Low Anion Gap

Classically, we are taught to look out for an elevated anion gap in patients with a metabolic acidosis. Although much less common, a low anion gap can also be a useful sign and there are a variety of causes.

The commonest cause is lab error, particularly in the measurement of the serum sodium. As previously discussed, high serum lipids or high serum proteins can lead to spuriously low serum sodium measurements thus altering the AG. Severe hypernatremia can also lead to errors in measuring the sodium concentration (usually underestimating the real result) and will lower the AG. Similarly, errors in measuring the chloride or the HCO3 will alter the perceived AG. The bicarbonate is usually measured indirectly and allowing the sample to sit without separating the cells can lead to increased production of CO2 and thus lower the AG.

Apart from lab errors, the commonest cause of a low AG is due to alterations in serum protein levels. Most of the AG is due to negative charges on circulating proteins, primarily albumin so that if the albumin concentration falls, the AG will fall also. It is generally accepted that the AG should be corrected upwards by 2.5 for every 1g/dl fall in the serum albumin. This applies also for patients with an elevated serum albumin; the AG should be corrected downwards in that scenario. Although they do not normally contribute significantly to the AG, immunoglobulins can be important in patients with paraproteinemias. IgG tends to be cationic while IgA is an anion. Thus, patients with an IgG paraproteinemia and a high tumor burden can have a low or even negative AG. In contrast, patients with IgA paraproteinemia will have an elevated AG.

Calcium and magnesium could theoretically decrease the AG if they are significantly increased. In practice, however, hypercalcemia does not usually cause a lowered AG unless it is due to hyperparathyroidism. Other causes of hypercalcemia are not associated with changes in the AG. It is uncertain why this is the case. Hypermagnesemia usually does not affect the AG because it is normally accompanied by sulphates and as these are unmeasured anions, they balance each other out.

Several drugs are associated with reductions in the AG. As mentioned by Nate before, bromide intoxication is a rare cause of a negative anion gap. At first, this does not appear to make sense; bromide is an anion, similar to chloride. As a result, elevated bromide levels should cause an increase in the AG. However, bromide interferes with the chloride analyzer – every 1 mEq increase in bromide leads to a reported 3 mEq increase in chloride. Thus, patients with bromide intoxication can have extremely negative AG. Iodide can also interfere with the chloride assay and lead to a negative AG.

Lithium is a cation, in the same family as sodium and thus lithium poisoning will lead to a reduction in the AG although usually only when the level is above 4. This can be a clue to a lithium overdose in a patient with suspected poisoning where there is no ready access to lithium levels.

I would recommend an excellent review of the uses of the anion gap published in CJASN in 2007 that addresses all of these in great detail.

The ABCs of ADME in AKI

The pharmacokinetics of a drug refers to the study of the absorption, distribution, metabolism and elimination of that drug (often referred to as ADME). Each of these characteristics can be greatly altered in a patient presenting with acute kidney injury (AKI). Historically, dosing in AKI has not been distinguished from that of chronic renal insufficiency (CRI). Newer evidence suggests that pharmacokinetic alterations differ between AKI and CRI, and; therefore, dose adjustments may also be different.

Absorption

The bioavailability of a drug can be influenced by GI transit time, gastric pH, and intestinal drug metabolism. Gastric pH can be increased in patients presenting with AKI, which may decrease dissolution and ionization of the oral drug and lead to reduced absorption. In CRI, intestinal metabolism can be reduced potentially resulting in increased absorption. The effect of AKI on intestinal metabolism has not been well-studied.

Distribution

Drug distribution is dictated by many factors, one of which is a medication’s ability to bind to plasma proteins, such as albumin. Patients with AKI may present with low serum albumin levels, leading to a higher free-fraction of albumin-bound drugs (e.g. warfarin, phenytoin, valproic acid, and salicylates) and consequently, increased biological effect.

Other factors affecting drug distribution include serum pH and fluid status. AKI is frequently associated with acidosis, which may affect the ionization and ultimately the distribution of the drug into the tissues. Lastly, increase in fluid volume in the blood can lead to low drug concentrations.

Metabolism

Many drugs undergo metabolism prior to elimination. A myriad of co-morbid conditions frequently associated with AKI may affect drug metabolism such as liver and cardiac dysfunction. Non-renal clearance can be decreased in the setting of CRI, possibly due to a chronic accumulation of uremic by-products causing an impairment of drug metabolic enzymes. As this is a chronic process, the same may not hold true in the early stages of AKI.

Elimination

AKI may have opposite effects on drug elimination. While significant nephrotic syndrome may increase the clearence rate of large molecules and highly protein-bound drugs, acids and bases may accumulate in AKI and compete for transporters, thus diminishing tubular secretion of drugs eliminated by anionic and cationic transport systems.

In sum, the pathophysiologic process in AKI is different from that of chronic CRI, and the pharmacokinetic parameters of medications may differ in the two disease states. Therefore, drug dosing principles studies in CRI may not hold true for patients presenting with AKI, and further research will be necessary to ensure proper dosing of medications in AKI and better guide us in our daily clinical decisions.

Craig A. Stevens PharmD, PGY1 Pharmacy Practice Resident

Steven Gabardi PharmD, BCPS, Organ Transplant Clinical Specialist at BWH

References

Zhang Y, Benet LZ. The gut as a barrier to drug absorption: combined role of cytochrome P450 3A and P-glycoprotein. Clin Pharmacokinet 2001;40:159-68.
Klotz U. Pathophysiological and disease-induced changes in drug distribution volume: pharmacokinetic implications. Clin Pharmacokinet 1976;1:204-18.
Power BM, Forbes AM, van Heerden PV, Ilett KF. Pharmacokinetics of drugs used in critically ill adults. Clin Pharmacokinet 1998;34:25-56.

AKF Kids Calendar Art Contest 2013

The American Kidney Fund’s Calendar Kids Art Contest recognizes kids with kidney disease for their artistic talent and helps to increase awareness of kidney disease. The contest winners have been selected but help is needed to choose the artwork for the 2013 calendar cover!

This lucky winner will receive a trip to Washington, D.C., and will attend the American Kidney Fund’s annual gala, The Hope Affair.

Follow the link to browse the artwork below and vote for the image that you want to see on the cover!

Isolated C3 deposits on an inflammed glomeruli

Six months after a kidney transplant, a patient developed a rising creatinine, significant proteinuria (~2g/day), hematuria and low C3 levels. A kidney graft biopsy showed severe glomerulonephritis with mostly occluded capillary loops with immunofluorescence staining negative for immunoglobulins but strongly positive for C3 (representative picture on left). On EM, subendothelial and mesangial electron dense deposits were visualized. The features are characteristic of the so-called C3 glomerulonephritis (GN).

C3 GN is part of the same family as dense deposit disease (DDD) and fall into the new proposed classification of C3 glomerulopathy. Compared to C3 GN, DDD is characterized by extremely electro-dense intra-membranous deposits on EM. Both entities can present with features of MPGN, once significant chronic endothelium glomeruli damage occurs. These glomerular pathologies shared in common its pathogenesis, which involves complement dysregulation.

Classically, immunoglobulins that deposit in the glomeruli are the major triggers of glomeruli inflammation. In rare settings such as C3 GN, complement proteins are present in the glomerular lesions in the absence of immunoglobulins. Abnormal activation of the alternative pathway is implicated on this finding. Either an acquired or inherited defect in the control of alternative complement pathway should be investigated.

The following tests are generally recommended:

** Levels of C3 and complement factors B/H/I

** Presence of C3 nephritic factor (C3 NeF)

** Genotyping for certain complement mutations (common in kids)

Our patient underwent complement testing and was found to have circulating C3 nephritic factor. This factor is an IgG autoantibody that directly stabilizes the C3-convertase activating complex of the alternative pathway and thereby prevents the normal inhibitory action of complement factor H, leading to continuous activation of the complement cascade and consequent deposition of complement by-products in the glomeruli.

Although atypical hemolytic uremic syndrome (aHUS) is also strongly associated with a dysregulation of the alternative pathway, glomerular lesions in aHUS do not exhibit C3 deposits or electro-dense deposits on electron microscopy, differentiating from C3 glomerulopathies. How changes in complement regulation leads to very diverse presentations might be related to the underlying defect. Nonetheless, atypical HUS could be placed in one side of this spectrum of renal diseases associated with alternative complement dysregulation (figure below; adapted from Servais et al. 2007).

While the pathogenesis is complicated, even harder is the treatment challenge of C3 GN in our patient above. There are a couple of new promising approaches and markers that might help guide therapy. I will try to cover them on my next blog.

Antibiotics and encephalopathy

Recently I was involved in the care of a renal transplant recipient who was admitted with C. Difficile colitis that was complicated by a bowel perforation. He had a history of hepatitis C with relatively preserved hepatic function. He had a complicated post-op course requiring prolonged treatment with intravenous antibiotics but was gradually improving clinically.

Over a period of 24-48 hours, he developed altered mental status. He had myoclonus, initially was perseverating and eventually became relatively unresponsive. He had a low grade fever with no obvious source. His renal function was improving towards baseline and his serum ammonia level was normal. A CT brain was also normal. He was treated with thiamine, electrolyte repletion and antibiotics but showed no improvement after 48 hours.

At that point, the ID attending suggested stopping his cefepime. 24 hours after stopping, he was already less confused and within 2 days, he was back to baseline.

Cefepime-induced encephalopathy is a rare but important complication of this antibiotic that is more common in patients with renal disease and appears to be dose-related. It is characterized by decreased consciousness, agitation, aphasia, myoclonus progressing to convulsions and coma and carries a high mortality. It is not limited to cefipime but can happen with any cephalosporin. EEG findings include diffuse slow-wave activity. The treatment is prompt cessation of the drug and this diagnosis should be considered in any patient with renal failure who develops otherwise unexplained encephalopathy while on a cephalosporin.

In our patient, his measured creatinine probably overestimated his GFR because of his marked muscle-wasting. he was being treated with high-dose cefepime for presumed ascending cholangitis and this accumulated over a period of days.

Survey for Fellows and Fellowship Directors

The good people at East Carolina University’s Brody School of Medicine are doing a survey study of the quantity and quality of nephrology fellows’ end-of-life care education and their readiness to provide that care to the elderly.

If you're interested you can take the Fellowship Program Directors survey here. Or the Fellows survey here.

Picture: Ball's Pyramid off the coast of Australia

Handling anticoagulation peri-kidney biopsy

Kidney biopsy is considered the most invasive procedure nephrologists are involved. Though complication rates are small, bleeding requiring surgery has been reported to occur in 1 in 1,000 kidney biopsies. More commonly, patients may develop a decrease in hemoglobin by 1 point (~50% of cases) and/or gross hematuria (3-18%). The risk of bleeding complications become much higher in patients that require peri-biopsy anticoagulation.

A new evidence-based guideline was just published on Chest 2012, summarizing the best approach to anticoagulation in a number of different scenarios. Overall, the new recommendations are more conservative than before regarding anticoagulation peri-procedure.

To illustrate that, let’s use a theoretical patient on anticoagulation with coumadin (6mg daily) due to Factor of V Leiden mutation and prior history of thrombosis (more than 6mo ago).

In preparation for the procedure, the physician would recommend stopping coumadin 5 days prior to the kidney biopsy and bridging with either UFH or LMWH. This is usually started on day 3 prior to the procedure. The major difference in approach now is related to when should the bridging anticoagulation be stopped and restarted. The novel guidelines recommend the following:

* If on IV heparin, stop infusion 4-6 hours prior to procedure

* If on LMW, last dose should be 24 hours prior to procedure (rather than 12 hours before)

* Resuming coumadin should occur 12-24 hours after procedure if no evidence of bleeding

* Bridging anticoagulation with LMWH or UFH should be restarted 48-72 hours after the procedure (rather than 24 hours after surgery). Since most of the bleeding after kidney biopsy will occur in the first 24 hours, I believe delaying for another 24 hours would only be warrant in major surgeries with higher bleeding risks)

Most of these recommendations are grade 2C (weak), therefore individual interpretation is warranted.

My take-home summary of anticoagulation peri-kidney biopsy in high risk patients for thromboembolism would be:

Stop coumadin 5 days before procedure; admit the patient with renal failure 3 days prior to biopsy for bridging with UFH; stop UFH at least 4 hours prior to procedure; resume coumadin/UFH 6-24 hours after bx if no evidence of bleeding (stable Hb, vital signs and no significant hematuria).

Though this is a general suggested approach, remember to assess the thromboembolic risk for each individual patient before proceeding with a kidney biopsy. As an example, I would favor restarting anticoagulation much earlier after bx in a patient with history of multiple clots (6 hours after biopsy).

Below additional general recommendations about anticoagulants from the new guidelines:

- Dosing of UFH: 80U/kg bolus followed by 18U/kg/hour

- Dosing of coumadin: loading with 10mg daily for first 2 days [[personal opinion: this loading dose may be too high for elderly or cachetic patients]]

- Dosing of enoxaparin: 1mg/kg BID; if GFRb below 30 ml/min: 1mg/kg daily

- Dosing of fondaperinox: 5mg daily if less than 50kg; 7.5mg if 50-100kg and 10mg if more than 100kg. Avoid if GFR less than 30 ml/min.

- Dosing of dalterapin : 200 U/kg daily. Accumulation expected in renal failure but no specific dose adjustment has been recommended, so should likely be avoided until trials available.

- Despite recent publications about benefits of genotyping in predicting response to coumadin, the guidelines recommend against this practice.

Origins of Renal Physiology Course

We've posted several times about the 'Origins of Renal Physiology' held in the Mount Desert Island Biological Laboratory every year. Fellows who have taken the course over the past 5 years have consistently raved about it, with many describing it as transformative in their careers as researchers, teachers and clinicians. It's on again this year September 2-9, 2012.


This year for the first time, 'Origins' will be free for all renal fellows who are admitted to participate.  The organizers are able to do this thanks to a five year R25 research education grant from the NIDDK/NIH. Lodging and meals are included, so the only costs to you are travel.  

Applications are now being accepted; the application will close on April 15.Head over to the course website: www.mdibl.org/courses/The_Origins_of_Renal_Physiology/114/, for a description of the course and the online application form.  

Under Pressure

As a medical student I was taught the CKD hypertension gospel straight from the good book of JNC VII: Thou shalt lower the blood pressure to less than 130/80! This was many years after David Bowe and Freddie Mercury but I got the song stuck in my head when I started thinking about the post so I had to put it up there.

I lived happily with this for many years until one day someone questioned me. Why should you lower the blood pressure to less than 130/80 in someone with chronic kidney disease? Well 'cause the JNC VII says so! Check it out...


Right there in red, blue and black. And supported by two references no less! One of them is the American Diabetic Association going on about diabetes (another story) but reference 21 is KDOQI on CKD... So the rabbit hole gets deeper.

Over at KDOQI we get the following...


They say "controlled trials in essential hypertension conclusively show a beneficial effect of lowering blood pressure to <140/90 mm Hg. Controlled trials in high-risk individuals with diabetes or heart failure suggest beneficial effects of reduction of blood pressure to even lower values. Based on these studies, and on observational studies, a number of guidelines for patients with either diabetes mellitus or congestive heart failure recommend a goal blood pressure of <130/80 mm Hg. There are few studies regarding blood pressure goals for CVD risk reduction in patients with CKD. Thus, the Work Group elected to extrapolate the recommendations for high-risk patients to patients with CKD."

Uhh so, we have no evidence so we took some evidence from other diseases and said do the same thing. It not quite that bad. There is some evidence for less than 130/80 but it has caveats.

The MDRD study randomized patients to aggressive vs standard blood pressure control with achieved average values of 126/77 and 133/80 respectively. At the end of the study there was no overall difference between the two groups in terms of kidney function but in post-hoc analysis the aggressive BP arm had statistically slower rates of renal function decline in patients with over 1g per day of proteinuria mainly driven by patients with over 3g of proteinuria per day. Unfortunately, the aggressive control group were more likely to have received ACE inhibitors than the standard control group so the post-hoc data is a bit muddled.

In the recently published long term followup of the AASK trial, African Americans with hypertensive kidney disease who were initially randomized to either intensive or standard BP control were subsequently followed in a cohort phase in which the BP target was the same in both groups. Followup extended out to 12 years from the initial randomization. The achieved BPs during the trial were 130/78 mm Hg vs 141/86 mm in the intensive and standard groups respectively. In the cohort phase BPs were much closer as expected (131/78 and 134/78 in the intensive and standard groups respectively).

The story is similar to MDRD, among all patients there was no difference in the primary composite outcome of ESRD, doubling of serum creatinine or death throughout the trial and cohort phase. However, in the subgroup with baseline proteinuria of greater than 220 mg per day a significant difference between BP target groups appeared favoring more intensive control.


So no clean randomized prospective data to support the JNC VII target of less than 130/80 in CKD patients. There is a hint from the above subgroup analyses that CKD patients with proteinuria might benefit from having blood pressures controlled to below 130/80. The proteinuria cutpoint at which this might occur is unclear.

It will be interesting to see how JNC VIII, expected sometime later this year, handles the above. Additional information will hopefully come from the randomized prospective SPRINT trial which is looking at systolic BP goals of 140 vs 120 in a large cohort with a reasonable proportion of CKD patients.

Water deprived

Recently in the clinic we were asked to review a patient with suspected diabetes inspidus. She had been taking lithium for more than 20 years for bipolar disorder that was very well controlled. During a routine medical examination, her blood tests revealed a serum creatinine of 1.4 so she proceeded to have a 24-hour urine collection. The result of this showed that her GFR was moderately reduced at 40mls/min but the striking finding was a 24 hour urine volume of 10 liters. The patient herself had no complaints regarding this as she was accustomed to drinking large volumes. She had been advised many years before to take a high salt diet in order to reduce the potential for nephrotoxicity (this sodium would compete for Li uptake in the DCT). Reducing her salt intake cut her urine volume by half which in itself was a great result.

One thing that did not fit entirely with the story was that her serum Na was never >140mEq/L. The impetus for water intake in DI is a high serum Osm but she was often in the 137-138 range suggesting that she was actually keeping her Osm lower than would be expected. The question arose as to whether or not there was a component of polydipsia here unrelated to the possible DI so we admitted her for a water deprivation test.

As mentioned by Nate before, the protocol for this test involves restricting a patient’s access to water and then measuring the plasma and serum osmolarity every 1-2 hours until:

(a) the urine osmolality reaches a normal value (e.g., above 600 mosm/kg, suggesting that both ADH secretion and response to ADH are intact).

(b) the urine osmolality is stable on two successive measurements despite a rising plasma osmolality, or

(c) the plasma osmolality is greater than 295-300 mosm/kg.

At that point DDAVP is administered.

There is one caveat, in the case of this patient, her initial urine Osm was 104 with a serum Osm of 307. According to the protocol above, this would be the time to give her DDAVP. However, her serum Na was only 141. The additional Osmoles were a result of a slightly elevated fasting blood sugar and a high BUN (because of her CKD). Her calculated Osmolarity was 306. As a result, we postponed giving DDAVP at that stage. Her results during the day were as follows:

Serum Na 141 144 149 153 154

Serum Osm 307 315 319 326 329

Urine Osm 104 126 142 154 153

We administered DDAVP when her serum Na was 149 and allowed her to drink again as soon as the next lab was taken. Her final result was after she had been allowed to start drinking again and she was already preventing her Na from increasing any further. The lack of response to DDAVP indicates a diagnosis of nephrogenic DI, almost certainly due to lithium.

The take home points for me here were that a low serum sodium in the steady state does not necessarily mean that the patient does not have DI – in someone like this who has had this problem for years, she has just become accustomed to staying ahead of her thirst. The second point was that a serum sodium always has to be sent with the serum osmolarity as if there are other osmoles around, they can give you a misleading result.

NYT: 60 Lives, 30 Kidneys, All Linked

Interesting article on chain donation in the NYT.

New to the Blogosphere: CJASN eJournalClub

The latest entrant into the blogging community comes to us from CJASN in the form of their new eJournalClub. It's a neat site, the editors choose an interesting article, put it up with an editorial and then have a forum for the public and authors to have at it. The site does require you to login with your ASN membership and has a close to seizure inducing flashing icon of recent CJASN covers that could be toned down.

This month my buddy and co-fellow Cristina Arce, had her recent article on hispanic ethnicity and vascular access use selected for the site which is very cool.

So we've got eAJKD, Kidney International Podcast, the JASN app and now eJournalClub from CJASN. What's going on NDT?

There's no such thing as a contraction alkalosis

We recently discussed an excellent paper on the classification of metabolic alkalosis. The three suggested subtypes were primary and secondary stimulation of collecting duct ion transport and exogenous alkali administration. Another interesting editorial was just published in JASN that further expands on the idea that chloride deficiency is central to the maintenance of a metabolic alkalosis.

The traditional view of a contraction alkalosis was that in a volume depleted patient, there would be increased reabsorption of sodium in the proximal tubule. Because this sodium must be reabsorbed with an anion, bicarbonate was also reabsorbed in the proximal tubule along with this in preference to chloride, thus perpetuating the alkalosis. The first challenge to this viewpoint came in the 1960s when it was shown that a chloride deficient alkalosis generated by diuretics or gastric aspiration was corrected by treatment with NaCl or KCl but not with Na or K repletion without Cl. This did not however deal with the issue of volume depletion.

More recently, the authors of the editorial have shown that a chloride deficient alkalosis could be corrected in rats by infusion of a chloride containing solution despite ongoing volume depletion, while restoration of the ECF volume with albumin did not correct the acid-base abnormality. In fact, the urinary excretion of bicarbonate increased in the rats that received chloride while it fell further in those that received volume expansion with albumin alone.

Finally, they treated normal human subjects with a low chloride diet along with furosemide and Na and K supplementation. These subjects developed an alkalosis that was maintained for 5 days and corrected with oral KCl alone without any expansion of plasma volume. This elegantly demonstrated that volume is not the issue in these cases and that it truly is an effect of chloride depletion alone.

So what is the mechanism for the maintenance of the alkalosis? Previous posts have discussed the role of Pendrin, the HCO3-Cl exchanger in the collecting duct. The main stimuli for pendrin activation are decreased distal delivery of chloride and intracellular alkalosis. However, where there is little or no distal Cl delivery, it is not available to exchange with HCO3 and thus the alkalosis is maintained. This also helps explain the alkalosis induced by hypokalemia. Hypokalemia induces intracellular acidosis which inhibits HCO3 excretion by pendrin thus exacerbating the extracellular alkalosis.

Can we now finally get rid of the concept of a contraction alkalosis?

Extend Medicare Coverage for Kidney Transplant Patients!

Currently many kidney transplant recipients lose their Medicare coverage 36 months after receiving a transplant. In some cases these individuals are then unable to afford the cost of anti-rejection medications and subsequently lose their kidney. When this happens these individuals return to the more costly option of dialysis which is covered by taxpayers.

Let's end the madness. The current policy makes no sense for patients and makes no sense for taxpayers.

Take the time to sign the petition started by Ajay Singh over at The Kidney Doctor in support of the Immunosuppressive Drug Coverage for Kidney Transplant Patients Act introduced into the Senate back in September.

Lead Nephrotoxicity

I saw a patient in the clinic who was referred for evaluation by his PCP with CKD, a bland urine sediment and a history of hyperuricemia and gout. He had no history of diabetes or hypertension and had no obvious (to me) reason for his CKD at first glance. He was a non-smoker and had no family history of renal disease. He worked as a plumber and his examination was entirely normal.

My attending came in and asked him if he was still using as much lead these days as he had in the past – apparently he was down to 4 times monthly. He was using it to fix joints and was regularly exposed to lead vapor. Even at this, his exposure was significantly less than it had been when he was younger before work practices changed.

Lead toxicity is an under-recognized cause of chronic kidney disease. Commoner in the past when lead was ubiquitous and likely less important now as an environmental cause of renal disease, it should be suspected in people who still work with lead regularly (or had a significant past exposure). Plumbers, fishermen (who make their own weights) and hunters (who make their own shot) continue to be at risk.

The renal signs of lead toxicity depend on the duration and degree of exposure. Acute lead toxicity leads to proximal tubular inclusions and an acute fanconi syndrome. Chronic lead toxicity causes a chronic interstitial nephritis with a relatively bland urine sediment. Patients typically have gout and this condition has sometimes been confused with uric acid nephropathy. Even low levels of lead exposure appear to be associated with a decline in GFR. A study in 1992 in the NEJM found that a 10-fold increase in blood lead concentration was associated with a 10-13mls/min decline in GFR in a population of asymptomatic patients. There is a chicken and egg issue here however, as a lower GFR can lead to decreased lead excretion.

The diagnosis is made by first determining if the patient has been exposed to significant amounts of lead and then measuring lead levels in the blood. In patients with a historic exposure, this may not be reliable because of sequestration in the bone and x-ray fluorescence is more reliable.

The treatment involves removing the sources of exposure and, in patients with substantial lead toxicity, chelation therapy. This is not entirely without risk and has been associated with acute renal failure in children. Chelation in the presence of ongoing exposure will actually increase toxicity as it will lead to an overall increase in blood levels.

We are in the process of getting the XFR scan for this patient and it may be that he does not have lead toxicity after all; but it is definitely one to think about in the future.

A picture is worth...

Often on rounds with medical students or housestaff we will review why a serum creatinine of 0.8 mg/dl in a 40 year old athlete...


may mean a much higher creatinine clearance than a creatinine of 0.8 mg/dl in a sedentary 74 year old grandfather...


due to the much lower muscle mass and subsequent lower creatinine production in the older individual.

The beautiful cross sectional MRI images above are a stunning visual reminder of muscle mass differences that we only guess at from external appearances.

The good news is that aging alone does not relegate one to inevitable muscle mass decline and frailty. The images are taken from an interesting study in The Physician and Sportmedicine examining muscle mass and function in men and women in each of four age categories: 40s, 50s, 60s and older than 70. The subjects were all considered masters level athletes engaging in training exercise 4-5 times per week.

In these individuals muscle mass and function did not decline with age though they did gain body fat. Compare the muscle area and appearance of the 74 year old sedentary male above to the 70 year old male athlete below...


The lesson: Stay active, keep your kidneys healthy and keep that creatinine of 0.8 mg/dl reflecting the same creatinine clearance at 70 years old as it did at 40!

Femoral versus Jugular: part three

Previous posts have discussed various iterations of the cathedia study, a study comparing femoral and jugular placement of dialysis catheters in patients in the ICU. As mentioned before, the femoral route was not associated with a higher rate of infection than the jugular route, except in patients with a BMI>28.5, and catheter dysfunction rates were lower in the femoral and R jugular sites compared to the L jugular.

The same group has published another follow-up paper, this time in CJASN, analyzing patients who crossed over from a jugular to a femoral line or vice versa. 134 patients were included in total and again, using the patients as their own controls, there was no increased incidence of infections and no change in catheter dysfunction in the femoral group compared to the jugular. One major limitation of this study was that they did not use ultrasound to insert the lines which must be standard practice in most institutions these days. It should also be said that all three of these papers are from the same database, which adds a significant bias, and it has not yet been replicated. Still, for a fellow planning on inserting a line late at night and wondering what the best practice is, it provides further evidence that the femoral route is safe in most cases and that at least you are not doing any harm by utilizing this route for access.

In a Few Words

“A doctor, like a writer, must have a voice of his own, something that conveys the timbre, the rhythm, the diction, and the music of his humanity, that compensates us for all the speechless machines.”

-Anatole Broyard
Intoxicated by My Illness

It's funny how small the world is. In this month's In a Few Words in AJKD two of my former colleagues have a beautifully written piece on Advance Directives and the challenges they sometimes present.

The piece reminded me that I've been meaning to write something for Dena for a while but always seem to fall short. I always enjoy the section and the well done Podcasts that often augment it. I'm hoping that a little crowd sourcing will help rectify my own shortcomings.

If interested in submitting, In a few Words aims to give voice to the personal experiences and stories that define kidney disease. They will accept for review nonfiction, narrative submissions of up to 1,600 words, regarding the personal, ethical, or policy implications of any aspect of kidney disease in adults and children.

Footnotes or references are discouraged. Any submission which refers to real patients must be either unidentifiable or approved by the patient(s) described. Submissions from physicians, allied health professionals, patients, or family members are welcome.

You can submit pieces for consideration via AJKD’s manuscript handling site.

Azathioprine in pregnancy

We recently discussed this issue in conference and I thought it might be worth sharing a few interesting points:

Azathioprine is normally converted to the active metabolite 6-mercaptopurine. However, in pregnancy the placenta can metabolize azathioprine to thiouric acid, an inactive metabolite. In addition the fetal liver does not have inosinatopyrophosphorylase which therefore largely protects the fetus from exposure to active compounds.

Azathioprine has been classed as FDA category D - positive evidence of risk.
Despite conflicting data, general expert opinion suggests that azathioprine may be considered for use during pregnancy in certain situations (where the potential benefits outweigh potential risks).

In terms of breast feeding, in a small study, active metabolites have been detected in small quantities in breast milk. Overall the significance of this remains to be fully determined. Manufacturers have taken the official stance to warn against breast feeding while taking the drug.


As with all considerations of alterations in immunosuppressive dosing, careful consideration of risks and benefits should be explored in detail with the treating physician before any change is undertaken.

Cell Polarity and Cystic Diseases

There was an interesting article and accompanying editorial in JASN this month about the role of polarity in the development of cystic renal diseases. The maintenance of epithelial cell polarity is vital for the normal functioning of the renal tubules and the usual interpretation of this is the way in which a cell is organized into basolateral and luminal compartments (e.g. in intercalated cells, there is a luminal H+ ATPase and a basolateral anion exchanger and it is this polarity that facilitates acid excretion). In a similar way, mislocalization of the Na-K-ATPase has been noted in patients with ADPKD and is a putative mechanism for cyst formation.

However, there is another facet to polarity which appears to be just as important – planar polarity – this is the correct orientation of cells and specialized structures within cells along the plane of the epithelial sheet. Much research is continuing into the genes responsible for the development and maintenance of polarity. One of the means by which a loss of planar polarity may induce the formation of cysts is through the loss or dysfunction of primary cilia.

The authors in JASN found that both a gain and loss of function mutation in ErbB4 led to a loss of cell polarity. Members of this receptor family have been shown to be responsible for the development of polarity in neurons and in certain cancers.

From the RFN archives: The Brenner Hypothesis

The Brenner Hypothesis--developed by Barry Brenner of the Brigham and Women's Hospital, author of the well-known Brenner & Rector "The Kidney" textbook--states that individuals with a congenital reduction in nephron number have a much greater likelihood of developing adult hypertension and subsequent renal failure. This hypothesis is supported by the observation that there is a strong epidemiologic relationship between intrauterine growth retardation (IUGR)/low birth weight and adult hypertension. The mechanistic explanation for this phenomenon is that compensatory hyperfiltration by the remaining nephrons--similar to what happens in diabetic nephropathy--results in accelerated renal decline. While this theory is appealing at several levels, it does not explain everything: for instance, why most kidney transplant donors, who instantaneously lose 50% of their nephron mass, for the most part do well post-transplant without developing hypertension or renal disease.

The Brenner Hypothesis is part of a larger body of work which posits that many common adult diseases (including diabetes and hypertension) are caused by factors which are established during early growth and development, the "fetal origins of adult disease" hypothesis.

Originally posted by Nate Hellman

Hold the potassium

It was not an unusual event during my clinical fellowship to get a call from the cardiac team asking for dialysis in a patient with hyperkalemia and acute renal failure. On a few occasions the hyperkalemia seemed disproportionate to the level of renal function and on further investigation, this was found to the as a result of the zealous correction of the potassium level to >4 mEq/L in patients in the cardiac unit. I have often wondered about this practice and whether or not there was firm evidence for keeping the potassium in the 4-5 mEq/L range (or even 4.5-5.5 as suggested by some authors) and so it was with interest that I read this paper that just appeared in JAMA.

As mentioned in the paper, the data suggesting that low potassium levels are associated with increased mortality are relatively old and date from an era when ventricular arrhythmias were more common following an MI. They were also generally relatively small studies. The authors of this study used a database of patients presenting to 67 US hospitals with an ICD9 code for MI and increased cardiac biomarkers. In total >39,000 patients were included.

They were looking primarily at post-admission potassium levels and their relationship with in-hospital mortality and the occurrence of arrhythmias. AS one would expect, there was a U-shaped curve for the relationship between in-hospital mortality and the potassium level. What was unexpected, however, was that the lowest mortality was seen in patients with a potassium between 3.5 and 4.5 mEq/L and that the mortality doubled in patients with a potassium between 4.5 and 5 mEq/L.

This was borne out in the fully adjusted model. The OR for in-hospital mortality was 1.96 (CI 1.64-2.34) for patients with a potassium between 4.5 and 5 mEq/L. Interestingly, the risk of a ventricular arrhythmia was the same in patients in the midrange of potassium values and only increased in patients with a potassium of below 3 or above 5 mEq/L. This contrasted with the mortality data and the authors suggested that this might be in part a result of incorrect coding of ventricular arrhythmias and is a potential limitation of the study. Also, this study certainly does not prove that replacing potassium to a level above 4.5 mEq/L is dangerous. This could only be answered by a randomized trial. There may be some residual confounders that have not been accounted for in the model. Still, as the authors point out, this study challenges current guidelines and suggest that a better target for potassium in patients following an acute MI would be 3.5-4.5 mEq/L. Perhaps we might see less of this particular consult in the future?

Classification of Metabolic Alkalosis

Dr John Gennari had another typically excellent review of metabolic alkalosis in AJKD in October. He suggests an alternative means of classifying a metabolic alkalosis according to the etiology of the alkalosis along with the physiological basis for the maintenance of the alkalosis once it has occurred. He also goes into some detail explaining the key role that chloride depletion has in the development and maintenance of a metabolic alkalosis.

The 3 subtypes that he suggested are:

1. Secondary stimulation of collecting duct ion transport:

This is the commonest type and results largely from a secondary increase in the activity of ENaC in the distal nephron leading to increased sodium reabsorption and hydrogen ion excretion. The commonest causes are chloride depletion syndromes (GI losses, CF) and the use of thiazide and loop diuretics, with congenital disorders such as Bartter and Gitelman syndrome being rarer. Severe potassium depletion can also precipitate a metabolic alkalosis. The mechanism is complicated but it includes increased proximal tubular hydrogen ion secretion, decreased activity of the Na-2K-Cl transporter in the loop of Henle (with increased NH4 transport in this segment also contributing) and subsequent increased activity of ENaC due to the higher distal delivery of sodium. This form of alkalosis is perpetuated by chloride depletion.

2. Primary stimulation of collecting duct ion transport:

This is almost always due to a pathological increase in sodium reabsorption with consequent hypertension and volume expansion. The commonest cause is primary aldosteronism. Other rarer causes include Cushing’s Syndrome, CAH, Liddle’s Syndrome, 11-hydroxysteroid dehydrogenase inhibition (licorice) or deficiency and exogenous mineralocorticoids.

3. Alkali intake or administration:

This is largely an issue of excess alkali administration in patients who are unable to excrete it rapidly – i.e. patients with abnormal renal function

This paper is highly recommended for anyone wanting to understand more about the pathophysiology of metabolic alkalosis

Is the glass half empty or half full?

Recently, we were asked to see a patient on the consult service with a rising creatinine, a BUN of close to 200 and decreased urine output. The patient was a diabetic who had an STEMI several months previously complicated by pneumonia and cardiogenic shock. He was cachectic, did not have any edema or ascites and because of his trach-collar, I put “unable to assess JVD” in my note. His BUN had been high (above 100) for more than 4 weeks (not on TPN, steroids, no GI bleeding) as he was aggressively diuresed for heart failure and his creatinine had been rising slowly which, given his low muscle mass, indicated a significant reduction in GFR. My attending also assessed the patient and felt that his JVP was elevated and recommended diuresis. The primary team, in contrast, felt that his JVP was low and they recommended fluids. The assessment of the JVD is a notoriously difficult exam and very hard to master if one does not do it appropriately as described in a previous post. The patient received 2 liters of fluid and his cardiac status worsened so he was started on dialysis several days later for worsening renal function and volume removal.

This case illustrates the difficulty in accurately assessing volume status in patients in general.

When was the last time you assessed a JVD comfortably? We often say "this patient is dry" or that he needs diuresis but how accurate are our assessments based on the clinical exam alone?

A previous post discussed the JVP and its use as a tool for volume status assessment and cited a systematic review stating that there is a “poor relationship between the isolated inspection of CVP and prediction of blood volume and fluid responsiveness.” One of my attendings gave me an article on this topic several weeks ago: "Clinical assessment of extracellular fluid volume in hyponatremia". The article assessed the clinical judgment of volume status by one of the authors (including cardiac parameters, JVP, orthostatic changes, skin turgor, moisture in the axillae, hydration of mucous membranes) and volume status was 'objectively' assessed by spot urine samples of sodium and creatinine and BUN, norepinephrine and plasma renin concentrations. The clinical assessment was only able to identify 47 % of hypovolemic patients and 48% of normovolemic patients whereas the spot urine sodium clearly separated hypovolemic from normovolemic patients.

The "Bible" of physical examination - Evidence Based Physical Diagnosis by Steven McGee - attributes a low sensitivity or specificity or both to the most common findings used when assessing hypovolemia (the highest likelihood ratio was 2.8 for a dry axilla; in contrast, dry mucous membranes, tongue furrows, sunken eyes, confusion, weakness or unclear speech did not have a significant likelihood ratio). Capillary refill time has been compared only once to a diagnostic standard and was found to have no diagnostic significance.

An intriguing series in JAMA about the rational physical exam stated in the conclusion that "in patients with vomiting, diarrhea, or decreased oral intake, few findings have proven utility, and clinicians should measure serum electrolytes, serum blood urea nitrogen, and creatinine levels when diagnostic certainty is required."

The bottom-line I learned from all of this is: our examination at the bedside is notoriously unreliable in making accurate statements about a patient's volume status and objective parameters need to be taken into account to get a complete picture. A previous post discussed the use of urine electrolytes as a more objective tool for assessing volume status in addition to clinical examination.

Posted by Florian Toegel

Timing of Dialysis Initiation: The Billion Dollar Question

One of the true arts learned during renal fellowship is the timing of initiation of dialysis in outpatients with advanced chronic kidney disease. This a crucial skill to develop as the beginning of dialysis has major implications for the patient's lifestyle, finances and well being. In this regard, the publication of the IDEAL trial (reviewed by Matt and one of our top stories of 2010) was a landmark in helping to guide management in these situations, highlighting the safety of waiting for signs and symptoms of advanced chronic kidney disease rather than pursuing early start dialysis solely based on eGFR in closely followed individuals.

Does this differ from what's been going on in practice for the last 10-15 years? A quick look at the USRDS shows that back in 1996 less than 20% of patients started dialysis with an eGFR of greater than 10 ml/min/1.73m2. In stark contrast by 2009 a full 20% were starting with an eGFR of over 15 ml/min/1.73m2 and greater than 50% were starting above the 10 ml/min/1.73m2 mark.

Why the heck did this happen when uremic signs and symptoms, at least in the IDEAL trial, in general seem to occur at GFRs below 10 ml/min/1.73m2?

A variety of explanations have been put forward (well reviewed by Rosansky and colleagues here and here). A commonly proffered argument is that perhaps uremic signs and symptoms are occurring earlier in our aging and increasingly ill population. However, in a study of 2402 nursing home residents who initiated dialysis, the authors found that seven signs and symptoms commonly associated with declining kidney function, such as volume overload and cognitive or functional decline, accounted for less than one third of all cases of early dialysis initiation including less than half of all cases of early outpatient dialysis initiation, suggesting that dialysis initiation may be primarily prompted by laboratory values in a large number of patients.

Regardless of the reasons, the trend is clear, early start was the rule rather than the exception building through the late 90s into the 2000s.

What has this meant for patients and US societal economic cost? A very nice paper from O'Hare and colleagues tells part of the story, using information from a large integrated health care system in Seattle, the group was able to estimate the rate of eGFR decline prior to the onset of dialysis in a subset of patients. This in turn allowed them to predict how many additional days on dialysis patients spent in 2007 versus 1997 by looking at the mean eGFR at time of dialysis initiation in patients listed in the USRDS and then back calculating (this relied on the assumption that the rates of decline were similar in these groups).

These estimates showed that dialysis was initiated on average of five months earlier in 2007 compared to 1997 and almost 8 months earlier in patients over 75! Doing some back of the envelope calculations the group guessed that early initiation in the US had cost an additional $1.5 billion dollars during 2007. This is slightly higher but similar to the over $1 billion dollar additional yearly cost estimate made using slightly different assumptions by the AJKD editorialists for the economic analysis of the IDEAL trial (this was the US estimate - the IDEAL trial was conducted in Australia and New Zealand).

Given that early initiation of dialysis in asymptomatic closely followed patients has no proven benefit (and may even be harmful if you look at recent retrospective data) part of our charge as emerging nephologists is helping to reverse this expensive and unhelpful trend.

(Photo: Stanford Chapel at Night)

Top nephrology-related stories of 2011

 

2011 proved to be another exciting year in the world of nephrology.  2010 was dominated with big clinical trials (SHARP, FHN, IDEAL), APOL1 gene variants, Propublica article on HD in the US, and medicare bundling.  2011 proved to be a big year in basic science.  Below is a list of the top 10 nephrology-related stories as voted by the readers of RFN. This is by no means a complete list of all of the major news stories.  Feel free to add to this list in the comment section below.  I will summarize each of these studies/stories below in increasing order of votes as received in our year-end poll.

10. FDA approval of belatacept for use in kidney transplant induction therapy (15%)-  In June the FDA approved the use of the selective T-cell costimulatory blocker (anti-CTLA-4) belatacept (Nulojix) for use in kidney transplantation as both induction and maintenance therapy.  This was after the FDA reviewed both the BENEFIT and BENEFIT-EXT trials published in Transplantation in 2010. These trials examined the use of belatacept for induction therapy and as a replacement for calcineurin-inhibitors for maintenance therapy. The hope is that calcineurin-inhibitor based regimens can potentially be avoided in the future as these are associated with a decline in eGFR over time. These trials both showed an improvement in eGFR at 3 years as compared to cyclosporine based regimens with slightly more acute rejection. However, the major concern for belatacept is the increased risk of post transplant lymphoproliferative disease hence it cannot be given to EBV negative patients. Another issue with giving belatacept is that it is given IV at different schedules after transplant which could impart challenges.  Nephron Power has a post about this story.  

9. Success in treating myeloma kidney with bortezomib plus plasma exchange published in NEJM June (17%)- Using plasma exchange to treat myeloma cast nephropathy has been a controversial topic in the field of nephrology. The benefit in clearing free serum light chains with plasma exchange has become an increasingly popular approach. Investigators from the Mayo Clinic published a letter in NEJM in June of this year describing their experiences with using bortezomib in combination with plasma exchange in 14 patients with known or suspected myeloma cast nephropathy.  12 of the 14 patients (86%) treated with plasma exchange had a partial or complete response to the therapy.  6 of the 12 had a complete response with normalization of creatinine after 6 months.  Only 2 were on HD after treatment. These results are encouraging, however a randomized clinical trial will be needed to confirm this.

8. Eculizumab for shiga associated HUS published in NEJM (21%)- The major outbreak of E. coli O104:H4 secondary to contaminated sprouts that occurred in Germany dominated the international news from May to June of this year. About 4000 people were infected and at least 46 died. Nephrologists in Germany were hit with an unprecedented number of patients with hemolytic uremic syndrome (HUS). This coincided with a report published in the NEJM in June of this year which demonstrated the complete resolution of Shiga-toxin-producing E. Coli- HUS in three children treated with eculizumab. This supported the concept that shiga toxin may activate complement directly and direct inhibition of terminal complement complex formation by treating patients with eculizumab. This lead to an ad hoc committee from the German Society of Nephrology to recommend all patients with renal or neurological and hematological symptoms treated with plasmapheresis. If no short-term improvement was seen then they recommended use of eculizumab. This has resulted in wider-spread use and now a clinical trial. This was definitely a positive outcome to a devastating condition.  I'm sure we will see more of this drug in clinical use in the near future.

7. The DOSE study of bolus or drip diuretics in CHF (24%)- This was an interesting study of a common clinical conundrum (Do you give diuretics by bolus or continuous infusion in compensated CHF?) that was published in NEJM in March of this year and discussed on RFN by Finnian. This was a prospective double-blind randomized controlled trial consisting of 308 patients from 26 clinical sites testing 2 questions; how do high-dose (2.5 x home dose) vs. low-dose (home dose) diuretics and IV continuous vs. IV bolus loop diuretic strategies impact the 1.  Efficacy (symptoms) or 2.  Safety (change in creatinine) in patients with compensated heart failure? There were no significant differences between either of these endpoints in either high vs low and continuous vs. bolus diuretic administration. The high-dose group did have more improvement in dyspnea but a higher creatinine level was reached. Read Finnian's conclusion on his blog post.    

6. sFLT-1 removal in preeclampsia published in Circulation in August (25%)-  Another exciting development in nephrology is the publication of a pilot study aimed at removing the soluble fms-like tyrosine kinase 1 (sFlt-1) in women with preeclampsia which was published in the journal Circulation in August of this year. Nate originally discussed sFlt-1 role in preeclampia on RFN and it is interesting to see how far research has progressed since then. This study looked at the feasibility and safety of removing sFlt-1 using extracorporeal apheresis in 5 patients with preterm preeclampsia and elevated sFlt levels. The pilot study confirmed that this technique is possible and safe however, it was not able to address whether or not this approach will prolong pregnancy and improve both maternal and fetal outcomes. I'm sure a clinical trial will be forthcoming.

5. Bardoxolone for diabetic nephropathy published in NEJM July (27%)-  The preliminary results from this trial were originally presented at ASN Kidney Week in 2010 which I discussed on RFN in December. The final results were published in NEJM in July and discussed by Gearoid on RFN and Joel on PBF. This was a phase 2, double-blind, randomized, placebo-controlled trial looking at 227 adults with CKD treated with various doses of the oral antioxidant inflammation modulator Bordoxolone or placebo for 52 weeks.  This trial showed improvement of GFR at 24 and 52 weeks compared to placebo.  However, much of this GFR improvement was lost at 56 weeks (4 weeks after stopping the drug). I think these results are provocative, however I am anxiously awaiting the results of the larger phase III clinical trial termed BEACON which is currently enrolling patients.

4. ACT trial of acetylcysteine in contrast nephropathy (30%)-  This trial published in Circulation in August and discussed by Graham on RFN was another long debated clinical question in nephrology- (how do we prevent kidney injury when patients receive iodinated contrast agents?). This trial randomly assigned 2308 patients undergoing an intravascular angiographic procedure with 1 risk factor for contrast-induced acute kidney injury to either acetylcysteine (1200mg twice daily 1 day before and 1 day after the procedure) or placebo. Both groups received normal saline at a rate of 1ml/kg per hour 6-12 hr before and after. They did not find any difference between any of the primary or secondary outcomes comparing acetylcysteine vs. placebo. Read the conclusion and comments from Graham's RFN post. Overall, it appears that  acetylcysteine's days for preventing contrast nephropathy are almost over.        

3. Increased mortality in dialysis patients after 2-day break (41%)- This study published in NEJM in September examines how patients that receive thrice weekly dialysis fare over the 2-day interdialytic interval. This study retrospectively examined the death rates and cardiovascular related hospital admissions on the long 2-day interval vs. other days in 32,065 patients currently undertaking thrice weekly hemodialysis using the USRDS database. They found that indeed the 2-day interval was associated with increased all-cause mortality, infection-related mortality, cardiac arrest, MI, CHF, stroke and dysrhythmia as compared to other days. Evidence is continuing to point towards a more physiological dialysis regimen with daily dialysis. However, this study did not compare thrice weekly to nocturnal or daily dialysis.

2. The lupus nephritis maintenance phase of the ALMS trial published in NEJM November (44%)-  Coming in at number 2 is the much awaited results of the maintenance arm of the Aspreva Lupus Management Study (ALMS) trial. The induction arm of the ALMS study compared Cyclophosphamide to Mycophenolate (MMF) and was published in JASN in 2009 and showed difference between the two therapies in inducing remission in lupus nephritis. The maintenance phase randomized patients that responded in the initial phase to either MMF or Azathiprine. 227 patients were randomized into each group. The patients randomized to MMF had better outcomes as compared to Azathioprine and puts MMF firmly on the map for both induction and now maintenance of lupus nephritis. However, there has been some conflicting data as was reported by the smaller MAINTAIN study that did not show a difference between these two regimens. This was a well conducted clinical trial that adds evidence to a difficult to treat condition. This is a welcome addition to patients with lupus and the nephrology and rheumatology communities.     

1. suPAR as a cause of FSGS published in Nature Medicine in July (54%)-  Coming in at number 1 in the 2011 nephrology poll at 54% of votes received was a basic science article published in Nature Medicine and discussed by Gearoid on RFN exploring the mechanism of focal segmental glomerulosclerosis (FSGS). This study showed that level of serum soluble suPAR urokinase receptor was present at higher concentrations in patients with FSGS. They then showed in 3 different animal models that elevated suPAR was capable of causing proteinuria and foot process effacement. We will see how these findings will be translated to human studies just as the discovery of the M-type phospholipase A2 receptor is for membranous nephropathy.

Again, quite a busy and exciting year in the world of nephrology in 2011. Thanks to all of the contributors and readers for keeping the site fun, interesting and educational.

Thanks for supporting RFN and happy holidays.