insulin molecule courtesy wikipedia.

Insulin resistance is a term many doctors and scientists are already familiar with. However not that many patients have a concept of exactly what is meant by resistance to insulin. Other than its role in the causation of type 2 diabetes, Ginsberg considers insulin resistance a major underlying abnormality driving cardiovascular disease, the major cause of morbidity and mortality in much of the world.

Although most of the research produced thus far focused on the role of insulin resistance in diabetics, it is now apparent that insulin resistance is important in its own right.

Insulin resistance is a syndrome that has been linked to increased risk for cardiovascular disease. However its effect is believed to act via promoting dyslipidemia, hypertension, hypercoagulability, and atherosclerosis.

In terms of kidney disease it has been shown by other authors that insulin resistance correlated linearly with decline in renal function. Independent variables related to insulin resistance were bicarbonate and Apo A-1/B levels in patients with chronic kidney disease. Low serum bicarbonate has been implicated in increased bone disease of renal failure and poor cardiac function as well increasing the pace of progression to end stage renal disease an effect that can be ameliorated in part by the prescription of bicarbonate. It would therefore not surprise me if insulin resistance were associated in some future study with increased progression to end stage renal disease. The Treatment of insulin resistance will likely then be a significant issue for patients with kidney disease.

Rosiglitazone is an oral drug that reduces the amount of sugar (glucose) in the blood. It is used for treating patients with type 2 diabetes. It is one of the few drugs currently available capable of reducing insulin resistance. The drug itself is not without side effects, there have been warnings issued regarding a propensity for the development of heart failure in some patients on this drug.

Type 2 diabetic patients on dialysis may derive benefits from this drug both in terms of glucose control as well as reduced insulin resistance. While the question of the safety of rosiglitazone among patients on dialysis still remains to be fully answered, a study of 24 patients on CAPD treated with rosiglitazone has revealed interesting evidence that the drug has no long term negative effects on cardiac function in CAPD patients. Although the study was small, it is somewhat reassuring that the drug may also be safe in patients with lesser degrees of kidney failure.

Once the drug is deemed safe in patients with kidney disease it would be interesting to see a randomized control trial sufficiently powered to determine if rosiglitazone has any impact on the progression of renal disease. If the answer is no then insulin resistance may just be another marker of the inflammatory state that is uremia instead of a driver of progression in and of itself.