MAKE this a better outcome

The PRESERVE Trial, which was recently published in the NEJM was a large study of a variety of preventive measures for contrast-induced nephropathy. It used a 2x2 factorial design to test the efficacy of NaHCO3 vs. normal saline and n-acetylcysteine vs placebo for the prevention of CIN. The trial was stopped early as there were no signals that any of the treatments were better than any other suggesting that the best treatment for CIN right now is likely the use of both saline and the smallest possible quantity of low-osmolar contrast. The overall decline in the rates of CIN over the last few years are likely more related to the change in the way that contrast is used rather than any special benefit that we were imparting using novel measures to prevent CIN.

The trial was enriched to try and increase the rate of AKI - it included patients with an eGFR between 15 and 45 (non-diabetic) increasing to 60 in diabetics. The overall mean eGFR was 50 so perhaps there were not quite enough patients with advanced disease but given that more than 5000 patients were included in the study, it is hard to really draw the conclusion that it was underpowered for subgroups. Patients with AKI were also understandably excluded and it is unclear what the risk is in this subgroup of patients.

The other thing that was really interesting about this study was the outcome used. Traditionally, studies on CIN have used AKI as the outcome. This being defined typically as some change in creatinine in either absolute or percentage terms. The current AKIN definition of stage I AKI is a 0.3mg/dl increase. This study used an increase of 0.5mg/dl. AKI of this magnitude has been shown in large studies to be associated with adverse outcomes including increased length of hospitalization and mortality but there is always a lingering question about how clinically significant it is in the long run when it tends to resolve in most patients.

Because of these concerns, there has been a recent move towards using MAKE (major adverse kidney events) as a composite outcomes in trials of kidney disease. This concept, stolen somewhat from the cardiology literature is thought to be more meaningful as it results in real, long-term harm to patients. In this study, the authors chose MAKE90 - a composite of death, need for dialysis and permament 50% increase in creatinine at 90 days as the outcome. Overall, approximately 9% of patients had AKI following contrast administration and about 4.5% had a MAKE90 event (2.5% died, 1.5% required dialysis and 1% had a permanent decline in renal function). Another thing I would take away from this study is that we should not let people tell us that CIN does not exist (which I have heard around the halls more often than I like over the last year or so).

Overall, I think this move towards MAKE as an outcome in clinical trials is a welcome one. It is a well defined outcome that demonstrates clear harm to patients. There is no reason to chuck AKI out completely - it is a perfectly good secondary outcome - but in terms of figuring out who are the patients most likely to benefit from interventions in the future, MAKE is the way to go

The perils of Gabapentin

One of the things that I always highlight when teaching fellows and residents is the importance of appropriate drug dosing for patients on dialysis and one of the drugs that is most often inappropriately dosed in my experience is gabapentin. Today, an article in JASN highlights again the importance of not overusing this drug in the dialysis population. 

Gabapentin and pregabalin are often used in patients with CKD primarily to treat neuropathic pain and restless leg syndrome and given the high prevalence of diabetes in this population, the proportion who receive these drugs is very high. In patients with normal renal function, the maximum dose of gabapentin is 3600mg daily in divided doses. However, gabapentin is renally cleared and so the dose needs to be adjusted according to the GFR. For patients on dialysis, the recommended dose is 100-300mg post dialysis on dialysis days only. However, this is routinely exceeded in clinical practice. 

The study in JASN looked at medicare prescriptions for gabapentin and pregabalin in dialysis patients examined the relationship between the doses used and a variety of outcomes including altered mental status, falls and fractures. 20% of the dialysis population received at least one prescription for these drugs in 2011. Even at the lowest doses (less than 300mg daily), there was an association between the use of these drugs and AMS and falls while doses greater than 300mg daily were associated with a 40% increase in the risk of fracture. Similar results were found for the higher doses of pregabalin. 

Of course, this was an observational study and there may have been unmeasured confounders that may have biased the results but the authors did account for other medications that can increase the risk of falls. 

Overall, this should serve as a reminder to the community that we need to more carefully police the dosing of medications in our dialysis population, particularly when they are admitted to hospital.

Panda Eyes

I recently saw an elderly woman in clinic. She had a background history of migraine headaches and had been investigated over the past 18 months for recurrent syncopal episodes. She had at least 5 episodes that began with palpitations usually on minimal exertion. Apart from these episodes, she was fit and active. Her ECHO showed only mild LV hypertrophy and mild pulmonary hypertension. EKGs were unrevealing.

Two years ago she had been seen by a dermatologist for sun-related skin lesions and had mentioned that she had recurrent bruising around her eyelids. She had taken a photo of these lesions and they were noted to be purpuric. They would come and go and usually last for a couple of months when they were there.

She was referred to my clinic for investigation of mild albuminuria. She had ~500mg albumin for approximately 5 years with no significant change. Her renal function had always been otherwise normal apart from one single increase in creatinine was unexplained and returned to normal in a few days. She had no significant risk factors for kidney disease apart from long term NSAID use for her migraines.

As part of her investigations, she had an SPEP and free light chains. The results showed that she has an IgG lambda paraprotein likely related to an underlying multiple myeloma. Re-review of her ECHO images showed that they were consistent with infiltrative disease and she is currently undergoing work-up for AL-amyloidosis.

Periorbital purpura is a rare finding in patients with amyloidosis occurring in about 15% of patients. It is thought to be a result of Factor X deficiency due to binding of Factor X by the amyloid fibrils. It is generally atraumatic and tends to recur without treatment of the underlying amyloid. It is almost pathognomic of amyloid and its presence should prompt testing for AL amyloid.

Image from NEJM

Hemodialysis Simulator

I ran into a colleague from Children's Hospital over the weekend and she pointed me in the direction of this great education website that they have created for the education of students, residents and fellows. In particular, they have designed a hemodialysis simulator that allows you to run a dialysis session from start to finish. It includes all the patient parameters: labs, examination, fluid inputs and outputs. It then asks you to set up the circuit and start the dialysis. All of the usual parameters can be changed at any time.

This is a great teaching tool and I highly recommend it. It is geared towards pediatric patients - I doubt if many of our patients weigh 22kg - but the general concepts are the same. They also have a peritoneal dialysis simulator.

Angiomyolipomas

I got an econsult this morning on a young patient with an incidentally-discovered lesion on her kidney which was consistent with an angiomyolipoma. It is not uncommon to see these on ultrasound and there are a few clinical pearls that I thought I would share:

• Angiomyolipomas (AML) are benign tumors comprised of blood vessels, adipose tissue and smooth muscle. Very occasionally (more commonly in patients with tuberous sclerosis complex), they can be malignant. Malignant AMLs are more likely to be fat-poor, hypoechoic tumors (termed epitheliod AML).
• The prevalence is about 2% in the general population and they are 4 times more common in women
• The presence of multiple AMLs suggests the possibility of tuberous sclerosis complex and the possibility that patients have subclinical disease should be kept in the back of your mind.
• Confirmation of the ultrasound findings should be done with CT or MRI as there are some renal cancers that can be hyperechoic on ultrasound.
• The hyperechoic nature of these lesions on ultrasound is due to fat in the tumor rather than the vascularity.
• For unkown reasons, more of these tumors are found on the right side
• Most of these tumors are slow growing and do not require treatment (surgery or embolization) unless they are >4cm in diameter. mTOR inhibitors may be useful in some patients with unresectable tumors. Patients should be followed-up yearly with ultrasound.
• Patients on estrogen therapy are more likely to have rapid tumor growth and should be followed up more often.

Image from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-72032014000800377

Infections and intravenous iron

An interesting study appeared in my email this morning examining the association between the use of iv iron and outcomes in hemodialysis patients with systemic infections. Current guidelines from all of the major societies suggest that if patients are admitted with bacterial infections in particular, iv iron should be stopped. There are both basic and clinical data supporting this recommendation although it should be said that the evidence is weaker than one would imagine.

The biologic plausibility argument rests on the fact that high iron concentrations have two negative effects in the context of infection. First, iron appears to impair the function of both neutrophils and T-cells. Patients on dialysis with iron overload have been shown to have reduced neutrophil function and phagocytosis. Similarly, impaired PMN function has been seen when neutrophils from healthy controls are incubated with ferric compounds. However, it should be pointed out that iron is vital for normal neutrophil function and individuals with iron deficiency also have impaired function. Clearly there is a sweet spot for neutrophil function but we are uncertain what it might be.

The evidence for a clinical effect for iron infusions on increasing infection frequency and severity is based on two separate strands (well summarized here). First, multiple observational studies have shown that high ferritin levels (particularly when >1000) are associated with an increased frequency of bacterial infections. There are clear limitations here. First, this finding is not consistent across all studies (4 of 14 studies did not find this association). Second, ferritin is an acute phase reactant itself and is not necessarily always elevated due to iron overload. Third, most of these studies were done in the pre-ESA era where much of this iron overload may have been due to transfusions. Finally, all of these studies were observational. As such, it is impossible to say if the risk of infection may not have been due to other factors which also lead to a higher iron requirement/ferritin levels.

The second strand of evidence is observational studies showing that higher doses or frequency of iron infusions are associated with a higher risk of future infection. Again, all of these studies are observational and so the same criticism as above applies. Similarly, there is a lack of consistent results across all studies although it should be said that the largest studies with the most patients did find an effect. However, in the most recent large study of ~120,000 medicare patients, while there was an increase in the risk of infection with higher doses of iron, the HR for infection for high vs. low dose was only 1.05. None of these studies examined the effect of ongoing iron administration on the severity of infection in dialysis patients. One could say that they are an argument against using iron in dialysis patients (which is not realistic) rather than arguments for stopping during an infection.

Today's email is thus especially welcome. This is a study published in CJASN which examines the relationship between ongoing iron use and severity of infection in Medicare patients. In total, 22,820 individual who had received iv iron in the 14 days prior to admission with a bacterial infection were included. 10% of these patients also received the iron while they were inpatients or shortly afterwards and were included as the cases. The controls were individuals who did not receive iron (i.e the iron was stopped per guidelines). The receipt of iv iron was not associated with increased short or long term mortality, LOS or likelihood of readmission in the next 30 days.

What is the explanation for this finding? One important question is why those 10% of patients did not stop iv iron after admission despite the clear consensus suggesting that it should be done? Looking at the table of demographic and clinical characteristics, there was nothing sticking out that suggested a reason for this difference and there may have been unmeasured characteristics that explained the difference. The outcomes were hard (as they would have to be given the source of the data) but may miss some subtle differences in outcomes related to the infection itself. That said, mortality and readmission are probably the most important outcomes. Finally, again this study was observational and needs to be interpreted as such.

All that said, this is an excellent addition to the literature which raises many more questions that it answers. These are important questions - too much of what we do in nephrology is based on consensus rather than clinical trials. Perhaps this might stimulate someone to do the necessary trial to answer this question once and for all.

Gearoid McMahon

Renal Effects of Anti-Cancer Medications

With the proliferation of new therapies for cancer including novel targeted therapies, it is difficult to keep up with the potential renal problems related to these medications. Thankfully, Nature Reviews Nephrology have published a comprehensive review of the nephrotoxic effects of targeted anticancer therapies that could serve as a reference for practicing nephrologists. As is pointed out in the review, this is a rapidly evolving field and novel toxicities are being recognized with real world use that may not have been seen in the initial trials..

Of particular interest was the fact that many of these agents cause severe electrolyte abnormalities. For example, approximately 17% of individuals receiving cetuximab (an EGFR inhibitor used in the treatment of some lung cancers) develop hypomagnesemia. It turns out that TRPM6, a DCT  magnesium channel, it regulated by EGF which is highly expressed in that area of the nephron and cetuximab therapy leads to inhibition of Mg reabsorption and subsequent hypomagnesemia (along with hypocalcemia and hypokalemia).

The figure below shows a list of the commonest adverse effects of chemotherapeutic agents. Click on the picture for a larger image:

EVOLVEing past Cinacalcet

One of the regular criticisms of nephrology is the lack of good quality randomized controlled trials. This is particularly the case in the world of renal bone disease where we target surrogate endpoints without necessarily knowing for certain what the effect this has on the most important outcome - patient survival. The EVOLVE trial was once such trial which examined the role of cinacalcet in preventing all-cause and cardiovascular mortality. The results of this trial were somewhat ambiguous in that the overall results were negative but this could have been affected by the slightly older age of the treatment group (after adjustment for age, there was a benefit to cinacalcet). There was, however, a wonderful rebuttal to this particular argument in a letter to the editor published later in the NEJM by Giovanni Tripepi.

Overall, the number needed to treat to prevent a single death was 500 and this is balanced by a 62% drop-out rate in the treatment group. There was also a lower rate of parathyroidectomy in the treatment group.

Last month NDT published and ERA-EDTA position statement on the use of calcimimetics in patients on dialysis. Based on a meta-analysis (which was largely derived from the EVOLVE trial), they made the definitive statement that cinacalcet should not be used in patients on dialysis to reduce cardiovascular or all-cause mortality. Further, they pointed out that although the original trials showed that PTH could be successfully lowered using these drugs and that this could reduce the rate of parathyroidectomies, there is no evidence that this has any benefits either beyond the prevention of surgery. They called for a randomized trial of parathyroidectomy vs. cinacalcet for the treatment of intractable hyperparathyroidism with hard endpoints. I second that call.

Metformin Guidelines

Metformin is one of the most useful drugs in patients with type 2 diabetes and yet its use in patients with CKD is limited by the perceived association with lactic acidosis. These concerns are due to the association of a prior biguanide, phenformin, with a marked increase in the rate of lactic acidosis. The mechanism for this appears to be reduced peripheral glucose oxidation and increased lactic acid which occurs with even small increases in phenformin levels. The drug was eventually removed from the market because of a number of fatal cases.

Metformin, in contrast, does not appear to be as closely associated with lactic acidosis. Most of the reported cases are in patients who would appear to have other reasons for lactic acidosis (although this case series including patients on dialysis that appears to be reasonably convincing and there are multiple smaller case series in patients on HD). A large meta-analysis of clinical trials if metformin showed no increase in the rate of lactic acidosis in patients on the drug. However, it should be pointed out that these trials did not include patients with advanced CKD.  Metformin is not protein-bound and is largely cleared by the kidneys so there is clearly accumulation of the drug in patients with CKD. However, it is unknown what the real "safe" level is and no studies can ethically be performed to establish this.

As a result, in general, guidelines regarding the use of metformin have been conservative. The insert for the drug suggests that it is contraindicated in individuals with a serum creatinine >1.4mg/dl (women) or 1.5mg/dl (men). Personally, I find these guidelines to be insufficient and frustrating because of course, a creatinine of 1.5mg/dl can mean entirely different things depending on the context (age, weight, race etc.) So it is gratifying to see that the diabetes associations have moved forward with newer guidelines.

The ADA published a paper with new guidelines for the use of metformin in 2011 incorporating eGFR. This paper also summarizes very nicely all of the evidence for and against the use of metformin in CKD. In summary, they suggest that for individuals with eGFR>45, metformin can be safely initiated. For those with an eGFR between 30-45, it can be continued with caution if it is already in use. Finally, it is contraindicated in patients with eGFR<
30. These guidelines make more physiologic sense and although they may still be too conservative, in this era of automatic reporting of eGFR, to me, it is the better approach to take.

Creatininase

There was a fascinating case published a couple of months ago in the American Journal of Medicine. I have a particular interest in this case as it was my clinic mentor, Julian Seifter, who made the diagnosis and published the case. I have waiting for a long time to write a post about it but couldn't until the paper came out.

The case is a 50yr old man with a history of CKD, quadraplegia and an ileal conduit who was being investigated for CKD. His serum creatinine was 3mg/dl and a creatinine clearance was done to estimate his GFR. His urine creatinine concentration was 175mg and his calculated creatinine clearance was only 3 mls/min. At this point, RRT was recommended and the suggestion was that his serum creatinine overestimated his GFR because of reduced muscle mass. 

However, because the urine creatinine still seemed inordinately low and he had no symptoms, an inulin clearance was done which revealed a true GFR of 21 ml/min. What could explain this discrepancy?

A urine culture grew diphtheroids, staphlococcus and streptococcus. Although creatinine, once it is produced in the muscle cannot be metabolized in humans, some bacteria produce creatininase and as a result are able to break it down. Corynebacterium is a diphtheroid that has been associated with the production of creatininase. Dr. Seifter suspected that there was a creatininase-producing bacterium in the ileal conduit that was metabolizing the creatinine leading to a falsely low creatinine clearance. To confirm this, he took a sample of the patient's urine, added a known quantity of creatinine and incubated it for 24 hours at 20 degrees. The results are shown in the figure below.

Our GI tract has some creatininase-containing bacteria but under normal circumstances, the amount of creatinine clearance that they contribute is negligible - less than 2 ml/min GFR equivalent. However, in individuals with advanced CKD, both the relative and total clearance contributed by these GI bacteria increases such that in people with a GFR <10 the contribution of gut clearance can be as high as 4ml/min or approximately 50%. The opposite can also occur. The highest serum creatinine I ever saw was in a 50yr old woman with inflammatory bowel disease. She weighed 40kg but her admission creatinine was 38mg/dl. Despite this, she felt relatively well. She had previously undergone multiple bowel resections and had almost no functional bowel remaining. As a result, she had no gut clearance of creatinine and no upper limit to her serum creatinine concentration.

One final note, the urea clearance was not useful in the above patient either - his urine also contained urease -  the clue to this was a very high urine pH (>9) in the presence of a mild metabolic acidosis and no history of RTA.

No more folic acid

Although tangetial to nephrology in some ways, I believe a recent study published in JAMA Internal Medicine has important lessons for anyone involved in clinical medicine and should make us think about the things that we do reflexively without really thinking about the reasons.

In 1998, the US government mandated that all cereals be fortified with folic acid. Prior to this point, folate deficiency was a real problem. Now, not so much. In fact, folate deficiency has pretty much disappeared as an important clinical problem. Researchers at the Beth Israel Hospital in Boston examined their clinical database to see whether or not this change had lead to any difference in the number of folic acid tests performed and if the number of low serum folate diagnoses was substantial. The results are fascinating. There was no change in the pattern of ordering this test over the 11 year period covered by the paper. In total, 84,000 tests were performed of which 47 (0.056%) were low. The cost if this test to the institution is $2, the charge is $128 while medicare reimburses $20 per test. Thus, the cost per positive result was $35,800.

It is clear based on this that routine testing of folic acid levels is inappropriate and yet it is still often ordered as a routine test in working up individuals with anemia, dementia and neuropathies. Alan Wu, in an accompanying editorial suggests that clinical laboratories should retire this test and in fact his institution, San Francisco General, now includes this as a send-out only that has to be clinically justified.

The reflexive ordering of laboratory and other tests is a problem that has only gotten worse with computerization. When I started working, as interns we had to write individual lab requests on paper and leave them on patient's wards. There was an explosion in testing when interns were finally able to order labs with just a click of a button. I wonder what tests in particular in nephrology we should be ridding ourselves of or at least ordering far less often?

CJASN Activities

Two ASN-related activities to mention happening in the next couple of months. First, CJASN eJC will be hosting a twitter conversation about the recently published commentary "Training the Next Generation's Nephrology Workforce. This will be hosted by Amar Bansal, a fellow at UPenn who is the author of the article. It will take place on September 10th at 9pm and the hastag is #CJASNeJC.

The second event is a fellows luncheon at the ASN annual meeting on November 13th from 12.45 to 1.45pm. This is titled "Improving the journal club experience for fellows" and will be moderated by Drs Gary Curhan and David Goldfarb. An email will be sent in September/October to all registered fellows with the ASN.

Courses

A bit of housekeeping here - I noticed that all of our current course announcements were out of date. These have now been updated with the most recent versions of each course including the following courses coming up shortly:

ASN Board Review Course - August 2-8 2014
HD University - August 15-16 2014
Brigham Renal Board Review Course - August 4-8 2014
Medstar Kidney and Pancreas Transplantation Course - October 11, 2014
Ultrasonography for Nephrologists - October 25-26 2014 (which I recently attended and thought was excellent)

All of these courses have substantially reduced fees for trainees.

Here is the list of courses

Edit: Just to mention that the director of the ISHD meeting, John Daugirdas, contacted me and let me know that the new edition of the Handbook of Dialysis will be out later this year. If you were thinking of buying it (and I did in the past), you might want to wait until then.

Exams Are Coming

This season's Game of Thrones finished last night and as a nephrology-themed homage, a trainee from Malaysia, Lee Jun, created this poster during downtime while studying for his exams. Enjoy.

Immortality

A few months ago, a paper was published in the International Journal of Epidemiology that caused a sensation in it's home country - Denmark. Using registry data, and the diagnosis of non-melanomatous skin cancer as a proxy for sun exposure, the authors found that the OR for mortality in individuals who developed skin cancer compared to those who did not was 0.53. The p-value was an unfeasibly low 2x10E-308. However, when the results were stratified by age, the OR was a much more reasonable 0.97 in the sun-exposed group. This fact was conveniently forgotten when the study was reported in the media which uncritically stated that people who get more sun will live longer - something which upset the Danish cancer societies immensely.

So why was there such a disparity between the two results and how could it be possible that individuals with cancer could live so much longer (8.5 years on average) than those who did not get cancer. This month, a mea culpa editorial was published in IJE explaining their mistake along with an article discussing the entire issue. What the authors did in this case was fail to account for the immortal time bias. In this study, individuals entered the cohort when they were 40 years old. However, most people did not develop skin cancer until they were in their 60s or 70s. As a result, for the skin cancer cohort, there were approximately 20 years where they could not have died (they had to survive until they developed cancer and were "immortal" until that time). Someone who did not develop skin cancer could have died at any time during that 20 year period. To demonstrate how this works, the authors of the follow-up study, using the same dataset, randomly allocated a "lottery prize" to a proportion of individuals with a mean age of 68 who lived in Denmark over the last 20 years. Again, in this case, a person who received the prize would have had to have lived until the time that it was awarded while those who did not get the prize could die at any time. The results of the simulation study were very similar to the skin cancer study with an OR for all-cause mortality of 0.5 for the prizewinners and a similarly outrageous p-value.

This issue was first described in the 1800s when it was noticed that generals and bishops live longer than lieutenants and curates. Again, this is because one has to survive to an older age to become a bishop or a general and not because there is something inherent in these ranks that lead to an improvement in mortality.

This example is particularly egregious and the editors of IJE have to be congratulated for the way that they dealt with it. However, there are more subtle examples, one of which, highlighted in the follow-up article, appeared in JASN in 2010. This paper found that survival after transplant failure was improved by nephrectomy. However, the mean follow-up in this paper was only 2.93 years and the mean time to nephrectomy was 1.66 years. Thus, about half of the follow-up in individuals who had a nephrectomy was immortal time - they could not die during that follow-up period because they had to survive to the time of surgery. Most of the difference could be accounted for by this bias.

Similarly, a study in JASN in 2007, found that individuals enrolled in a multidisciplinary care clinic were more likely to survive than those who were not. Again, the time of the first MDC clinic was about 1 year after enrollment in the study. Individuals who entered the MDC program had a year of immortal time compared to individuals who did not enter MDC. This was pointed out in a follow-up article in KI. The authors of the original paper reanalyzed their data to account for this bias and found that MDC was still associated with improved survival although the magnitude of the effect was substantially less.

This is a fascinating issue and probably affects more cohort studies than we think. As a reviewer, I'll certainly try to look out for it in the future.

Unusual transplant immunology case

File this under something that we are never likely to see in clinical practice. In 2002 a fascinating case report was published in the New England Journal of Medicine concerning unusual findings during a work-up for a living related kidney transplant. A 52-year old woman had FSGS and was approaching ESRD. Her three sons were willing donors but when they went for HLA typing, there was a problem. Although all of her sons had a HLA haplotype from their father, two of the three had a HLA haplotype which, while identical to each other, did not match either of their mother's HLA haplotypes suggesting that she could not be their mother! Further investigation revealed that her sons' non-paternal HLA haplotype was identical to that of the patient's brother and had ultimately been derived from her deceased father.

Further analysis of the patient's blood found that there was no evidence of two distinct cell populations. However, hair follicles, buccal mucosa, bladder samples from a prior cystoscopy and thyroid cells from a prior resection found 4 haplotypes in these tissues. Only two were present in her peripheral blood. There was a normal number of chromosomes in all cells. This was a case of tetragametic chimerism. It is likely that there were two fertilized embryos in utero and that they fused at some point during development to form a single individual. It turns out that under experimental conditions inducing chimerism in mice, it is not unusual for such individuals to express a single haplotype pair in the peripheral blood while continuing to have all 4 haplotypes in other tissues. No-one really knows how common this condition is although the authors suggest that it may be more common than we appreciate. It has important implications in particular for forensic science.
One of the more interesting aspects of this case was that the patient had a HLA identical brother and a HLA haploidentical brother. Although she appropriately lysed cells from control individuals, she did not react to cells from her brother despite the fact that her lymphocytes carried a different HLA haplotype. She was fully tolerant to her brother.

A couple of years later, a woman in Washington State was in the middle of a paternity suit after separating from the father of her two children. She was pregnant with the third child at the time. Testing revealed that he was indeed the father of the children but that she was not. She was charged with fraud and accused of taking part in a surrogacy scam. Her children were taken off her and when her third child was born, this child was tested too and also found not to be her child. Her lawyer found this case report and asked for further testing - results of a smear test revealed that the DNA in that sample matched her children - she was a chimera also. Her children were promptly returned.

Hyponatremia Guidelines - NephJC

Tomorrow night will be the 4th edition of the Nephrology Journal Club on twitter.The article this week is unusual - it is a clinical practice guideline for the management of hyponatremia that was published in NDT, the European Journal of Endocrinology and Intensive Care Medicine. It is an interesting piece of work that has been expertly summarized by Joel Topf over at PBFluids. Even if you do not feel up to reading the entire paper, consider having a look at his executive summary as it raises a number of important (and eminently debateable) points.

See also the summaries at NephJC.com and Nephron Power. Join everyone for what is likely to be a lively discussion tomorrow at 9pm ET on twitter using the hashtag #NephJC.

SGLT-2 and the genesis of hyperfiltration

Over at eAJKD, Swapnil Hiremath has a nice post about the potential for SGLT-2 inhibitors to prevent diabetic nephropathy based on a review article published on the topic in AJKD. Essentially the theory is that increased serum glucose levels leads to an increase in the filtered load of glucose. This is reabsorbed in the proximal tubule along with sodium and chloride. This leads to a reduction in the load of NaCl delivered to the macula densa. The kidney senses this as a low effective circulating volume state leading to afferent renal vasodilation and an increase in GFR.

The advent of SGLT2 inhibitors has allowed us to test this theory in both animal models and humans. Recently, a small physiologic study was published in Circulation which tested the effect of SGLT2 inhibition in individuals with type 1 DM stratified by the presence or absence of hyperfiltration at baseline. GFR was measured using inulin clearance. The figure above is taken from the paper and shows the putative mechanism for hyperfiltration and the role of SGLT2 inhibitors. In this paper. empaglifozin treatment for 8 weeks lead to a significant decrease in weight, BMI, daily insulin dose and carbohydrate intake in both groups. In the normofiltration group, it had no effect on renal hemodynamics. However, in the hyperfiltration group, there was a significant reduction in GFR (-33ml/min), renal plasma flow, renal blood flow and an increase in renal vascular resistance. These results are remarkable but to me it does beg a question.Why is there such a dramatic effect in the hyperfiltration patients and what makes them different in the first place. Based on the evidence of this study, most of the hyperfiltration is indeed related to increased TGF. Looking at table 1 gives a hint of what might be the correct answer.

The baseline BMI and insulin doses were similar in both groups. However, the HbA1c was marginally higher in the hyperfiltration group as was the baseline carbohydrate intake. 24 hour glucose excretion was identical in the two groups. Following treatment, the daily carbohydrate intake increased significantly in both groups but to approximately the same extent. However, the increase in 24 hour urine glucose was substantially higher in the hyperfiltration group. What this suggests to me is that the hyperfiltration may be driven by higher overall carbohydrate intake despite relatively similar HbA1c levels. Because the 24 hour glucose excretion was the same in both groups prior to treatment, this suggests that the majority of the filtered glucose was being reabsorbed. Because the hyperfiltration group were taking in more carbohydrate, this would lead to an increase in the delivered load of glucose to the proximal tubule with a consequent increase in NaCl reabsorption. Treatment with empaglifozin prevented the kidneys from reabsorbing this excess glucose and this is reflected in the fact that the 24 hour urine glucose increased more in the hyperfiltration group than the normofiltration group.

I should point out that this is my theory alone based on the reading of this paper and that many of these between group differences were not statistically significant because of the low numbers of patients involved. Still, this paper at least provides elegant proof of the role of proximal glucose reabsorption on the maintenance of hyperfiltration.

The ongoing debate about the definition of CKD in the elderly

In NDT this month, there is a nice series of articles outlining the ongoing debate about whether or not an eGFR<60 should be considered a disease, particularly in the elderly. The pro side was argued by Giuseppe Conte and the anti by Richard Glassock. Finally, there was a moderator's opinion written by Stein Hallan and Ron Gansevoort.

Dr. Glassock makes the familiar argument that age-related decline in GFR is ubiquitous and should not be considered a disease (with the associated anxiety and insurance issues that accompany such a diagnosis). This is particularly the case in elderly patients with stage 3a CKD and no albuminuria who almost never progress to ESRD and, in fact, whose eGFR declines at a rate of approximately 1ml/min/year. Labeling these patients as "CKD" leads to a huge expansion in the number of individuals diagnosed with CKD over the age of 75 in particular encompassing a significant proportion of the US population who reach this age.

In this, he is countered by both the con side and the moderator who take the position that CKD 3a is something that should not be ignored and should not be considered a part of normal aging.The most convincing argument in favor of this position is the relative risk of death from cardiovascular disease in patients with moderate reductions in eGFR relative to those with preserved renal function. It is well known that CKD is associated with an increased risk of CVD. Although the relative risk of CVD decreases as individuals age, even in elderly patients, those with CKD stage 3a are approximately twice as likely to die of CVD than those without CKD. This risk is present whether or not individuals have proteinuria. As the moderator points out, in the 1970s, high blood pressure and high cholesterol were ignored in the elderly as they were seen as being a normal part of aging despite the fact that epidemiologic data suggested that these were associated with adverse outcomes in the elderly too (although, as with CKD, the relative risk was reduced compared to younger individuals). eGFR-defined CKD is an independent risk factor for cardiovascular disease. The fact that there is an absence of specific therapies that could be used in this population to slow decline or attenuate CVD risk (beyond traditional risk factor treatment) does not mean that it should be ignored. In fact, given the high prevalence of this condition in the general population, and the number of excess CVD deaths that can be attributed to CKD, this is an area where research should be focused to determine how we can reduce risk in these patients. I'm afraid I have to go with the moderator and Dr Conte on this one.

Nephmadess is Back

Nephmadness, the renal counterpoint to the NCAA tournament is back again this year. It is being hosted by eAJKD and the new website looks great. I am looking forward to setting my bracket when the tournament starts on March 16th. Go to nephmadness.com to get more details.