Oral Dialysis

It's an important anniversary for the Brigham and Women's Hospital and as a result there are events planned in all departments of the hospital over the next year. Not to be left out, the Renal Division invited some senior nephrologists to come and talk about their experiences with the world of early dialytic therapies and we had a special Grand Rounds presentation this morning on the topic.

John Merrill was one of the early pioneers of dialysis (and has been called the father of dialysis). He was an advocate for the use of dialysis at a time when many believed that it was unethical and experimental. I realized during the lecture this morning that reviewing the published literature of Dr Merrill would be a good way to learn the history of the dialysis. The first paper that I came across was published in 1949 and describes the early experience using the modified Kolff kidney in the Brigham to treat both AKI and metabolic disorders. My favorite quote from this article comes from a postscript added to the paper by a discussant which suggests an alternative means of dialyzing a patient as an alternative to "in vitro hemodialysis" as HD was then termed:


DR. J. EDWIN WOOD, JR. [Charlottesville, Virginia] : We are fortunate
to hear this excellent presentation and view quantitative results with the
artificial kidney.
It may be interesting to compare results from upper intestinal lavage
with the ones just presented. With a Miller-Abbot tube about three feet
below the pylorus and a Levine tube down to the pylorus we can wash
through and recover a large quantity of suitable lavage fluid in a twentyfour
hour run. Actually, we have been able to remove by this method
as high as 11.9 to 23.2 grams of urea nitrogen in twenty-four hours, and
from 90 to 102.5 mEq of potassium at the same time.
Dr. Thorn's artificial kidney obviously accomplishes the desired result
in a shorter period but intestinal lavage removes enough in twenty-four
hours to warrant serious consideration.

I'm glad that this is not one of the alternatives that we are offering patients today.

(Picture from Flickr user Rob Koopman via Wikipedia)

suPARBaby?

The American Journal of Kidney Diseases published a fascinating letter this month from Jochen Reiser's group concerning the transmission of the suPAR from a mother to her newborn infant. The patient in question had a history of primary FSGS and after her baby was born, the infant had proteinuria which eventually resolved. At the time, this was published as a letter in the NEJM and was used as evidence for the existence of a soluble FSGS "factor" which had yet to be identified.

Now, more than 10 years later, they got their hands on blood from the mother and the infant. The level of suPAR in the mother was 4635pg/ml and in the child was 5225 pg/ml. This compares with a mean of 2884 pg/ml in controls. Unfortunately, the family moved away from the area so there were no follow-up samples. However, the patient's pediatrician reported that the baby's urine was negative for albumin at one year of age.

Although this does not definitively prove that suPAR is the causative agent in primary FSGS, and there is some debate about the true pathogenicity, this, along with recently published data in JASN, adds to the weight of evidence suggesting that this may be the elusive factor we were looking for. Interesting times indeed.

Πάντα ρεί - once more on the (right) fluids

Yet another manuscript evaluating fluids for IV replacement was published in JAMA this week underscoring the importance and controversial nature of the topic. A large meta-analysis involving 10,868 patients from 38 trials showed that hydroxyethyl starch (HES) was associated with an increased risk of mortality and renal failure (RR 1.27; 95% CI 1.09 - 1.47). Of note, a recent large trial published in the NEJM in 2012 did not show an increased mortality but more patients who received resuscitation with HES were treated with renal-replacement therapy.

HES is mainly used by anesthesiologists and surgeons and has the potential advantage of decreasing the amount of total administered volume and sustaining intravascular volume for longer periods of time. The discussion about mortality and renal failure associated with HES has been going on for a long time, as has the discussion about the relative benefits of colloids vs. crystalloids. Despite the lack of strong evidence of superiority of HES over crystalloids, the clinical use has been increasing - even with the associated higher cost and safety concerns.

A major drawback for the supporters of HES was the realization that one of the leading authorities in the field and major proponent of HES, Joachim Boldt, has conducted one of the biggest cases of fraud in anesthesia with “false data published in at least 10 of the 91 articles examined, including, for instance, data on patient numbers/ study groups as well as data on the timing of measurements“. 80 articles have been retracted because the research was deemed unethical. A Cochrane review from 2012 did not find a significant difference in mortality even when the fraudulent studies were excluded. However, the current meta-analysis not only excluded the studies by Boldt, but also included 3 trials published in 2012 contributing more than half of the patients to the collective examined, thereby adding more weight to their analysis over prior ones. There was no difference in mortality when the Boldt papers were included in the analysis.

Side effects of HES mainly occur in the kidney but the exact pathophysiology of AKI associated with HES is unclear. Vacuolization as an injury pattern can be observed as discussed in an earlier post in this blog. In vitro HES showed a dose-dependent decreased viability of HK-2 cells (human immortalized proximal tubular cells) after incubation with HES130/0.4. A necropsy study suggested HES accumulation in the kidney might cause toxicity. 

What can we learn from this? Rigorous analysis and ongoing discussion and evaluation of data are of crucial importance in Medicine and scientific fraud, driven by motives such as recognition and money can cause data to shift to the wrong direction. There does not seem to be a major advantage of using HES over crystalloids and data on mortality and renal failure are tied between no difference and increased mortality/AKI in the HES group. From my perspective there seems to be no indication to use HES and this might be better for the kidney.

Posted by Florian Toegel

eJournal Club

This month's eJournal club concerns early initiation and withdrawal from dialysis in Canada. Over the last 20 years, there has been a move towards starting people on dialysis earlier, at least when this is defined in terms of eGFR. This study found that there was an increased incidence of withdrawal from dialysis in the last 10 years and that the majority of those who withdrew dialysis were >75 years old. Early initiation (defined as a higher eGFR at initiation) was associated with higher rates of withdrawal.

So what does this mean? Are nephrologists watching the eGFR and deciding to start earlier based on this number alone? I think not. In one way, this shows the limitations of using eGFR in epidemiological studies, particularly in the very elderly and in those with very low GFRs. The patients who withdrew from dialysis were more likely to have dementia, cancer and were older. Also, apart from age, the factor with the highest HR for withdrawal was a BMI of  less than 18. This suggests that using creatinine to estimate eGFR may have overestimated GFR in these patients because of a low muscle mass. It would be interesting to know how well their MDRD eGFRs correlated with their true GFRs.

The outcomes for renal replacement therapy in very elderly populations is poor and the higher rate of withdrawal may reflect poor patient choice - should these patients have been started on dialysis in the first place? This is an interesting study and it highlights the importance of proper discussion with patients and families about the consequences of dialysis initiation.

Head over the eJournal Club for the discussion. The paper is available for free here.

It's that time of year again...

The 2013 ASN In-Training Examination for Nephrology Fellows will be administered on Thursday, April 11, and Friday, April 12.  Nephrology fellows may sit for the examination on one of two testing dates. Testing will begin at 8:00 am local time each day.

Registration for the 2013 examination closes on Thursday, February 28.

To register, fellows must be ASN members.  ASN membership is free to nephrology fellows.  When registering, nephrology fellows must choose only one test date (Thursday, April 11, or Friday, April 12) and one testing center.  Fellows may not register at an institution with which they are not currently affiliated without prior permission from the training program director at that institution and ASN.

The registration fee for the exam is $260, payable only by credit card.  If the institution is responsible for payment, the fellowship coordinator must contact ASN Education Coordinator Ryan Russell at rrussell@asn-online.org.

Register here for the 2013 examination.  If you have questions about the ASN ITE for Nephrology Fellows, please contact ASN Education Coordinator Ryan Russell at rrussell@asn-online.org.

International Update on Glomerular Disease

On April 27th 2013, a course on glomerular disease will take place at the North Shore University Hospital in Manhasset, New York. This course is being organized by Dr Kenar Jhaveri who is well known to the blogging community. There is an impressive list of speakers and this one day course is designed to provide an update on the management of glomerular diseases.

Best of all, registration is free for medical students, residents and fellows in training. Here is a link to the course description. and application form.

Does nephrology need personalized medicine?

Systems biology is one of science’s growth areas. Sequencing technologies and software tools developed on the back of the human genome project have reduced the cost of, and therefore increased access to, large and complex datasets (ending in -ome) of genome sequences (genomics), gene expression (transcriptomics) and proteins and metabolites (proteomics and metabolomics). Systems biological techniques integrate these datasets and provide insights into how phenotypes may emerge from interacting biological processes rather than isolated genes or proteins.

A recent editorial in the journal Nephrology Dialysis Transplantation examined this field in general and its relevance to nephrology. The authors mention that –omic datasets have been useful in modeling “self-organized highly interconnected networks”, and that such networks have implicated unexpected candidates in disease pathogenesis (see for example, this paper on cardiac hypertrophy). 

The review goes on to suggest that using the tools of systems biology to finely phenotype individuals will usher in an era of truly personalized medicine. However, it is not clear to me that a definite sequel to this type of analysis will be the personalization of treatment or even that the concept of personalized medicine is particularly suited to our current view of what constitutes clinical evidence.

Diseases such as the ANCA-associated vasculitides (AAV) are now known to exhibit genomic variability. Randomised controlled trials (RCTs) in AAV (such as here and here) have been hampered by: 

1. Short follow-up times 
2. Inter-group heterogeneity which may have affected outcomes. These factors have contributed to ongoing debate about the applicability of the results of these trials (see correspondence here). 
3. Additionally a recent trial in membranous nephropathy, likely to represent another disease with distinct –omic subsets, was marked by slow recruitment. 

 

All these points together suggest that it may be difficult to conduct meaningful clinical studies of distinct –omic subtypes in nephrological diseases. Currently, primacy is given to RCTs when evaluating the efficacy of new treatments; and in nephrology the community is finally beginning to produce the RCTs which have been absent historically. 

If the focus is to switch away from RCTs with their large, well-matched study groups and towards splitting groups up by some -omic fingerprint I am able to envisage a time when one has to choose between giving more credence to the results of larger, “non-personalised” trials or smaller studies featuring –omic data but lacking the controlled element of RCTs.  Would this represent progress?

The Brave New World of Renal ACOs

This past week CMS announced the formation of a new form of payment and service delivery for patients with ESRD - the ESRD Seamless Care Organization (ESCO) - essentially an ACO specifically and exclusively for individuals with ESRD.

The basic guts of the model require that at least a dialysis provider, nephrologist and one other Medicare provider be involved.  The "one other Medicare provider" bit is likely meant to capture the obvious need that dialysis patients have for a multitude of services beyond dialysis and renal specific care.  The ESCO has to have at least 500 members all of whom need to be on dialysis - patients with functional kidney transplants are not eligible.

The hypothesis behind ESCOs is that an alignment of financial incentives with clinical care goals will produce superior outcomes and patient experience at lower per capita health spend than traditional fee for service Medicare where providers are rewarded for the volume of services they deliver.   The 10,000 foot view of "alignment of financial incentives" is that ESCOs will be able to earn a fraction of savings when health care spending is lower than a pre-determined base line and will be at risk for a fraction of overruns when spending is higher.

In order to avoid rationing of high value services, the ESCO model requires that participating groups report and achieve a defined set of quality metrics in order to earn their fraction of savings.  These cross a wide variety of areas including preventative health, chronic disease management, care coordination, patient safety, patient and caregiver experience, and patient quality of life.

The slide deck below from the CMS open door forum forum this past week digs a bit deeper into the details.

Keeping up with the Neighbours

These days, the proliferation of medical journals makes it difficult to keep up with all the changes in our field. There are a number of means that people employ to manage their reading. I personally use google reader and follow all the major renal journals. Another resource that I find useful is Nephrology Now which aggregates some of the more important papers recently published in the field.

One suggestion from Nephrology Now last week was an ipad/iphone application called "Read". This application allows you to follow selected journals but will also pull out articles of interest from journals that you are not necessarily following if they align with your interests. It also allows you to directly search pubmed from within the app, save searches and, if it is freely available, download the pdf of the paper that you are interested in. Best of all, this is free.

I would appreciate any further suggestions from readers regarding ways to stay current.