#NephMadness 2017- A Message from the President of the World Ciliopathy Society**

The results are out and the first round is a shocker. What was the panel thinking? KT/V beating depression was a shock to me but just shows how obsessed nephrologists are with numbers. But it was the choice of podocytopathies over ciliopathies that really pushed me over the edge – there’s NephMadness and then there’s just crazy behavior!

The primary cilium is an unassuming structure, its tiny hairlike form apparently no match for better known and more loved podocytes. Ciliopathies are not merely an expanding group of conditions, they are a disease group in which clinical genetic testing, research level genetic testing and functional genomics are dramatically broadening our knowledge base. As it becomes apparent that phenotypically disparate conditions, from isolated retinitis pigmentosa to Bardet-Bieldel syndrome, can result from mutations in the same gene, the importance of understanding the structure and function of the primary cilium becomes increasingly obvious.

Conversely, that disparate genetic mutations affecting different proteins can cause identical multi-system phenotypes, such as Joubert syndrome, has changed how these diseases are classified. Is it enough to define a disease by how it affects the patient? Should it be defined by the molecular change or by the genetic mutation itself? How do co-mutations, mutation type, or the concept of oligo-genetic inheritance impact on cilial function?

For this renal geneticist, deciding between podocytopathies and ciliopathies should have been simple – choose the multi-system disease group where research is expanding scientific knowledge.

Can someone explain to me why the podocytes won?

Post by Cathy Quinlan follower her @KidneyCathy

**This post is not actually from the president of the world ciliopathy society. This is a parody in the spirit of NephMadnes

#NephMadness 2017: The Gut Microbiota and Kidney Disease- Will it Survive the Hype? #NutritionRegion

I was very excited to see delightful topics in the Nutrition Region of this year’s #NephMadness, especially the Gut Microbiome and Kidney Disease. Before starting my Ph.D., I was aware that the colonic microbiota existed, but I acquired a very different perspective by being in contact with many researchers investigating the effects of our microbial friends in animal models of certain diseases (e.g., obesity, inflammatory bowel disease, and menopause), but also in humans (e.g., changes throughout the life cycle, autism-spectrum disorder, effects of exercise). I began to read about the topic and was amazed by the data linking metabolites of microbial origin and kidney disease progression, cardiovascular disease, mineral and bone disorder, and mortality.

Despite all of the aforementioned convincing studies, data on the gut microbiota structure (what microbes are there?) and their function (what are they doing?) is very scarce among patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). In 2013, Vaziri et al. showed that the bacterial species richness is decreased in patients undergoing hemodialysis (HD). Specifically, bacterial families that have been traditionally associated with positive outcomes, such as Lactobacillaceae and Prevotellaceae, were decreased. Also, it was revealed that bacterial families that have been associated with detrimental effects are enriched in hemodialysis (HD) patients. Then, the same group later showed in an in silico analysis that bacterial families that possess the enzymes needed for two of the most famous bacteria-derived uremic toxins (indoxyl sulfate and p-cresyl sulfate, which are derived from the fermentation of tryptophan and tyrosine, respectively) are enriched in the microbiota of HD patients. In 2016, in a very elegant study, Devlin et al. showed that by knocking out the tryptophanase gene in Bacteroides thetaiotaomicron, the production of indoxyl sulfate was eliminated in mice.

These studies are remarkable, but how can we modulate the presence/absence of specific bacteria in CKD and ESKD? Several studies have demonstrated that fermentable dietary fiber (bacteria’s favorite food), may be beneficial. Bacteria that have been traditionally considered beneficial, degrades these carbohydrates. Meijers et al. supplemented 20g of oligofructose-enriched inulin (the adequate intake of fiber recommended for healthy females and males is 25g/d and 38g/d, respectively) to HD patients and found out that after four weeks of treatment, the levels of p-cresyl sulfate were reduced by 20%, but there was no change in indoxyl sulfate. Poesen et al., similarly supplemented 20g of arabinoxylans and found a small decrease in trimethylamine N-oxide (TMAO), another unwanted bacteria-derived metabolite, but not p-cresyl sulfate or indoxyl sulfate. Other researchers have used synbiotics (pro + prebiotics) with the thought that, by providing “beneficial” bacteria and the food for these bacteria, a shift in the microbiota would occur. Rossi et al. supplemented 15g/d of a mixture of fermentable dietary fibers (inulin, fructooligosaccharides, and galactooligosaccharides) and 90 billion CFU probiotic strains/d from the Bifidobacterium, Lactobacillus, and Streptococcus genera to CKD patients. The authors concluded that the synbiotic decreased p-cresyl sulfate, but not indoxyl sulfate. In addition, it was revealed that there was an increase in the relative abundance of Bifidobacterium and a decrease in Ruminococcaceae. Given these findings, the supplementation of prebiotics and synbiotics has resulted in certain positive outcomes; however, these results have been inconsistent.

Therefore, what should researchers do next? In my opinion, we should be looking into what patients are eating, instead of just supplementing them. Diet is one of the main determinants of the gut microbiota. CKD and ESKD patients have very distinctive diets characterized by a restriction of dietary phosphorus, sodium, and potassium. This approach may lead patients to limit their intake of foods that are high in dietary fiber, such as fruits, vegetables, legumes, whole grains, and nuts. These food groups additionally contain other compounds, such as phytochemicals, which may also affect the gut microbiota. To date, however, no studies are assessing the effects of the traditionally restrictive renal diet in comparison to a more “liberal” diet on the gut microbiota structure and function of CKD and ESRD patients.

In conclusion, will the gut microbiome in kidney disease survive the hype? In my opinion it WILL. There are several ongoing studies and many studies to be performed since we already know that metabolites that are produced by our microbial friends (or enemies?) affect the progression of kidney disease in addition to outcomes in this population. Additionally, newly high throughput technologies will enable us to perform it into more detail, not only to find out who is there, but also what they are doing and how are they doing it.

Annabel Biruete
Ph.D. student in Nutritional Sciences at the University of Illinois at Urbana-Champaign
#NSMC intern
follow her @anniebelch

Attention Fellows: Attend the Origins of Renal Physiology Fellows Course 2017

The National Course for Renal Fellows: Origins of Renal Physiology (August 27 – September 3, 2017), is filling up fast.

This 1 week course provides a strong foundation in renal physiology for future renal investigators, teachers and clinicians.

Join 28 of your colleagues from around the country at the Mount Desert Island Biological Laboratories for this highly rated, transformational course.

Origins of Renal Physiology is entirely unique among national renal short courses. The course provides participants with research tools that give them a deeper understanding of concepts of physiological homeostasis which is difficult to attain during normal clinical training schedules. In this course, trainees will perform experiments involving both classical physiological models, as well as modern reductionist approaches and confocal microscopy to follow trafficking of transporter proteins in cultured cells. In addition to the curriculum itself, fellows will benefit from close interactions with senior investigators in renal physiology, who will guide them through the performance of the experiments, share meals with them in the dining room, and take the time to discuss their career goals with them. In addition, fellows will benefit enormously by working closely with other fellows from different programs, and sharing their insights into renal research. The course is organized around several laboratory modules and one enrichment module in Responsible Conduct of Research. Participants will complete three of the rotations over the six-day course. The first day of each rotation involves intensive experimental work, and the second day involves analysis and presentation of the work to the entire conference group.

Apply here. 

Note: This is a fantastic opportunity. Don't even think twice about it. SIGN UP and GO!!! I would go back in a heartbeat. Matt Sparks (2008 Alum)

Lupus Podocytopathy

I recently finished my 2^nd month on the consult service which was a very exciting time for me because I saw patients with every class of Lupus with different kinds of presentations. It was especially rewarding because I biopsied majority of these patients myself and then followed their course through diagnosis, initiation of immunosuppression and witnessed improvement in subsequent clinic visits. I find Lupus Nephritis most fascinating among all the GNs.

One of the most interesting cases I saw since the beginning of fellowship was of a 36 yrs. old woman who presented with joint pain, malar rash, photosensitivity, worsening generalized edema and nephrotic range proteinuria of 8 grams. She had 2 prior renal biopsies- one with a diagnosis of Minimal Change Disease and the second one 2 years ago with FSGS tip lesion and Class 2 lupus Nephritis.

On her current presentation, she met the ACR criteria of diagnosis of SLE. We biopsied her again and essentially found the exact same lesion- FSGS tip lesion with Class 2 lupus nephritis.  There were only scant mesangial deposits, no endocapillary proliferation or necrosis and weak but full house staining on IM. EM showed diffuse foot process effacement. We diagnosed her with Lupus Podocytopathy and she was started on high dose steroids and immunosuppression with MMF with subsequent rapid resolution of symptoms and proteinuria to 0.8 grams within 2 weeks. It remains to be seen how she continues to respond to the treatment and if she remains in remission. She still is likely to relapse in future and switch to a different class of lupus nephritis along her course.

Podocytopathy is a glomerular disease which occurs due to extrinsic or intrinsic primary podocyte injury. Lupus Podocytopathy occurs in association with new or relapse of SLE signs and symptoms.

It is a rare presentation of Lupus Nephritis - the reported incidence is 1.33% of patients with Lupus Nephritis. So far there have been 22 reported cases in literature. Up until the early 2000s, nephrotic syndrome in a patient with class 2 lupus was deemed as a coincidence.  The work of Dube et al, Hertig et al and Kraft et al lead to an understanding that the appearance of nephrotic syndrome in a patient with Class 2 lupus (without any endocapillary proliferation or GBM deposits) coincided with Lupus flare or appearance of Lupus symptoms. Among these patients, the nephrotic syndrome appears best correlated with podocytopathy rather than subepithelial electron dense deposits, mesangial deposits, or mesangial hypercellularity. The currently used ISN/RPS classification of Lupus Nephritis does not include Lupus Podocytopathy.

A more recent article in CJASN in April 2016 studied a cohort of 50 Chinese SLE patients (the largest so far) with diffuse Foot Process Effacement and class 1 and 2 lupus nephritis.  They included minimal change  disease (MCD) in 13 cases, mesangial proliferation in 28 cases, and FSGS in nine cases.They have proposed a list of criteria to diagnose Lupus Podocytopathy and suggest revision of ISN/RPS classification of Lupus nephritis to include Lupus podocytopathy as a distinct entity. The immunologic and molecular mechanism of Lupus podocytopathy has not yet been fully studied but the T-cell abnormalities in both the disorders could be the unifying pathogenic mechanism in the occurrence of MCD or FSGS in SLE.

There is very limited data currently on the treatment of this group of patients as almost all of it comes from observational studies. But so far, we know that patients with Lupus Podocytopathy are highly steroid responsive. Those who have an FSGS lesion are prone to more relapses and incomplete remission as compared to the ones with MCD, and also need immunosuppressive agents with steroids. Both nephrologists and renal pathologists need to be aware of this entity as a cause of nephrotic syndrome in patients with SLE

Posted by Manasi Bapat, Nephrology Fellow, Mount Sinai Hospital, NY

PPIs and CKD association present after exclusion of AKI

PPIs have been associated with AKI including acute interstitial nephritis; CKD development; and CKD progression to ESRD. That is, in over 10,000 Atherosclerosis Risk in Communities participants followed for at least 10 years, incident CKD developed among PPI users with a hazard ratio of 1.5 compared to non-users in models that adjusted for co-morbidities, demographics, and concomitant medications. In addition, the current researchers have published similar results in their earlier work, showing that new PPI users are at a higher risk for poor renal outcomes even against a 1:1 propensity score-matched cohort of non-users and users of H2 blockers. This was covered in detail by Praveen Malavade on RFN last year and the number 2 story on Top Nephrology Stories of 2016.

It was previously thought that AKI events were largely driving the association seen between PPI use and CKD.

A recent study from Xie et al in Kidney International aimed to examine the relationship between PPI use and renal outcomes over five years in those without AKI.

Methods: The researchers gathered a cohort of 144,032 veterans (125,000+ new to PPIs and 18,000+ new to H2 blockers). They then created survival models with Kaplan Meier curves to show survival probability for their four renal outcomes: incident eGFR < 60 ml/min/m2, incident CKD, eGFR decrease >30%, and ESRD or >50% decrease in eGFR. Participants were censored at the time of AKI. All efforts were made to exclude subjects with AKI, even before cohort entry. Of note, AKI was defined in four different ways, but the researchers were not able to detect unrecognized AKI (i.e., outpatient AKI that occurs and resolves between lab checks). Covariates used in their multivariate logistic regression model included numerous co-morbidities, medication use such as NSAIDs or ACEI/ARBs, and patient characteristics such as age, race, and BMI.

Results:
New PPI users had an increased risk of

• all renal outcomes compared to users of H2 blockers including eGFR < 60 ml/min/m² with a hazard ratio of 1.19 (95% CI 1.15-1.24)
• incident CKD with a HR of 1.26 (95% CI 1.20-1.33)
• eGFR decline >30% with a HR of 1.22 (95% CI 1.16-1.28)
• ESRD or >50% decrease in eGFR with a HR of 1.30 (95% CI 1.15-1.48).

Discussion: The researchers conclude their data suggest a true association between PPI use and CKD even in those patients that do not develop an AKI along the way. Besides AKI, other possible, underdeveloped explanations for the observed relationship between CKD and PPIs include altered gut microbiome; reduced cell regeneration; upregulated heme oxygenase-1; and increased oxidative stress. The researchers conclude that further investigation is needed and that caution should be applied when considering long term PPI use as well as monitoring kidney function in PPI users.

Personal reflection: Observational data from two cohorts (ARIC participants and veterans) analyzed by two research groups (Lazarus et al and Xie et al) show an association between PPIs and CKD. While this work is not based on randomized controlled trial data nor has it been replicated numerous times over by several different investigators, it is noteworthy. Yet, association is not causality. Should clinical practice change? And to what degree should it change given the many other considerations that can influence renal function including diabetes and hypertension? While we wait for more evidence, my practice has been to discuss PPI use with my patients and encourage alternatives when possible if no clear indication for the medication exists. This is stems from the above information as well as an effort to reduce pill burden and improve medication compliance. Specifically, I ask patients to discuss PPI use with their primary care doctors (or whichever provider started the medication) and suggest the following: weaning down and then off of the medication; avoiding known food triggers; and using H2 blockers as needed.

Melissa Makar, Nephrology Fellow, Duke

Time for #NephMadness 2017

NephMadness 2017 has 32 nephrology concepts divided across 8 different topic areas, called regions. Each region has 4 concepts which compete against each other in a single elimination tournament. We have selected content experts from each topic to help us determine the best concepts and vet the information we provide to make sure it is accurate, unbiased, and interesting. The selection committee includes:

1. Biomedical Research: Benjamin D. Humphreys | @HumphreysLab
2. Diabetic Nephropathy Region: Anna Burgner | @annaburgner
3. Dialysis Region: Jonathan Himmelfarb | @xpotasn
4. Disparities Region: L. Ebony Boulware | @ebonyboulware
5. Genetics Region: Matthew G. Sampson | @kidneyomicsamps
6. Glomerulonephritis Region: Richard J. Glassock
7. History Region: Neil Turner | @neilturn
8. Nutrition Region: Kamyar Kalantar-Zadeh | @kamyarkalantarz 

Click here to fill out your brackets

Prize Categories

• Top score
• Top Med Student score
• Top Resident score
• Top Fellow score
• Top Attending score
• Best Tweeter
• Best Blogger

Prize Update: In addition to the above categories we will be awarding a Group Prize to the group that has the most individuals affiliated with it. To be eligible for this prize, you will be prompted during bracket submission to indicate your group (for example, your affiliation with a particular Fellowship Program/Residency Program/Group Practice/Medical School etc). Please note we will only accept one group affiliation per entry. We hope to encourage a little friendly competition between rival programs, so make sure to get as many people from your program to participate in NephMadness 2017!

Details available here.

Schedule

• March 7: Bracket entry opens
• March 24: Deadline for entering contest
• March 26: First round results | Saturated 16 named
• March 29: Saturated 16 results |Effluent 8 named
• March 31, Friday: Effluent 8 results |Filtered 4 named
• April 3: Filtered Four results | Finalists named
• April 5: NephMadness 2017 Champion crowned

Follow the AJKD NephMadness Team (listed below) on Twitter, engage away, and get a head start on claiming the Best Tweeter prize!

• Joel Topf @kidney_boy
• Matt Sparks @Nephro_Sparks
• Tim Yau @Maximal_Change
• Silvi Shah @silvishah
• Anna Burgner @anna_burgner
• Edgar Lerma @edgarvlermamd
• Paul Phelan @paulphel
• Warren Kupin @wkupin
• Swapnil Hiremath @hswapnil
• Nikhil Shah @dr_nikhilshah
• Kenar Jhaveri @kdjhaveri
• Brian Stotter @StotterMD

 

Dialyzing a patient with an intracranial hemorrhage

Patients with intracranial hemorrhages often develop cerebral edema, which can create unique challenges when providing maintenance hemodialysis. Conall also covering this on RFN a few years back. Hemodialysis can worsen cerebral edema through a rapid decrease in serum osmolarity (urea is rapidly cleared from the blood by the dialyzer but urea transport across brain cell membranes lags behind). As a result, a fairly rapid increase in brain water content develops. Besides worsening cerebral edema, maintenance hemodialysis can also reduce cerebral perfusion if systemic hypotension occurs during dialysis. For these reasons, patients either require continuous renal replacement therapy or modified hemodialysis as outlined below. To reduce the risk of worsening cerebral edema, hemodialysis should be modified to include

• small dialyzers
• slower blood flow rates
• slower dialysate flow rates
• reduced dialysis times

To further reduce changes in osmolarity, one should

• increase the dialysate sodium concentration (consider setting it to 5-10 mEq/L higher than serum sodium).
• Lower the dialysate bicarbonate concentration (consider setting it to 30-32 mEq/L)
• avoiding intracellular acidosis
• subsequent increased intracellular osmolarity
• cell swelling

Other details to reduce overall risk include

• cooling dialysate temperatures to reduce risk of hypotension
• avoiding heparin administration. 

As an aside, patients with intracranial hemorrhage are often treated with hypertonic saline. Dialysis patients, in particular, are at risk of developing intravascular volume overload as a result of the large sodium load. This can lead to not only peripheral edema but also pulmonary edema, making ventilation difficult. An alternative to hypertonic saline administration or as an adjunct to reduce the overall sodium load is hyperventilation without humidified air. This will slowly create the desired hypernatremia from free water loss. Something to consider the next time you see a hemodialysis patient with an intracranial hemorrhage.

Melissa Makar, Nephrology Fellow, Duke