Tuesday, January 17, 2017

Renal Grand Rounds: Correlate Clinically

I recently presented the case of a middle-aged patient with ESRD secondary to Goodpasture syndrome. She presented with AKI 3 months after a kidney transplant. Her creatinine had normalized to 0.9mg/dl post-transplant. However, over the next few months she had multiple hospitalizations for infections, perinephric fluid collections and three episodes of AKI. Her creatinine finally stabilized at 1.5mg/dl. Due to concerns that she was overly immunosuppressed, her mycophenolate was discontinued during her last admission and her prednisone was stopped per weaning protocol. She was continued on tacrolimus. At her post-discharge follow up, she was found to have recurrent AKI with Cr 2 mg/dl She had 1+ blood on UA, but no proteinuria. GBM antibody was negative. She was admitted for a transplant kidney biopsy.

The biopsy demonstrated diffuse linear staining of the glomerular basement membrane. There was no evidence of active glomerulitis or crescent formation. Mild mesangial expansion and moderate thickening of the GBM were noted with no signs of cell-mediated or antibody-mediated rejection.

This prompted the million dollar question: Is this diffuse GBM staining early recurrence of anti-GBM disease or something else?

The inciting event of anti-GBM disease is still unknown (correlations with smoking, cocaine use, solvent exposure, and infections), however the pathophysiology is fairly well established - an insult causes a conformational change of the type IV collagen network in the GBM resulting in exposure of the non-collagenous portion of the alpha-3 chain which elicits an immune response. Based on multiple uncontrolled studies, these patients can be transplanted 6-12 months after their GBM antibody titers become negative and they have similar transplant outcomes when compared to other causes of ESRD.

But how often does it recur after transplant? In 2013, Tang et al retrospectively analyzed 58,000 patients in Australia and New Zealand started on RRT and found 449 diagnosed with anti-GBM disease, 224 of whom were transplanted. Of those transplanted, 2.7% developed biopsy proven recurrence. So... it recurs, but rarely.

What about a false negative GBM antibody titer? Our patient's titer was negative, and the reported false negative rate for the ELISA and western blot is 2-3% making it unlikely. However, there have been case reports of anti-GBM disease with negative ELISA and weakly positive western blot suggesting low or transient antibody production. In addition, alternative immunoglobulins not picked up by the ELISA, such as IgG4, and alternative GBM antigens have been proposed based on case reports.

What else could produce diffuse GBM staining? In monoclonal immunoglobulin deposition disease the physicochemical properties of the monotypic light chains result in high affinity for the GBM and diffuse linear staining. In addition, in diabetic glomerulopathy, there is thought to be a loss of negative charge in the GBM which allows negatively charged species such as immunoglobulin and albumin to collect in and expand the GBM. Our patients SPEP and SFLC were normal, and the donor didn't have a known history of DM. 

In the end, we couldn't answer the million dollar question definitively, but we decided to treat with plasmapheresis, rituximab, and restarting prednisone and mycophenolate. Rituximab was used instead of cyclophosphamide due to previous complications during her initial treatment.  She's currently doing well with Cr stable at 1.5mg/dl

Posted by Patrick Reeves

(Picture is Dr. Ernest Goodpasture who first described this condition while studying victims of the Spanish Flu in 1919)

Tuesday, January 10, 2017

Renal Grand Rounds - What Lurks in the Gap

I recently presented the case of a middle-aged man with a history of a remote Roux-en-Y gastric bypass, chronic diarrhea, and colon cancer on chemotherapy who initially presented with progressive fatigue and weakness in the setting of increased diarrhea. Shortly after admission he developed agitation that progressed to encephalopathy with dysarthria. His baseline labs from a month prior to presentation were notable for a chronically low serum bicarbonate of 15-17 with no anion gap. When he presented he was hypokalemic to 2.5 and his bicarbonate had dropped to 11 with a new elevated anion gap of 25 and normal L-lactate. Metabolic acidosis was confirmed on VBG. Interestingly, his urine electrolytes demonstrated a positive urine anion gap of 26.

He was ultimately diagnosed with D-lactic acidosis based on his clinical presentation which was confirmed with a serum D-lactate of 6.28. For the week prior to admission, he had been drinking 1.5 L of Gatorade (224 g of sugar!) daily to replace diarrhea losses.

This was a classic presentation of D-lactic acidosis in which overgrowth of gram positive anaerobes in the setting of short bowel syndrome is combined with a large carbohydrate load resulting in bacterial fermentation and D-lactate production.  He even had the classic neurologic findings!  His chronic non-gap acidosis likely represented chronic diarrhea and D-lactate production, and his rising anion gap when he presented was consistent with increased D-lactate production.

In D-lactic acidosis, the findings of hypokalemia and a positive urine anion gap can provide a helpful clue. With elevated serum D-lactate levels, the fractional excretion of D-lactate approaches 100%, i.e. everything that's filtered is excreted. This is because the stereospecificity of the sodium-L-lactate cotransporter in the proximal tubule results in poor reabsorption of D-lactate relative to L-lactate. The negatively charged D-lactate essentially drags positively charged sodium and potassium into the urine causing hypokalemia as well as a positive urine anion gap (Na + K - Cl) due to the increased urine sodium and potassium.


This patient did well after his Gatorade was cut off and he was treated with antibiotics to address gram positive anaerobic overgrowth.

Posted by Patrick Reeves

(Image taken from here - an educational blog for ED residents)

Monday, January 9, 2017

Nephrology Business Leadership University

See below for details on a very interesting looking course for Renal Fellows:
We are excited to introduce a new innovative program available to Nephrology Fellows -   Nephrology Business Leadership University (NBLuniv.com)
NBLU is a unique week long program that brings together a diverse faculty of practicing Nephrologists, hospital and dialysis provider executives, and other healthcare professionals who will share their insights on leadership, the business of nephrology, and the evolving healthcare landscape.  Most sessions are held in a workshop format and are highly interactive and individualized.  

Fellows attending a NBLU rotation can expect to leave with:
1.Ability to evaluate potential employers for the ultimate fit
2.Enhanced leadership and business understanding to bring to potential employers
3.An understanding of the ever-changing payment / reimbursement landscape
4.The know-how to embark as a solo practitioner or as a high impact member of a group practice
5.Confidence approaching the interview process
6.Knowing you have the tools to start your career in the right direction

Topics Covered:
-Billing & Coding Workshop
-CV and Interview Tips
-ACOs, ESCOs Basics
-How to find the right job
-Growth Strategies for your practice
-Marketing 101
-Practice Management
-How to Review Employment Contracts
-Financial Planning
-Much Much More.......

NBLU will hold its second annual program from August 7th to August 11,2017 in Plano, Texas.
Since we would like to keep the sessions very interactive space is limited. 

Registration is free and can be done on the website NBLuniv.com

Travel support, hotel accommodations, and most meals are provided to all fellows that are attending.  There should be little to no out of pocket expenses to the fellow or their training program.

Program Organizers - University of California San Diego Division of Nephrology  & Dallas Renal Group (dallasrenalgroup.com)

TESTIMONIALS FROM FELLOWS ATTENDING LAST YEAR CAN BE VIEWED ON WEBSITE!  NBLUniv.com
Nephrology Business Leadership University

If you or your program director has any questions please feel free to contact me at cmiracle@ucsd.edu

Wednesday, January 4, 2017

Renal Grand Rounds - A Chilling Case of Hyperkalemia

A 62 year old man with ischemic cardiomyopathy (EF 35%) and CKD (baseline Cr ~3 mg/dl) had a witnessed out-of-hospital cardiac arrest.  EMS arrived within 3 minutes.  He received CPR and was shocked out of ventricular fibrillation (VF).  He was intubated and therapeutic hypothermia was initiated in the field. He was admitted to the CCU, where therapeutic hypothermia was continued for 24 hours.  He received aggressive KCl repletion for hypokalemia (see graph below) and supraventricular arrhythmias.  On the second hospital day the patient was rewarmed, developed severe DIC (INR 10), worsening shock requiring 3 pressors, and renal was consulted for hyperkalemia and oliguric AKI on CKD.


Clinical pearls: Hypokalemia is a frequent complication of hypothermia for two major reasons: 
1) cold diuresis, which is believed to result from peripheral vasoconstriction, increased venous return, and increased ANP; 
2) catecholamine-induced shift of KCl into cells.  
Interestingly, the latter seems to depend on the type of protocol used to induce hypothermia.  Core cooling increases norephinephrine but not epinephrine, and therefore does not cause a shift of K into cells.  In contrast, external cooling (which was used in this case, with the application of cooling pads) increases epinephrine disproportionately to norepinephrine.  The B2 agonist actions of epinephrine cause a shift of K into cells.  It is therefore critically important to avoid KCl repletion during rewarming due to the risk of rebound hyperkalemia, particularly in oliguric patients such as this one who are unable to deal with the excess potassium load once it moves back out of the cells during rewarming.
Posted by David Leaf


Come to KIDNEYcon April 7-8 2017 for hands on learning

When- April 7-8, 2017
Where- Little Rock, Arkansas
Who should attend- Internal Medicine Residents, Pediatric Residents, Adult and Pediatric Fellows, Attending Nephrologists

**if you are an adult nephrology fellow and interested in coming please note that you should take the in-service exam  April 5 or 6. talk to your program director or coordinator

Travel Grants- Available to Adult and Pediatric Residents and Fellows (DUE DATE Feb 17th)

REGISTER HERE

Mission Statement
KIDNEYcon is an annual two day educational event with a mission of fostering enthusiasm for careers in nephrology among residents and fellows and to provide educational updates on relevant kidney topics. An additional focus is to develop collaborative research projects between academic and private nephrologists.
Director- John Arthur, MD, PhD
Professor and Chief of Nephrology
University of Arkansas for Medical Sciences

Co-Director- Shree Sharma, MD
Nephropathologist
Arkana Laboratories, LIttle Rock, AR

Education Director- Matthew A. Sparks, MD
Assistant Professor and Associate Program Director
Duke University

KIDNEYcon is an annual conference designed to provide updates in the latest advances in kidney care in a hands-on collaborative format. A key component of KIDNEYcon's mission is to build enthusiasm for the field of nephrology among residents and fellows. We also aim to facilitate collaborative research projects among participants of the conference. The conference is a platform for nephrologists and medicine trainees to interact with experts from across the nation and learn about and discuss recent advancements in the diagnosis and treatment of kidney disease. The conference consists of Friday workshops targeted primarily to medicine residents, nephrology fellows and early stage nephrologists and a Saturday scientific and clinical conference with broader applicability.

KIDNEYcon 2017 will feature four interactive hands-on workshops
  1. The Kidney Biopsy Academy 
  2. Vascular Ultrasound for Assessment of Volume Status Workshop 
  3. Interventional Nephrology Workshop
  4. Social Media in Nephrology Workshop 
The Saturday session will be an educational meeting with multiple interactive sessions featuring case-based studies and audience response technology, followed by Q & A sessions with the expert panel.
One of the first duties of the physician is to educate the masses — Sir William Osler

Please consider coming to the conference. I am really excited about this years conference and our goal is to break the mold of the traditional conference. You will leave KIDNEYcon with more confidence and knowledge.

Matt Sparks

Monday, January 2, 2017

Wash U Web Episode - Kidney Pathology 101, "Welcome to 2017 Edition"

Happy New Year to all RFN visitors!  This month's nephrology web episode coming from Washington University is a primer on kidney histology.  Most of us can recognize the silver stain from the trichrome, but how many times have we looked at the H and E stain and confused it with the PAS?  Unfortunately, I have been guilty of this myself during many biopsy conferences.

Check out the video below:


Wednesday, December 28, 2016

Clinical Pearl - Bleeding and Liver Disease

Bleeding is a common complication of liver disease and given that we as nephrologists are sometimes asked to place lines or perform renal biopsies on patients with cirrhosis, it is important to know the physiology behind the reason for excessive bleeding in these individuals. Here is a nice clinical pearl from our Hematology colleagues at MGH:

Endogenous tPA is cleared by the liver and therefore circulating levels of tPA are elevated in patients with cirrhosis. This is the main reason that these patients bleed. Phrased another way, the main hemostatic defect in liver disease is not thrombin generation (defective production of procoagulant clotting factors) but rather accelerated clot lysis. Therefore, an antifibrinolytic treatment (like amiocaproic acid) that inhibits the binding of fibrinolytic molecules (plasmin, plasminogen) to fibrin and thus helps prevent breakdown of existing clots is an elegant and effective way to treat bleeding in cirrhosis. A reduced dose should be given in patients with renal dysfunction and it should be noted that this drug has been associated with AKI in some patients due to urinary tract obstruction and ATN.

Posted by Rebecca Karp Leaf MD and Walter Dzik MD.

Sunday, December 25, 2016

Top nephrology-related stories of 2016

2016 marks the 7th year of the Top Nephrology Stories post on RFN. When this list first started in 2010 it was more challenging to get the stories. Now 7 years later, everything has changed. In my mind the advent of Twitter and NephJC has changed all of that. We are more informed and better read on nephrology topics. All you need to do is go over to NephJC and look at what is being talked about. Everything is there. Discussion is deep and constant.

Announcement:

  • NephJC will host the #TopNephrology stories starting in 2017. 
  • We will use analytics from each of the chats throughout the year plus feedback from the NephJC team to create a #TopNephrology list. 
We hope these changes will result in an improvement and reflect the Top 10 stories that you need to be aware of. RFN is not going away and we have big plans for RFN. If you are a fellow and interested in posting to RFN please send me an email or DM.

Below are links to the last 6 years of the top nephrology stories hosted on RFN.

2010
2011
2012
2013
2014
2015 

10. HLA-incompatible live kidney donation survival benefit in NEJM (5%)- Coming in as a tie for number 10 is a study reported in NEJM (March 2016) and covered by NephJC. It is well known that kidney transplantation is the best form of renal replacement therapy. However, there is a limited number of organs to meet the growing demand. Furthermore, patient related factors such as the presence of anti-HLA antibodies are another factor lengthening the wait time and often preventing transplantation. This study looked at matched patients (not a randomized trial).

  • One group of kidney transplant recipients undergoing a desensitization protocol with a live donor incompatible kidney transplant
versus
  • A matched group who underwent deceased donor kidney transplant with a match or remained on the wait-list. 
The study looked at multiple kidney transplant centers between '97-'11 The results were striking. Patients who underwent a live incompatible kidney transplant with desensitization protocol had a significant survival advantage compared to wait-listed patients and wait-listed + deceased donor. However, it must be noted that the desensitization protocol itself has side effects and careful consideration is needed before using this method. This study is important because it represents a significant advance in generalizing the use of desensitization for patients unable to obtain a kidney transplant because of preformed antibodies.

10. ELAIN Trial of early versus late HD in the ICU in JAMA (5%)- This spring started off with a bang. Back to back presentations of renal replacement therapy in the ICU showing different results. First the AKIKI Trial (our number 3 story) was presented at the Critical Care meeting in San Diego and reported in NEJM and showed no difference in early versus late. A few weeks later came the ELAIN (Early vs Late Initiation of Renal Replacement Therapy in Critically Ill Patients With Acute Kidney Injury) Trial. This was a single-center randomized trial presented at the ERA-EDTA Congress in Vienna, and reported in JAMA. They found a significant reduction in 90-day all-cause mortality in the early initiation group. Some important caveats.

  1. This was a single center study (AKIKI was multicenter).
  2. Majority of patients were surgical ~80% (AKIKI ~80% medical) 
  3. 100% were CVVHDF (AKIKI ~30% CRT) 
  4. Only 4% in late group avoided RRT (~50% in AKIKI). 
Bottom line- these were very different studies and hence had very different results. Could a select group of patients with a more defined ischemic insult benefit from early RRT in the ICU? Jury is still out but the ELAIN Trial would suggest this to be true.

9. EuLite Trial of high cutoff dialysis in myeloma presented at UK Kidney Week (6%)- The long awaited results from the EuLite Trial were presented at UK Kidney Week this year. See Paul Phelan's post on RFN from way back in 2013. Unfortunately, the EuLite Trial isn't published just yet so we have is the live Twitter coverage from the meeting. The premise is that High Cutoff (HCO) Dialysis would provide benefit from removing toxic free light chains in myeloma cast nephropathy. HCO dialyzers employ high flux membranes with particularly large pores (up to 50kDa Vs 15kDa for conventional high flux) facilitating the removal of large plasma proteins such as FLC (kappa and lambda light chains have molecular weights of 22kD and 45kD respectively). The EuLite Trial is a randomized clinical trial testing the use of HCO dialysis versus standard dialysis  in patients with myeloma case nephropathy. Unfortunately, HCO Dialysis arm of the study had more mortality compared to the standard HD arm hinting at harm. We all eagerly await the full publication to be reported to we can really delve deep into this study. Looks like the early enthusiasm for HCO dialysis in myeloma cast nephropathy is fading as well.

7. Contrast nephropathy study in JASN (8%)- September brought a bombshell of a study. The Wilhelm-Leen, Montez-Rath and Chertow paper looked at the risk of acute kidney injury in the days following a dose of radiocontrast. And the researchers could find no hint of AKI. To say this counters nephrology dogma is an understatement. If Moses had brought down the Nephrology Ten Commandments, Thou shalt avoid radiocontrast would probably be in the top three, following only by Thou shalt monitor and control one’s blood pressure and Thou shalt not eat so much salt. The investigators used NIS, the largest publicly available all-payer inpatient care database, this covers 96% of the US population and used diagnosis and procedure codes to find exposures and acute kidney injury. Despite that limitation the result is so provocative that it begs relooking at this toxicity with open eyes. Of note similar findings have been published in the radiology literature for years: McDonald JS, Bruce RJ, while others have upheld the orthodoxy.

7. "Fistula First" survival benefit is due to patient factors in JASN (8%)- If contrast nephropathy is really just a figment of confirmation bias, then at least we know that fistulas are the best hemodialysis access and convey a true survival benefit. Or maybe we don’t know that. The same issue of JASN brought us the work of Robert Brown, Bhanu Patibandla and Alexander Goldfarb-Rumyantzev. The thread that triggered this investigation was the repeated observation that every study that revealed a survival benefit for starting with a fistula (all observational and retrospective data) also showed that catheter patients were different from patients starting with a fistula. Often the catheter patients were older, more urban, shorter pre-ESRD nephrology care, more diabetes, more cerebrovascular disease, and more heart failure that the patients starting with a fistula. The authors looked for a way they could separate fistula patients from these inherent biases that could explain the survival benefit these patients enjoyed. The authors divided elderly new starts to hemodialysis into three groups:
  1. Started dialysis with a fistula 
  2. Started dialysis with a central venous catheter, but had a fistula that was maturing when they started dialysis 
  3. Started dialysis with a central venous catheter 
If the fistula was driving mortality, group 2, that is dialyzed with a catheter, should have outcomes similar to group 3. If the patient characteristics were driving the survival advantage of the fistula, group 2 should look like group 1.

The money quote from the conclusion
although this study has confirmed the approximately 50% decreased mortality experienced by patients initiating hemodialysis with an AVF compared with a catheter, it showed that about two thirds or more of this mortality benefit is also seen in those initiating hemodialysis with a catheter but who had previously undergone unsuccessful fistula placement. Thus, these observational data suggest that the actual mortality attributed to the catheter itself is much less than previously considered and may be explained in large part by differences in patient factors. 
Similar conclusions were published in JASN this October using Canadian data. That team is planning on confirming these results with a randomized controlled trial of fistulas versus catheters (see this Medscape article, log in required). That will be amazing!

6. US Congress expands Medicare coverage for acute dialysis coverage (10%)->In June of 2015 the nephrology world suddenly became very interested in the Trade Preferences Extension Act of 2015. Because politics is hard, an important bill for acute kidney injury got stapled to this larger "Transporter bill". On June 29th President Obama signed the bill and section 808 became law.
Specifically, Section 808 of the law amends the Medicare statutes to provide coverage for “renal dialysis services furnished … by a renal dialysis facility or provider … to an individual with acute kidney injury.” 
This overturned a CMS ruling from 2012 that forbid medicare reimbursement to dialysis providers for the condition of acute kidney injury. This left lots of patients in a lurch. Patients unfortunate enough to develop AKI often would recover from their acute illness but they would have to remain in, or close to, the hospital as their acutely dtysfunctioning kidneys recovered or didn’t. Until a nephrologist was willing to give up hope and declare the patient ESRD, that patient would not be able to receive dialysis anywhere but the hospital. This esoteric bureaucratic red tape of where and when people could get dialysis hurt patients and it is nice to see this straightened out, even if it was passed in 2015 and doesn’t go into effect until January 1, 2017.

5. Nephrology societies embrace social media (11%)- Most of the nephrology societies have had a social media presence for many years (see this Twitter list from Joel Topf) however, 2016 marked some sort of a watershed in the seriousness, enthusiasm and effort taken by many of them to really engage with social media.

The American Society of Nephrology (ASN) has a very active Twitter presence, and actively tweets out the latest breakthroughs in research and other news in the nephrology universe. Along with ASN Kidney News and ASN Advocacy, the two flagship journals, JASN and CJASN, also have active Twitter handles, and are progressively using the medium effectively for communication. But two other initiatives stand out in all the things the ASN does on social media this past year: #askASN and ASN communities. Once every month, the ASN brings forward an expert for the #askASN chats (some of the featured guests include Richard Lafayette who runs Kidney News, POTASN Ray Harris and PEOTASN Eleanor Lederer, KidneyWk organizers Roy Zent and Patrick Nachman, and SPRINT investigators George Bakris and Bill Cushman) to answer questions from the nephrology Twitterverse. Secondly, a few months ago, spearheaded by Zachary Cahill, the ASN launched a forum, ASN Communities. It has gathered steam, and now boasts 8 separate communities (the Open Forum and Patient Care being most active, with Onconephrology, Transplant, AKI, Basic Science, Supportive Care, Training Program Directors being the others), with over 3,000 discussion threads!

The ERA-EDTA has been on Twitter for a while, but they publish two journals, and until recently didn’t have a social media presence. But they stepped nicely to a request, and @NDTsocial and @CKJsocial were born. Both have been actively tweeting out snippets of the latest nephrology literature (with CKJ continuing to be an #openaccess journal) over the last year.

The International Society of Nephrology (ISN) is ramping for the upcoming World Congress of Nephrology, scheduled to be held in Mexico in 2017. The ISN does have an active education committee and holds regular webinars, but for the WCN, they have established a WCN 2017 social media task force make up of 20 nephtweeters from around the world. We look forward to their coverage of the WCN2017.  Now only if someone could persuade Kidney International to join Twitter…

The National Kidney Foundation (@NKF) is also active on Twitter and actually sets the record for number of followers ~19,000. The NKF Spring Clinical Meeting (@NKFClinicals) was much more active this year and featured a live social media workshop. Next years meeting is featuring a social media ambassadors program at SCM17. Of course AJKD was an early adopter of social media and a leader in the space with AJKD blog,  NephMadess, and AJKDonline Twitter handle.

4. Empagliflozin approved for CV indication by FDA (13%)- A common refrain in the diabetes literature has always been a lack of benefit seen for hard outcomes with hypoglycemic agents, with metformin being a lone exception. This all changed with the EMPA-REG trial, which made it to the #TopNephrology stories in 2015 as number 2. At that time, we just had the late breaking trial to work on, but it was already huge news. The subsequent publication in NEJM was covered at a #NephJC session too. The need for this trial to be done is very interesting – until recently, showing a drug lowers blood sugar was the most important aspect of getting FDA approval. After the debacle behind rosiglitazone (avandia) and the possible risk of greater cardiovascular events despite lower blood sugar, the FDA mandated larger trials to demonstrate CV safety. EMPA-REG was one such trial, and demonstrated remarkable benefit in lowering CV outcomes. The FDA followed suit, and on Dec 2 announced a new indication for empaglifozin – for reducing cardiovascular death in patients with type 2 diabetes. The SGLT-2 inhibitors have indeed come a long way in a short period of time.

3. AKIKI Trial of early versus late dialysis in the ICU in NEJM (20%)- Coming in at #3 in this years poll is AKIKI. AKIKI was also the winner of the #NephJCKidneys at KidneyWk for Study of the Year. The timing of renal replacement therapy has been rated as a top priority for research in the AKI world. Indeed, in the last few years, clinical practice has slowly crept ahead of evidence, as it often does, and dialysis is being initiated earlier and earlier for acute kidney injury. And then came along the Artificial Kidney Initiation in Kidney Injury (AKIKI) trial, to do what IDEAL did for timing in the chronic dialysis field. In this trial, 620 patients with AKI were randomized to either early strategy (with RRT initiation at stage 3 AKI per KDIGO criteria) or delayed strategy, when a clinical indication occurred (eg hyperkalemia, pulmonary edema, or persistent oliguria > 72 hours). There was no difference in mortality, with only half the patients needing dialysis in the delayed group, who also had significantly less bloodstream infections. Check out the #NephJC coverage for more details.

2. PPI and CKD risk in JAMA Internal Medicine and JASN (22%)- This was big. Another important paper dropped in nephrology literature during springtime. We had AKIKI, ELAIN and now PPI causing CKD all Feb to April. The PPI leading to CKD story was first reported in JAMA Internal Medicine then in JASN. NephJC covered this and you can view the background and both chats here. While a rare association between PPI use and interstitial nephritis has been known for a while. Their association with chronic kidney disease had not been reported before. The JAMA Internal Medicine paper is an observational, prospective cohort study with two cohorts. The first is the Atherosclerosis Risk in Communities (ARIC) study, of which 10,482 participants were included. The second was the much larger Geisinger Health System Replication (GHSR) Cohort, with 248,751 participants. Participants using either PPIs or H2 antagonists were compared with each other to evaluate their respective risk of developing kidney disease. A propensity score-matched analysis was conducted to minimize confounding variables and identify whether baseline PPI use was associated with CKD. It is important to note that PPI users in both cohorts were more likely to have a high BMI, hypertension, cardiovascular disease, and exhibit polypharmacy (with antihypertensives, aspirin, diuretics and statins). They found that PPI use is associated with a higher risk of incident CKD. The JASN paper from Xie et al used a Department of Veterans Affairs national databases to build a primary cohort of new users of PPIs (173,321) and new users of H2 blockers (20,270) and followed these patients over 5 years to ascertain renal outcomes. In adjusted Cox survival models, the PPI group, compared with the H2 blockers group, had an increased risk of incident eGFR decline less than 60, incident CKD, and a graded association between PPI duration and risk of renal outcomes. Both of these studies point to a fundamental issue in medicine. Polypharmacy. We need to remain vigilant to remove medication that have no clear indication. PPIs once thought of as innocuous now have real risk associated with them.

1. suPAR from bone marrow myeloid cells in Nature Medicine (64%)- Coming in at # 1 this year is a basic science paper just published a few weeks ago in Nature Medicine. Just like the Gli1 story of 2014 we will also have to add an asterisks to this win. The suPAR aficionados really came out in force with heavy voting and it is not a surprise for us as suPAR has been a consistent story for the last 7 years. suPAR graced the TopNephrology stories in 2011. In fact, it hit the number 1 spot with the original Nature Medicine paper describing its potential link to FSGS. Then in 2015 suPAR was unable to crack the top 10 and landed at number 14 with the NEJM paper linking suPAR to CKD in a cohort of patients at Emory undergoing cardiac catheterization. Now in 2016, suPAR does it again. Our #1 story. The current study seeks to identify with cellular source of soluble urokinase plasminogen activator receptor (suPAR) which the above studies have implicated in CKD. Most notable is the fact that if a patient with FSGS receives a kidney transplant unfortunately their is a high chance of recurrence. Thus, implicating an extra renal "factor" like suPAR leading to kidney damage. Utilizing a combination of bone marrow chimera, ablation and cell transfer studies that suggest that Gr-1lo immature myeloid cells of bone marrow origin is the source of suPAR and a key contributor to glomerular damage. A very interesting observation that will no doubt lead to more studies on the link between bone marrow derived cells and kidney function.

Another busy and exciting year in the world of nephrology in 2016. Thanks to all of the contributors and readers in the nephrology online community for keeping nephrology fun, interesting and educational. Next year the #TopNephrology stories will be moving to NephJC.

Thanks for supporting RFN and NephJC. Happy holidays from the entire team.

Can't wait to see what 2017 has in store!

Don't forget to sign up for the NephJC email to keep up to date

Post by Matt Sparks, Swapnil Hiremath, and Joel Topf

Wednesday, December 14, 2016

Renal Grand Rounds: Fevers on Dialysis - Not always an Infection

At renal grand rounds this week, I presented a case of a gentleman who presented with fevers, confusion, and lower extremity pain during dialysis. The patient would spike low grade fevers pre-HD and then fevers up to 105 post-HD. He had a tunneled HD line, but blood cultures were negative, and his fevers persisted in spite of changing the line. We were initially concerned for a dialyzer membrane reaction, but the time course of fevers was not consistent with either type A or type B reaction, and his symptoms persisted even after switching to an Exceltra membrane. The patient was worked up further, and his serum electrophoresis revealed 2 M components, serum free light chains showed an elevated Kappa/Lambda ratio, and he had a positive urine Bence Jones protein. His CH50 and C4 levels were undetectable, but C3 was only mildly low. Cryocrit was sent, and was positive for a type 2 cryoprotein with a predominant IgM Kappa component.
It was unclear why the symptoms of cryoglobulinemia worsened with dialysis; it was hypothesized that hemoconcentration with ultrafiltration, along with exposure of blood to cooler temperatures within the dialysis tubing led to transient complement consumption and an inflammatory reaction. The symptoms of mixed cryoglobulinemia are typically nonspecific, and patients usually present with arthralgias, fatigue, palpable purpura, and peripheral neuropathy. C4 and total complement are usually dramatically low, as in this case.
Treatment of cryoglobulinemia usually involves the use of plasmapheresis to remove circulating cryoglobulins. Steroids are suppressive in some patients, and rituximab quells formation of new cryoglobulins.  There are no studies aside from case reports about the use of eculizumab for cryoglobulinemia. Trendelenburg et al analyzed the role of complement in glomerular inflammation using mice models, and showed that mice deficient in C5 had reduced glomerular infiltration by neutrophils. Eculizumab inhibits the conversion of C5a to C5b and subsequent formation of the membrane attack complex; it therefore be theoretically useful in treating cryoglobulinemia, which causes complement mediated renal failure.
The patient was treated with 2 doses of eculizumab and then rituximab for cryoglobulinemia, and is now doing well and tolerating dialysis.
Posted by Shruti Gupta, Renal Fellow MGH/BWH

Thursday, December 8, 2016

The Painless Guide to Mastering Clinical Acid Base

Apologies to Ben for the delay in posting about this.

Ben Abelow is an MD in New Haven who has long had an interest in teaching basic acid base physiology. In the late 1990s he published a primer for acid base that was very well received. Earlier this year, he published a new book, also on acid base physiology called "The Painless Guide to Mastering Clinical Acid Base". The purpose of this book is to help medical students and junior trainees grasp the basics of how to approach acid base problems while also give them the tools that they need to effectively teach acid-base in a simple and easy to understand way.

The first part of the book in particular very simply explains the basic chemistry behind acid base physiology and is very useful - I learned a few pearls that I will be using on rounds in the future. The rest of the book may be a little simple for renal fellows but it is short and very accessible so I think it is well worth reviewing at least once.

Ben's book is available on Amazon. He has also offered it for free to all first year renal fellows in the US. He is contacting program directors around the country to send them the book. If they are not responsive, he will be able to provide the books to individual fellows.

Thanks again Ben for this - students are always complaining that Renal Physiology is too complex but this really does make it simple

Green dialysis: what to do with discarded water used during dialysis?

Global warming is a growing threat to our health. Dialysis, while sustaining the lives of millions worldwide, has a significant environmental impact. Think of your last dialysis order. Perhaps the Kd was 500 ml/min for four hours. That’s 120 L. Dialysis units may waste up to 2/3 of the reverse osmosis (RO) water used for making dialysis. So add another 240 L. If you include additional saline used for used for priming and cleaning HD machines we may use between 400-500 L of water per 4-hour treatment. And that’s with a modest Kd of 500 ml/min.

Considering the global dialysis population, over 150 billion L of water are likely used every year with potentially 2/3 of that water discarded prior to dialysis. That’s about 40,000 Olympic swimming pools filled with wasted water. It should be noted that depending on your unit’s specific water system there may be less waste and increased recycling opportunities, but overall this remains a significant area of impact for dialysis on the world. And these concerns do not include the power and plastic needs generated by dialysis, which are also significant.

Does it have to be this way? RO “reject” water is more than just potable. It went through particulate filters, carbon filters, and water softeners prior to reverse osmosis. What emerges is practically expensive mineral water. It passes the WHO/EPA requirements for drinking water though is not legally considered potable.

Instead of going down the drain, RO reject water could be used for:
  • Steam generation for hospital sterilization 
  • Laundry services 
  • Sanitation services 
  • Landscaping 
  • Almost anything you already use water for 
Reusing dialysate is more challenging given the higher conductivity (salinity) and the requirement for either recurrent RO or sorbent therapy. This can be cost-prohibitive and technologically challenging.

How much RO water does your unit’s system reject?  
Is there a way to use that water if it is not already being used? 
Beyond that, can recycling be further emphasized for both in-center and home patients? 
Perhaps in some places solar-assisted hemodialysis is an option?

One day perhaps rejected RO water can grow fruit and veg on the roofs of dialysis units. Providing sustainable, affordable nutrition to those who need it most.

If you are intrigued, the following resources offer a starting point to making dialysis more environmentally sustainable.


Robert Rope, Nephrology Fellow- Stanford
 

Sunday, December 4, 2016

Top Nephrology- Related Stories of 2016: The Nominees Call


It's that time of the year. Time to create the Top Nephrology Stories of 2016. These can range from basic to clinical research, and even include news stories. Basically anything that made an impact. Before the voting begins put your story in the mix by placing a nomination over at this Googledoc or comment below.

Thursday, December 1, 2016

Nephrology Web Episode #12 - Understanding the Free Water Deficit

Understanding that serum Na abnormalities almost always imply a problem with water is something that has been hammered into us since pre-clinical med school years.  And whenever a nephrology attending asks you what is going on with a patient with hypernatremia, you can always answer "Not enough water!" and be 100% correct.

However, when it comes to the free water deficit, many renal fellows still pull out their smartphone apps and med students still pull out their pocket notecards.  This video will hopefully demystify this equation, reinforce your understanding of water repletion, and provide a clinical shortcut for you to quickly estimate a patient's water deficit within seconds.  Hopefully you find it helpful!


Saturday, November 12, 2016

2016 #KidneyWk Tweetup and Get Out the VOTE Reminder

This years 7th annual Tweetup at ASN Kidney Week in Chicago will be held at Benny's Chop House on Friday night from 7:30 to 10pm. We would love to see everyone show up. The night will include The Year in Nephrology Social Media Review by Joel Topf, NSMC Internship Graduation, and the handing out of the inaugural NephJC Kidney Awards. The last day to vote for the NephJC Kidneys is THIS Sunday so get it in. Link is below.






Sunday, November 6, 2016

The #NephJCKidneys: What's up with that?

NephJC is gearing up for Kidney Week in Chicago. NephJC is also sponsoring the inaugural NephJC Kidneys. You thought the Grammys or Emmys were big? Well, wait until you see the Kidneys hosted by none other than Kidney Boy!


This is a a way to say thanks to so many of you who use social media as a means to learn and share information. Renal Fellow Network (RFN) was one of the first blogs to really show the power of social media in educating so many. The founder of RFN was Nate Hellman and as such the Social Media Initiative of the Year Award is named in his honor. What Nate did in founding RFN is quite remarkable. This was before Twitter and right when Facebook was taking off. Nate put down the foundation for what is now a vibrant international community. I know if he were still with us he would be the one running NephJC or NephMadness or who knows what he would have created.

We wanted to reward as many individuals as possible but we know that many others are just as deserving.

Winners will be announced at the annual TweetUp on Friday Night at Benny's Chophouse.

NephJC Rookie of the year:
J Brian Byrd 
Eoin O. Sullivan 
Silvi Shah 

Engaged Scientist of the Year: 
EXTRiP Workgroup 
Stephane Gaudry 
Ben Humphreys 
Rafael Kramann 
Stuart Goldstein 

Most Valuable Player of the Year: 
Kevin J Fowler 
Rob Peel 
Malvinder Parmar 
Daniel Coyne 
Florian Buchkremer (@swissnephro)

Nathan Hellman Award for Social Media Initiative of the Year:
Timothy Yau for WashU Nephrology Web Episodes
H. Sternlicht for Concepts in Hypertension  e-newsletter
Tejas Desai for NephOnDemand Analytics
Zach Cahill for ASN Communities

Study of the Year:
EMPA-REG
Proton pump inhibitor use and risk of chronic kidney disease
SPRINT
AKIKI

The first 3 categories are voted on my members of the NephJC work group while the last 2 are public voting. Google login required to prevent multiple votes.

Friday, November 4, 2016

BWH Path Conference - AIN... or is it

Nephrology was consulted by the general medicine service for AKI in an elderly man with endocarditis. He had MSSA bacteremia for which he was being treated with oxacillin and rifampin. There was no report of rash or recent fever. He had no aminoglycoside, IV contrast, or NSAID exposure, and no severe hypotension. His creatinine had risen from 1.1 on admission to 1.8 mg/dl. Urinalysis showed 3+ blood, 2+ protein, and trace leukocytes. Urine sediment showed 5-10 WBC, WBC casts and dysmorphic RBCs. He had no RBC casts, and no granular casts. He had a peripheral eosinophilia (2%). Urine eosinophils were negative. Serologies and complement levels were normal. Oxacillin was discontinued under the presumptive diagnosis of AIN secondary to beta-lactam antibiotics. Despite this intervention, his creatinine continued to rise and a renal biopsy was obtained. The biopsy results are shown below:
Two glomeruli with diffuse hypercellularity of the tuft. There is minimal interstitial inflammation


The infiltrating cells in the glomerular capillaries are predominantly mononuclear cells with isolated neutriphils.



Scattered deposits of IgG are noted along the peripheral capillary walls and in the mesangium.


EM shows large and confluent subendothelial electron dense deposits.

Diagnosis: Diffuse proliferative glomerulonephritis, most likely post-infectioius and related to the patient's sepsis.

This case appeared to be a relatively straight-forward case of AIN based on the exposure to a common culprit medication, the presence of eosinophilia and urinary white cell casts and the time course following admission. The presence of dysmorphic red cells was atypical although this is observer-dependent and there were no red cell cats which, while specific, are not very sensitive for the diagnosis of an acute GN. Traditional treatment comprising withdrawal of the offending medication and potential exposure to steroids may have been detrminetal in his case leading to inadequate treatment of his MSSA bacteremia.

The classic constellation of clinical signs in AIN is present in a minority of cases. For example, rash is present in ~15%, fever in 27%, eosinophilia in 23% and the triad in only ~10% of patients. White blood cell casts are sensitive but are a non-specific marker of intra-renal inflammation and are associated with a wide differential diagnosis. Urinary eosinophils are neither sensitive or specific and should not be used to make the diagnosis of AIN.

This case highlights the difficulty in making a clinical diagnosis of acute interstitial nephritis and the importance of a renal biopsy to confirm the clinical suspicion.

Posted by Katherine Garlo

Saturday, October 8, 2016

2 Free Kidney iBooks Available (yes FREE)



Paul G. Schmitz (Saint Louis University TPD) recently published 2 new textbooks useful for students, residents, and fellows interested in kidney disorders. These are both FREE downloads from the iBooks store. These are both self-published and interactive (Macs, iPhones, or iPads for now). Content updates will also be free and will be performed by student, resident, and fellows.

Check them both out and provide Dr. Schmitz some feedback. They look fantastic.

Wednesday, October 5, 2016

Young adults and kidney donation - To do or not do.

A short article was recently written on Washington Post by a medical student who donated a kidney at age 18 to his brother's stepfather and now regrets it. Worth a reading (link here).

 He questioned the informed consent and the poor quality data we have for long-term outcomes after donation, including the fact that we don't have a donor registry that captures all donors in the USA.

 Age of donation is an important factor to consider when assessing the potential long-term risk of kidney donation. Younger kidney donors have a greater chance of suffering a second-hit leading to kidney injury through their lifespan, in particular with life expectancies surpassing 80 years in many countries. Therefore, it is generally recommended to be more stringent in the selection of younger donors. But how should we as a Society respond to this? How individual centers approach younger donors below 30yo? Would love to hear our community thoughts on this.

 Figure from Kidney Transplant iBook (adapted from Mjoen et al. Kidney Int 2014)

Monday, October 3, 2016

Video CPC - Renal Pathology Episode #011

Try your diagnostic and biopsy reading skills as we work through an unknown case that demonstrates some very interesting renal pathology. Dr. Gaut, section head of nephropathology at Washington University in St. Louis and Dr. Younus, a 2nd year renal fellow, will read a complicated biopsy together. The diagnosis is purposefully not revealed here because the case is a real zebra!  Check out the video below.

Monday, September 5, 2016

Video Introduction to Understanding Lupus Nephritis Classification - Wash U Episode # 010

The 10th episode of the Washington University Nephrology Web Episodes delves into lupus nephritis.  This video discusses the evolution of classifications over the years from the early WHO to the most recent ISN/RPS classifications, in addition to demonstrating active and chronic lesions.  You can view the homepage here, and a link to the most recent video below.