Sunday, March 26, 2017

#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

Thursday, March 23, 2017

#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

Tuesday, March 21, 2017

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)

Wednesday, March 15, 2017

Lupus Podocytopathy

I recently finished my 2nd 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

Tuesday, March 14, 2017

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

Tuesday, March 7, 2017

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!
 

Thursday, March 2, 2017

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
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

Saturday, February 25, 2017

Awesome HTN Trial Cheat Sheet and info for becoming an ASH Specialist in Clinical Hypertension

https://dl.dropboxusercontent.com/u/54306245/HTN%20Trials%20Summary.pdf
Nephrologists treat hypertension! And not just in our advanced CKD/ESRD patients.

For folks (including fellows in training) who are perhaps more interested in hypertension than the average nephrologist, certification from the American Society of Hypertension (ASH) can offer a greater understanding of hypertension physiology and management (through preparation) as well as a notch in your CV and expertise to advance your career. If you are intrigued, ASH offers some education materials online as well as an explanation of the certification process.

Trainees who have passed their ABIM boards and are enrolled in relevant fellowships (e.g. renal, cards, endo) are able to take the boards. You do not have to pass your nephrology boards first apparently.

If you are interested consider discussing this with your TPD.

Since hypertension is perhaps the most overwhelming area of nephrology, at least in terms of clinical trials, here is a quick cheat sheet of key trials. Not all encompassing but a good start.

Rob Rope, MD Nephrology Fellow, Stanford

Friday, February 24, 2017

ASN Communities Onconephrology Live Journal Chat

On Monday, February 27 at 9:00 pm EDT the Onco-Nephrology community is hosting a journal chat on immune checkpoint inhibitors and all ASN members are invited!

Here is how you can participate: 
  1. Join the Onco-Nephrology Community, if you haven't already
  2. Set your community notification settings for the Onco-Nephrology Community only to “Real Time”
  3. Read the Topic Summary on line or listed below.
  4. Watch your inbox on Monday for the discussion to start and participate in the chat
If you have any questions about setting up your notifications, please contact ASN Communities Associate Zach Cahill

Summary of topic by Mona Doshi, MD

The goal of any course of cancer treatment is to prevent and/or kill future growth of malignant cells. Sometimes this can be challenging as some cancer cells gain the ability to “trick” the immune system into thinking the cancer cells are normal healthy cells. Doctors are seeing promise in a group of drugs called immune checkpoint inhibitors, which actually “open up the immune system” and allow the immune system(T-cells) to recognize and attack the cancer. Two recent reviews published in early 2017 have summarized the effects of immune check point inhibitors (ICI) on the kidney.
We shall be discussing NEJM letter published on Jan 12th 2017. While effective in most cancer patients, this course of treatment has been less successful in kidney transplant patients because activating the immune system causes the patient’s body to start rejecting their donor kidney.  Five prior cases published in the literature of renal transplant patients getting PD-1 inhibitors have resulted in rejection. The rejections were mostly seen in PD-1 inhibitor based therapy compared to CTLA-4 therapy. In addition, the 2 cases of liver transplant where these agents were used and 1 case of heart transplant didn’t lead to a rejection episode.  But in the renal transplant patients, 5 cases have now been reported of leading to acute cellular and antibody mediated rejection when PD-1 inhibitor was administered. In a recent case correspondence in NEJM Jan 12th 2017 issue, the authors observed during the treatment of a patient living with cancer who had a kidney transplant that the combination of steroids and sirolimus (an immunosuppressant that has anti cancer properties),  could prevent a patient’s body from rejecting the organ during  cancer treatment with ICI.
In the case the authors observed the treatment of a 70 year-old Caucasian male who received a kidney transplant in 2010 and recently underwent treatment for small bowel cancer which had spread to the liver. The patient was given prednisone, a steroid, and sirolimus prior to incorporating an immune checkpoint inhibitor (nivolumab). The steroids were started 1 week prior to the starting of nivolumab and continued at a tapered regimen as mentioned in the manuscript to prevent the immune mediated reaction seen in prior cases. Steroids didn’t hinder the shrinkage of the cancer. There was significant response in tumor burden (as shown in the appendix) and the serum creatinine remained stable (as shown in appendix). There were no clinical or immunological signs of rejection.
In this forum discussion, as nephrologists, we can try to come up with ways to answer few questions for the oncologists.
1. What is the best treatment strategy for ICI induced AIN (dose, duration of steroids)?
2. What is the best preventive strategy for patients who have had ICI induced AIN and need to continue the targeted therapy?
3. Given the above single case report, can the above mTOR inhibitor+ steroid strategy be employed in all transplant patients receiving PD-1 inhibitors?

If you have questions about the content of the chat, contact any of the ONC leaders.
Sincerely,

The Onco-Nephrology Leadership Team

Tuesday, February 21, 2017

Angiomyolipomas

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

  • Angiomyolipomas (AML) are benign tumors comprised of blood vessels, adipose tissue and smooth muscle. Very occasionally (more commonly in patients with tuberous sclerosis complex), they can be malignant. Malignant AMLs are more likely to be fat-poor, hypoechoic tumors (termed epitheliod AML).
  • The prevalence is about 2% in the general population and they are 4 times more common in women
  • The presence of multiple AMLs suggests the possibility of tuberous sclerosis complex and the possibility that patients have subclinical disease should be kept in the back of your mind.
  • Confirmation of the ultrasound findings should be done with CT or MRI as there are some renal cancers that can be hyperechoic on ultrasound.
  • The hyperechoic nature of these lesions on ultrasound is due to fat in the tumor rather than the vascularity.
  • For unkown reasons, more of these tumors are found on the right side
  • Most of these tumors are slow growing and do not require treatment (surgery or embolization) unless they are >4cm in diameter. mTOR inhibitors may be useful in some patients with unresectable tumors. Patients should be followed-up yearly with ultrasound.
  • Patients on estrogen therapy are more likely to have rapid tumor growth and should be followed up more often.
Image from: http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-72032014000800377

Spontaneous Tumor Lysis Syndrome

A 70 year old Ghanaian man was recently admitted under our care.  He had been diagnosed with aggressive myelodysplasia 2 months previously after presenting with fatigue and abnormal blood results (WBC 50.3, platelets 130 and LDH 928 at the time of diagnosis).  A plan was made for palliative chemotherapy. One month after his diagnosis he developed a large pericardial effusion and had 1L of haemorrhagic fluid drained.  At this point his creatinine was 200 umol/L (2.26 mg/dL).  Routine and TB culture of the fluid was negative, as was cytology and immunophenotyping.
Image result for swissnephro uric acid
Two weeks after this admission he represented with abdominal pain.  A CT showed bilateral renal and bladder calculi without obstruction.  He was oliguric with a creatinine of 577 umol/L (6.5 mg/dL) rising to 709 umol/L (8 mg/dL) over the next 12 hours.  His uric acid level was 18.0 mg/dL, which had not been checked previously.  Phosphate was 1.86 mmol/L (5.75 mg/dL), Ca 2.1 mmol/L (8.4 mg/dL) and K 4.6 mmol/L.
Our diagnosis was of a spontaneous tumour lysis syndrome (TLS; see previous RFN posts here & here).  Nucleic acids released from tumour cell lysis are broken down into xanthine and then uric acid by xanthine oxidase.  Renal failure is caused by uric acid precipitating in renal tubules causing a mechanical obstruction and inflammatory reaction.  While TLS is typically seen following initiation of chemotherapy causing a rapid breakdown of cancer cells, a spontaneous form has been described in acute leukaemia and NHL.  Our patient was at high risk of converting into AML but had no rise in peripheral blasts to suggest this.
Interestingly, spontaneous tumour lysis syndrome is associated with hyperuricemia but often without the hyperphosphatemia (and hyperkalemia) seen in the classical form of the disease– thought to be because the released phosphorus is quickly used up in the generation of new tumour cells.  This would fit with our patients results.
Our patient was commenced on dialysis which gave reductions in uric acid levels of 50% per treatment, but they quickly rebounded.  He was no longer fit for treatment of his myelodysplasia making longer term management more difficult.  Given his African ethnicity, we checked his glucose-6-phosphatase levels, which were normal, before he received rasburicase (recombinant urate oxidase). Rasburicase reduces uric acid levels by converting it into allantoin.  It may cause severe oxidative hemolysis if glucose-6-phosphatase deficient. Uric acid fell to undetectable levels following this however he had an ongoing dialysis requirement (note that rasburicase retains in vitro activity in the blood bottle so sample should ideally go on ice).  Allopurinol as a longer term medication to reduce uric acid formation may be useful, but may not manage to suppress formation sufficiently.  
In addition to tumour lysis syndrome, acute urate nephropathy can be caused by other states of tissue catabolism such as seizures, in primary overproduction of uric acid or in cases of reduced urate reabsorption in the proximal tubule. Urinalysis can show uric acid crystals (birefringent with polarisation; see image) or can be normal (as in our patient) perhaps due to a lack of output from obstructed tubules. 
This case raised several points to me. Was his pericardial effusion also caused by a urate infiltration?  No clear cause was ever identified at the time and he did not appear ‘uremic’ despite his renal dysfunction.  Could any of this have been prevented if treatment for his hyperuricemia had been commenced earlier?  I also learned:
  • The nuances of spontaneous tumor lysis syndrome (often phosphate & K not hugely elevated).
  • Rasburicase is contraindicated if glucose-6-phosphatase deficient (approximately 20% of Africans).
  • The ‘undetectable’ result of urate after rasburicase administration appears to be due to in vitro activity of the drug in the blood bottle.

Image thanks to Florian Buchkremer @swissnephro

Post by Ailish Nimmo

Thursday, February 9, 2017

Should you use intravenous immunoglobulin (IVIG) in the treatment of BK nephropathy?

Nice debate on ASN Transplant Community about the use of IVIG for BK nephropathy.

Personally, I have used IVIG in a handful of patients with refractory BK nephropathy in the past. However, I have convinced myself that there is no data supporting that.

Most case series used IVIG in combination with reduction of immunosuppression (Sener et al. Transp 2006), preventing any conclusion on the matter. We had a nice debate with Jay Fishman (MGH Transplant Infectious Disease expert) on last AST Fellow's Symposium about this issue. 

The conclusion was that an effective viral response requires cytotoxic T cells to kill infected cells (Figure above). Antibodies against the virus may help neutralize circulating virus but alone are not capable of stopping an ongoing infection. In particular, prior immunity against BK (IgG BK positive prior to transplant) does not seem to protect against post-transplant BK infection (different than CMV exposure). However, one must keep in mind that there are at least 4 different BK genotypes and immunity against one genotype does not equal immunity to all genotypes, which may explain some of the controversies on the topic (Pastrana et al. PLOS Pathogens 2012).
Overall, reduction in immunosuppression remains the cornerstone of BK viremia treatment.
Remaining controversial topics: 
  • Should you give steroids if intense inflammation? Some data suggest it may not be good... 
  •  Should you stop or just reduce antiproliferative dose? Unclear on my view, but intensity of viremia and allo-immune risk must be balanced here. 
  • Should you switch to an mTOR inhibitor? Some interesting data suggesting that mTOR inhibitors suppress BK replication (similar to suppression to other virus like CMV) (Hirsch et al. AJT 2016)
More data still needed... 

Thursday, February 2, 2017

Cidofovir nephrotoxicity and Probenecid

I recently saw an interesting case. A woman was being treated with cidofovir for adenovirus which was presumed to be responsible for an acute cardiomyopathy. Concurrent with cidofovir, she was also receiving probenecid for renoprotection, which I was not familiar with.
Cidofovir is a nucleotide analogue used primarily to treat CMV retinitis in patients with AIDS. However, cidofovir is also used to treat a number of DNA viruses including adenovirus. The main toxicity of cidofovir is nephrotoxicity, which can manifest as AKI, proteinuria, or a Fanconi-type syndrome with proximal tubular dysfunction. Nephrotoxicity can be reduced by co-administration with iv fluids and probenecid (the dosing regimen for the latter is 2g po 3 hours prior to the dose, then 1 g po 2 hours and 8 hours after.
How does probenecid reduce cidofovir nephrotoxicity? Over 80% of cidofovir is excreted unchanged in the urine in 24 hours. Most of this occurs via glomerular filtration, but cidofovir is also actively taken up from blood by the kidneys via the "organic anion transporter" located on the basolateral side of renal proximal tubular cells, and is then more slowly secreted into the tubular lumen. Renal clearance of cidofovir therefore exceeds the corresponding GFR.
The relatively slow secretion of cidofovir into the tubular lumen, in comparison to uptake from the blood, results in a long intracellular half-life of the drug in the proximal tubular cells which appears to underlie the nephrotoxicity. Probenecid, by inhibiting the organic anion transporter, prevents tubular uptake and protects the kidneys. This was demonstrated nicely in a pilot study in HIV patients. Interestingly, and somewhat paradoxically, this means that probenecid reduces nephrotoxicity while also DECREASING the renal clearance of the drug and thus INCREASING serum cidofovir concentrations as much as two-fold.
Probenecid is a banned drug for athletes for a related reason - because it blocks entry of certain drugs into the urine, it has been used as a masking agent for other banned performance-enhancing drugs including steroids. 
Posted by David Leaf

Wednesday, February 1, 2017

Hyponatremia and ESRD

Hyponatremia can be seen in patients with end-stage renal disease (ESRD), often as a consequence of a patient’s increase in free water intake in the setting of the kidneys’ diminished ability to regulate sodium and water homeostasis. I recently received a question from a resident asking for some insight into the management of such patients.
To begin, it should be noted that uremic patients with chronic hyponatremia are thought to be protected from osmotic demyelination syndrome (ODS) after hemodialysis. In this situation, urea may act as an effective osmole, whereby the decline in blood urea nitrogen (BUN) levels during dialysis could offset serum hypertonicity.  Additionally, animal studies have shown that azotemic rats were protected from ODS due to a reaccumulation of organic osmolytes  such as myoinositol and taurine within two hours of correction of hyponatremia
Though rare, case reports of ODS in uremic patients with hyponatremia do exist. One case described a uremic patient who developed ODS after being initiated on hemodialysis with an initial serum Na of 100 meq/L that corrected to 121 meq/L after three hours against a dialysate sodium concentration of 140 meq/L. It is important to note that ESRD patients in other case reports who went on to develop ODS had other risk factors for the development of the disease, such malnutrition and chronic alcoholism.
I recently helped care for an ESRD patient who was admitted with probable sepsis. His serum sodium on admission was 122 meq/L.  Because we had no outside records available at the time, we assumed his hyponatremia had been present for at least 48 hours. The patient had no uremic symptoms and had no need for urgent small solute clearance or volume removal. Nephrology was consulted for routine dialysis needs.
In choosing our dialysis prescription, we attempted to limit the increase in sodium to no more than 1 meq/L/h, or 3 meq for a 3-hour treatment.  We elected to reduce the blood flow rate to 100 ml/min, use the lowest possible sodium concentration bath allowed in the dialysate (130 meq/L), and use a dialysate flow rate of 600 mL/min.  Cocurrent flows were not used.  After a 3-hour dialysis session, the patient’s serum sodium rose to 125 meq/L, and hourly measurements of serum sodium during dialysis revealed that the patient’s sodium had indeed risen by 1 meq/L/h.
Our calculation was derived from a helpful approach described by Wendland and Kaplan, which showed that the rate in rise of serum sodium could be estimated by the product of the concentration gradient between the patient’s sodium and the dialysate sodium multiplied by the clearance. To do this, we would begins with the following formula:
Change in total body Na = Clearance (L/h) * (dialysate Na – patient Na)
By minimizing the blood flow rate to 100 mL/min and maximizing the dialysate flow rate to 600 mL/min, we assumed that there would be near-total equilibration between the patient’s serum sodium and the sodium concentration of the dialysate bath.  Thus, clearance would be approximately equal to the blood flow rate.
Thus, using our patient as an example:
Change in total body Na = Blood flow rate (L/h) * (130 meq/L – 122 meq/L)
A blood flow rate of 100 mL/min = 6 L/h
Therefore, the change in total body Na after 1 hour of dialysis would be:
6 L/h * 8 meq/L = 48 meq/h
Our patient’s total body water was 48L.  If we add 48 meq Na to our patient’s initial total body Na of 5856 meq (48L * 122 meq/L), we obtain the new total body Na after 1 hour of dialysis: 5856 meq + 48 meq = 5904 meq.
Dividing this value by the patient’s total body water would give us the new serum sodium after 1 hour of dialysis, assuming no ultrafiltration or volume changes.
5904 meq/48L = 123 meq/L
Thus, the patient’s serum sodium would rise by approximately 1 meq/L after 1 hour.
It would be interesting to discuss other options are available for managing ESRD patients with chronic hyponatremia.  Assuming there is no urgent need for small solute clearance, would continuous renal replacement therapy be a safer option?  If uremia is indeed “protective” against ODS, should we avoid low dialysate flow rates and concurrent flows?  How would the prescription change if the patient were to need more aggressive small solute clearance?
It seems that there is more than one way to manage these patients, and factors such as co-morbidities and electrolyte abnormalities need to be taken into consideration when formulating a dialysis prescription.
Posted by Devika Nair, MD
Nephrology Fellow, Vanderbilt

Tuesday, January 31, 2017

February Renal Path Video - Wash U Nephrology Web Episodes!


For anyone wanting to unravel an unusual case and brush up on their renal pathology, check out the February episode of the Wash U Nephrology web series.


Tuesday, January 24, 2017

Point of Care Ultrasound for the Nephrologist at #SCM2017

Want to up your ultrasound game... Attend the point of care ultrasound for the nephrologist pre-course at the NKF Spring Clinical Meeting in Orlando, FL April 18 2017

click here to register

The nephrology consultant needs knowledge of lung ultrasound to determine volume status, renal and bladder ultrasound to evaluate for obstruction and knowledge of vascular access guidance to assist in placement of catheters. This course will focus on the above elements in point of care ultrasonography.
  • Image acquisition will be practiced on human models using high-quality ultrasound machines and supervised by experienced faculty. Training sessions give you practical, hands-on training with a 1:3 teacher-to-learner ratio, so you benefit from personal instruction.
  • Image interpretation during group sessions under the supervision of experienced faculty members offers relevant practice. Numerous ultrasound images demonstrating normal and pathologic findings will give you a comprehensive learning opportunity. As you improve your skills, you will be further challenged with unknowns and case-based image sets.
  • Knowledge base will be enhanced with lectures that focus on important aspects of point of care ultrasonography applicable to the renal consultant. Discussions will have immediate application within your practice. 
Learning Objectives:

Upon completion of this course, participants will be able to:
  • Discuss how to perform lung ultrasonography and ultrasonography of the renal system.
  • Identify appropriate uses of ultrasonography in renal practice.
  • Demonstrate appropriate image acquisition techniques required for renal ultrasonography.
  • Interpret image-based clinical cases to help identify abnormalities.

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)