Saturday, June 23, 2018

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

Monday, June 11, 2018

Minimal Change Disease

The next session of GlomCon's Nephropathology Essentials will be held this Tuesday, June 12th at 11 am EDT. Dr. Helmut Rennke will be leading the session which will focus on Minimal Change Disease and FSGS (see below for session details).

Minimal change disease (MCD) is the most common cause of nephrotic syndrome in children > 1 year of age. Adult MCD is much less common but remains an important cause of nephrotic syndrome in this population. Here are some quick points to remember in adults with MCD:
  • Bimodal presentation: young children and very old adults
  • The slight male predominance (2:1) found in children disappears in the adult population
  • More common in atopic patients
  • Clinical presentation: Abrupt onset of edema, nephrotic range proteinuria, severe hypoalbuminemia and severe hyperlipidemia
  • There is a long list of secondary causes of MCD, but important ones to remember include: NSAIDs, Lithium, and Lymphoma 
  • Microscopic hematuria is seen in 10-30% of cases
  • AKI is present in 20% of cases (higher risk in older age, males, and presence of HTN)
  • Best initial treatment is corticosteroids 
    • Prednisone 1 mg/kg (maximum 80 mg) daily or alternative-day dosing of 2 mg/kg (max 120 mg)
  • Time to complete remission is much longer in adults, requiring 12-16 weeks
  • Relapse rates in adults with MCD are high
This is reviewed nicely in the following articles

MCD was also covered in this past GlomCon session. For further on both MCS and FSGS pathology, make sure to join the session on Tuesday.

GlomCon's Nephropathology Essentials Details:
To join the meeting go to: and select 'Join a Meeting'. Enter the Meeting ID into the web site (or connect directly from your Zoom app).
Meeting ID: 394-801-817
You HAVE to be logged into ZOOM to join the session. You may either create a free ZOOM account, or sign in through a Google or Facebook account (if you have one).  
Alternatively, use your institution's 'Polycom' system, enter IP address:
US West:
US East:
Then, enter the Meeting ID: 394-801-817

Posted by: Pravir Baxi, Rush University Medical Center

Wednesday, June 6, 2018

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.

Sunday, June 3, 2018

GlomCon Nephropathology Essentials

The goal of the GlomCon Teaching Platform is to enable Nephrologists, Nephropathologists, and trainees in Medicine, Nephrology, and Pathology to connect with each other to 1) Discuss challenging cases, 2) Share clinical experiences and 3) Obtain the expertise of participating faculty and invited speakers. Access to this resource is completely free!

Going forward, every Tuesday (same time weekly, 11am EDT) there will be a case-based conference, fellow's interactive conference, or renal pathology seminar.

You are invited to the inaugural session of GlomCon Nephropathology Essentials on Tuesday, June 5th at 11 am EDT. The first session will be led by Dr. Isaac E. Stillman and will focus on the basic principles of renal pathology.

For more on the Nephropathology Essentials webinars, visit:

To join the meeting go to: and select 'Join a Meeting'. Enter the Meeting ID into the web site (or connect directly from your Zoom app).
Meeting ID: 394-801-817

You HAVE to be logged into ZOOM to join the session. You may either create a free ZOOM account, or sign in through a Google or Facebook account (if you have one). 

Alternatively, use your institution's 'Polycom' system, enter IP address:
US West:
US East:
Then, enter the Meeting ID: 394-801-817

Sunday, May 27, 2018

The Role of the Gut for Potassium Homeostasis in CKD

Recently the FDA approved one of the newer exchange resins (Lokelma, ZS-9) for the treatment of hyperkalemia. (Veltassa, Patiromer), a calcium based cation exchange resin, was recently developed and approved since 2015 for the treatment of hyperkalemia. These two new drugs, which each have large randomized placebo controlled trials confirming their effectiveness, now seem bound to replace the ancient but much experienced Kayexalate (Sodium Polystyrene Sulfonate; SPS) for the management of hyperkalemia. However, they are not approved in Canada and their cost makes them less enticing options in a publicly funded health care system. Also, what about safety concerns? SPS has been used since the 1950s, however it took decades for case reports to come out possibly linking fatal colon necrosis to Kayexalate use. This association remains hotly debated. A systematic review in 2013 found a total of 58 cases of biopsy confirmed bowel injury that were “possibly” related to SPS use based on the WHO causality criteria. Interestingly, these cases were not limited to patients using SPS with sorbitol, nor to the post-operative population as was once thought to be the major risk factors for adverse GI events from SPS. On the other hand, a retrospective single-centre review over a 10 year period found only 3 cases of colon necrosis among 2,194 patients having received SPS. When they compared this incidence of colon necrosis to control patients having not received SPS, they found a non-significant RR of 2.10 (0.66-6.64; P=0.2). Many nephrologists will argue that SPS has a long standing proven track record and that colon necrosis is such a rare side effect that it is unlikely to be related. While no one knows if this is truly the case, the uncertainty surrounding this issue is one of the major reasons that led to the development of the newer exchange resins: ZS-9 and patiromer.

Before praising and widely accepting these newer, expensive products, would it not be wise to use the same caution we would for SPS? It can take years for such a rare adverse event as colon necrosis to manifest itself, how do we know we won’t be facing this GI safety issue 5 to 10 years from now?

Perhaps we could look for other ways of trying to enhance GI elimination of potassium.

--> BK-channel in colon enterocyte (Source: Sandle et al. QJM. 2010 Feb;103(2):85-9)    
The colonic enterocyte has an ability to excrete potassium in stool. This may be an important physiologic property in patients with advanced CKD who lose the ability to renally excrete potassium. In fact, patients with ESKD are known to have a greater excretion of potassium in their stool compared to individuals with normal kidney function. An important transporter involved in this process is the BK-channel located on the apical side of the colonic enterocyte within the colon crypts (see Figure). This channel is responsible for actively secreting potassium in the GI lumen. Aldosterone stimulates this channel, enhancing K secretion in the stool, similar to its effect in the kidneys. In fact, a study in the 1970s of patients suffering from acute cholera showed that within 12 hours of receiving a single dose of 100mg of spironolactone, there was a significant decrease in stool loss of potassium and an increase in stool loss of sodium. This likely is a major reason explaining why anuric patients with ESKD may still have from hyperkalemia if given RAAS blockade. The BK channel will also be stimulated by various diarrheal states such as Ogilvie’s syndrome, villous adenoma and certain laxatives such as bisacodyl. Bisacodyl is a stimulant laxative which enhances peristalsis through parasympathetic nerve activation, but also stimulates cAMP production within the colon enterocyte. This cAMP is thought to enhance K excretion via the BK-channel. A study performed in 2005 used immunohistologic analysis of colonic enterocytes in patients with ESKD and showed that BK-channels are upregulated in these patients compared to controls with normal kidney function. The upregulation of BK-channels probably represent an adaptation to chronic potassium load in order to maintain homeostasis. Interestingly, a small study in 2003 tested the effect of Bisacodyl on potassium in patients with ESKD. Eight controls normal kidney function and 13 patients with ESKD were given Bisacodyl 5-10mg PO titrated to achieve 2 soft bowel movements per day and these were compared to 5 ESKD patients given lactulose 10ml PO titrated also to 2 soft bowel movements per day. After 2 weeks of treatment, they found that the ESKD patients with Bisacodyl had a significant decrease in potassium from 5.9 to 5.4mmol/L whereas the controls given Bisacodyl and the ESKD patients given lactulose had no change in potassium values after 2 weeks of therapy. This suggests that Bisacodyl increases potassium excretion in the stool in patients with ESKD through a mechanism not simply related to its laxative effect, but likely through stimulation of the BK-channel of the colonic enterocyte. It is unfortunate that no further studies have looked into this therapeutic option for maintaining potassium homeostasis in patients with advanced CKD. Unfortunately, we don’t know if Bisacodyl would work as well in the non-dialysis population since we could expect these patients may not have as upregulated BK channels as in ESKD who are faced with more chronically elevated potassium loads. However, this would be an interesting study to pursue since Bisacodyl would be a cheap and safe way of controlling potassium in patients with advanced CKD by enhancing the body’s natural adaptation to potassium handling.

David Massicotte-Azarniouch
Nephrology Fellow
University of Ottawa

Sunday, May 20, 2018

Dear Future Independent Investigator in Nephrology ...

As part of an effort to organize some materials relevant to career development for budding physician-scientists in my division, I wrote the following letter and deposited it on a shared drive. Since it might be helpful to other renal fellows thinking about starting a research career, I wanted to also leave it here on RFN. I hope someone finds it helpful!

Dear Future Independent Investigator in Nephrology,

If you are reading this letter, congratulations! You either have chosen or are seriously considering a challenging but rewarding career path as a Physician-Scientist in one of the most complex fields in medicine. Your efforts will contribute much needed work in improving the lives and longevity of patients with kidney disease. You are a rare bird: during a time when the American nephrology work force hasn't been at its peak, you have proven yourself to be an excellent clinician and are poised to ask the most pressing and relevant scientific questions that will actually make a difference in clinic.

The purpose of this letter is to arm you with as much information as possible for you to land your academic dream job. In a perfect world, we wouldn’t have to worry about grants and papers – we could just do the science we love. And yes, you should absolutely work on the questions that keep you up at night. But to make that dream goal a reality, there are a few milestones to hit, which will be addressed here. During the fellowship / instructor years, you will need to work towards obtaining a career development award (CDA) - this is your golden ticket to getting a job as an independent PI. Someone high up the political ranks at a prestigious institution once told me that really the CDA, especially a non-institutional NIH K, is a "hunting license" to go land a job. It's a nod from the NIH that yes you can successfully obtain extramural funding and is a good stepping stone towards developing your own research program and obtaining future R-level funding. But let's get back to where you are right now, as a fellow.

The Science. Your first task at hand is to pick a feasible primary project that truly fascinates you. Don't pick one that you think will just lead to a convenient paper; if you're not interested in what you're studying, your motivation levels will be down, and on top of that you won't sell the strongest pitch to grant and paper reviewers. Your curiosity about your project will be a strong motivating factor to keep pushing it along. Do pick one that will lead to 2-3 solid first-author papers over the course of your training period. Be sure to have one primary project and at least one smaller low-risk side project, in case the primary project does not quite work out. With a good research mentor, this task shouldn't be too difficult; if there are problems with the project and you feel at odds with your mentor, you should seek advice from your other mentors, which brings me to my next point.

Mentors: It Takes a Village to Raise a Physician-Scientist. Having good mentoring is a key ingredient to success. It doesn't matter how smart you are; if you don't have solid mentoring, you may not be able to find your way. But here's the rub: there is no such thing as one great mentor who would be everything to you. Your primary research mentor may be absolutely fantastic, but he or she cannot be or provide everything you need. You'll have your primary research mentor, a separate career mentor who may or may not be directly in your field, a life mentor who is not your parent, and your peer mentors who have their boots on the ground and can provide directly helpful tips but also empathize with the day to day frustrations. And don't forget to be a good mentee - be organized, be receptive to feedback, take ownership of your projects/career/mistakes/successes, and make the most of your time with your mentors. To succeed, you'll be building your own village of mentors who can provide complementary perspectives and also keep you sane. Doing so takes effort, which brings me to ...

Persistence. The path you have chosen is certainly not the one of least resistance. Some people get lucky, but you can succeed even if you don't come across a scientific windfall. To succeed, you must persist. You must never give up. You will have good days, and you will have bad days, but through the bad days your resilience and drive will keep you moving forward. And yes, you will see on social media that your med school and residency classmates are enjoying expensive cars and vacations while you are still on a fellow / instructor salary, but you just have to refocus on the task at hand, even if it's a bad day. One of my friends and colleagues said to me, "You know, we are in this either because we love it so much that we won't give up, or because we are so bull-headed and stubborn that we keep hanging on because we don't want to admit ourselves that we made a crazy choice, or both." Some things might be out of your control, but how you respond to the unexpected in terms of bouncing back with resolve and determination will allow you to get the final outcome you want. 

Planning. Being organized and hitting the milestones outlined by your division and mentors will be key to making sure you are moving towards your goals in a timely manner. Plan out your projects, grants you may be expected to obtain, manuscripts to write – having a concrete timeline for these things will keep you on track career-development-wise so that you can continue to do the science you love.

Productivity. You can have all the most brilliant ideas in the world, but no papers means no street cred for funding. For the F32, you don't necessarily HAVE to have a first author paper to be funded, but it would certainly help as those awards also go to competing PhD candidates. For the K, you will definitely need more than one first author original research manuscript to be competitive, so this is a factor that needs to be planned - the papers can be small, so get what you can into print. Don't hold on to everything for the one Nature paper you're hoping to put out; publish and present as often as you can in the beginning because the feedback is part of your training too and because no one expects you to have a Nature paper as an MD fellow. Review papers don't count as much, but they are good to have in your Biosketch and can provide the background / significance of your grants.

Creating an Emerging National Profile. Part of the benefit of presenting at meetings is to get your name out there. It is also good to network when you can - sometimes good ideas and collaborations spring up from these interactions. Also, it is good to have that national profile building for the job search and to have it as a foundation for the more distant future when you are being considered for promotion. Yes, Twitter can help a little, but you want your reputation to be built on concrete achievements such as data presentation at meetings or engaging in concrete roles in national societies.

Taking Ownership. So physicians who haven't taken time off from school to go work in a non-academic job have a special phenotype of living an extended adolescence during training. This is good and bad, but now that you are emerging from the training phase of your life, it is important to understand that the next phase of your career development will require you to take control and ownership of how you want to shape your career. I sound like I am stating the obvious, but having such structured GME curricula and sometimes micromanagement during clinical service can leave you in the habit of passively going through the motions of completing requirements. Outside the GME umbrella, you are in control of your own destiny and chasing opportunities. I quite like that aspect of graduating from GME and actually found it empowering.

 *** When all of these elements are cooking together, you will get what you need in terms of funding to start your career. It is an exciting time to join the Physician-Scientist workforce in nephrology - there is much work to be done, and your success will benefit the lives of your patients. You've got this!

Jennie Lin, MD MTR
May 17, 2018

Thursday, May 17, 2018

Hemodialysis failure due to Hydroxocobalamin

Hydroxocobalamin is an antidote that was recently approved by the FDA in 2006 for the treatment of cyanide poisoning. For decades, cyanide poisoning has historically been treated using the cyanide antidote kit that contained a concoction of amyl nitrite, sodium nitrite and sodium thiosulfate. The problem with this antidote kit is that it can lead to hypotension and reduced oxygen-carrying capacity. In contrast, hydroxocobalamin does not cause these complications and therefore has become more widely used for suspected cyanide intoxication. 
We encountered a case of a young man who was found unresponsive and profoundly hypotensive. On arrival to the emergency room, he was in extremis with significant agonal breathing. His GCS was 3, he was hypothermic and hypotensive. He had AKI (creatinine 1.3mg/dl) and a severe anion gap metabolic acidosis (lactate >20). A bedside echocardiogram showed severely diminished cardiac function. Blood and urine toxicology screen were negative. Cyanide poisoning was suspected and as a result, he was given iv hydroxocobalamin.
Over the next few hours, he had an increasing pressor requirement and the decision was made to start dialysis to treat his acidosis and potentially remove any ingested toxins.
Hemodialysis was initiated emergently using a Fresenius 2008K machine, however this was confounded by a recurrent “blood leak alarm” that repeatedly shut down the machine despite there being no evidence of a leak occurring. After multiple trials to initiate hemodialysis with replacement of the dialyzer and the machine, this was aborted with plans to initiate CVVH.
Hydroxocobalamin causes an orange/red discoloration of bodily fluids and can permeate dialysate. This can lead to dialysis failure due to defraction of light from discolored dialysate, resulting in triggering of the blood leak sensor in certain hemodialysis machines. The case highlights the need for an awareness of hydroxocobalamin effects in hemodialysis and its potential to delay initiation of emergent dialysis in critically-ill patients.
More information on the case can be found here.
Posted by Kenneth Lim

Wednesday, May 16, 2018

Donor specific antibodies made easy

Donor specific Antibodies (DSA) are one of the established biomarkers for predicting antibody mediated rejection (ABMR). This blog is a short synopsis on DSA and their complex characteristics  in kidney transplantation.
DSA may be preformed (before transplantation) or de-novo (developing after transplantation). Preformed DSA can lead to hyperacute/early ABMR and graft loss. De-novo DSA can lead to late ABMR and poor graft prognosis. But DSA need not always be pathogenic- often they may act in a ‘benign’ fashion, with stable graft function.
The main sensitizing events include organ transplant itself pregnancies and blood transfusions. It is important for the clinician to take the history of shared children with a partner who is a potential live donor. Sensitization is generally represented as the % panel reactive antibody (PRA), the proportion of a representative population that the recipient has anti-HLA antibodies to. This also estimates the likelihood of a positive cross match to potential donors.
DSA identification
We have come a long way from the less sensitive complement based cytotoxic assays and ELISA to the newer and more sensitive multiplexed particle based flow cytometry (e.g. Luminex, see image). The newest kid on the block of sensitive testing for DSA is next generation sequencing (NGS). Single bead antigens assessed on a Luminex platform can identify the precise antibody present. This information is used in identifying preformed antibodies against a potential donor on a virtual cross match (so called because single antigen beads are added to recipient serum, without donor cells being involved). When ABMR is suspected, the presence of de-novo DSA or rising titers of pre-existing DSA contributes to the diagnosis.
DSA Pathogenesis
De-novo DSA can develop in 30% of transplant recipients who were previously not sensitized. De-novo DSA mainly develop against HLA Class II antigens (often DQ). The risk factors for de-novo DSA formation include:
  • High HLA mismatches (especially DQ).
  • Inadequate/non adherence to immunosuppression.
  • Graft inflammation which leads to increased immunogenicity  (viral infections like CMV, cellular rejection episodes or ischemic injury).
DSA cause graft injury via complement activation, antibody dependent cellular cytotoxicity, and direct injury of the endothelium via VEGF, fibroblast growth factor upregulation and ligand binding. These latter two non complement mediated mechanisms may explain the c4d negative ABMR.

Importance of DSA class & IgG Subclass
DSA target specific epitopes in the polymorphic regions of the HLA antigens (see NephMadness for more on epitopes/eplets).
HLA Class I: A,B,C antigens; present on all nucleated cells, one alpha chain and a beta2-microglobulin; epitopes located on the polymorphic alpha chain.
HLA Class II: DR, DQ, DP; present on all antigen-presenting cells, one alpha & 1 beta chain; both chains are polymorphic.

Complement binding

Most abundant
Weakly complement binding
Complement binding (best)

Mainly associated with acute ABMR
Does not bind complement at all

Biomarker of mature alloresponse and chronic graft injury

Class I and Class II DSA
Class I antibodies are usually of IgG1 or IgG3 subclass so are usually complement binding. They are unusally associated with acute ABMR and graft loss. Class II antibodies are usually IgG2/4 subclass and are usually detected late and are not complement binding. Usually quite persistent and associated with chronic injury.
What are complement binding DSA?
Complement binding DSA, as judged by C1q fixing on single bead assays, is associated with a worse allograft prognosis, with some evidence that C3d fixation may also be important (previous RFN post here). This is a controversial area as complement fixation may be induced by concentrating DSA and lost by dilution so antibody strength may explain at least of this association. Why might this be important? C1q represents the early part of complement activation whereas C3d and C4d are more downstream mediators of complement activation
DSA Strength
Usually expressed as the Mean Fluorescence Intensity (MFI) on the solid phase (single bead) assay. There is no standardisation currently and each transplant center develops their own cut-offs. Important points to consider regarding DSA strength (see NephMadness for more): (i) Prozone effect: False negative or low titers may occur despite high levels of antibody in the presence of inhibitors (serial dilutions help mitigate prozone effect). (ii) DSA against shared epitopes may be diluted across the beads giving lower individual MFI.

Relationship between DSA and C4d deposition in the kidney
C4d is the degradation product of the classic complement pathway. It binds covalently to the endothelial basement membrane. Positive C4d staining in peritubular capillaries serves as an immunological foot print of ABMR – seen as a linear pattern best seen in frozen tissue section. It is important to note that not all ABMR will be C4d positive and that isolated C4d positivity may not portend a bad prognosis (graft accommodation in ABO incompatible transplantation is a well known example).
Post by Rajeeva Parthasarathy

The Kidney in Diabetes: Not Always Plain Vanilla Diabetic Nephropathy

Diabetic nephropathy (DN) is well recognized by the glomerular basement thickening (GBM), mesangial matrix expansion and formation of nodules in the mesangium - the classic Kimmelsteil Wilson lesions. The very sight of these lesions makes a pathologist confirm the diagnosis of DN. However it`s not always as straightforward as it seems and these typical lesions do not always dominate the microscopic picture.

Crescents always makes us wonder about the presence of underlying immune-mediated disorders. We investigate the patient extensively with antibody profiling, complement work up and other battery of tests. Sometimes a crescent may appear unexpectedly in the biopsy of a diabetic patient. A diabetic patient can have ANCA vasculitis after all. If the clinical picture is suggestive of immune disorder, the work up for these diseases will help in arriving at the diagnosis. Immunofluorescence and electron microscopy are also crucial in this regard.
But what if it is a crescent of non-immune etiology? Also described as superimposed lesions of collapsing glomerulopathy (CG) on DN, it is characterized by proliferation of parietal epithelial cells (PECs). These 'crescents' do not show inflammatory cells and GBM has continuity, without any breaks and there is no fibrin in the Bowman space. CG lesions in DN are associated with an increased rate of progression of disease with earlier onset of ESRD. PEC markers like Claudin-1 show strong positivity in Bowman space in these lesions. In fact the cells in Bowman`s space in these crescents show double positivity with Claudin-1 and Nephrin (a visceral epithelial cell marker) in one study. This indicates de-differentiation of PECs into podocytes, forming cross bridges across the urinary space with the PECs trying to replace the latter as podocytopenia is a prominent feature in DN.
There are no definite treatment recommendations for these lesions in DN. Based on few case reports available, aggressive control of diabetes, hypertension and use of ACEI/ARB`s might help to some extent. But the overall prognosis is grim. This highlights the need for careful assessment of such patients. Diabetic patients may have true crescentic , but not all 'crescents' in diabetes are crescentic glomerulonephritis!
Post by Sriram Sriperumbuduri
Image from

Tuesday, May 8, 2018

Nodular Glomerulosclerosis – beyond diabetic nephropathy

A glomerular nodule, i.e. an acellular hyaline structure, can have varied etiologies. Most commonly we see it in the setting of diabetic nephropathy (DN). In these cases, it posesses all the associated features of DN on light microscopy (LM) with glomerular basement membrane (GBM) thickening, mesangial matrix expansion and arteriolar hyalinosis.  These nodules stain well with PAS & silver stains. Immunofluorescence (IF) shows linear IgG deposits along the GBM & tubular basement membrane (TBM) and occasional IgM & C3 trapped in the sclerotic areas. Electron microscopy (EM) shows similar features.
A differential diagnosis is amyloidosis, associated with enlarged glomeruli but poor staining with PAS and silver stain. The striking feature of this condition is red appearance of nodules on Congo staining with characteristic apple green birefringence under the fluorescent microscopy. In the most common form of amyloidosis, the AL type, IF shows light chain restriction with lambda > kappa predominating. EM has the characteristic amyloid fibrils, 7-12 nm in diameter with indefinite length and random orientation.
Among immune mediated glomerulonephritis (GN), MPGN also presents with nodules on biopsy. LM is highlighted by a proliferative morphology with splitting and duplication of the GBM. Cryoglobulinemic GN is associated with pseudo-thrombi in capillaries, which in fact represent large sub-endothelial deposits. IF shows IgG and C3 deposits in GBM. Cryoglobulinemia is associated with IgM and predominance of kappa deposits (Type 1). EM reveals electron dense deposits in sub endothelial, mesangial and sometimes in sub-epithelial locations.
Monoclonal immunoglobulin deposition disease (MIDD) can shows nodules. They stain with PAS and silver stains (see image) and have refractile, PAS-positive deposits in the TBM too. IF is characterized by linear deposits along GBM & TBM with kappa>lambda deposits in LCDD (light chain variant) and IgG in HCDD (heavy chain). EM shows powdery deposits in inner GBM, outer TBM and in the nodules.
Fibrillary and Immunotactoid GN have diffuse a proliferative GN/MPGN pattern, sometimes with crescents. They stain with PAS & silver as well, a feature they share with DN. IF is positive for polyclonal IgG and C3 in Fibrillary GN. The immunotactoid variant has monoclonal IgG with kappa/lambda chains. EM shows large, randomly arranged fibrils (16-20 nm in diameter) in the former, and parallel arrayed microtubules (20-50 nm diameter) in the latter.
Fibronectin glomerulopathy is characterized by nodules positive with PAS and negative with silver. EM shows sub-endothelial electron dense deposits. Immunohistochemistry staining for fibronectin is diagnostic.
The last differential is Idiopathic Nodular Glomerulosclerosis. This entity resembles DN in all aspects except that patient is non diabetic. It is associated with long standing hypertension and smoking. Smoke contains glycation adducts which form AGEs and through oxidative stress is thought to create pathology similar to diabetes.

Thus, a nodule in the glomerulus has a wide differential with definite need for various stains, IF and EM to establish the final diagnosis. The other key feature here is most of the above mentioned diseases can have a similar clinical presentation in the same age group.
Post by Sriram Sriperumbuduri (Images from Paul Phelan)

Saturday, May 5, 2018

Registration Open for UAB CRRT Academy

Registration is now open for UAB CRRT Academy

When: August 30 and 31, 2018
Location: Doubletree Hotel, 808 20th Street S, Birmingham, AL, 35205

Seating is limited to 80.

In addition to CRRT didactics, the course includes hands-on workshops and interactive cases, as well as a session on CRRT quality metrics and optimization of acute intermittent dialysis in the ICU. A new pre and post-test will be given.

Ten $700 travel grants are available for fellows in training on a first-come first serve basis and requires a letter from the program director. One letter per institution. Download form here.

Instruction Form for travel grant and registration are here. Grants are limited in number. Awards will be paid on the 2nd day of the conference. I have attached travel grant information, and registration. Some small changes may be made prior to final program. All travel grant recipients must register.

The website for registration is here

Saturday, April 28, 2018

Hydrochlorothiazide—Its time is up

Hydrochlorothiazide (HCTZ) is the most commonly prescribed anti-hypertensive worldwide and the most frequently prescribed diuretic in the United States. More than 95% of prescriptions are for doses of 25mg or less. Despite these unequivocal prescribing patterns, HCTZ has rarely been studied at these low doses, particularly as monotherapy, and has yet to be compared head-to-head with thiazide-like diuretics such as chlorthalidone or indapamide. In contrast, multiple landmark trials have demonstrated consistent reductions in cardiovascular (CV) morbidity and mortality with thiazide-like diuretics as dosed in contemporary practice.

While no trial has directly compared low-dose HCTZ monotherapy with a thiazide-like diuretic, the MRFIT trial offers the closest comparator with the results offering cautionary lessons regarding the benefits of HCTZ at historically prescribed doses (50-100 mg/day). Published in 1982, patients were randomized to placebo or combined lifestyle/drug therapy with HCTZ or chlorthalidone as the initial agent. Not only did HCTZ treated patients have higher all-cause mortality rates compared to those in the chlorthalidone arm but there was a trend towards increased all-cause mortality when HCTZ patients were compared to placebo. Moreover, when those randomized to HCTZ were switched to chlorthalidone, rates of death from coronary artery disease fell below those recorded in the placebo arm.

In contrast, nearly every seminal trial showing improved CV outcomes with diuretics has utilized the thiazide-like diuretics chlorthalidone or indapamide at contemporary daily doses of 25 and 2.5mg, respectively (ADVANCE, HDFP). The SHEP trial was the first large study to address the treatment of isolated systolic hypertension with more aggressive blood pressure goals; compared to placebo, those randomized to chlorthalidone had far fewer CV events. The ALLHAT study, which compared the efficacy of full dose chlorthalidone (25mg/d) with lisinopril (40mg/d), norvasc (10mg/d), and doxazosin (arm terminated prematurely), found that chlorthalidone resulted in the lowest blood pressure among treatment groups. It was not only as effective as the other agents in preventing the primary CV outcome but was superior with respect to the secondary outcome of heart failure (although this may have been related to improved blood pressure control rather than the agent itself). Moreover, truly elderly patients appear to tolerate the more potent thiazide-like diuretics. For example, the HYVET trial was the first study to evaluate the effects of tighter BP control among (relatively healthy) individuals over 80. Those treated with an indapamide-based regimen not only had far fewer fatal strokes but lower rates of adverse events compared to those on placebo.

Small “proof of concept” studies offer possible explanations for these differences in outcome. In a 24-hour ambulatory blood pressure monitoring study comparing equi-potent doses of HCTZ (12.5mg day) and chlorthalidone (6.25mg/day), chlorthalidone distinguished itself by its extended duration of action resulting in blood pressure control throughout the 24-hour period. The pharmacologic property is critical as agents with 24-hour efficacy protect against the morning “surge” in blood pressure, a time when patients are most vulnerable to stroke and myocardial infarction 26821625).

In light of the unequivocal therapeutic efficacy of thiazide-like diuretics and the lack of evidence supporting HCTZ as mono-therapy, the nephrology community should serve as the exception to the aforementioned trend in thiazide prescription patterns. Concern that chlorthalidone/indapamide may be too potent for the elderly are well founded but as the above trials in the aged demonstrate, low-dose therapy (e.g. indapamide 1.25mg/d) can be prescribed, allowing for less volume depletion and metabolic sequelae while providing the extended anti-hypertensive response that may be the key to their superiority over HCTZ.

Conflicts of Interest: None

Hillel Sternlicht, MD
Hypertension Specialist
Author, Concepts in Hypertension Newsletter- Subscribe for free

Friday, April 27, 2018

April Nephrology Web Episode - The Renin Angiotensin Story

This month's video is a 10 minute medical history lesson on the renin-angiotensin story - from Tigerstedt to the Goldblatt kidney.  Hope you find it useful!

Sick of being sick – sickle cell burden and the importance of understanding mechanisms in rare diseases

When we think of the most common causes of kidney failure, usually we think of hypertension and diabetes. The prevalence of hypertension and diabetes in US is approximately 30% and 10%, respectively, and there is no question about the economical and individual burden of these chronic diseases. But what about rare diseases? There have been comments made that because they are rare and thereby by definition affect less people, that we should not focus our efforts on improving diagnostics, treatment options, or  clinical care practice for these diseases. What some people may forget, is that even rare diseases affect our communities, and investing resources into understanding these diseases also informs us about other pathways that may also be dysfunctional in more common diseases.  The classical example is Sickle Cell Disease. The National Organization for Rare Diseases and the NIH put sickle cell disease in the category of rare blood disorder. But if we look at the same disease from a little bit different angle we will see that it is actually the most common genetic blood disorder in US, the prevalence is significantly rising and due to the increased average lifespan in these patients.  The average health care cost reaches almost 1 million dollars per patient (which makes the cost of the health care for sickle cell patients in the US exceeding 1.1 billion dollars annually). Moreover, currently there are only 2 clinically approved drugs for the treatment of sickle cell disease, and neither of them target sickle cell associated renal complications. That really underscores the urgent need for the development of new therapeutic therapies for chronic complications of this “rare” disease. 

Sickle cell disease is caused by single mutation in the hemoglobin gene that results in hemoglobin polymerization, erythrocyte sickling, endothelial activation and vaso-occlusion that subsequently leads to chronic tissue hypoxia and organ damage. Sickle cell nephropathy is the second leading cause of death and at the average age of 23 approximately 20% of sickle cell patients are diagnosed with end-stage renal disease (ESRD).  Sickle cell patients with ESRD have a very high mortality rate, with most surviving less than 3 years after the diagnosis. This level of disease burden occurs due to unknown mechanisms that underlie sickle cell nephropathy. In other words, if we can figure out why and how the pathophysiological processes work within the sickle kidney we will be able to block or prevent it disease progression. So now the question is how can we do that? The answer is very simple; if we want to unravel and better understand the unknown mechanisms we need to start from basics. Basic science gives us this great ability to test potential injury mediated mechanisms in a setting of the disease. 

Lets think about the disease setting for a second from a basic science perspective. We know that central characteristics of the sickle cell disease milieu include hypoxia, oxidative stress, or even thrombosis. These same processes are established inducers of endothelin-1 (ET), a signaling peptide produced by diverse cell types that exerts its physiologic and pathophysiologic actions by binding to two receptor subtypes, ETA and ETB. Elevated endothelin-1 has been demonstrated in sickle cell disease patients. Moreover, in the kidney, endothelin-1 has been widely implicated as a mechanistic contributor to the development of various forms of CKD. Therefore we accepted the challenge to elucidate the mechanisms of sickle cell associated kidney injury and designed the study investigating the renal protective potential of endothelin receptor antagonism in the treatment of sickle nephropathy. We utilized a mouse sickle cell disease model, which is characterized by knocked-out mouse globin genes and knocked-in correct and mutant human globin genes.  This mouse develops full-blown sickle cell nephropathy (by 12 weeks of age). Sickle cell and control mice were treated with selective ETA receptor antagonist or dual ETA and ETB receptor antagonist starting at the time of weaning (when they can live without mom) and continued for 10 months and at the end of the study kidney structure and function were assessed. Our results demonstrated reno-protective effect of selective ETA receptor blockade evidenced by preserved GFR, prevention of proteinuria, and protection of tubular structure and function. Dual ETA and ETB receptor antagonism provided only some of the protection observed with selective ETA receptor antagonist, highlighting the importance of exclusively targeting the ETA receptor in sickle cell disease associated nephropathy. 

Taking into account clinical observations reported in sickle cell patients and rigorously planning and performing basic science studies, we were able to identify selective ETA receptor-mediated signaling pathway underlying the progression of sickle cell nephropathy. Thus, targeting this single receptor we can potentially offer novel and effective reno-protective strategy for sickle cell patients. The significance of this particular approach is supported by the fact that selective ETA receptor antagonist is already approved by FDA and available on the market for pulmonary hypertension, thus the potential kidney-targeted therapy for sickle cell associated nephropathy would be available fairly shortly. There is no doubt that appropriately designed and prospective clinical trials should be preformed to confirm the safety and effectiveness of this novel approach, however the barriers to the next steps of clinical investigation are minimal. This study was recently published (Kasztan et al. JASN 2017)

In conclusion our study is one out of many examples representing the beauty of the translational character of basic research and the great potential that may benefit million of patients with “rare” disease. We should strive to understand the mechanisms of disease and thereby try to prevent disease (or reduced disease progression), improve diagnostic tools, therapeutic interventions, and clinical care for all people, regardless if this is a “rare” or “common” in our society.  

Malgorzata Kasztan PhD
Joseph A. Carlucci Research Fellow of the ASN 
University of Alabama at Birmingham
Birmingham, Alabama

Wednesday, April 11, 2018

ATTN Nephrology Fellows: Origins of Renal Physiology fellows course now open for applications

Jeff during a trip to MDIBL
As a senior resident at the Beth Israel Deaconess Medical Center, I was fortunate enough to have had the opportunity to attend the Mount Desert Island Biological Laboratories even before I knew there a course for Renal fellows. It was there that I learned of the importance of comparative physiology in our understanding of the Renal physiology we see every day as nephrologists. For anyone who has attended the Renal Fellows course at MDIBL, the Animal House region of this year's NephMadness undoubtedly made you smile. In fact, choosing a winner was like picking your favorite child. How could you decide between how toads and camels solve their osmolality problems?! They didn't even mention why seagulls "spit" (they excrete salty fluid that drips onto their beaks...and it flies off when they shake their heads!). See what you're missing?

5 years after my first trip to MDIBL, I have been back every year since, teaching in the BIDMC and Hospitalist courses. But I will always have a special place in my heart for the Renal Fellows course, where I learned more in 1 week about basic science, renal physiology, and how lucky I was to be a future nephrologist than I ever thought. We worked hard...and we played hard. When not in the lab, we were exploring Acadia National Park on foot and on bicycle, eating obscene amounts of shellfish in Bar Harbor, and getting to know our fellow fellows and some of the most influential physician-scientists in the field.

In fact, I loved the course so much that I decided to study it! Here is our published paper about just how great the Renal Fellows course is So here's the deal,...if you want to go, you have to APPLY. Your course tuition is on the house! (the NIDDK is footing the bill). This year, it's happening from August 18th through 25th.

Visit the website for all the detail. Application Deadline is July 30th (Seats fill fast)

If you have questions, please don't hesitate to e-mail me -

Jeffrey William, MD
Instructor of Medicine, Harvard Medical School
Beth Israel Deaconess Medical Center  

 Check out all of the posts about this course on RFN

Friday, April 6, 2018

CHANNELing basic science to understand renal electrolyte handling

Let me start with a folktale: an old and very senile king wants to know which of his daughters loves him the most. The elder sister says she cherishes him more than the whole kingdom. The younger one, though, loves him “as dear as meat loves salt”. The king gets upset and orders her execution. As most fairy tales, it has a happy ending:  the king is served dinner without salt, learns his lesson, stops the execution and everyone lives happily ever after. In the modern world this story of a salt-loving family might have another sad “end” – end stage kidney disease, and a broke king spending a lot of gold coins on healthcare. It might have ended differently for him though if we had a better understanding of renal electrolyte handing during a high salt diet. This is a million-dollar question (actually, it’s more like hundreds-of-millions-of-dollars-question – I hope someone at NIH reads this blog); we need to know what happens in the kidney at the molecular and cellular level in a disease state. Knowing all the tiny details would be immensely helpful to discover new pharmacological targets. One of the most studied drug targets for renal diseases are ion channels, and electrophysiology is a sophisticated method for measuring ion channel activity.

In my lab at the Medical University of South Carolina among other things we use electrophysiology to uncover the mechanisms that underlie salt-sensitive hypertension.  Since the Nobel Prize in Physiology and Medicine awarded to Erwin Neher and Bert Sakmann for their “discoveries concerning the function of single ion channels in cells" in 1991, electrophysiology has been an immense help to basic and clinical science. Although this technique is very widespread in brain and cardiovascular research, there is only a handful of labs that use it to answer nephrological questions. I have learnt it during my postdoctoral training in the laboratory of Dr. Alexander Staruschenko (Medical College of Wisconsin) where it has been successfully applied to study kidney function for years.

So what exactly is electrophysiology? Basically, it is a technique that allows direct measurement of how ions (Na+, K+, Cl-, Ca2+ - you name it) move through ion channels in the cell membrane. Using a tiny glass micropipette with an electrode in it, and a micromanipulator, we can press the tip of the pipette to plasma membrane of the cell, and isolate a patch of it that is under the tip (hence the other name of the approach – patch clamp). Since ions have a charge, their movement through the channel to the other side of the membrane generates current that can be sensed by the microelectrode in the pipette. Of course, sensing movement of single ions requires sophisticated amplifiers, filters, digitizers, grounding, knowing Ohm’s law and having a graduate degree in physics (kidding – though I have one, and it does help), and a ton of patience. When performing a patch-clamp experiment we control the environment that the cell is in (we choose the extracellular solution, what we put in the patch micropipette, what voltage we apply to the membrane etc), and this allows us to use different tricks to identify ion channels and then learn how to tweak or test their activity. Using cultured cells, tissues isolated from animal models, or human biopsies, we can directly measure the activity of ion channels and assess what happens in a certain disease condition.

Over the years, scientists have discovered dozens of crucial renal ion channels conducting sodium, calcium, chloride, potassium, magnesium… more are discovered every year. Gain- or loss-of-function mutations that lead to renal diseases have been reported for pretty much each and every one of them. In disease states such as salt-sensitive hypertension a handful of ion channels are known to work improperly, and in order to advance our treatment strategies we need to know how these channels are mediated, what signaling pathways affect them, and what pharmacology can be used to change their activity. As an example, in Dr. Staruschenko’s laboratory it has been shown that epithelial sodium channel (ENaC) in the cortical collecting ducts can be overly active in salt-sensitive hypertension (PMID: 28003189), which meaningfully contributes to an increase in blood pressure. Therefore, specific targeting this ion channel could be a successful means to combat blood pressure in this setting.

One of my good colleagues once compared ion channel electrophysiology to fishing. I have never fished in my life, but since I’ve done a lot of patch-clamp I feel I could easily have an alternative career as a fisherwoman. Nevertheless, although patch clamp electrophysiology is a “long wait – high reward” approach, this unique technique is crucial for our understanding of renal electrolyte handling, and – in skilled and patient hands - it has tremendous potential to push the medical field forward.

Daria Ilatovskaya, MS, PhD, 
Past Ben J. Lipps Research Fellow of the ASN  
Medical University of South Carolina 
Department of Medicine, Division of Nephrology 
Charleston, SC