Kidneys Inc.

medicine and nephrology updates and interesting cases by a practicing nephrologist in USA

Archive for the category “News”

Idiopathic(primary) FSGS and suPAR(soluble urokinase Plasminogen Activator Receptor)

Focal segmental glomerulosclerosis (FSGS) is a clinicopathologic syndrome that could be idiopathic(primary) or secondary(genetic, infectious like HIV & parvo B19, drug induced IFN-alpha, pamidronate, lithium, Reflux nephropathy, hyperfiltration, HTN, obesity, Sickle cell etc). Clinically, it manifests as proteinuria with patients being asymptomatic to nephrotic. Proteinuria is non selective. Other features are HTN, Hematuria. with normal serological tests & complement levels. FSGS accounts for up to 1/3 of idiopathic nephrotic syndrome in adults and is the most common cause of nephrotic syndrome in african americans. Left untreated it frequently progresses to ESRD (End stage Renal disease.

While the management of secondary FSGS is directed at treating the cause when applicable, treatment of primary or idiopathic FSGS usually is nonspecific and targeted towards decreasing proteinuria, controlling BP, lipid control and low protein diet. In severe cases treatment is with steroids (tapering dose for at least 6 months) and for those who develop complications or are intolerant cytotoxic therapies like cyclosporine, tacrolimus, mycophenolate or cyclophosphamide. There are experimental therapies that include plasmapheresis.

 

It has long been speculated that there is a permeability factor playing a major role in the pathogenesis of idiopathic FSGS.

Recently it has been found out that suPAR (Soluble urokinase plasminogen activator receptor) is elevated in up to 2/3 of patients with primary FSGS. Evidence that higher SuPAR levels correlate with increased risk for recurrent FSGS after transplantation in patients with FSGS further supports the theory of this circulating factor in the pathogenesis of this condition. Importantly, molecular studies have also shown that the molecular size of suPAR is very close to the predicted molecular size of the “permeability factor” that has been considered to play a major role in the pathogenesis of idiopathic FSGS.

 

How does suPARwork?

 

suPar activates the podocyte beta 3 integrin (necessary for anchoring the podocyte foot processes to the glomerular basement membrane & also maintain cellular structure) causing foot process effacement, proteinuria & glomerulopathy.  Since it plays a major role, removing this factor by plasmapheresis or interfering SuPAR- beta 3 integrin interaction through antibodies will abrogate the pathogenesis of this disease

 

This opens up the therapy of plasmapheresis for such patients. It not only potentially keeps patients away from renal replacement therapy, but also may inhibit the progression of the disease at early stages to prevent its complications. However, It has to be noted that plasmapheresis has been shown to be effective in some patients with recurrent FSGS in a renal allograft, but not in patients with FSGS in their native kidneys. Could this be explained by presence of more than one such circulating factors or could it be due to patient selection?

 

For now, it is exciting to know more and more “idiopathic” glomerulopathies have prospects of entering the ‘treatable’ category of kidney diseases

BARD for Diabetic nephropathy

This week in NEJM, there is a major article with results from a new study BEAM, showing efficacy of a medication, Bardoxolone methyl (BARD) an oral antioxidant, in chronic kidney disease due to diabetes. We have always known of medications that decrease renal function. This would be the first medication that improves renal function. It works by inhibiting renal injury by oxidative stress and inflammation in diabetic kidney disease. However, Its role in other conditions with the same pathophysiology has not been tested, yet. Type 2 Diabetes being the most common cause of CKD (chronic Kidney disease) this new drug (if tested safe and effective in long term studies), might give the much needed major turn in management of diabetic kidney disease.

Summary from the NEJM article:

Sponsored by Reata pharmaceuticals, an employee of the sponsor wrote the first draft of the manuscript. study design by first author and representatives of the sponsor.

Glomerular Filtration Rate GFR estimated using the four variable (Modification of diet in Renal disease) MDRD equation

Patient characteristics: similar in all four groups. mean age 67 y, well controlled blood sugars, 98% were receiving ACE, ARB or both. Mean GFR was about 32 +/- 7 ml/min/1.73m2. Albumin to creatinine ratio (ACR) was distributed almost in thirds.

Exclusion criteria: type 1 diabetes, nondiabetic kidney disease, a glycated hemoglobin level of more than 10%, hepatic dysfunction, or a cardiovascular event within the previous 3 months.

Results:

Primary outcome: Change from baseline of estimated GFR Bardoxolone methyl vs placebo at 24 wks –> upto 12ml/min/1.73 m2 difference in eGFR between placebo and the BARD group

Secondary outcome: change in eGFR at 52 weeks–> upto 10 ml/min/1.73 m2 difference in eGFR between placebo and BARD group

Exploratory outcomes:

a) Cumulative changes in estimated GFR from baseline to 52 wks –>54% in placebo group. ~ 20 % in 25 mg group and 75 mg groups, 27% in 150 mg group

b) Time to and percentage of patients with > 25% reduction in eGFR 13% in placebo vs 2% in BARD group

c) Slight but significant increase in ACR in 75 & 150 mg BARD group at 24 & 52 wks.

d) Significant decreases in levels of blood urea nitrogen, serum phosphorus, uric acid, and magnesium, as compared with placebo at 24 wks

Adverse events: more in bardoxolone group 18% vs > 50%

1. muscle spasm most common in first 12 wks, resolved spontaneously with continuation of drug

2. Hypomagnesemia (not related temporally to 1.)

3. Alanine amino transferase elevation, mild and transient

4. GI side effects (nausea, vomiting, decreased appetite)

5. Last but not least : The BARD group had slight but significant increases in ACR. Authors explain it by attributing it to increased GFR but decreased tubular reabsorption.

Discussion: Oxidative stress and inflammation is the final common pathway for chronic kidney disease in diabetic nephropathy. Bardoxolone activates the Keap1-nrf 2 (kelch like ECH associated protein1nuclear factor E2 related factor) pathway thus ameliorating damage, hence preventing deterioration the pathogenic agents. It interacts with cysteine residues in keap1, causing translocation of Nrf2 to nucleus and upregulation of several cytoprotective genes. Bardoxolone activates nrf2 expression in glomerular endothelial cells and peritubular capillaries, increased hemoxygenase 1 in tubules and interstitial leucocytes. BARD also exerts inhibitory effect on nuclear factor kB pathway. This leads to decreased inflammation, BUN, and amelioration of both glomerular and tubular injury

Side note: Nrf2 deletion causes inflammation/oxidative stress.

Conclusion:

Treatment with BARD lead to sustained and significant improvement in GFR in patients with CKD due to diabetes. The effect was sustained after 4 weeks after discontinuation of the drug.

Increases in the estimated GFR was independent of changes in albumin excretion

The absence of a significant decline in the estimated GFR among patients receiving placebo may reflect the fact that most patients did not have macroalbuminuria at baseline and their important risk factors (e.g., blood pressure and glycated hemoglobin levels) were well controlled with standard medical care

However, bringing skepticism to the table: we know that proteinuria is a not only a major marker for renal function but also mediates injury. If the glomerulus is in some way protected by BARD, it has to be reflected by decrease in albuminuria. or there might be a possibility that the protection conferred by BARD might be negated by increased proteinuria.

Important questions that pop up:

The GFR was estimated by creatinine based equations. Does BARD have any effect on serum creatinine itself outside of its reported protective effect, either in laboratory measurements or in its production or secretion. In any of such situations, it can lead to a falsely higher GFR on calculations. There is reference (Number 28) that says no.

By excluding patients with poorly controlled diabetes, with higher glycated hemoglobin levels is there a selection bias where only patients with better predicted outcomes were studied. Note that the placebo group

But being optimistic, if it works out, this medication could potentially play a major role in many disease processes that are mediated by the Keap1-Nrf2 pathway.

Green dialysis

Some stats & facts

Average american family 400 gallons of water a day

Dialysis uses tremendous amounts of water — 32 gallons (120L) required during a typical dialysis session. Water purified by reverse osmosis prior to entering dialysis machines & water rejected by reverse osmosis goes down the drain.

7.13 billions gallons of potable grade A water wasted per year, with high salt content being its only problem. After desalination, it meets standards set by WHO & united nations food and agriculture organization for use in irrigation & landscape.

All the water, if saved and used, is enough to supply a city as big as salt lake city

It has already been done in Australia. more details in this link

http://www.renalbusiness.com/articles/2011/03/making-dialysis-green.aspx

Some more facts from the Australian Pilot Project

The RO water, better than drinking water wasted at 1100ml/min. It also fell within all national and international requirements for drinking water.

This otherwise rejected water was stored in tanks. They supplied the central sterilization department, the rest was used for cleaning, gardening, laundry and toilets.

The australian practice also adapted solar power that powered the reverse osmosis machines and also the dialysis machines. The cost of setting all this up turns out to be lesser than conventional expenses (electricity and waterbills) in the long run. It even becomes an income generator, once the cost is paid back.

The morality and rationale behind rationing “the beans”. Egalitarian or utilitarian?

here is a regular periodic meeting in all transplant centers, when doctors, nurse practitioners, transplant coordinators, social workers get together and ‘decide’ which patients in their center are eligible to get a kidney transplant and which ones need have to be removed from the waiting list. This important decision depends on a multitude of factors including but not limited to criteria such as time on waiting list, co-existing co-morbidities, social and family support, financial and employment status of the patients, insurance coverage, mobility and functional status of patients. Although pre-emptive transplantation is the ideal one, we are still far away from its realization, merely due to demand-supply discrepancy. Currently, age is not a factor for denying a kidney transplantation and donor kidneys are allocated on a first come first serve basis. Simply put, having age as a criterion would amount to ‘age discrimination‘. The OPTN/UNOS (Organ procurement and Transplant Network/United Network of Organ Sharing) committee is proposing a change that prioritizes younger patients, allocating younger kidneys to younger recipients. I think this will decrease* the ‘age discrimination’ as well as organ-recipient age discrepancy. Sounds like a paradox?.. Read on.

The number of patients on the kidney transplant waiting list, continues to increase sharply, growing 6 percent in 2008, and reaching more than 77,000 by 2008. Only about 17,000 end up getting transplants every year. The waiting time also continues to rise, varies geographically with a median duration being bat 3-4 yrs and could be as high as 8-9 yrs in areas like new york. Now with aging population and better healthcare technologies, lifespan of people with ESRD (End Stage renal disease) is getting longer and so is the waiting list for donor kidneys. This is mutifactorial:

The median age of the prevalent ESRD population has increased 3.2 percent since 2000, reaching 59.4 in 2008.

The adjusted incident rate of ESRD has grown 9.4 percent for patients age 75 and older, to 1,718 per million population in 2008, while the rates for those age 20–44 have increased by only 5.5 percent,

The adjusted rate of prevalent ESRD for patients age 65–74 has increased 25 percent since 2000, while the rate among those age 75 and older has grown 31 percent, to 5,266. Among those age 20–44 and 45–64, in contrast, growth has been just 11.0 and 17.5 percent, respectively. Meanwhile, the relative scarcity of donor organs is getting worse, despite measures taken to expand the donor pool as the number of organs available is not catching up with the number of waiting eligible recipients.

It is important to note in this context that the pediatric age group has a separate waiting list to avoid long waiting time as the outcomes are maximized both from medical and economical standpoint. These approaches, in my opinion, has apparently created a ‘donut hole’ in the list of patients waiting for a donor kidney. It seems like younger patients, who are neither too young to be in the pediatric group, nor too old enough to have accumulated a long waiting times were being pushed down the long waiting list. They are being denied kidneys that would provide them (and the kidneys) more additional years when compared with a similar older recipient higher on the list. Moreover, older patients have a higher chance of dying with a functioning transplanted kidney. The DWF (death with functioning graft) can be as high as 38% and amounts to about 42% of the kidney transplants. In some ways this situation is similar to the blood group and HLA matching discrepancy that made it harder for the O blood group ESRD patients to get a donor kidney and lengthened their waiting times. Also I can see this as an extension of the ‘pediatric allocation concept’. A 30 y old is relatively a ‘pediatric when compared with a 70 yr old.

Recent proposal to consider age and hence overall ‘predicted life years’ is the most drastic of the changes that have been made, in the last 25 years, to the algorithm of choosing recipients for the available kidneys. The new change is aimed at maximizing the outcomes for both the recipient of the kidney and the kidney itself. This is a good approach because

-The sooner an ESRD Patient gets a kidney, the better the outcomes are

-The longer the graft survives, the longer the patient survives

-The younger the recipient, more likely he/she will outlast the graft, and when that happens, they still have blood vessels and peritoneum in a good shape to last long enough

-It results in more patients with ESRD staying away from dialysis thus decreasing the budget deficit of medicare, which is the main coverage provider for patients with kidney disease

However, being a major and a fairly comprehensive shuffling of criteria by UNOS, major ethical, political, medical debates over the rationale of rationing will soon follow. More interesting would be to know what happens to the existing list where the older patients already predominate the higher parts of ‘the list’. With my quick research, I found out that a separate group will be formed for the youngest of the waiting list, so the younger kidneys are more likely to end up in younger patients. And the rest would follow in real time.

While this change is very appropriate where there organ scarcity and government is spending for the care of recipients, it raises an important question about healthcare that should be, by principle, equally distributed and equally available to everyone. If implemented, the same effect is bound to trickle down other aspects of health care, like end of life care, therapies for malignancies and end stage heart disease. The infamous “death panels” come to mind. But no matter what name they are given, such panels are important for healthcare, where everyone is fighting for a bite.

Some questions arise that cannot be left unaddressed. Medicare only pays for patients for a limited period for post transplant medications and one of the major reasons for failed transplants is non-adherence to those much needed medications, due to prohibitive costs. Should we then prioritize rich recipients over poor ones? Patients that are/were more productive over the unemployed?

While trying to get away from discrimination, do we end up doing just that? Can judgment based on sound scientific evidence and strong statistical data be accused of being discriminatory? Should we stratify both recipients and donor kidneys based on characters to form multiple short waiting lists?

Health policies are made based on population studies and statistical analysis, emphasizing greatest good for the greatest number. Rightfully so, because, when there are way too many people wanting the cake, some one has to decide, who benefits the most by having it, based on available scientific evidence. But more importantly, whoever gets the power to decide will take the blame for playing god.

The policies based on outcomes or consequences are more meaningful than those based on principle without support.

While I am writing this, a random thought flickers and I wonder if there is an end to our dependence on donated organs.  Is there an implantable metallic kidney in the future, ending this rough battle for the ‘beans’?


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