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 
Pulmonary
  • 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
Nephrologist
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:

Commerce: 

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?

Contagion: 

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