Mercury rising

A patient who had been working in a recycling company that handled thermometers presented with fever, dry cough, fatigue and rash. Based on imaging (CXR showed massive radio-opaque material in the lungs, right atrium and right ventricle; skeletal survey showed radio-opaque deposits in the kidneys, bowel wall, and bladder wall), symptoms, and a positive history of exposure, a diagnosis of mercury intoxication was made. The patient developed multi-organ failure including anuric acute renal failure, and nephrology was consulted. Further background details on the case can be found here. What is the treatment and the role of dialysis in mercury intoxication? 


Metallic mercury has a widespread use both within industry and in many everyday objects such as thermometers, dental amalgams, batteries, fluorescent light bulbs, and many others. Mercury intoxication can result from vapor inhalation, resulting in severe respiratory symptoms, or from injection, usually in cases of attempted suicide. 


The chelating agents 2,3- dimercaptopropanesulfonic acid (DMPS) and meso-2,3-dimercaptosuccinic acid (DMSA) are central to the management of mercury toxicity. DMSA is given orally, and can cause leucopenia and elevated liver enzymes. DMPS is an intravenous medication and its use is associated with hypotension. In our patient, DMSA 500 mg po q 8hrs was given for 4 days, before it was discontinued because of elevated LFTs and leucopenia. We then started DMPS with CRRT but unfortunately, after two weeks of supportive treatment, the patient died. 


Chelators such as DMPS and DMSA work by mobilizing mercury and facilitating its excretion through the kidneys. This creates a management conundrum in the anuric patient, as this route of excretion is not available. Consistent with this, our patient’s blood mercury levels rose dramatically during chelator treatment, despite CRRT. We hypothesize that the administration of DMPS mobilized mercury from extracellular deposits and redistributed it to the blood and organs, but it failed to be adequately eliminated from the body because of anuria. For this reason, intensive CRRT with a high-flux dialyzer is a critical adjunct to chelator therapy. If this is not available, continuous renal replacement therapy with chelators have showed better mercury clearance than conventional dialysis, whereas peritoneal dialysis has been shown to be ineffective at clearing mercury. These principles should be borne in mind in other heavy metal poisonings also. Other management pearls I took from this unusual case were to initiate dialysis early and to give DMSA at a lower and more frequent dose to avoid serious side effects. 


Tarek Alhamad M.D.

MPGN: Think Different

In the week that Steve Jobs stepped down as CEO of Apple, it seems appropriate to tip our cap to that guru of simplicity, and take a stripped down, simplified approach to one of the biggest quagmires in nephrology, membranoproliferative glomerulonephritis (MPGN). The existing classification of this entity is a shambles, and it understandably had Emily reaching for the bottle when she recently attempted to get her head around it. To make matters worse, we probably need to throw out all the old literature on immunosuppressive treatment for MPGN and start afresh, as the existing trials were conducted at a time when the full heterogeneity of MPGN was not appreciated. Few evidence-based treatment recommendations are possible based on these data. Well, help is at hand, in the form of a practical and comprehensive new classification. My thanks to Dr. Sanjeev Sethi, MD, PhD at the Mayo Clinic for sending me a copy to review.


My main gripe with the existing classification system is that it places the focus firmly on “primary” causes of MPGN (Types I, II, III, Burkholder variant, Strife and Anders variant etc.), demoting secondary causes to the bottom of the differential. Although idiopathic forms undoubtedly exist, they are increasingly uncommon, and an underlying cause can be found in the vast majority of cases.

First off, it is vital to appreciate that MPGN is not a disease, but a pattern of injury with a broad differential. For a nephrologist to say their patient “has MPGN” just doesn’t cut it, no more than an ID doc saying their patient “has infection”. The classic presentation is a child or young adult with persistent proteinuria, often with overlapping features of the nephrotic and nephritic syndromes, and depressed C3 (occurs in over 80%). Spontaneous remission is rare and the condition typically grumbles on to ESRD over many years, unless a treatable underlying cause can be found. The hallmark biopsy finding is the double contour on light microscopy (adjacent figure). The double contour may be thought of as the fingerprint of chronic and persistent immunoglobulin/complement-mediated endothelial injury. Endothelial and mesangial cells attempt to repair the ongoing injury by generating basement membrane–like material, which traps immune complexes and cellular elements in between to form double contours.


The proposed classification system is similar to that used for rapidly progressive or crescentic GN, where classification by immunoflourescence pattern on the the renal biopsy into linear, granular and pauci immune staining is extremely helpful in narrowing down the equally broad and complex differential. The proposed MPGN classification divides it into 3 IF pattern groups: Immunoglobulin staining with C3, C3 staining without immunoglobulin and no staining (figure below; modified version of that which appears in article).

Immunoglobulin and C3 +ve: If immunoglobulin staining is present, the patient should be worked-up for infection, monoclonal gammopathy and autoimmune disease. Regarding infective causes, the organisms to think about tend to be classically associated with chronic infection (HCV, HBV, TB, coxiella, brucella, nocardia) or a carrier state (mycoplasma, Neisseria, strep), presumably acting as a source of chronic, low-grade antibody production. When infective and autoimmune causes are excluded, an underlying MGUS is found in over 40% of cases (Mayo clinic series). This is best identified by immunofixation, although IF microscopy on the biopsy specimen using monoclonal protein–specific Abs is often very helpful. Less common associations include myeloma, lymphoma and CLL.


C3 +ve and immunoglobulin -ve: Isolated C3 staining (i.e.without immunoglobulin) suggests an abnormality of the alternative complement pathway. When this pattern occurs in children, it suggests a genetic mutation is responsible, whereas complement autoantibodies are more likely to be responsible in adults. The prototypic diseases are dense deposit disease and MPGN with isolated C3 deposits, however there are many others. A detailed interrogation of the alternative complement pathway will probably require an immunologist’s input. However, before calling them, a good initial screen of the  alternative complement pathway comprises 4 tests: C3 and C4 levels, serum MAC levels, an alternative pathway functional assay (APFA) and hemolytic complement assays.


No staining: Chronic injury to the endothelial cell due to thrombotic microangiopathy also causes an MPGN pattern. However, staining for immunoglobulin and C3 is absent. Causes to consider include TTP, HUS, anti-phospholipid antibody syndrome, drug-associated TMA, nephropathy associated with bone marrow transplantation, radiation nephritis and malignant hypertension.


Hopefully, using this system, you will be able to quickly hone in on a manageable differential diagnosis, leaving you more time to... think.

Renal Fellow Network the Subject of ASN's Monthly Podcast

Post-transplant Lymphoproliferative Disease

Although the term Post-transplant Lymphoproliferative Disease (PTLD) encompasses all lymphoproliferative disorders post transplant, it generally refers to extra-nodal B-cell lymphomas due to Ebstein-Barr virus (EBV) infection. PTLD is a B-cell disease caused by iatrogenic T-cell dysfunction: in people with normally functioning immune systems, activated T-cells regulate B-cell proliferation, whereas in the transplant setting pharmacological T-cell inhibition permits proliferation of EBV-infected B-cells. PTLD is the commonest post-transplant malignancy in children, the second most common in adults and is the commonest cause of cancer-related post-transplant mortality. 


PTLD requires a high index of suspicion and must be on your radar. Early disease is often easily managed by lowering immunosuppression, but late detection is a disaster. Clinical presentations vary from a benign infectious mononucleosis syndrome to a severe malignant lymphoproliferative disorder; 3 distinct clinical syndromes are described:

1. Polyclonal B-cell proliferation with malignant transformation, widespread disease, and multiorgan involvement. This accounts for 30% of patients and presents within weeks of transplant. You’re less likely to miss this presentation, as patients are often closely monitored during this time.

2. The majority of cases (over 50%) present as an infectious mononucleosis within a year of transplant. This is due to a benign polyclonal proliferation of B cells. This is easily missed, which is a tragedy as this presentation is very responsive to lowering immunosuppression.

3. A minority present late with a monoclonal B-cell proliferation, extra-nodal disease, and visceral involvement late post-transplant.

Diagnosis is by tissue biopsy (preferably excisional biopsy), and is based on histological, cytological and microbiological evidence: lymphoproliferation that disrupts tissue architecture, oligoclonal or monclonal cell lines and the presence of EBV in the tissue. One group that deserves particular attention is EBV –ve recipients who receive EBV +ve kidneys (EBV D+/R-). This small, single-center study of 34 such patients teaches us a lot about PTLD and makes the case for closely monitoring EBV D+/R- recipients:

1. Of those EBV D+/R- recipients who were not monitored (n=6), 50% developed PTLD and lost their transplants
2. Of the remainder, 60% developed EBV viremia and had their immunosuppression reduced; only 1 developed PTLD. This underscores how efficacious reducing immunosuppression can be.
3. 6/20 with persistent viremia received rituximab; none got PTLD or lost their transplant. This needs to be replicated but is very encouraging.

Here are some PTLD management pearls:

1. The graft is a commonly affected site. Isolated allograft dysfunction can be a presentation PTLD, as is allograft dysfunction developing after an increase in immunosuppression.
2. Check EBV in all flu-like illnesses; doubly so if lymphadenopathy is present; triply so if during the first post transplant year.
3. Antivirals don’t work. EBV do not express thymidine kinase, the target of ganciclovir/acyclovir
4. Reducing immunosuppression does work, if instituted early. A typical regimen would be to cut CNI by 50%, discontinue MMF/AZA, and continue the same or 50% less steroid
5. Main risk factor is the EBV D+/R- recipient, and they need monitoring for EBV infection. Other risk factors include extremes of age, heavier immunosuppression especially anti-lymphocyte antibody use and CMV infection

PTLD: Preventable with Timely Lowering of Drugs

Risk score for predicting ESRD in CKD patients

In something of a first for Nephrology, today sees the simultaneous release of a powerful tool for predicting ESRD risk in CKD patients at the World Congress of Nephrology, in JAMA and as a mobile application (free download; see screenshot). Whereas most research slowly permeates the medical community over months to years, this type of collaboration harnesses the power of modern technology to get people using this valuable information from the get-go.


The ‘Kidney Failure Risk Equation’, developed by researchers from Tufts, will be presented at the WCN in Vancouver this morning at 11am. It provides the 2 and 5 year probability of ESRD for patients with CKD Stage 3 to 5. The risk score includes the following variables: age, sex, estimated GFR, albuminuria, serum calcium, serum phosphate, serum bicarbonate, and serum albumin and had a c-statistic of 0.92. This is really remarkably high, as similar published models typically have values ~ 0.7 (0.5 is a coin-toss). The score was validated in two independent populations of CKD patients (n = 8,391, 57% men and 38% diabetes). ESRD occurred at a rate of 11% and 24% over a median follow up of 2 and 3 years respectively.


This has been a long time coming. We've often written on this site about the need to stratify risk in CKD patients, including promoting the idea of a renal stress test, as has been done so effectively in cardiology. Today is a welcome step forward, as this model could potentially illuminate patient-doctor dialogue, guide triage and management of nephrology referrals and the timing of dialysis access placement, and help properly structure kidney transplantation protocols. Time will tell its true impact, but as someone interested in using technology to advance nephrology, this is an exciting day.

Argatroban

Critically ill patients receiving continuous renal replacement therapy are frequently given heparin to maintain circuit patency. In the presence of active HIT-II or HITT, even in the absence of clinical thrombosis, systemic anticoagulation with a direct thrombin inhibitor (DTI) decreases the incidence of thrombotic complications, if given until thrombocytopenia has resolved. In this scenario, anticoagulation to maintain CRRT circuit patency is a bonus. In critically ill patients requiring CRRT with a history of HIT-II, but not active thrombocytopenia or thrombosis, avoidance of heparin exposure is still recommended, and argatroban is currently a common choice of DTI if systemic anticoagulation is required. As this is a drug that nephrologists need to be very familiar with, here's a list of essential facts about argatroban in the form of a mnemonic, for those of you who get off on that kind of thing.


A nticoagulant of choice in active HIT-II or HITT.
R enal dose adjustment not necessary – hepatically cleared only.
G oal aPTT is 2-3 times above baseline (as for heparin).
A ctivated PTT is monitoring test of choice, but note argatroban increases ACT and PT/INR also.
T wo mcg per kg per minute is the usual starting dose (2mcg/kg/min)
R eversal not possible, so careful monitoring essential.
O .5 mcg/kg/min starting dose in liver disease (0.5mcg/kg/min)
B olus not required before infusion (unlike heparin). Steady state within 3 hours.
A lbumin: Low albumin is an important clue to hepatic synthetic dysfunction. Reduce starting dose by 75% if present.
N ormalised ratio: When transitioning to warfarin, once the INR is 4 while on both drugs, the INR will be therapeutic once the argatroban infusion is stopped. The alternative is the measure the chromogenic factor x level (goal less than 45% for efficacy).

ACE-inhibitor induced hyponatremia

I’ve always been skeptical about ACE inhibitors as a cause of hyponatremia, despite there being almost 20 case reports of this complication in the literature. Given the fact that so many patients I see are taking an ACE inhibitor, I’ve always felt I’d have encountered this problem more often if it were real. Anyway, I’ve now seen 3 convincing cases and have had to reconsider my position. The following is one such case, and is interesting as it suggests a possible mechanism:

Case: An elderly man with dementia and type 2 DM was admitted following a protracted diarrheal illness associated with poor oral intake. Clinically, he appeared volume depleted, although his blood pressure was normal. He was hyponatremic, with a high urinary sodium and high Uosm (numbers below). The primary team had given him a lot of saline (~6L over 48 hours), which aggravated his hyponatremia, but he continued to appear volume depleted. Urine sodium remained high (65-80), as did his urine output. Despite this Addisonian-type picture, the cort-stim test was normal; renin and aldo were pending.

We were called 3 days into the admission, and decided to stop his lisinopril and continue with normal saline. The results were pretty dramatic, as you can see from the graph below. He immediately became sodium avid (Una fell to less than10 meq/L) and had a water diuresis, correcting his plasma sodium to 132 meq/L over the next few days.

It seems to me that lisinopril was preventing a normal physiological recovery from volume depletion i.e. mineralocorticoid production. Once the ACE was stopped, he became salt-avid under the influence of aldosterone, allowing him to correct the volume depletion and switch off the physiological stimulus to ADH production (hence the water diuresis). This was not SIADH - his ADH axis was functioning normally, as evidenced by his ability to produce dilute urine and correct his plasma Na once the ACE was stopped.

The other 2 cases of ACE-associated hyponatremia I have seen have been remarkably similar to this, where severe volume depletion developed in a patient on chronic ACEi therapy. As such, in my limited experience, the presentation differs from other types of drug-induced hyponatremia, where the sodium falls shortly after the introduction of a new agent, say an SSRI or a thiazide. This insidious mode of presentation may explain why ACE-induced hyponatremia may not be on most people’s radar. Another reason for this may be that ACE-inhibitors can also paradoxically help correct hyponatremia in CHF patients, by improving cardiac output. I’m very interested to hear if anyone else has seen a similar case, as this is a controversial topic (as I’m sure the comment bar will attest!).

The ECG: QT Interval Abnormalities and Sudden Death in Dialysis Patients

Sometimes overlooked, QT interval abnormalities, namely prolongation and dispersion, are important predictors of sudden death to watch out for in the dialysis unit. Of these two, prolongation of the QT interval is the better studied. The QT interval is a measure of the duration of ventricular de- and re-polarization. Early after-depolarizations, which develop because of a failure of normal repolarization in diseased myocardium or due to certain drugs, result in delayed repolarization and QT interval lengthening. This is an ideal substrate for the development ectopic circuits and arrythymia. Prolonged QT is a well-established risk factor for torsade de pointes, ventricular fibrillation and sudden cardiac death.


Acquired QT prolongation in a dialysis patient has a long list of potential causes, but most important are electrolyte abnormalities (all the hypo’s: hypokalemia, hypomagnesemia, hypocalcemia) and medications. While significant electrolyte abnormalities are (hopefully) rarely missed, as they’re checked and flagged all the time, it is particularly important to pay attention to medications. A study of the prescription claims of almost 5 million patients found the unacceptably high prescription rates of QT-prolonging medications and dual therapy with two or more QT-prolonging drugs. In fact, 0.5% were taking 5 concomitant QT prolonging agents! The paper included 50 medications that prolong the QT interval and 26 that inhibit their hepatic or renal clearance. The commonest culprits are antibiotics (clarithromycin, erythromycin, levofloxacin) and anti-depressants (fluoxetine, amitriptyline, sertraline, venlafaxine).


QT interval dispersion (QTd) is less well recognized and often overlooked. QTd, the longest minus the shortest QT interval on a standard ECG, is a marker of variability in ventricular repolarization. A difference of 50 msec or more has been used as a cut-off in several studies (each small box on the ECG is 40ms). QTd is a risk factor for ventricular arrhythmias and sudden death in the general population. It also appearsto be a useful measure to identify dialysis patients at an increased risk for sudden death, based on the following:

• At least 6 studies show that the dialysis procedure is associated with an acute increase in QTd.
• QTd is associated with arrhythmias on Holter monitoring in uremic  patients.
• In a Japanese study of 48 ESRD patients, divided into those who did and did not develop increased QTd post-dialysis, there was an increase in cardiac events and cardiac mortality in the group with an increase in QTd postdialysis
• In 147 HD patients followed for up to 9 years, QTd was an independent predictor of total mortality (RR 1.53; P = 0.0001) and cardiovascular mortality (RR = 1.57; P = 0.028) and a trend towards arrhythmia-related mortality (P = 0.06).

Finally, it is worth remembering that QTd may be an epiphenomenon, as it is associated with LVH and structural heart disease, which are themselves strongly associated with sudden cardiac death in ESRD.

Windows to the Soul...and the Vasculature

Continuing the theme of useful Nephrology bedside clinical signs, today we’ll focus on band keratopathy (BK). Often overlooked, this is a band of calcium deposition across the central cornea commonly seen in patients with advanced CKD. It reflects chronic positive calcium balance or hypercalcemia, and is seen in a wide variety of calcium overload states, including myeloma, sarcoid, hyperparathyroidism and renal tubular acidosis. Interestingly, it can regress with treatment of hypercalcemia, (occasionally dramatically, as in this patient) and will often regress following renal transplant too. Calcium is deposited on the corneal surface (directly under the epithelium) as a horizontal band that begins at the periphery and moves centrally as BK becomes more severe. The BK severity grading system reflects this process, with the mildest grades most peripheral (see figure). Deposits begin as a gray haze, progressing to dense white with a pebbly surface. They can lead to pain, a foreign body sensation and recurrent erosions, but are not a cause of visual loss.

The pathophysiology is not fully understood, but passive calcium precipitation is believed to be responsible. Tears and aqueous humor contain calcium and phosphate at concentrations approaching their solubility product. As tears evaporate from the intrapalpebral area, the concentration increases and precipitation occurs. The most severely affected area is the junction of the middle and lower thirds of the cornea, which is the area of maximum atmospheric exposure. Elevated serum calcium increases the likelihood of precipitation occurring. It is worth remembering that a passive precipitation model used to be proposed as the mechanism of vascular calcification in calcium overload states. This has since been debunked; vascular calcification is an active process involving a phenotypic switch in the vascular smooth muscle cell, which comes to resemble an osteoblast. We may yet learn that calcification occurring on the eye is also more complex than just passive deposition.

This last point is relevant as BK and vascular calcification are closely linked: the presence of BK is associated with a ten-fold increased prevalence of vascular calcification, and over half of dialysis patients with BK have radiologic evidence of VC. Furthermore, BK has recently been shown to independently predict 1-year mortality in dialysis patients, with each increment in the BK severity index being associated with a 25% increased mortality risk in multivariate analyses. It would be interesting to study whether BK also predicts calciphyllaxis. When I encounter BK clinically, I tend to treat it as I would extraskeletal calcification at any other site. As it implies chronic positive calcium balance, it prompts me to consider measures to reduce calcium balance in the patient, such as reducing the dialysate calcium bath, switching to a non-calcium containing phosphate binder and/or a non-calcemic vitamin D analog.

Jugular venous distention- the physical exam, continued...

Following on from Finnian's last post, here are some remarkable videos from the 1950's on JVP examination (physical examination of JVP begins at 3:38):

Minocycline for the prevention of osmotic demyelination in hyponatremia

There’s a reason that 3 the 10 of the most frequently accessed in “Up to Date” articles relate to the management of hyponatremia. It makes doctors nervous, and I think the main reason for this is the threat of the terrifying osmotic demyelination syndrome (ODS). A murky and poorly understood entity, ODS hangs over every management decision you make and, even if you’ve done all the right things (kept the rate of rise in sodium to less than 8 meq per day, paid attention to the K, given DDAVP and H2O back if necessary) you may still get burned, particularly in alcoholics, cirrhotics and the malnourished. Worst of all, you may not learn your fate until over a week later, when early signs of severe neurological injury start to appear.

During hyponatremia, exchangeable intracellular solutes are redistributed to prevent cerebral edema, leading to gradual loss of intracellular organic osmotically active particles. It can take over 5 days to rebuild these stores. A rapid rise in serum Na forces cerebral vascular endothelial cells to contract, opening the blood-brain barrier and allowing pro-inflammatory cells and cytokines to enter the brain. This causes oligodendrocyte injury, microglial activation and demyelination. An agent that could be given to hyponatremic patients before attempting Na correction, and which prevents this dreaded complication occurring, has enormous appeal. In this month’s JASN, two studies in rats suggest minocycline might be just that.

Minocycline is a tetracycline antibiotic most widely used for the topical treatment of acne. It also appears to prevent spots on the brain, having protective properties in animal models of CNS injury, including demyelination, where it seems work by preventing microglial activation. Both of these JASN studies test its effectiveness, when started several hours before rapid Na correction, in preventing ODS in rats. In the first study, minocycline-treated rats showed less microglial activation, less inflammatory infiltrate and much better survival, although some demyelinating brain lesions did still occur. In the second study, minocycline resulted in a marked reduction in the incidence and severity of neurologic symptoms, although half of the rats died.

These are important studies, not least because they highlight the central role of inflammation and microglial activation in ODS, which I formerly held to be a form of direct osmotic injury. Given that ODS is so rare, it’s going to be quite difficult to study the effectiveness of minocycline in humans. So, don’t be surprised if you start to hear suggestions to give minocycline “just in case” in the ICU. I would resist this for a few reasons. First, I develop a little demyelination of my own (from banging my head against the wall) each time I see a renal patient prescribed N-acetylcysteine -but no iv fluids- pre-contrast. Untested therapies can creep into clinical practice, diverting focus from proven interventions and, once established, are very difficult to expunge. Second, very large doses were used in these animals. We’re a long way from knowing how to dose this in humans. Finally, minocycline frequently causes causes vestibular disturbances (dizziness, ataxia, vertigo and tinnitus), particularly in women (50-70% of the time!). Personally, I can’t think of anything more stressful than being called in the middle of the night because the patient I’m treating with hypertonic saline has just developed nystagmus or ataxic movements. No thanks!

Should you stop ACE inhibitors prior to major surgery for renoprotection?

I must admit that I have always routinely advised holding ACE/ARB prior to major surgery, given the possibility of hemodynamic instability and assumed risk of AKI due to impaired renal autoregulation when perfusion pressure is low. I’m prepared to accept that I might be biased, as so much of the AKI I see relates to ACEi use, especially in the elderly. But, as it turns out, the question of continuing ACEi pre-operatively is surprisingly controversial. It seems cardiac surgeons are completely split down the middle on the question. Of 167 practicing UK cardiac surgeons who were asked “Do you think it’s beneficial to stop ACEi pre-surgery?” 40% said yes, 40% said no and 20% just grunted. Some even advocate their use for the prevention of AKI. So, you may yet have a friendly tete a tete with your local cardiac surgeon over this issue, and a brief recap of the evidence may stand to you in such an event.

What is immediately striking when you begin read around this issue is the existence of 2 pitched positions, similar to the ongoing debate on renal artery stenting. On the one hand Nephrology journals mostly carry studies supporting ACE avoidance, whereas Anesthetic/Cardiothoracic Surgical journals only seem to have trials that support of ACE continuation. This observation is of itself unsettling, as it suggests to me the existence of publication bias.

Evidence for continuing ACEi:

1. Although small (N=14 CABG patients), this prospective study of 48 hours of iv enalaprilat vs placebo showed that cardiac index, SVR, renal plasma flow (measured by hippurate) and creatinine clearance (measured by timed urine collection) were all significantly improved in the treatment arm and the effects lasted up to post-operative day 7.

2. This small placebo-controlled double blind trial (enalapril vs. placebo) of 40 patients with LVEF < 35% undergoing CABG also showed improved GFR in the treatment arm (GFR increased from 66 to 80; p=0.009 vs no change in placebo).

3. Finally, a prospective multivariate analysis of 536 patients undergoing on-pump CABG, where AKI was defined as a 50% decrease in GFR. The authors observed a reduced rate of AKI associated with pre-op ACEi use (ACE OR 0.48 0.23‐0.77 p = 0.04). The authors tried to reduce selection bias through the use of propensity scores – adjusting for likely group membership (i.e. ACE vs. no ACE) – which are controversial.

Evidence against continuing ACEi:

1. A larger study by Arora et al. (1358, mostly CABG patients), but retrospective and, again, employing propensity scoring to try and mitigate selection bias. Nonetheless, they did observe a 40% increased risk of AKI in multivariate regression analyses.

So where does this leave us? Two small, randomized, prospective studies show a benefit in hemodynamic parameters and GFR. These are consistent with the known vasodilatory effects of ACEi on the systemic and renal circulation, and I have no trouble believing them. However, they do not address the issue of response to a hypotensive insult while on an ACE, which is the crux of the problem in my opinion. Then, we have conflicting evidence from 2 larger observational studies, both of which are concerning for selection bias, with one suggesting the possibility of harm. Based on the above, I would agree with Thomas Berl’s assessment at this years ASN, and invoke Pohl’s rule: “Never trade an unknown benefit for a potential complication.” Given there is no convincing renal benefit to continuing ACE/ARB prior to surgery, and the real possibility of harm, I would hold these drugs for surgeries where post-op hemodynamic instability is likely.

Under Pressure!

Renal failure occurring in the setting of acute decompensated heart failure (ADHF) is traditionally believed to be due to renal hypoperfusion from poor “forward flow”. This mechanism has intuitive appeal, and appears to be borne out by our clinical experience of improvement in urine output following the introduction of inotrope support in such cases. However, objective testing using pulmonary artery catheterization does not support the “forward-flow” model: degree of renal dysfunction does not correlate with cardiac index, and improvement in cardiac index isn’t associated with improvement in renal function either. This has been observed in many trails, but most notably in the recent ESCAPE trial. So, what then is the explanation?


Evidence is mounting for elevated renal venous pressure and intra-abdominal pressure (IAP) as being prime movers in causing renal dysfunction patients with ADHF. Consider the following:

• In the ESCAPE trial, the only measure that was associated with serum creatinine was right atrial pressure, suggesting that renal congestion is more important than previously believed.
• Studies in dogs show that the kidney stops producing urine at venous pressures of 20-25 mmHg.
• Extrinsic pressure of the kidney to similar levels also causes significant renal dysfunction via increases in venous pressure in modern animal models, as well being frequently observed clinically in cases of the abdominal compartment syndrome.
• Reduction of elevated IAP, irrespective of the mechanism (intensive medical therapy, paracentesis, or ultrafiltration) improved renal function in a study of volume-overloaded patients admitted with ADHF.
• Changes in IAP correlate better with changes in renal function than any other hemodynamic variable.

Reduction in central venous pressure is a far more satisfying explanation for improvement in renal function with diuresis than any putative movement onto a more favorable portion of the Frank-Starling curve, as Nate previously observed.

The Secrets of Tassin

No, this is not the title of the next Dan Brown novel (although the quality of the writing may sometimes compare, you will not find phrases like “the famous man looked at the red cup” here). I’m referring to Tassin, France, a location famous in Nephrology circles for the fact that 95% of dialysis patients there achieve normotension without antihypertensive medication. Nephrologists in Tassin firmly believe in the importance of scrupulous attainment of dry weight (DW) using increased dialysis times. Maybe they have something to teach us.


The publication of the National Cooperative Dialysis Study was a seminal moment in the history of Nephrology. It was on the basis of this RCT that dialysis time was deemed not to be an important predictor of outcomes (based on a p-value of 0.056), and the love affair with Kt/V(urea) effectively began. Nowadays, although Kt/V(urea) targets are slavishly met, hemodialysis patients continue to experience high rates of complications such as hypertension, LVH, CHF, hyperphosphatemia, malnutrition and death. Set this against the superior outcomes seen with longer treatments such as nocturnal HD, and you begin to wonder if they may be onto something in Tassin. There, longer dialysis times aren’t just instituted for their own sake; they permit the attainment of target dry weights that are almost impossible to reach in a shorter session i.e. it’s not the time that’s important, it’s what you do with it that matters. Here I’ll present some of their clinical pearls for achieving DW based on several review articles they have written on the subject:


First, a clinically meaningful definition of DW: "that body weight at the end of dialysis at which the patient can remain normotensive without antihypertensive medication, despite fluid accumulation, until the next dialysis."

1. At DW, a patient’s BP should remain in the normal range during the entire interdialytic period. If BP remains high after dialysis or is elevated before the next session, they are, by definition, above their DW.
2. Dialysis session times of 5-6 hours are usually required, particularly when determining the DW for the first time. Trying to achieve the necessary ultrafiltration over a shorter time will cause hypotension and cramping, and lead to treatment failure.
3. Go slowly! It takes 2-3 months to achieve DW in a new dialysis patient. During this time carefully controlled persistent UF and a strict low salt diet are used, while antihypertensive medications are weaned off entirely.
4. It is essential that all BP medications be tapered down and stopped early in the process. Otherwise it will be impossible to achieve DW.
5. Hypotension and cramping will often occur when nearing DW, and are a common cause of treatment failure. These symptoms do not indicate a patient has reached DW, rather the patient has hit their max refill capacity (Crit. lines predict hypotensive episodes, but do not assess dry weight for the same reasons). If a patient remains hypertensive while experiencing such symptoms, longer dialysis times are indicated to achieve UF goals.
6. Be aware of the “lag phenomenon”. BP does not immediately change in response to changes in volume. Blood pressure may only normalize a few weeks after ECV has returned to normal.
7. Do not wait for obvious signs of volume overload (oedema, hypertension, etc.). Pay attention to small signs such as headache or slight increase BP at the end of a session.
8. Weight falls rapidly after initiating dialysis due to saline removal. However, as a rule of thumb, weight should return to pre-initiation levels after 1 year on dialysis due to muscle and fat build up, with BP now under control (see figure).
9. In difficult cases, ambulatory blood pressure monitoring is an invaluable tool, as it gives the best estimate of the 'true' interdialytic BP (see point 1).

The road to an accurate determination of DW is hard and long. Expect some lightheadedness, cramping and bouts of intense frustration. For the patient, it can be even worse. However, as a great man once said, “Everything is possible. The impossible just takes longer…”

Epo: The honeymoon is not over

Having just returned from my own honeymoon, I was taken by this recent hypothesis-piece by Fishbane et al. They have made some observations on the natural history of untreated renal anemia from examining the placebo arm of the recent TREAT RCT. Briefly, placebo-treated patients in TREAT received rescue therapy with Epo only if their Hgb levels fell to less than 9.0 g/dl; Epo was discontinued and patients returned to placebo as soon as their Hgb levels rose above this level. By this design, the placebo arm of TREAT sheds light on a very conservative approach to anemia management in pre-dialysis CKD.

Interestingly, analogous to patients with newly diagnosed type 1 DM who commonly experience a sharp reduction in their insulin requirement after initial presentation, there appears to be a similar “honeymoon period” after initial presentation with renal anemia, during which the hematocrit stabilizes or even increases (see figure) without treatment. An explanation may be that CKD patients presenting with an acute event such as infection may experience an abrupt, transient, decline in serum erythropoietin levels, and worsening of anemia. As they recover from the presenting event, serum erythropoietin levels and Hgb may also improve. However, this improvement would be masked in patients already initiated on maintenance outpatient Epo.


Many Nephrologists feel as though they are stuck between a rock and a hard place when it comes to Epo administration post-TREAT. This observation may encourage them to hold their nerve in CKD patients who initially appear to require Epo, as the anemia may well improve given time, at least in the short term. Of course, most patients with progressive CKD (save those perhaps with APCKD) will ultimately develop intractable anemia. A further RCT is required to know how to treat them, perhaps with a “TREAT placebo arm” vs. “no Epo at all” design. Perhaps, it could be called the DIVORCE trial (Darbepoetin Intermittently Vs Observation in Renal anemia of CKD).

This isn’t meant to be happening…

A paradigm of modern genetic studies, such as GWAS, is that there is a natural balance to allelic variation, with common variation in the population conferring mild disease risk and, conversely, genes of strong disease effect being rare. This phenomenon is formally described by the ‘common disease/ common variant’ (CDCV) and ‘multiple rare variant’ (MRV) models. The CDCV model predicts the existence of common genetic variants (present in 5–50%) that confer low to modest disease risk (e.g relative risks of 1.1–1.5). Complementing this is the MRV model, which holds that complex traits result from many different mutations, each of which is individually rare (a few percent at most and perhaps orders of magnitude less common), but with very strong effect (for example, relative risks 5 – 10, or even more; see figure). This phenomenon is thought to explain why the search for causative genes derived from GWA studies has been relatively unsuccessful, where only a handful of causative genes have been discovered in follow-up sequencing studies. It is assumed that this difficulty in finding culprit genes is due to these modest effects making them difficult to recognize. Undiscovered common genes of strong effect are simply not thought to exist…

So what is going on in Nephrology? Within the space of a few short weeks there have been 2 separate, high quality studies identifying common disease-causing gene polymorphisms of very strong effect. First, there was the identification of 2 independent APOL1 variants, present in over 30% of African-American chromosomes, that carry odds ratios of 10.5 in idiopathic FSGS and 7.3 in hypertension-attributed ESRD. Analagous to HgbS-mediated protection from malaria, these APOL1 risk variants appear to have risen to very high frequency in Africa as they cause resistance to trypanosomal infection, thus protecting from sleeping sickness. Although the mechanism by which APOL1 variants cause kidney disease are not known, the mechanism of trypanosomal resistance has been described, and offers the hope for a new treatment of this life-threatening infection.

And now this morning, investigators from Hong Kong, reporting in JAMA, describe finding another set of common gene polymorphisms of strong effect. This candidate gene study of Chinese patients with type 2 diabetes, identified several variants of the PRKCß 1 gene as being associated with incident ESRD and, in a follow-up analysis, CKD. The adjusted risk for ESRD was 6.04 (95% CI, 2.00-18.31) for individuals with 4 risk alleles compared with those with 0 or 1, and allele frequencies were high (7-12.2%). PRKCß 1 is an excellent candidate for kidney disease risk in diabetes, with a prior RCT of blockade of its gene-product, PKC-ß, demonstrating slowed disease progression and reduced proteinuria in diabetic patients already on maximal medical therapy.


So, recent studies in Nephrology are bucking the trend in genetic epidemiology, and challenging one of its most basic hypotheses. Whether this is because the assumptions themselves are flawed, or that Nephrology research is just catching up with other fields, remains to be seen.

Stopping statins in dialysis patients

It can often be difficult to stop something once it's been started; take statins for example. It seems that despite consistent evidence from two large, randomized controlled trails demonstrating the lack efficacy of statins for preventing cardiovascular mortality in dialysis patients, there has been little impact on the prescribing habits of nephrologists. This study shows that in the 2 years following the negative 4D result, the rate of statin prescription in diabetic hemodialysis patients actually increased by 10%.

There are probably several reasons for this practice, such as scepticism about the result in ESRD patients given the proven efficacy of statins in other groups, or a reluctance to engage in therapeutic nihilism. Personally, I worry about precipitating a cardiovascular event by stopping these drugs; the 4D and Aurora trials do not address the issue of discontinuation. With such a high rate of cardiovascular events in this population, aren't you just asking for trouble by drawing a line through the Lipitor on the medsheet? It's a thorny question, and one we may put to poll on this blog next week.

The PPI Paradox

Millions of people take long-term proton pump inhibitors for acid-related GI complaints. These agents are very effective and appear to have an excellent safety profile. However, they may also have interesting effects on calcium and phosphate balance that I recently became aware of.

PPIs act via inhibition of the parietal cell H+/K+ ATPase, producing an ‘inhibitory complex’ which blocks HCl secretion and results in loss of the normal acidic environment of the upper GI tract. Ordinarily, this acidic milieu facilitates the release of ionized calcium from insoluble calcium salts, improving calcium solubility, which is necessary for its absorption. Reduced absorption of calcium is believed to explain the increased rates of osteopenia and fracture seen in medical states associated with achlorhydria, such as pernicious anemia and post-gastrectomy. Furthermore, several studies show that long-term PPI therapy, particularly at high doses, is associated with an increased risk of hip fracture. Also, long-term PPI use can lead to hypomagnesemia with a low fractional excretion of Mg, suggesting a similar mechanism may be responsible.

Based on these observations, I began to wonder if PPIs would decrease the efficacy of calcium-based phosphate binders, via a reduction in the ionized fraction available to bind phosphate in the gut. There is almost nothing written on this, apart from a single, small, prospective Japanese study that did indeed show that acid suppression significantly reduced the phosphorus binding ability of calcium carbonate, resulting in impaired phosphate control in hemodialysis patients.

Then, just to keep things interesting, I found another study that suggests that PPIs may have the opposite effect when given with non-calcium containing binders. In a retrospective analysis of 108 HD patients, more patients taking a PPI plus a phosphate binder achieved phosphorus control, defined as an average phosphorus level below 6 mg/dL and "a calcium × phosphate product level less than 55, than did those taking only a phosphate binder (76% vs 24%; P = .001). However, the benefits were only observed in those taking sevelamer; these authors did not replicate the findings from the aforementioned study from Japan. The mechanism behind this observation are not known.

So there you have it: there is a suggestion from this rudimentary evidence that PPIs may potentially impair phosphate control when given with calcium-containing binders, but paradoxically improve control when given with non-calcium containing binders. This could form the kernel of an interesting clinical study…

Economist discussion on whether trading organs should be allowed

Following on from recent posts on the subject by Jamil, The Economist are hosting a live web debate on the issue of organ trading now. Join in on the discussion here.

World Cup fever

Congratulations to the USA and England on going through to the second round of the World Cup today. As an Irishman, I will confess to a modicum of schadenfreude at the humiliating exit of France yesterday, but we won't dwell on that... Unlike high-contact sports such as Rugby or American football, it seems possible to play soccer to a high level after a renal transplant. Ivan Klasnic, a Croatian who plays for Bolton in the English Premiership and the Croatian National team, is one such example. He developed ESRD in January 2007 and received his first transplant from his mother later that month, but unfortunately this was lost to rejection 5 days post-transplant. However, a second transplant from his father 7 weeks later was successful. He was back playing for FC Nantes one year after first becoming ill, wearing a protective belt over the transplant site. He went on to play a starring role in the Croatian National team in Euro 2008, the first transplant patient ever to do so, scoring in both the group stages against Poland and the quarter-finals against Turkey.

It hasn't all been plain-sailing though - England's controversy-prone John Terry allegedly punched him in the transplant during a match last year... a crime only marginally worse than a deliberate handball in the closing minutes of a crucial world cup qualifier, but maybe I'm biased...