Saturday, February 24, 2018

Snake Bites and Kidney Injury

Snake bite is a common and frequently devastating environmental and occupational disease, especially in rural areas of developing countries in tropical regions. Clinical manifestations depends on the dose of venom injected, bite to needle time, potency and adequacy of anti-venom. Envenomation may cause a very wide variety of complex effects, ranging from insignificant lesions at the site of the bite, to extensive local necrosis, and life threatening systemic effects of disseminated intravascular coagulation, acute kidney injury, acute respiratory distress syndrome, septicemia and sudden cardiac death from arrhythmia. Isoenzyme of the phospholipase PLA2 in snake venom is responsible for systemic manifestations of local capillary damage, tissue necrosis, and anticoagulant action. Complex clinical syndrome is characterized by hypotension, kidney injury, bleeding, and pituitary failure.

I saw a challenging case of Russell’s viper bite during my nephrology ward rotation. A fisherman was transferred with oliguric acute kidney injury (AKI) and history of Russell’s viper bite. He was in a critical conditions and was managed by supportive measures and hemodialysis. His hospital course was complicated by pituitary hemorrhage, following which he was put  on hormone replacement therapy.

So, what are the renal manifestations in snake bite? Kidney is a highly vascularized organ and susceptible to venom toxicity. Clinical manifestations occur within few hours to 72 hours of viper bite.  Renal features include loin pain, hematuria, hemoglobinuria, myoglobinuria, oliguria, and AKI. AKI is developed in up to 60% of Russell’s viper bite patients. Oliguria usually lasts for 4-15 days, and prolonged oliguria is common in elderly. Other manifestation may include acute interstitial nephritis, extra capillary proliferative glomerulonephritis and cortical necrosis. Mortality rates from snakebite-related AKI is estimated to be up to 35%. Recovery is usually complete except in cases with cortical necrosis or severe tubular necrosis with marked interstitial changes. The figure below elucidates the clinical  presentation and pathophysiology of snake bite.

Management of snakebite includes first aid, local wound care, anti-venom and supportive measures. Immobilization of the whole patient, especially the bitten limb is needed, and transportation should be arranged to the nearing medical center. Tight tourniquets must be avoided so that limb loss is minimized. Anti-venom is the only specific treatment.

Supportive measures include

  • correction of coagulopathy
  • antibiotics for secondary infection
  • fluid management
  • dialysis support to AKI
  • replacement of cortisol and thyroxine in hypopituitarism

Raising community awareness about prevention of snakebites is the most effective strategy for reducing snakebite morbidity and mortality. Concerted strategies with improvements in basic public health, region-specific guidelines and protocols, efficient preventive measures, increased access to effective medical care, adequate supply of anti-venom and timely referral of patients with established AKI to centers with dialysis facilities are essential to mitigate the preventable deaths from snakebite. WHO emphasizes on snakebite envenoming by comprehensive snakebite control strategy and international focus on neglected tropical disease snakebite to substantially improve the outcomes of the patients and communities.

Hopefully, we can save the preventable deaths of snakebites.
Attending Physician, Myanmar
NSMC Intern, Class of 2018

Friday, February 23, 2018

An Artificial Implantable Kidney: Basics for Nephrologists and Fellows

Has a patient ever asked you about the artificial kidney? At this point many nephrologists and patients have heard about the latest advances, and it has even reached the mainstream news. A simple Google search for “artificial kidney” brings a host of articles from popular online websites (,,,, describing the road to the artificial kidney and the benefits it could provide to patients with kidney disease worldwide. UCSF’s “The Kidney Project” website including a section regarding frequently asked questions are also among initial Google results. The Facebook page is followed by approximately 22,000 people.

What is The Kidney Project? 

The Kidney Project is a collaboration between Bioengineering and Nephrology, led by Dr. Shuvo Roy, biomedical engineer at UCSF and Dr. William Fissell, nephrologist at Vanderbilt University, to design an implantable artificial kidney. The Kidney Project was inspired by the work of Dr. H. David Humes, nephrologist at University of Michigan, who used a conventional CRRT hemofilter lined by monolayers of renal cells to create what he termed a renal tubule assist device (RAD). Though Dr. Humes and colleagues did not find a statistically significant difference in the primary outcome of 28 day survival using the RAD compared to conventional CRRT, they did find a significant improvement in their secondary outcome of survival over 180 days. Critically ill patients with AKI trended toward earlier renal recovery in the RAD group though this was also not statistically significant. The potential benefits were hypothesized to be secondary to the immunoregulatory role of tubule cells in stressful clinical conditions.

Recognizing that the RAD has shown promise in critical care, but is too large, labor-intensive, and costly for treatment of ESRD, The Kidney Project was launched with the aim of using silicon nanotechnology, which has thus far been applied to mostly non-biomedical applications, in combination with human renal tubule cells to create an implantable device. In an ideal setting, it would be designed to alleviate the need for an external pump, immunosuppressives, anticoagulation, or dialysate fluid. As stated by Dr. Roy in a recent Grand Rounds at the UCSF Division of Nephrology, “we aim to build what we cannot grow [the filter], and grow what we cannot build [the tubular cells]”.

From a kidney perspective, what are the considerations necessary to achieve these goals? 

Building What Cannot Be Grown 

Filtration – The glomerulus is the natural hemofilter and consists of uniform, slit-like pores that allow for selectivity. Dr. Roy and the Kidney Project have introduced silicon, thus far used in many electronic devices (hence “Silicon Valley”), to build a membrane with geometric dimensions that mimic the natural hemofilter of the glomerulus. Important characteristics include high enough permeability to allow for filtration with cardiac perfusion pressure alone (to obviate necessity for an external pump), but with high permselectivity, to allow small and middle-sized molecules to clear without sacrificing important molecules, like albumin.

Clotting – Silicon is an element that is derived from naturally occurring silica in sand (silicon dioxide or silica). As a non-biologic substance, silicon can provoke an inflammatory response. As we have seen with other biomechanical devices (artificial heart valves, ECMO, etc.), the activation and consumption of pro-coagulant and anti-coagulant factors can lead to both bleeding and thrombosis, with high morbidity and mortality, and thus patients exposed to those devices are treated with anticoagulants. In addition, silica, which forms on the surface of silicon when exposed to oxygen, and this also accelerates blood clotting. To prevent this, Dr. Roy and The Kidney Project team have developed zwitterionic thin coatings, such as polySBMA, applied one molecular layer at a time (to prevent clogging the filter pores), to protect against these complications without the need for blood thinners.

Growing What Cannot Be Built 

Static vs. shear conditions – Growing cells in a culture allows us to study them in static conditions, but cells lining the artificial membrane will be exposed to shear conditions from constant blood flow. While the cells can get their oxygenation and nutrition from exposure to the blood and ultrafiltrate, it is imperative that the cells lining the membrane are able to withstand the shear conditions. Thus far, Dr. Roy and his team have demonstrated that the cells in their animal models can survive for at least one month, and the next step is to aim for longer cell survival times in human patients.

Transport – Ideally, the cells lining the membrane would transport water, electrolytes, and drugs, among other important molecules. Optimizing the rate of transport of important molecules will prevent the need for dialysate fluid or for the patient to have to drink extra fluid to stay hydrated, and this is an active area of work in The Kidney Project. To address this, one consideration is ultrafiltration rate. Considering a normal filtration rate of 60-100 mL/min, Dr. Roy and his team believe that bioengineering with a goal of approximately 30 mL/min may be a reasonable target. Other ideas for improving transport have included increasing the surface area of the device or using different cell types, such as genetically engineered cell lines, to augment transport.

Membrane immuno-isolation – Similarly, a uniform and precise pore size will allow for transport of nutrients, but avoid transport of immunoglobulins that may attack the artificial kidney, to prevent the need for immunosuppressive medications.
When will The Artificial Kidney be ready for human trials? 

The Kidney Project is working closely with the US FDA as part of the Innovation Pathway 2.0, which is a staged development plan to allow the project to move safely and effectively from research into clinical trials and eventually clinical practice. Collaborating with the FDA allows for pre-defined targets (such as demonstrating safety and efficacy in animal models for one month) and also allows for the technology developed to be simultaneously investigated for other purposes, if applicable and worthwhile, including in-hospital CRRT or home hemodialysis.

Transitioning to human clinical trials will require first utilizing the silicon nanopore membranes in otherwise-healthy dialysis patients in order to show that the materials in the hemofilter are safe for exposure to human blood. The next steps would be to test the filtration, then test the cellular component, and finally move into a stage where the artificial kidney can be implanted into human subjects. The process is fraught with financial and regulatory barriers, and according to The Kidney Project’s website, it is anticipated that human clinical trials may be complete by 2020, after which the bioartificial kidney could become available to the public.

Additional future challenges include moving beyond proximal tubule functions like clearance and volume management, and incorporating the fine-tuning which happens more distally. Additionally, it is likely that despite the implantable device, patients will need close medical management (such as erythropoietin), more akin to a patient with advanced kidney disease than to a post-transplant patient.

The current advances in The Kidney Project are a culmination of years of hard work and dedication by very talented physicians and scientists, and the potential impact on our ESRD patients is enormous. There are many challenges ahead and for anyone hoping to get involved, there are undoubtedly many opportunities, which may be particularly appealing to up-and-coming trainees. Stay tuned!

Diana Mina
Nephrology Fellow
UC San Francisco
NSMC Intern 2018

Thursday, February 22, 2018

My Experience with Twitter for Teaching

Teaching should be a fun, sweet, and rewarding process. Perhaps like eating a piece of cake with some kidney on it.

I am currently a third year internal medicine resident, and I always pondered on the ideal and the most effective way of teaching. I would like to highlight my recent experience in teaching during my nephrology ward rotation during a busy call day, when my team interns gave case presentations on their patients. We talked about interesting and challenging cases like access infection, dialysis initiation, and chest pain during dialysis. Even though their presentations were good and to the point, they seemed nervous. I knew something was missing.

Earlier during the week, our attending physician had asked questions from students and resident about phosphate binders. Even though the teaching session included a 10 minute talk, students and trainees had become disinterested during the teaching session. On discussing further, they mentioned that they were nervous and somewhat lost. It was their first week on nephrology service, and they were still learning the field. I noticed the effort put by the attending physician in the lecture, who was passionate. I wondered, what could have been done better in this situation. What is the best way to teach and make it an effective learning experience? I am passionate about teaching, and would like to make teaching, a great experience for my team.

In the current times, students and residents are increasingly using internet resources for medical information and learning. Up-to-date is one of the excellent resources which is available. Another one is Twitter; in fact, I got introduced to Twitter about a year ago, when I was attending KIDNEYcon conference. We were told that we could use Twitter to follow the conference and ask questions from the presenters. At that time, I thought this would not be very helpful, but since I was already using social media, why not give it a try? Using Twitter during the conference gave me the power to ask questions from the presenters easier. I had time to look up material before asking questions, go over data one more time, look through other attendees’ questions, and finally, learn more than ever. Little did I know that this experience would change my academic life.

I decided to connect my two experiences together- bedside teaching and use of online resources. I came up with the idea to post questions on Twitter for my students and interns. Instead of the traditional way of teaching on rounds, they had the time to answer the questions online. Having already had the exposure to the topic, we had a ten minutes discussion about it the following day. There were no surprises and no competition on rounds—Just a focus on teaching. Having poll questions on Twitter made it more interesting to them. The students and interns frequently discussed the questions amongst them, and I noticed the enthusiasm and passion in them. Using social media to post questions was a bridge to their lives outside the hospital. I once had driven and brilliant students who initially answered the question incorrectly, researched the guidelines to find the correct response, and then commented on my post that they wanted to change their answers. During my month long nephrology rotation, 4 students and 4 interns participated in the online teaching activity on Twitter. At the end of the rotation, I got amazing feedback from all of them. They only had one request: to post more questions on Twitter. Below is an example of the type of twitter questions that I have posted.

In present times, social media is an excellent tool that can be used for teaching. My experience with Twitter as a teaching tool for residents has been both rewarding and exciting. I believe that, In addition to the traditional teaching, we can use online tools to make teaching a fun, sweet and rewarding process.

Sayna Norouzi,
Internal Medicine Resident
St Louis University
NSMC Intern, Class of 2018

Eliminate the Unnecessary… Less is More

The medical profession is one of the few professions in the world where the person remains a student for life. We are perennially in this stage of learning some more …a bit more…a little more…And not surprisingly this ‘More’ seems to be a never ending process.But recently I have realised one startling truth to this phenomenon of ‘More’ and that is that the ‘More’ you learn the ‘Less’ you do. In other words as you grow in age and experience you realize that ‘Less is more’.

When I was a medical student and even when I was an internal medicine fellow, every patient that I attended to in the out-patient clinic never left empty handed. They had to be prescribed something. If nothing , they had to go with at least a prescription of Multivitamins. After all they had come to the doctor with the hope of being “treated”. Today as a qualified and practicing nephrologist, I realize that those unnecessary prescriptions of multivitamins were more an act of cowardice than practicing Medicine. I just didn’t have the guts to turn around and tell the patient that the common cold he had was just a self-limiting viral infection that would get cured irrespective of any intervention. And believe me I wasn’t alone. I had more than enough company. And the consolation given to our perennially overactive conscience was ‘At least the multivitamin did no harm’…or so we think.We still haven’t mustered the courage to practice minimalism. To do less.

In general, it is always easier to overdo than to stay calm and “underdo.” It is often easier to do something rather than nothing. The same holds true in Medicine. Recent literature questions the use of N-Acetyl cysteine (NAC) to prevent contrast induced nephropathy (CIN). The PRESERVE trial showed no benefit of oral NAC over placebo among patients with high risk for renal complications undergoing angiography. Actually we are questioning the existence of CIN itself. And yet I see the rampant use of NAC. This behaviour is justified by the same argument…”At least it does no harm”. Another example of this futile ’more’ treatment is the role of renal replacement therapy in the critically ill. The AKIKI study and the pilot phase of the STAART-AKI study presented evidence that can probably help us change our practice and safely say that ‘More dialysis’ in terms of early initiation had no added advantage. In this case it may actually cause harm. The use of plasmapheresis for a whole lot of renal diseases has a low quality evidence but we continue to use it in the face of the paucity of evidence. It’s time we question the use of unproven therapies and accept the probability that in addition to providing no benefit they may cause real harm to our patients. Apart from this we need to take into consideration all the literature that is already published and the evidence that keeps changing. We can’t keep ignoring these changes and continue to practice what we think is right.

Bob Dylan crooned long ago…”Then you better start swimmin, or you ll sink like a stone, For the times they are a-changin”. 

Today, is the time of evidence based medicine. Eminence based medicine is sinking like a stone.

The less is more paradigm is gaining popularity in the critical care speciality. Practices are evolving in the direction of minimalism with a preference for fewer interventions, shorter durations of treatment, less invasive monitoring, and decreased use of screening tests. Especially in the critically ill, we need to realise that the stress of an illness cause a lot of parameters to change beyond the normal range which may be protective. Trying to normalise each parameter may work contrary to two billion years of eukaryotic evolution that has endowed upon humans the complex but still poorly understood physiological adaptations that are part of the healing process. Just keep it simple…simplicity is the ultimate sophistication. However at the same time let’s not confuse the less attitude with a laid back attitude. If a male patient presented to my clinic with an urinary tract infection and I do not investigate for an underlying urinary tract abnormality, I am being laid back about the patient’s condition. Laid back is ignoring potentially reversible parameters which may affect the short and long term patient outcomes. However, if I refrain from using cranberry supplements, I have successfully practiced the less attitude. The less attitude stresses better focussed and well researched patient care and throws out unproven therapies which have been used out of habit rather than well reasoned medical science.

As Warren Buffett said, ’The chains of habit are too light to be felt, until they get too heavy to be broken’. 

The other pertinent question that needs to be asked is that what does a therapy do in terms of the ‘patient’s outcome’ apart from the primary outcome? The use of hydroxyl ethyl starch for fluid resuscitation (6S study) increased mortality in the treatment arm along with an adverse primary outcome. The use of ultrafiltration in decompensated heart failure with cardio-renal syndrome (CARRESS-HF study) showed similar mortality in both arms along with an adverse primary outcome. It makes little sense in using a therapy that gives similar, worse or better primary outcomes as compared to the control therapy when it does little to change the patient mortality or morbidity. In other words we need to demand randomised controlled trials that give us patient centric results (hard outcomes) rather than laboratory based or clinical parameter based results.

Medical science is ever changing and evolving. A judicious yet restrictive approach with avoidance of unproven therapies will simplify our care while simultaneously promote efficient resource utilisation. Newer evidences come in, older theories are rejected. We evolve and improve our thinking. We need to change our practices as we grow wiser. The need to do at least something must be replaced by the need to do what is necessary and proven.

We need to live as John Keynes suggested when he stated, ‘When the facts change, I change my mind…what do you do sir?’ 

Mayuri Trivedi
PD Hinduja Hospital
Mumbai, India
NSMC Intern Class of 2018

Wednesday, February 21, 2018

Outside my Comfort Zone: The Overlap Between Nephrology and Obstetric Medicine

As a current Nephrology trainee I recently decided to do a side step and rotate through obstetric medicine (looking after medical problems in pregnant women). I was interested in this for a few reasons. Throughout my medical training I had encountered pregnant or postnatal women with various problems e.g. severe pneumonia, fever of unknown origin, chest pain. Although these were common medical presentations, in a pregnant patient it was always accompanied by a heightened degree of angst, being more challenging than typical day-to-day cases- extra differentials, changes to normal parameters and two patients to think of.

In nephrolgoy training I then came across a new problem – being asked to consult on patients with complicated preeclampsia. Barn door preeclampsia is easily handled by the obstetric teams, without our input. We were generally only consulted when there was something not quite fitting in e.g. refractory hypertension, severe AKI, oliguria, nephrotic range proteinuria, superimposed preeclampsia. In the early days, my lack of experience with even ‘simple’ preeclampsia made it pretty challenging to deal with these more difficult cases!

My interest was really piqued during my first renal advanced training rotation, when we looked after a patient who came to our attention at 20 weeks gestation with CKD stage 5. She was started on 6 days per week haemodialysis and we looked after her throughout her pregnancy. In fact I went to see her to review her target weight while she was in the dialysis unit to find out she was in labour! We quickly arranged a transfer to the labour ward.

Given the overlap with nephrology, the relative frequency with which I encountered pregnant patients and the added challenges I decided first to do a rotation and then to also train in obstetric medicine. 

Excited about my new books =)
This blog post focuses on hypertension and pregnancy using some brief illustrative cases which are intended to highlight some important areas in this field. The guideline that I use, which I have also used to inform this blog is the SOMANZ (Society of Obstetric Medicine of Australia and New Zealand) Guideline for the Management of Hypertensive Disorders of Pregnancy. This guideline has the advantages of being both relatively recent (2014) and local (I practice in Auckland, New Zealand). *The below Case are not real cases but based on my experiences.

Case 1: 25 year old patient G1P0 (1st pregnancy- I had to remind myself when I started) with blood pressure 140/90 mm Hg at 30 weeks. No other symptoms or lab abnormalites and normally grown fetus. Mild oedema. No proteinuria.

What is her diagnosis? 

Diagnosis: Gestational hypertension. This is the onset of hypertension after 20 weeks of gestation without any maternal or fetal features of preeclampsia. This should return to normal within 3 months of delivery. Some people initially diagnosed with gestational hypertension are in the process of developing preeclampsia. Development of preeclampsia is more likely with more severe and early hypertension.

Case 2: 22 year old G1P0 presents with blood pressure 172/90 mm Hg at 33 weeks gestation. No other symptoms or lab abnormalities and normally grown fetus. Mild edema. No proteinuria.

How should she be treated? 

This patient has severe hypertension defined as a systolic blood pressure ≥ 170 ± diastolic blood pressure ≥ 110 mm Hg requiring urgent treatment. Treatment should be started in all women with a systolic blood pressure ≥160 mm Hg or a diastolic blood pressure ≥100 mm Hg.

Treatment of mild-moderate hypertension is not clear. Antihypertensive therapy does not prevent eclampsia or adverse perinatal outcomes. It does significantly decrease the development of severe hypertension. Arguments against treatment include worries about decreased fetal perfusion with low blood pressure.

The antihypertensives used during pregnancy are different than those we use day to day. Our local practice is to use labetalol (100-400mg q8h) or nifedipine (20mg -60 mg slow release bd) as our first line agents with methyldopa (250-750mg tds) added if required. Which medication to choose is individualised to the patient and their comorbidities.

Case 3: 40 year old woman G1P0 presents at 36 weeks gestation with blood pressure 150/100 mm Hg and right upper quadrant pain. Investigations revealed a raised ALT and AST. There was no proteinuria. Ultrasound revealed fetal growth restriction (FGR).

What is the diagnosis?

Diagnosis: preeclampsia Preeclampsia is a multisystem disease unique to human pregnancy. Diagnosis requires hypertension (>140/90 mm Hg after 20 weeks) and involvement of another organ system (see below) ± the fetus. Proteinuria is not required to diagnose preeclampsia.

Kidney involvement
  • Significant proteinuria –a spot urine protein/creatinine ratio ≥ 30mg/mmol 
  • Serum or plasma creatinine greater than 90 μmol/L
  • Oliguria: less than 80mL/4 hr 
Haematological involvement
  • Thrombocytopenia less than100,000 /μL
  • Hemolysis
  • Disseminated intravascular coagulation 
Liver involvement
  • Raised serum transaminases
  • Severe epigastric ± right upper quadrant pain
Neurological involvement
  • Convulsions (eclampsia)
  • Hypereflexia with sustained clonus
  • Persistent, new headache
  • Persistent visual disturbances
  • Stroke 
  • edema 
  • Fetal growth restriction (FGR) 
Case 4: 35 year old with IgA Nephropathy. Has hypertension and stable proteinuria (PCR 100 mg/mmol). Antihypertensives stopped in early pregnancy due to hypotension. At 32 weeks, blood pressure 145/90 mm Hg, PCR 220 mg/mmol. No other symptoms, signs or laboratory abnormalities. No FGR.

What is the diagnosis?

Diagnosis: This is a challenging case but most likely she just has pre-existing hypertension that, due to physiological drop in blood pressure in the first half of pregnancy, was not present earlier in pregnancy. After a nadir at 20 weeks her blood pressure will have started to increase back to preconception levels. Her proteinuria is likely exacerbated by pregnancy. She has no other features to suggest preeclampsia. However she is a high risk patient who should be monitored closely. The differential is superimposed preeclampsia. Substantial increases in proteinuria and hypertension should raise suspicion of preeclampsia but the diagnosis cannot be made without developing other maternal systemic features or fetal adverse effects.

Given our familiarity with hypertension and its treatment, proteinuria and renal impairment, a renal consult is often sought for gestational hypertension or preeclampsia. Importantly the thresholds for diagnosing severe hypertension requiring urgent treatment, significant proteinuria and a high creatinine are much lower than we would usually use, meaning we have to take extra care not to overlook them. As the theme for World Kidney Day this year is “Kidneys and Womens’ Health” this area is currently getting a lot of attention.

Sarah Gleeson
Nephrology Fellow (and Obstetrics)
Auckland, New Zealand
NSMC Intern, Class of 2018

Here is a post from Silvi Shah RE Pregnancy and Kidney Transplant when she was a NSMC intern. You can also review the entire Obstetrics region of NephMadness 2015

Evolution of PLA2R as biomarker, diagnostic tool and prognostic indicator in Membranous Nephropathy

Membranous nephropathy is among the most common causes of the nephrotic syndrome in non-diabetic adult. It is an immune complex mediated disease which occurs when circulating antibodies permeate the glomerular basement membrane and form immune complexes with epitopes on podocyte membranes. Complement activation occurs and results in sublytic levels of C5b-C9 complexes resulting in release of oxidants and proteases that damage the underlying GBM.
Although the majority of MN falls under the idiopathic category ~ 75%, it is important to eliminate secondary causes where relevant as this distinction has important clinical implications; treatment of secondary nephropathy relies on treatment of the underlying disease process whereas idiopathic MN is treated using steroids and/or cytotoxic agents depending on risk of progression.
PLA2R is expressed on the cell body of podocytes near the foot processes. It undergoes constitutive endocytic recycling at the plasma membrane, providing a constant source of PLA2R. Upon binding of PLA2R antibodies, immune complexes aggregate and are shed into the subepithelial space.  The identification of M-type PLA2R as the major target antigen in idiopathic membranous nephropathy in adults by Beck et al represented a paradigm shift in the diagnosis of MN. 70-80% of their patient population with idiopathic MN, but not those with secondary MN or controls, had circulating anti-PLA2R autoantibodies with a specificity is close to 90%–95% (see RFN coverage).  
Staining of kidney biopsy specimens either by immunofluorescence or immunohistochemistry provides an assay by which to identify PLA2R associated MN. Detection of PLA2R in subepithelial deposits in kidney tissue is both a sensitive (69 to 84% across various studies) and specific (close to 100%) technique to diagnose MN. The rate of concordance between tissue PLA2R testing and serological PLA2R testing is variable among studies. One study showed 98% of tissue positive PLA2R patients were also seropositive. Other studies have shown less concordance and have generally found tissue testing more sensitive than serologic testing. Tissue deposits may persist even after serum antibody levels decline and it has been shown that 74% of PLA2R tissue positive patients were seropositive if the sample was taking during a period of heavy proteinuria as opposed to only 32% of patients being seropositive if samples were taken at time of complete or partial remission. Tissue testing is of particular relevance early in the disease course; at this stage circulating anti PLA2R antibodies may not be detectable because the kidney acts as a “sink”, absorbing antibodies. In these instances, PLA2R will be detectable on immunofluorescence staining but serum antibodies will be negative. With disease progression, renal tissue becomes saturated with anti-PLA2R antibodies and becomes seropositive and therefore can be used as a diagnostic and serological biomarker. As patients enter immunologic remission, anti-PLA2R remits in the circulation however proteinuria persists and it is likely that these patients would remain tissue positive if a renal biopsy were to be repeated.
Much research focus has shifted to serum anti-PLA2R antibodies and their diagnostic and putative roles as a biomarker of disease activity in primary MN. There are two standardised test systems for the qualitative and quantitative detection of anti-PLA2R autoantibodies: Anti-PLA2R IIFT and Anti-PLA2R ELISA.  Studies a have shown a relationship between the presence and level of anti-PLA2R antibodies and disease activity. Immunologic remission usually precedes clinical remission by several months. This has particularly important treatment implications in that monitoring of PLA2R titres may help to identify those likely to achieve spontaneous remission and enable physicians to avoid immunosuppression. Antibody titres may also be important for prognostication at initial diagnosis.
  • Hofstra et al found that patients with high antibody titre at time of diagnosis were less likely to achieve spontaneous remission. In a further study, the group determined that when patients were commenced on immunosuppressive treatment, the antibody titre falls rapidly, preceding the fall in proteinuria and concluded that the chance of achieving remission is higher if the initial anti-PLA2R antibody titre is low.
  • Qin et al postulated that anti-PLA2R titre may have prognostic significance as there was a shorter time to clinical and biochemical remission in patients with low antibody titres. Levels at the end of treatment may also be beneficial in predicting long-term clinical outcomes.
  • Bech et al found that almost 2/3 of patients with  undetectable anti-PLA2R antibodies at the end of treatment in clinical remission, while all who had detectable anti-PLA2R antibody after therapy experienced clinical relapse.

In the time since PLA2R was reported as the specific podocyte antigen in primary MN, testing has become a standard part of the diagnosis and workup of MN. Assessment of both circulating PLA2R autoantibody and PLA2R in biopsy samples will likely have significant prognostic and therapeutic implications. The discovery of a reliable indicator of primary MN is particularly relevant given the “rule of thirds” and variable disease course.
Post by Laura Slattery, NSMC Intern 2018

Tuesday, February 20, 2018

Dialysis vascular access in the elderly – The jury is still out

What is the Fistula First Initiative? 

The Fistula First Initiative (FFI) is a national quality improvement project that was established in 2003 to increase the use of arteriovenous fistula (AVF) for hemodialysis (HD) access in incident and prevalent patients. The aim of FFI was to have a functioning AVF in 66% of the prevalent dialysis population. The use of central venous catheters (CVC) before FFI was quite high and was significantly associated with increased morbidity and mortality mainly due to catheter related blood stream infections as well as increased costs due to hospitalizations and other complications. A recent DOPPS report shows an improvement in AVF use among prevalent patients in the US, however 70% of incident HD patients still started with a CVC (See #VisualAbstract below).

What are the advantages and disadvantages of AVF? 

AVF was promoted as the best hemodialysis VA due to its superior patency, low complication rate (especially infection and thrombosis) and low overall cost. However, creating a functional AVF is sometimes not that simple and straightforward. It turns out that creating an AVF is not the only challenge, rather, the major hurdle limiting it is maintaining its patency. As the rate of AVF creations increased, the rate of primary failure increased as well, along with an increase in the use of central venous catheters (CVC) as a bridge for a maturing AV access. Factors contributing to fistula failure of maturation include; advanced age, female gender, diabetes, coronary artery disease (CAD) and peripheral vascular disease (PVD). Furthermore, the hemodynamic changes after AVF creation (see figure) can be of serious concern, particularly in patients with pre-existing cardiovascular diseases for e.g. in patients with heart failure, where a successful AVF may actually worsen the underlying heart failure.

Vascular access in elderly: 

Vascular access placement in the elderly is a prime example of why the FFI may not always be ideal. There are several reasons for this conundrum:

1. Timing of access placement. In a study published in JASN, 4283 elderly patients (out of 7701) initiated dialysis before AVF/AVG placement or at the day of surgery and were excluded from the study.

Also, 15% of included patients died before dialysis, and 17.5% did not need dialysis until the end of the study (denoting early VA placement). This makes predicting the optimal time for AVF creation more challenging.

2. Shorter survival of elderly patients with multiple comorbidities makes it more likely that these patients may die without ever requiring dialysis (as shown in the table above).

3. High rate of maturation failure
This remains one of the biggest challenges to increase the use of AVF, more so in the elderly. In the same study, 50% of elderly patients with an AVF, actually initiated dialysis via a CVC due to failure of maturation of the AVF. In contrast, only 28% of those with a predialysis AVG needed a CVC at start. Thus, Lee and his group suggested more liberal use of AVG for elderly CKD patients approaching dialysis. They concluded that an AVG creation, closer to dialysis initiation, may serve as a “catheter-sparing” approach.

The Unclear case for AVG 

An AVG has 2 main advantages: shorter time to cannulation and the less frequent need for interventions. This is supported by earlier findings that creation of AVF in elderly patients with CKD (6–9months) was not associated with better AVF success at dialysis initiation, but resulted in more predialysis interventional access procedures. Another important finding was that in patients with CKD aged greater than 80 years, predialysis AVF creation demonstrated no clear survival benefit compared with AVG creation.

However, the hypothesis that, AVG placement after dialysis initiation with a CVC will result in shorter CVC dependence and lower infections and mortality, was not supported by retrospective observational data. Instead, they observed that elderly patients initiating hemodialysis with a CVC undergoing an AVF placement within 6 months had fewer hospitalizations due to infections and a lower likelihood of death than those receiving an AVG, despite extended CVC dependence in the AVF group. (See #VisualAbstract below).

In conclusion, in the era of precision medicine and individualized care, one size doesn't fit all and fistula may not always be First! Elderly patients have high rate of primary access failure, which increase CVC use as a bridge for another access or AVG. Studies are needed to figure out how to predict which patient will have primary failure of maturation, so as we can plan for better management of his vascular access.

Mohamed Elrggal
Alexandria, Egypt
NSMC Intern, Class of 2018

Can You Say the C Word on the Ward? Chronicity, Cure, Care and the History of Hospital Medicine.

‘That was so cool! He looked a thousand times better! And his bloods too!’

Rob, our junior resident, was bounding down the stairs beside me, breathless with the thrill of the last 24 hours. We had met a drowsy man with AKI, his relative a faraway voice on an interstate call:
‘sure, whatever needs fixing’. We had catalogued his asterixis and acidosis, our medical student alongside - ‘What about frost! Have you ever seen frost?’ - and set him up for dialysis, plumbing the femoral vein and righting biochemical wrongs.

We reached the door to Emergency. ‘OK, Rob, we’ve got another admission.’ Peter was a retired teacher on haemodialysis for 3 years, now tired and off his food with what sounded like a diabetic foot infection. ‘Yes, cubicle 3. 76 year old man. I’ve pre-filled his history notes. The usual...’ I watched Rob’s shoulders hunch with a familiar burden: ‘..CKD5D, CAD, CCF, COPD…all the C words. Oh, and diabetes and OSA and gout.’

All the C words. In 1984, Mt Sinai Hospital’s director declared that, in hospitals, ‘chronic disease is an accusation’. Could this still be true?

We work in a healthcare model which, despite a comprehensive network of community services, maintains as its centre of gravity an acute-care-oriented hospital. These multi-storey hubs of teaching and learning are steeped in habits that condition even the most compassionate of us to attach more value to curing disease than to caring for chronicity.

Of course that’s not the case every day, everywhere. Incredible programs and individuals – nurses, dieticians, physiotherapists, carers, podiatrists, doctors – support people with chronic illness. We do a lot more of that than anything else. And it’s on the world agenda: the WHO has a global action plan for non-communicable diseases. But, if we want to hold up a mirror, keep improving, and support our trainees, it’s important to connect with the truth that almost all the machinery of our working lives - acute hospitals, bedside teaching, ward rounds, grand rounds, discharge targets, Kt/V, CRP, Kaplan-Meier curves – has facilitated much more chronicity than it was ever built for.

A short stroll back through the history of Western biomedicine reminds us that, in the medieval period, hospitals were mostly ecclesiastical shelters for the infirm, aged and poor alike. After the religious turmoil of the Reformation closed most of these facilities across Europe, the 18th and 19th centuries saw an entirely new type of professional institution rise in their place. The British Medical Journal in 1897 reflected that the ‘old idea of a hospital as an asylum or refuge’ had ‘given place to the modern notion that it is a great and complicated piece of machinery, every detail of which…has for its aim and object the cure of the patient’.

Many of the ‘big names’ that have brand penetration into medical schools and living rooms across the world today - Massachusetts General, St George’s, Addenbrooke’s - trace their origins to this period. These hospitals focussed less on care of the chronically ill than on scientific analysis and eradication of disease, a shift that was nowhere so evident as in their strict admission criteria. Addenbrooke’s in Cambridge was typical of these institutions in stipulating that no one with ‘infectious distemper, having habitual ulcers, cancers not admitting of operation, consumptions or dropsies…or judged incurable…be admitted as inpatients’.

What exactly was driving what the BMJ called ‘the elimination of the “chronics”’? What embedded this enduring prejudice against the ‘C word’? In fact, three different C words:


In the wake of the Reformation, the burden of caring for the sick was shared by a small number of hospitals with finite resources. Many of the hospitals opening in the 19th century were “voluntary” general hospitals, which, unlike royal chartered or posthumously endowed hospitals, relied on the ongoing philanthropic contributions of a subscriber base. Patients discharged cured were good for business. Langdon-Davies puts it bluntly in his history of Westminster Hospital: ‘it was get well or get out’. Sound familiar from your latest length-of-stay review meeting?


In this pre-antimicrobial era, contagion was the enemy. Long-staying patients were, as one 1771 doctor put it, ‘liable to contract a malignancy from the bad air of a hospital’. Thomas Percival advised in his 1803 Medical Ethics that medical men should keep their charges away from the ‘inbred diseases of hospitals’. Anyone who’s seen death from 21st-century nosocomial sepsis would probably agree.

Clinical skills: 

Beyond practical considerations, however, were the seismic shifts in medical ideology in the long 19th century. It is in this period that Michel Foucault locates what he called ‘the birth of the clinic’: the origins of modern biomedicine. Developments in clinical examination, such as percussion and auscultation, together with advances in pathological anatomy and bacteriology, enabled doctors to ‘map…disease in the secret depths of the body’ (Foucault, p167). Doctors honed their craft through close scrutiny and comparison of diseases in inpatients, and hospitals specifically wanted ‘acutely sick patients with interesting diseases for teaching purposes’. Fellow hospital doctors, look me in the eye and tell me you’ve never described your inpatient list as ‘slim pickings’ to a disappointed student prepping for exams.

Clinical examination and investigations radically reshaped the relationship between doctor, patient and disease. Where the pre-modern medical man was more likely to visit a short-winded person in their home, hearing a description of their ills whilst analysing the air and food of their environment, a 19th-century doctor honed his understanding of heart failure by lining up 10 patients in the ward, tapping and listening to each chest, and correlating with post-mortem findings. Nicholas Jewson’s landmark article, ‘The Disappearance of the Sick Man’ describes exactly this: the sufferer is no longer an individual sick man, but a patient. Not a subject, but an object.

Why should it matter that hospitals excluded the chronically ill? Given the financial burden, the risk of contagion, the incessant percussing and auscultating, wasn’t it nicer to stay away? While the wealthy could draw on many alternative medical services, the penniless with chronic illnesses found themselves on the street or in the workhouse. More important even, from our contemporary viewpoint, was the status of the 19th-century hospital as a prestigious hub of medical education and research at the core of the medical fraternity. Sir James Paget testified to a Royal Commission in 1882 that ‘the great hospitals…determine for the main part the character of the profession’. Today’s readers of NEJM’s case records of the MGH, or the Mayo Clinic Proceedings, might agree with him. In that truly formative period of medical history, professionals aspired for the first time to emulate prominent hospital doctors. And hospital doctors wanted to treat acute, curable disease. Henry Halford, then President of the Royal College of Physicians, told medical students in 1834 that the physician’s ‘one great object’ is ‘the cure of diseases’.

Given this legacy is it any wonder that doctors, particularly those training in hospitals, buckle under ‘frequent flyers’, ‘heartsinks’ and ‘long-stayers’, punctuated occasionally by the ‘real’ work of curing acute disease? Happily for all, we’re now infinitely better positioned to treat ‘dropsy’ than our pre-modern counterparts, and the intervening scientific progress is to be celebrated, but we could still learn something from them. 300 years ago saw a profound shift in what it meant to be a doctor. Perhaps the time is ripe for another one.

Back in Emergency, we approached Peter’s cubicle. ‘You’re Nephrology?’ said the floor manager, ‘Let me know ASAP if you can get him out of here, OK? He’s VRE and the ward’s bed-blocked.’ Peter gave us a weak smile of welcome. Rob efficiently assembled paperwork, syringes and blood culture bottles, and I perched at Peter’s bedside, listening for his story above next door’s alarming monitor. ‘Dialysis? It was alright to begin with. Couple of good years.’ He recalled afternoons tending his garden, his love of an outdoor BBQ dinner. ‘They’re trying their best, tweaking the machine and the tablets. I lie there as long as I can – 5 hours now. But I don’t feel like I did. I’m lying around so much my heel’s all motheaten. See? Looks like my poor roses since the caterpillars moved in.’ Rob put his head round the curtain, phone at his ear, and made eye contact with Peter’s foot. ‘It’s pretty black, yeah. Comorbidities, yeah, I know…’ – Rob’s voice tightened with a nervous laugh - ‘Listen, he lives at home, pretty sharp. OK great. 7am surgical ward round. Thanks.’ He ended the call, looking relieved. ‘Peter, don’t worry, we’re going to get you fixed.’

Long story short, Peter met the surgical team, and calmly, firmly, sent them away. ‘I’ve thought about it a lot over the years. If I’m not walking into dialysis on my own two feet, I’m not going at all.’ I listened, and nodded, and waited. I could feel Rob’s agitation - restless feet tapping, jaw clenching – and it eventually found voice: ‘Sure, but Peter, you could get through it. We can eventually get you up and around. We can cure this.’

Peter chose to move to a big room down the hall. He no longer went to dialysis, but the dialysis nurses all visited him, drawn by the chatter and the smell of barbecued lamb. Most mornings, Rob left the ward round before we got to the big room. ‘I’m busy with the discharge scripts. I’ve got to review that tachycardia.’ Late one evening, I walked past Peter’s room, and heard Rob’s voice. ‘See, the mechanism was jammed, that’s why the head of the bed wasn’t coming up for you. I’ve released it now.’ From the doorway I watched Peter relax back onto the pillow, [smiling] as his deep voice came quietly in reply: ‘Doctor Rob, you’ve got me all fixed.’ Rob caught my eye, and his face told me that, in a quiet moment, he‘d seen through the foot, through the patient, and found the man. And we were both breathless with the weight of it.

*Names and specific case details have been changed. 

Kate Robson Nephrologist
Melbourne, Australia
NSMC Intern 2018