Diarrhea and Tacrolimus

Recently, a patient presented to the transplant service with diarrhea and dehydration. He had been trying unsuccessfully to manage his diarrhea at home and was admitted for intravenous fluids. During his work-up, his tacrolimus levels were noted to be elevated and his dose was reduced. After resolution of his diarrhea, his tacrolimus dose needed to be readjusted because his levels were now sub-therapeutic. This increase in the level of tacrolimus that is seen in patients with an inflammatory diarrhea is well described but it seems to fly in the face of common sense. You would think that with the decreased intestinal transit times that are seen in patients with diarrhea, the level of tacrolimus would fall rather than rise as is seen with many other medications.

The reason for this is interesting and is related to the absorption of tacrolimus in the normal gut. Tacrolimus has a low oral bioavailability with only approximately 20% reaching the bloodstream. There are 3 reasons why this happens. The first is that it undergoes significant first-pass metabolism in the liver by the cytochrome p450 system. The second two specifically relate to the gut:

1. P-glycoprotein: This is a membrane associated protein that transports many substances across intracellular and extracellular membranes. It is thought to be important in the development of multidrug resistance to antineoplastic agents. In the gut, it transports drugs back into the intestinal lumen from enterocytes thus reducing bioavailability

2. CYP3A4: This enzyme is the most important member of the cytochrome p450 family and is primarily expressed in the liver. However, there is also significant expression of this enzyme in the small intestine making this an important site of metabolism of some drugs including tacrolimus

In the setting of an inflammatory diarrhea, both of these processes are downregulated in enterocytes. This leads to both increased absorption and decreased gut metabolism of tacrolimus thus increasing drug levels despite the faster gut transit times. Once the gut mucosa heals, these processes begin to function normally again and the drug levels fall.

This, at least, is the theory for why this occurs. There are not many studies that have addressed it directly although here was one study that looked at a model of inflammatory diarrhea in rats that suggested that this is the case. Others have shown that polymorphisms in the gene encoding for p-glycoprotein are predictive of drug levels after renal transplantation.

AKF: Pair Up

Pair Up is the American Kidney Fund’s new national campaign empowering women to protect themselves— and the people they love— from kidney disease. Laila Ali joined the AKF this past Thursday to kick off the Pair Up campaign at Military Island in Times Square.


The launch of the campaign coincided with the release of a national survey commissioned by the AKF revealing that most Americans who care for their loved ones’ health are unaware that diabetes and high blood pressure are the leading causes of kidney disease.


Pair Up asks women to join the fight against kidney disease by taking two simple actions:


1) Learn if they’re at risk for kidney disease.


2) Spread the word about kidney disease to friends and loved ones who also may be at risk.

Dialysis care in Bangladesh

Although diabetes and hypertension rates in developing countries is rising to match that seen in developed regions, care for patients with end-stage renal disease is still a nascent field.


I recently visited Dhaka, Bangladesh. I was able to visit 2 dialysis units there, one sponsored by a charity and another that was part of the National Kidney Hospital in Dhaka. The National Kidney Hospital in Dhaka is a major referral center for care for patients with acute kidney injury from other hospitals, and has one of the largest outpatient dialysis units (with 30-40 dialysis machines functioning at one time). My understanding is that less 10,000 patients are undergoing some form of dialysis or living with a transplant in the country.


It was so interesting to learn how dialysis is run in Dhaka. Nephrologists I met there mentioned that they take care of about 100 patients who are outpatients. Cost of dialysis in this particular unit is subsidized by the government, at about $8-10 per treatment. But most patients are only able to afford two times per week treatment, and it was excruciating to hear that nearly 80-90% “withdraw” from dialysis in 5-6 months as their families’ resources are depleted. In the charity unit I visited they had only had a handful of patients undertake dialysis for more than 1 year.


Typical dialysis prescription in Dhaka:
Access: fistula
Blood flow: 250 ml/min
Dialystate flow: 500 ml/min
Dialyzer: F6, fresinius machine
Length of time: 4hrs, typically 2x/wk


Most of the patients I saw were young or middle aged, much younger than the average US patient. The nephrologists mentioned that glomerulonephritis is the most common diagnosis among the outpatient dialysis patients in their unit, but I wonder if glomerulonephritis is indeed the most common cause of ESRD there or it’s simply that patients with diabetic ESRD are older and their families chose not to pursue dialysis treatment. Rates of diabetes in Bangladesh are estimated to be about 5-6% of the adult population, not too too far from the 11% rate usually seen in the US.


The financial constraints are even tighter for those not lucky enough to get one of the subsidized dialysis spots; in the private units, dialysis costs close to $40 per treatment. Again you can see how this may be completely cost prohibitive in a country where 50% of the population lives on less than $2 per day.


Peritoneal dialysis is not widely available. Only living renal transplants are performed; one of the largest centers is the National Kidney Hospital which performs1-2 transplants per week. The cost of a transplant is $3000 for the surgery and post op care. Not surprisingly, there was a recent scandal related to an “organ trafficking” ring that had reportedly gotten 200 poor people to sell their kidneys on the cheap.


The nephrologists I met were very committed and extremely well trained. It was really touching to see how proud they were of their work, from setting up the water facilities to getting research projects up and going.

When Pressed to Check the Pressure

Estimating a patient's intra-abdominal pressure (IAP) can be a challenge when the patient is not in an ICU setting and abdominal compartment syndrome or intra-abdominal hypertension are suspected.  Here is a quick method for estimating IAP. This is a much simpler version of the method reported by Cheatham et al and only requires a measuring tape, 25 mL of normal saline in a syringe and a tubing clamp.  The attached picture is of a patient that I tried this method on today. Only took 5 minutes from start to finish.

1.  Make sure that Foley's tubing is empty by draining all the urine into the bag.

2.  The patient should be supine.  Hang the urine bag up on the patient's IV stand 2.5-3 feet above the bed.

3.  Clamp (or pinch/kink) the tube just distal to the hub and then have the nurse inject 25 mL of normal saline through the Foley into the bladder.  The normal saline should be at room temperature.

4.  As the column of urine rises in the tube, measure the height of the column in centimeters by holding the measuring tape as shown with the zero approximately at the point of the iliac crest where the mid axillary line passes.

5.  Divide the height in centimeters of the column by 1.36 to get the pressure in mmHg.

The cut off (2) for intra-abdominal hypertension is 12 mmHg and that for compartment syndrome is 20 mmHg (with organ dysfunction).  In this patient with oliguric acute kidney injury developing after a bowel surgey, the pressure was 26 mmHg, suggesting abdominal compartment syndrome as the etiology.

Also see Mohmand and Goldfarb Editorial in NephSAP 10(3) May 2011.

Hashim Mohmand MD.

How bad is the long break for dialysis patients?

In this week’s NEJM, Foley and colleagues published a retrospective analysis of the End-Stage Renal Disease Clinical Performance Measures Project (CPM) cohort examining the association of the long interdialytic break (i.e. Friday to Monday for MWF patients and Saturday to Tuesday for TTS patients) and clinical outcomes. The study is already receiving plenty of press (Forbes.com, LA Times) and should be read by all.

Before diving into the study mechanics and results, a review of existing data on the “long break” is warranted. Bleyer and colleagues published 2 prior studies examining the timing of hemodialysis (HD) and patient deaths. The first demonstrated a higher rate of cardiac death on Mondays and Tuesdays. In a subsequent analysis, they found that HD patients had a 3-fold increased risk of sudden cardiac death (SCD) in the 12 hours prior to the 1^st HD session of the week. In a later study, Karnik and colleagues examined patient and HD-specific factors associated with a higher risk of cardiac arrest and SCD during dialysis. They corroborated Bleyer’s finding of increased deaths on Mondays (but, interestingly, not on Tuesdays) and identified low dialysate potassium, older age, diabetes, catheter use, and intradialytic hypotension as factors associated with sudden death. Similar findings have also been reported in Europe.

With growing evidence that alternative dialysis schedules (daily, nocturnal, quotidian, etc) improve outcomes (specifically LV mass, QOL), the authors of this new study hypothesized that the long interdialytic interval is associated with increased morbidity and mortality.

Study Basics:

-Design: retrospective cohort

-Population: 32,065 thrice-weekly HD patients from the ESRD CPM from 2004-2007

-Aim: compare rates of death and hospital admission on the day following the “long break” to rates on other days

-Outcomes: mortality (all-cause and cause-specific: cardiac, vascular, infectious, other) and hospital admission rates

Study Findings:

Mean age 62.2y, 45.1% women, 36.3% black, 43.7% w/ DM as ESRD primary dx, 27.7% w/ catheter use, mean vintage of 3.8y (24.2% had been on HD <1y), and mean DSL of 217min

Mean follow-up time: 2.2

Mortality rate: 41.1%

o Cardiac cause: 17.4%

o Vascular cause: 2.7%

o Infectious cause: 4.8%

Event (selected)	Event on Day after Long Break (Rate per 100 Person-Yr)
	Yes	No	P-value
All-cause Mortality	22.1	18	<0.001
Cardiac Mortality	10.2	7.5	<0.001
Infectious Mortality	2.5	2.1	0.007
Cardiac Arrest	1.3	1.0	0.004
Myocardial Infarction	6.3	4.4	<0.001
Septicemia	1.2	1.0	0.06
Hospitalization- MI	6.3	3.9	<0.001
Hospitalization- CHF	29.9	16.9	<0.001
Hospitalization- Dysrhythmia	20.9	11.0	<0.001

Limitations:

· Retrospective nature (potential residual confounding)

· Misclassification due to limitations in outcome adjudication (ICD-9 codes, CMS death forms)

· Study suggests association but not causation and provides little data to suggest the mechanism

Conclusion:

The long 72 hour interdialytic interval is associated with higher all-cause, cardiovascular, and infectious mortality as well as with higher rates of cardiovascular related hospitalizations

Potential Mechanisms: (almost all of which deserve further study)

· Elevated potassium levels and associated membrane destabilization

· Potassium shifts (high serum K⁺ against a low, and often unadjusted dialysate K⁺)

· High fluid burden and associated cardiac myofiber stretch and stress to the conduction system

· High ultrafiltration rates and associated cardiac stunning

· Catecholamine and cortisol surges and enhanced sympathetic nervous activation

Now What?

There is no doubt that a randomized trial of session timing, length, and schedule is needed. This new study provides further justification (and “clinical equipoise” as noted by the authors) for such. In the meantime, we are mired in a delivery system driven by strict schedules and tight budgets. What do we tell our patients? How do we alter practice now within the confines of the current system? Here are some thoughts:

· Potassium-directed (for patients w high pre-dialysis K⁺)

o More frequent monitoring of pre-HD K⁺ and subsequent tailoring of dialysate K⁺

o Avoidance of 0-1meq K⁺ dialysate baths

o K⁺ profiling to maintain a constant K⁺ gradient

o Target colonic excretion (bisacodyl for ex) of K⁺ over the long break

· Fluid-directed (for patients with high inter-dialytic weigh gain)

o Strict fluid and salt restrictions

o Extended dialysis session length to minimize ultrafiltration rates

· Alternative schedules

o Additional weekly session

§ Justified under current Medicare policy for patients w large weight gain, intolerance to ultrafiltration, and intradialytic hypotension

o Encourage home HD and PD for appropriate patients

What's next?: Further research is NEEDED before wide-spread practice alteration is warranted particularly given the profound policy implications, but our patients deserve this now. Specifically, we must determine:

o Optimal dialysis scheduling

o Patient preferences regarding frequency and duration (i.e.... will they come??)

o Cost-effectivness analyses (will more frequent HD reduce morbidity and thus cost?)

Posted by Jenny Flythe

ACT: Now more than thespians

As a kid growing up in the San Francisco ACT brought to mind guys in tights running around and projecting their voices at the American Conservatory Theater. Now I've got to adjust my association with the acronym with the recent publication in Circulation of the Acetylcysteine for Contrast-Induced Nephropathy Trial (ACT).


ACT is the largest randomized trial to date to evaluate the use of oral acetylcysteine prophylaxis in patients at risk for contrast induced nephropathy (CIN). In this multicenter trial, 2803 patients at risk for CIN undergoing an intravascular angiographic procedure were randomized to either acetylcysteine or placebo. Roughly 35% of patients in each group had eGFRs between 30-60 ml/min by MDRD and about 5% in each group had an eGFR of less than 30 ml/min.


The acetylcysteine group received 1200 mg of oral acetylcysteine q12 hours before and after the contrast load. The use of normal saline at a rate of 1 mL/kg per hour, from 6 to 12 hours before to 6 to 12 hours after angiography, was strongly recommended but changes in the total volume or speed of administration were permitted. In the end, 94% of patients received normal saline in both the treatment and placebo groups at some dose with 47% in both groups receiving exactly the recommended dose.


There was no difference between the treatment and placebo arms in terms of the primary outcome of CIN (defined as a 25% elevation of serum creatinine above baseline between 48 and 96 hours after angiography) or the secondary composite outcome of need for dialysis or death in the intention to treat analysis. Approximately 13% of patients in each group experienced CIN with 2% and 0.3% experiencing death or need for dialysis respectively.


This looks to be the end of the acetylcysteine in CIN argument. It's hard to imagine a larger or more well performed study. There was no hint in the subgoups that patients with more severe chronic kidney disease or diabetic nephropathy might benefit. This is clear evidence that we should drop acetylcysteine from the CIN prophylaxis tool kit and focus our efforts elsewhere.


Addendum:


So, the argument is not over. As noted in the commentary, the ACT results are limited by the low resolution of the description of the fluid strategies between groups leaving the bias door open a crack. The issue of generalizability is also raised in patients with advanced chronic kidney disease (and other high risk groups) given their relatively low numbers in the study. Although the ACT subgroup analyses give no hint that NAC might be of benefit in these groups the hypothesis of benefit for them remains to be adequately tested.

Free PD Calculator App

Here is a handy free PD calculator for your phone that I came across today. It includes an Access Care and Complications Manual that covers the management of PD catheters and infectious peritonitis, a PD Prescription Guide with PD Prescription calculator and a PD dosing manual that covers adequacy and modelling. Also included are Clinical Practice Guidelines including CSN PD Adequacy Guidelines and Recommendations 2011, ISPD PD-Related Infections Recommendations 2010 and ISPD Guidelines for Peritoneal Access. All in all a very useful app.

From the RFN Archives: Glucocorticoid-Remediable Aldosteronism

Glucocorticoid-Remediable Aldosteronism (GRA) is an inherited autosomal dominant disorder which causes early-onset (often childhood) high blood pressure, often occuring in individuals with Celtic ancestry.

It typically presents with standard symptoms of aldosteronism (hypertension, hypokalemia, and metabolic alkalosis) with a high aldosterone, low renin state.

The mechanism is pretty cool: the genes for both aldosterone synthetase and 11b-hydroxylase are adjacent genes on the same chromosome which are 95% homologous. Sometimes a crossover event occurs yielding a chimeric gene in which aldosterone synthesis is controlled by ACTH!

The treatment, therefore, is prednisone, to suppress ACTH (and therefore aldosterone).

Originally posted by Nathan Hellman

Sodium and seizures?

The development of acute hyponatraemia can have profound neurological consequences. After creation of an osmotic gradient between the intravascular compartment and the intracellular compartment, water must somehow gain access to the brain tissue.

This appears to be mediated, at least partially, by aquaporin 4, based on evidence from mouse knockout models. Those mice deficient in AQP4 had significantly less brain oedema compared to wild-type animals after the induction of acute hyponatraemia.

In very acute situations the brain does not have enough time to implement its adaptive response mechanisms (which involve loss of intracellular solutes and osmolytes), and so acute cellular oedema can occur. It is in this situation that acute neurological sequelae are more common.

What if a patient presents to the ED post-generalized seizure, and the labs come back with a serum sodium of 130mmol/L? Could this seizure be ascribed to hyponatraemia? It actually could - one potential explanation is that the patient may have a pre-existing brain lesion that is more susceptible to osmotic changes. The second potential mechanism lies with the downstream effects of the seizure itself. Following the seizure, skeletal muscle cells can take on substantial amounts of water. This in turn may result in a ‘rise’ in the serum sodium concentration, by up to 10-15mmol/L in some estimates (from one of Dr M. Halperin’s acid-base textbooks). Definitely something to keep in mind.

From The RFN Archives: "Full House" Immunostaining

Renal pathologists may throw out the term "full house" immunostaining...what does this mean?

This means quite simply that all five major immunofluorescent stains on a renal biopsy (IgM, IgG, IgA, C3, and C1q) are all positive.  The analogy holds true in that the "full house" in cards (3 of a kind plus a pair, to the left) is similar to the 3 types of immunoglobulins plus 2 types of complement which show positive staining.  

The classic situation for "full house" immunostaining occurs in lupus nephritis, in which there is immune complex deposition in the subendothelium and subepithelium.

Originally posted by Nate Hellman

Facing challenges: Hepatitis C and Kidney Transplantation

Hepatitis C virus (HCV) infection affects more than 180 million people globally, may lead to renal disease and is prevalent in 11-49% of patients with end-stage renal disease, depending on geographical location. With that picture in mind, we are faced with the question of choosing which patients might benefit from kidney transplantation and what is the current literature on that.

A potential recipient is HCV Ab positive. What is the best approach?

Getting a liver biopsy is the most important step after identification of HCV infection, since LFTs and viral loads do not correlate well with degree of liver disease. Despite no clear guidelines, advanced liver disease should be referred for possible liver/kidney transplant. Imaging of the liver is also essential in addition to AFP (higher risk of hepatocellular carcinoma)

Does kidney transplantation provide a survival advantage to HCV infected patients?

Yes. Despite the increased risk of death on the first 6 months after tx, HCV patients have a clear survival advantage, with significant decrease in cardiovascular mortality long-term (HR 0.2, p value below 0.001). Nonetheless, compared to HCV-negative patients, they still carry a higher risk of death (RR 1.79) and graft failure (RR 1.56).

What is the most worrisome complication of HCV infected patients after transplantation?

Using common sense, you might think that with the immunosuppression required by kidney tx, exacerbation of HCV infection would occur more frequently compared to patients on dialysis, with faster progression of liver disease. Indeed, HCV viral load might increase after transplantation, however, this is not associated with increased risk of posttransplantation liver disease. A recent retrospective study of 230 HCV-infected patients indicated that kidney transplantation does not accelerate liver injury, revealing that ~77% of recipients that underwent follow-up liver biopsies showed stable or improved liver histology. Progression of liver injury may be actually lower in tx recipients compared to patients on the waiting list. The most important complication was the increased risk of general infection on the first six months after tx.

What is the best immunosuppressive regimen in these patients?

Unclear at this point, though a subgroup analysis of a retrospective data (huge limitations) suggested lower liver fibrosis progression with Thymo compared to Daclizumab. No difference in maintenance immunosuppression was noted.

Can HCV infection be treated after transplantation?

The use of interferon alfa after transplantation has been associated with a very high risk of acute graft rejection and is currently only recommended for kidney recipients with HCV infection resulting in life-threatening vasculitis or fibrosing cholestatic hepatitis.


In face of organ shortage, could we consider transplanting a HCV + donor kidney to a HCV + recipient?

This is a controversial topic, but recent study suggests that this is a safe long-term strategy for HCV+ patients, in terms of patient survival, graft survival and liver disease.

Novel drugs like Telaprevir might change the natural history of HCV, however, recent study suggested that this protease inhibitor might not be recommended after tx due to significant interactions with CNI (P450 inhibition). It's never that easy...

(picture: day after Irene's storm in Cape Cod )

Don't forget the vitamins

In the absence of glucose, the brain requires a water-soluble, fat-derived fuel for metabolism and ketoacids serve this function. Unsurprisingly, as a result of this, the main factor controlling the production of ketoacids is the relative lack of insulin. This explains why type 1 diabetics, who certainly do not lack glucose, are prone to DKA when they go without insulin. Ketoacids are produced by the metabolism of acetyl-CoA in the liver. There are 3 main substrates for the generation of acetyl-CoA – fatty acids (in the setting of relative insulin deficiency), ethanol, and occasionally, the product of the metabolism by bacteria of some poorly-absorbed carbohydrates in the colon.

Alcoholic ketoacidosis most often occurs in the setting of a combination of high alcohol intake and poor nutrition. The decreased carbohydrate intake inhibits insulin production and increases ketoacid generation while the alcohol is itself metabolized to ketoacids via acetaldehyde and acetic acid. Commonly, patients present with a high anion gap metabolic acidosis and ketonemia although the picture can be muddied in certain situations:

1. Lactic acidosis induced by hypoperfusion

2. Metabolic alkalosis due to vomiting

3. In the setting of relatively normal renal function, the ketoacids are rapidly excreted in the urine. If these anions are excreted with Na or K, this can lead to a fall in the anion gap making the diagnosis less apparent.

The treatment is relatively simple, glucose and volume replacement. However, there is one important caveat. After successful treatment, ketoacids are no longer available as brain fuel and glucose again becomes the primary fuel. In order for aerobic glycolysis to proceed efficiently, pyruvate dehydrogenase is required. Thiamine (or vitamin B1) is an essential co-factor for this enzyme and in its absence, anaerobic glycolysis increases in areas of the brain with high metabolic rates leading to an accumulation of lactate and intracellular acidosis. Nutritional deficiencies in alcoholics encompass vitamin deficiencies and many of them lack thiamine. The lactate accumulation induced by this deficiency produces the symptoms of Wernicke’s encephalopathy. For this reason, it is vitally important that the thiamine is administered to these patients prior to treating the ketoacidosis.

New to the Blogosphere: The Kidney Doctor

If your looking for something new and interesting in the online Nephrology world check out Dr Ajay Singh's The Kidney Doctor.

Since starting up last month there has already been some great content including a post from the primary author(!) of the suPAR in FSGS paper that Gearoid posted on for us here at RFN.

Subclavian subterfuge and "Catheter Last"

While performing an electronic chart biopsy prior to examining a consult patient, I noticed a "nephrologic no-no," which can be seen on the patient's chest x-ray coursing under the right clavicle (see image). This finding was confirmed on my physical examination. The surgical team decided intra-operatively that the patient might need dialytic intervention so a right subclavian temporary dialysis catheter was placed. I had never seen one before, but I am sure many nephrologists who are no longer junior woodchucks like myself were around when subclavian dialysis catheter use was common. As my co-fellow Dr. McMahon pointed out in a previous post, the subclavian route was popular until an association was noticed between this route and subclavian thrombosis and stenosis.

Ted Steinman, one of our attendings at The Brigham, co-wrote a paper this year entitled, "Dialysis at a crossroads: 50 years later." In it, he and other pillars of nephrology propose a new path for dialysis therapy, and this is worth a read. One component of this path recommends changing the mantra "Fistula First" to "Catheter Last" given the unexplained augmented use of catheters and increased catheter-associated infections during the fistula first initiative. In other words, catheters should be the "last" choice for dialysis intiation given all of the complications caused by their use compared to grafts and fistulae. Furthermore, fistulae are not always attainable and cannot always be created in a timely fashion; thus, a graft is the next best thing and a very suitable alternative. The authors also propose that the Center for Medicare and Medicaid Services should consider catheter use to be sub-standard care. The overall premise behind the "Catheter Last" remains roughly the same, but this is an interesting way to think about our patients who are nearing the need for dialytic intervention that may motivate us more to prevent use of the dreaded catheter, especially when a subclavian one slips through the cracks.

Posted by Will Pendergraft

Fractional Excretion

The fractional excretion of sodium (FeNa) is a test that is often used in the setting of acute renal failure to help distinguish between pre-renal and intra-renal causes that has been mentioned in previous blog posts. In general, a FeNa of <1% suggests pre-renal disease, between 1-2% is indeterminate and >2% suggests ATN. There are some exceptions to this but overall, the specificity of this test is more than 80% and this increases if it is used in combination with the fractional excretion of urea.

By definition, the FeNa is the ratio between the quantity of Na excreted in the urine relative to the amount filtered at the glomerulus. So how can we make this calculation with a spot sample without reference to volume of filtrate or urine? Given that Na is freely filtered at the glomerulus, this means that:

Filtered Na = Plasma Na x GFR

And:

Excreted Na = Urine Na x urine flow rate

Thus:

FeNa = Excreted Na

Filtered Na

= urine Na x urine flow

plasma Na x GFR

Because the creatinine clearance is a surrogate for the GFR:

FeNa = urine Na x urine flow

(plasma Na x urine Cr x urine flow)/plasma Cr

= urine Na x plasma Cr

Plasma Na x urine Cr

Or to make it easier to recall:

= Two smaller numbers

Two larger numbers

It is important to remember to take the serum sample at the same time as the urine sample because if the GFR is changing, this will affect the results. Remember also that the test can be unreliable in the setting of a near-normal GFR and with the use of diuretics, which is why combining it with the fractional excretion of urea can be useful.

This derivation can be used to determine the fractional excretion of any substance that is freely filtered at the glomerulus. However, remember that if the substance that you are trying to calculate is partially bound to albumin, an adjustment will have to be made. For example, Mg is about 30% albumin bound so that the plasma level would need to be multiplied by 0.7 for an accurate result.

Thanks to Dr Seifter for his help with this.