Monday, June 29, 2015

Recurrence of Kappa monoclonal gammopathy after kidney transplantation

Monoclonal gammopathies generally arise from the development of an abnormal clone of B-cell lineage. The monoclonal protein can be intact immunoglogulin (often associated with free light chain), free light chain (FLC) in isolation, or more rarely immunoglobulin heavy chain, either in isolation or with associated free light chain. Monoclonal light chains have the ability to self-aggregate and form tissue deposits either in the form of beta-pleated fibrils (amyloid) or not (non-amyloid deposits).

Monoclonal gammopathies may lead to kidney injury through a variety of mechanisms, depending on the biochemical properties of the light chain and/or immunoglobulin. These include: cast nephropathy (usually kappa); monoclonal immunoglobulin deposition disease; crystal-storing tubulopathy; amyloidosis (usually lambda), cryoglobulinemia or MPGN (membranoproliferative glomerulonephritis).

Monoclonal gammopathies can frequently recur after transplant (Sethi et al. CJASN 2010). In a cohort of transplant recipients in our center, Dr Batal had reported 8 cases of IgG/Kappa MPGN, of which 3 failed post-transplant while 2 were still functioning; 3 were lost on follow up (Batal et al. AJKD 2014).

Recently, a 65 year-old Female with CKD secondary to MPGN/IgG Kappa monoclonal gammopathy underwent a living-unrelated kidney transplant. Creatinine came down to nadir of 1.2mg/dl three days after transplant and then started to rise up to 2.5mg/dl. An emergent kidney biopsy was performed which revealed aggressive MPGN (view picture above). Immunofluorescence staining was negative for IgG, kappa or lambda. However, when the biopsy sample was treated with pronase and restained, suddenly diffuse Kappa staining was uncovered, confirming recurrence of her primary disease. Pronase digestion has a denaturing effect on cell membranes, which may unveil sequestered antigenic sites. This was previously shown to be useful in other forms of monoclonal gammopathies such as in crystal-storing tubulopathy. Electron microscopy may also help in identifying the deposits and triggering additional tests to elucidate the composition of those. Unfortunately, prognosis of early recurrence is not good and requires aggressive treatment against the possible source of light chain (abnormal plasma cells) and removal of light chains from the circulation through plasmapheresis.

Tuesday, June 23, 2015

Point of Care Evidence-Based Nephrology Diagnosis

The use of evidence-based diagnosis is what we are taught that we should all do but in practice, this is quite difficult. EBM diagnoses rely on likelihood ratios but it is impossible to remember the diagnostic accuracy of the thousands of tests out there.

This is why I developed a simple tool to help with the scientific diagnosis of common nephrological problems, as well as diseases spanning most specialties. It is a database of more than 700 likelihood ratios of tests (history, physical exam, radiology, etc.). The likelihood ratios are completely free for all to access and are available on my website and on an app I developed for the iphone/ipad called DxLogic. Android users are not left out as the website is mobile-friendly.

The following examples will demonstrate how you to can use this resource to approach some common clinical nephrology situations in a probabilistic and rational manner. The screenshots found below are from the iOS application.

Example #1

You are consulted for a 50yr old man admitted with pneumonia who has developed AKI in hospital. He was started on ceftriaxone 10 days ago and, after examining the patient and a chart review, you wonder about acute interstitial nephritis secondary to antibiotics. You remember being told that urinary EOS are a great test for this disease. But does this test actually increase or decrease the possibility of this diagnosis? From the screenshot below, we see that the presence of EOS in the urine actually has no diagnostic value for AIN. You save the lab time and money by not ordering the test.




Example #2

A 30 year old woman presents to your clinic with symptoms and signs consistent with nephrotic syndrome. She also has a questionable malar rash and a family history of lupus.  You wonder if she could have lupus nephropathy. Using the resource we find that her probability of having lupus nephropathy before any tests are ordered is 14%,



You order an ANA titer and this comes back negative. Plugging this into that app we find that her probability of having lupus nephropathy on renal biopsy is now 3% - a low, but not an insignificant percentage. 



I hope this article has made you aware of the important role that likelihood ratios can play in nephrological practice. Please give my app/website a try and feel free to contact me with any comments or suggestions.

Contact information:
Michael Garfinkle
University of Calgary
Twitter –  @joyofmed 

Sunday, June 21, 2015

Renal Effects of Anti-Cancer Medications

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

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

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




Tuesday, June 9, 2015

EVOLVEing past Cinacalcet

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

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

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

Monday, June 8, 2015

Osteoporosis treatment in patients with renal failure: the gray zone...

Chronic kidney disease (CKD) patients develop significant changes in bone mineral density (BMD) and bone structure, which together with an increased risk for falls, put them at high risk for fracture. This can be due, in part, to renal osteodystrophy, since bone loss and reduced bone quality may be present in both low- (osteomalacia and adynamic bone disease) and high-turnover bone disease (osteitis fibrosa and mixed uremic osteodystrophy). In addition, some patients may have underlying traditional risk factors for bone loss, such as early menopause or smoking. The heterogeneity of bone loss in patients with CKD complicates its management, requiring frequently a combination of interventions. Performing a bone biopsy is the gold-standard to characterize potential etiologies though not frequently available in most centers. 


 One of the major challenges of treatment of osteoporosis in patients with eGFR below 30 mL/minute is the limited available data. Bisphosphonates are usually not advocated in this population since most agents have renal clearance and patients were frequently excluded from clinical trials. Post-hoc analyses of studies in postmenopausal women with grades 4 and 5 CKD and a definite diagnosis of osteoporosis revealed efficacy and short-term safety of bisphosphonates, denosumab, and raloxifene in addition to calcium and vitamin D supplementation. Bisphosphonates demonstrated increase in BMD, and reduction in vertebral fracture incidence regardless of degree of renal dysfunction. To date, anti-osteoporotic agents have not been recommended in CKD stage 5D due to lack of data on security and on its beneficial impact against fracture. Though some small studies have reported an amelioration of BMD with these drugs in hemodialysis patients. 



Monitoring: 
Patients with severe renal impairment are at higher risk for hypercalcemia due to calcium and vitamin D supplements, or for hypocalcemia if taking denosumab therapy. Therefore, serum calcium, phosphorus, parathyroid hormone, 25-hydroxyvitamin D should be monitored at least every four months. Furthermore, renal function should be routinely measured in patients taking bisphosphonates. Markers of bone turnover, including but not limited to C terminal telopeptide (CTX), N terminal telopeptide (NTX), and pyridinolines (PYR) are metabolized and/or excreted renally, and will accumulate in renal dysfunction. Therefore, they should not be used to monitor response to therapy in patients with eGFR below 30 mL/minute. Despite neither predicting fracture risk nor the type of renal osteodysthrophy, bone densitometry of the hip and spine may be performed to monitor for changes in BMD. In complex patients, a bone biopsy should be considered prior to initiating osteoporosis treatment. 

Recommendations: 
• For patients with low BMD (T-score below 2.5) associated with fragility fracture and grades 4 or 5 CKD, pharmacologic therapy might be considered after excluding all other CKD-related low BMD diagnoses. 
• Adjusted dose of oral bisphophonates are typically recommended based on clinical experience and existing data. 
• Intravenous (IV) bisphosphonates should be used as a last resort only in patients who cannot tolerate previous therapies and are at high risk for multiple fractures. 
• Nephrotoxicity is a significant potential problem with IV bisphosphonates (Zoledronic acid). It is dependent on both dose and infusion rates. 
 • The patterns of nephrotoxicity from IV bisphosphonates include acute tubular necrosis and collapsing focal segmental glomerulosclerosis. 
 • Strict adherence to guidelines for monitoring renal function prior to each dose and temporarily withholding therapy in the setting of renal insufficiency, may help prevent nephrotoxicity from these agents. Denosumab can be an interesting alternative since it is not renally excreted. Further studies are required in patients with CKD. 
• Medications that increase bone formation, such as teriparatide and anti-sclerostin monoclonal antibodies (romosozumab and blosozumab) seem to be promising alternatives for treating osteoporosis in CKD patients with low-turnover bone disease.

Sandra El Hajj, PharmD
Steven Gabardi, PharmD, BCPS, FCCP
Fellype Barreto, MD, PhD
Leonardo Riella, MD, PhD

Additional References: 


Wednesday, June 3, 2015

Remote ischemic preconditioning (RIPC)— Preparing your kidneys for surgery.

Prevention of perioperative AKI, mostly from ATN by ischemic insult, has been a major challenge in nephrology. Recent study (Zarbock et al. JAMA) showed a simple, non-invasive method—remote ischemic preconditioning (RIPC), could be a promising strategy.

This multicenter, double-blind study in Germany randomized 240 patients undergoing on-pump cardiac surgery, who had high risk for AKI (based on Cleveland Clinic Foundation score). Exclusion criteria included eGFR below 30 ml/min or transplant recipient. Intervention consisted of: 3 cycles of 5-minute inflation of a blood pressure cuff to 200 mmHg (or 50 mmHg higher than the systolic pressure) to one upper arm, followed by 5-minute reperfusion with the cuff deflated.

Primary endpoint was the incidence of AKI within 72-hour post-op (KDIGO criteria). They found significantly fewer patients in RIPC group developed AKI (37.5% vs 52.5%; p=0.02; RR, 71% 95% CI, 54-95%). Use of renal replacement therapy was also lower (5.8% vs 15.8%; p=0.01). Of note, the authors examined urine biomarkers: tissue inhibitor of metaloproteinases 2 (TIMP-2) x insulin-like growth factor-binding protein 7 (IGFBP7), as well as urine neutrophil gelatinase-associated lipocalin (NGAL) and high-mobility group box (HMGB). TIMP-2 and IGFBP were measured by Nephrocheck® (see previous blog entry for details). Biproduct of TIMP2 x IGFBP7 and HMGB increased right after RIPC, suggestive of cell cycle arrest as an epithelial defensive mechanism against ischemic insult, however, in 4-24 hours post-op, TIMP2 x IGFBP7 and NGAL were lower in RIPC group compared to control (schematic figure above from eSupplement), indicating less kidney damage.

 RIPC has been studied in kidney transplant field as well. The REPAIR trial recruited 406 live donor-recipient pairs and looked into 12-month post-transplant eGFR with or without early or late RIPC for both donors and recipients. The result was not significant, but as Zarbock et al. pointed out in their article, it could be due to differences in study protocols, confounding comorbidities, or surgical technique. Further studies to explain the mechanism of protection is warranted and it might be no exaggeration to say that RIPC would be a standard pre-op protocol for cardiac surgery in the near future. Are your kidneys ready for surgery?

Naoka Murakami

Monday, June 1, 2015

ASN Fellow's Survey

The American Society of Nephrology (ASN), in collaboration with a research team from George Washington University (GWU), is conducting its 2nd annual survey of fellows training in nephrology. The goal of this important survey is to better understand developments in the marketplace for nephrologists.
The survey gathers data on the types of positions, practice settings, and geographic locations where the next generation of nephrologists will be working. Responses will help determine whether there is an imbalance in different practice settings or regions. By administering the survey on an annual basis, the research team hopes to understand trends in nephrology fellows' plans and job market experiences over time. This is a great opportunity for nephrology fellows to share their experiences with the nephrology community.
Survey Results will be presented at ASN Kidney Week 2015, November 3–8 in San Diego, CA, and GWU and ASN will publish a final report by the end of the year. A report from last year’s survey, Findings from the 2014 Survey of Nephrology Fellows, is available at https://www.asn-online.org/education/training/workforce/.
ASN Fellow Members should have received an email with information on how to participate in the survey directly from ASN. If you haven’t received it or have any questions about the survey, please contact ASN Content and Media Analyst Kurtis Pivert at kpivert@asn-online.org.
We urge all fellows to complete this important survey.
Edward Salsberg, MPA
Leah Masselink, PhD
Leo Quigley, MPH
George Washington University

Washington, DC

Wednesday, May 27, 2015

The Revolution of Medical Learning - Exploring Novel Teaching Tools…

Textbooks and formal lectures were previously considered the main sources to build a solid medical knowledge. However, the advancements of technology have transformed our learning process. Nowadays, students, residents and fellows learn from a combination of resources including Internet, Uptodate, webcasts, podcasts, blogs and apps in addition to formal teaching. 

One of the limitations of this is that learning became fragmented… I have personally experienced this fact as an Attending since fellows would learn very well certain topics in transplantation such as treatment of antibody-mediated rejection though would lack basic concepts about histocompatibility at the end of their fellowship. They were interested in learning more about anti-HLA testing though did not have the time to visit the lab or to read about it, in particular since most books go into to excessive details for their learning needs. 

Ultrasound is another area where fellows really ought to learn more during their fellowship, since I am confident that performing a bedside ultrasound can significantly improve patient care by identifying earlier abnormalities such as an obstruction or a lack of blood flow in kidney grafts. Ultrasound books made by radiologists are also over detailed for the fellow and are rarely used in practice. 



Finally, learning to assess kidney transplant biopsies and nuances of the diagnoses of various conditions is critical for the appropriate management of patients. Most centers lack a formal teaching of how to consistently approach a kidney biopsy. Helmut Rennke and Vanesa Bijol, two fabulous renal pathologist at the BWH, were critical for my learning on this topic but there is no fellow-oriented resource to quickly overview this subject other than renal pathology books. 

 To overcome the above limitations, I have been working for the past 6 years in an interactive transplant learning tool that contains more than 300 original figures/illustrations, questions, key-points and videos to consolidate all aspects of transplantation in one place. Helmut and Vanesa have provided me with slides from all kidney transplant patients that I have attended on, allowing me to share individual cases with beautiful biopsy findings. 

It was a lot of work since I decided to do all by myself, including illustrations, collection of radiology images, videos, graphs, questions,… The goal was really to have a book with a consistent approach to topics and similar style through out. This would be impossible if I had invited multiple contributors… Videos were elaborated to explain difficult topics such as anti-HLA assays, and problem-based cases describe the thought processes, differential diagnosis and management of common conditions affecting kidney transplant recipients. Lastly, questions and review key-points on every chapter will test the reader’s knowledge and hyperklinks will allow direct access with one-click to key references on Pubmed. The end-product was just made available online two weeks ago. 

I hope students, residents and fellows would enjoy the format and really get the most learning possible while seeing transplant patients. Our beta testing last year with BWH fellows was excellent! 

Hopefully you will also enjoy it...

 Have fun! 

Leo Riella

PS1. Read more about it the iBook here
PS2. To download the iBook,  an iPad or Mac computer is required. 

Friday, April 24, 2015

Hyperkalaemia, ICDs and ECG changes.

I recently admitted a woman overnight with prerenal AKI and serum K+ of 7 mmol/L. A passing ED physician mumbled to me not to worry as their ECG didn’t require calcium gluconate, and besides, they had an ICD inserted recently.
As I looked over the ECG, I realised I had no idea what effect hyperkalaemia would have on a pacemaker. Furthermore I always suspected that ECG changes were not a sensitive method of alerting physicians to danger and just delayed treatment. So firstly, what effect does hyperkalaemia have on those pacing/ICD leads?

A recent review from europace describes 3 key changes:

1. The QRS complex can widen due to intraventricular conduction delay

2. The increased ventricular pacing thresholds can cause failure to capture

3. It can lead to over-sensing of spontaneous T waves and inappropriate shocks if the device is an ICD


An hour later this lady had multiple long runs of ventricular tachycardia and lost consciousness .The overdrive pacing spikes could be seen on the monitor but there was no electrical capture and after 20 seconds the device ultimately defibrillated the patient each time. Could this have been avoided with quicker initial treatment and administration of calcium? 
Given the potentially disastrous consequences of hyperkalaemia in a patient with a pacemaker, just fix it, and don’t rely on the ECG to reassure you!
So what about my suspicion that ECG changes are not particularly sensitive?

It would seem that physicians cannot predict clinical severity based on ECG changes alone. A blinded reading of 200 ECGs gave a best  positive predictive value for the presence of hyperkalaemia of 0.65. In addition to this, another study  in CJASN could find no correlation between T waves changes and serum K+. The problem worsens in dialysis patients who appear even less likely to ever manifest ECG changes. This is associated with having a higher serum calcium. Furthermore there are multiple case reports of profound hyperkalaemia both in patients with and without CKD who do not manifest any ECG changes. It is hypothesised that perhaps it if the rate of change that produces the ECG abnormalities, which makes some sense as to why the RRT cohort do not manifest these
Furthermore it has been shown worsening stages of CKD tolerate any given level of hyperkalaemia better, again perhaps due to the rate of change. I could find no good study showing that ECG changes, except for sinusoidal waves, predicted death or morbidity. The long described progression of t wave changes through to QRS widening and then sinusoidal waves is a physiologically pleasing one, it feels right and is very logical. The ECG itself however, would seem not to be particularly useful in treating real patients, and I am going to force myself to ignore normal ECGs. I think my assessment of the urgency will centre around how the patient looks and the rate of flux, background CKD, serum K+, likelihood of rapid improvement, medications and cardiac history.
A final point I stumbled across which I found interesting was the interaction between verapamil and hyperkalaemia. Both dogs and humans on verapamil have profoundly lower cardiac indexes when hyperkalaemic. I’m not sure is it the Ca2+ blocking effect worsening the hyperkalaemic effect on myocardium or the cumulative negative inotropy, but I can see a logical argument for empirical calcium therapy in those on verapamil and perhaps other calcium channel blockers.
Any thoughts?