Saturday, April 30, 2011

NKF Spring Clinical Meeting - Calcium reabsorption

Here are some points from one of the cases presented at the electrolyte workshop this afternoon:

The major teaching point was that the reabsorption of calcium closely follows that of sodium. Therefore, in sodium avid states, calcium tends to be reabsorbed also – conversely, in natriuretic states, calcium tends to be lost in the urine.

What about thiazides – they are associated with hypercalcaemia and hypocalciuria, but what is the mechanism there?
In the distal convoluted tubule, thiazides act by blocking the luminal Na/Cl cotransporter. There is also a luminal calcium channel called TRPV5, which allows calcium to be reabsorbed in the DCT via a transcellular route. Overall, this is felt to contribute around 15% of total tubular calcium reabsorption. It was thought that this channel might have played a role in the pathogenesis of thaizide-induced hypercalcaemia.

However, when they created a knock-out mice without TRPV5 and treated them with thiazides, hypercalcaemia still developed. So, it would appear that the mechanism simply involves decreased extracellular volume caused by the diuretics, leading to increased sodium reabsorption more proximally and consequent enhanced proximal calcium absorption. See this review.

Of note, the paracellular route for calcium reabsorption in the thick ascending limb is guarded by tight junctions between the cells. These are made up of proteins called Claudins. Genetic defects in Claudin proteins have been associated with impaired calcium reabsorption and subsequent hypercalciuria and stone formation, giving us some insight into the molecular level of calcium handling by the kidney.

This was a great meeting with lots of interesting discussions and talks. Roll on next year in Washington!

Thursday, April 28, 2011

NKF Spring Clinical Meeting - BP in CKD

I attended a very interesting talk from Dr Bakris today on the latest approaches to BP targets in the CKD population. The highlights are nicely illustrated in a systematic review published in the Annals this year.

They searched for randomized controlled trials comparing blood pressure targets in adults with CKD that had more than 50 participants per group; at least 1-year follow-up; with death, kidney failure, cardiovascular events, change in kidney function, number of antihypertensive agents and adverse events as the outcomes of interest. There were three trials that met these criteria, with a total of 2272 subjects contributing data.

Interestingly they found that there was no evidence to suggest that a target of less than 125/75 to 130/80 mm Hg was more beneficial than targets less than 140/90 mmHg.

However, the degree of proteinuria may be an effect modifier here – in this regard they found lower quality evidence to suggest that in those with macroalbuminuria (0.3 – 1.0g/day), the lower target may be beneficial.

The main limitation of this review was that the trials involved were limited to non-diabetic CKD patients.

The tide of opinion may be turning in relation to BP guidelines, so watch closely for any announcements from the major societies in relation to this. It’s important to avoid complacency though, and a relaxation of the target shouldn’t mean we place less emphasis on BP control.

Wednesday, April 27, 2011

NKF Spring Clinical Meeting - IgA

The NKF Spring Clinical meeting started today in Las Vegas. I thought I’d share of the interesting highlights from some of the talks I’ve attended. This post relates to Dr Appel’s lecture on IgA nephropathy, where he described the recent literature on pathogenesis and treatment and a relatively new classification system called the Oxford-MEST system.

This classification system was devised at an expert group meeting in England. Pathologists (blinded) retrospectively examined 265 biopsies from adult and paediatric patients with IgA, who had five-year follow up data available. The biopsies were scored on pathological variables and entered into a prediction system based on the follow-up data available. They came up with four features that were strongly predictive of renal outcomes:

M – mesangial hypercellularity; scored 0 or 1
E – endocapillary proliferation; scored 0 or 1
S – segmental glomerulosclerosis; scored 0 or 1
T – tubular atrophy/interstitial fibrosis; scored 0, 1 or 2

A notable absence in this classification system is presence of crescents – the reason why this is not included is simply that in the 265 samples they analyzed, there were too few samples with crescents to make any significant inference about.

Further validation of this score is ongoing in various samples, but it appears to be gaining recognition and popularity and is something we should be aware of.

Post-transplant malignancy 101

What are the most common type of cancers in kidney transplant recipients?

The three most common cancers are: non-melanoma skin cancers, Kaposi’s sarcoma and non-Hodgkin lymphomas. Compared to the general population, the risk of squamous cell carcinoma is 100x greater in transplant recipients. One interesting aspect about transplant recipients is that they have a much higher risk for a few specific malignancies but are not broadly predisposed to all cancers. As an example, the incidence of most common solid tumors in the general population (lung, prostate, breasts and colorectal) is only modestly increased or similar to the transplanted population. This suggests that other factors might play a role in the pathogenesis of malignancy post-transplantation.

What is the cause of increased risk of malignancies after transplantation?

There are several factors that seem to be associated with the development of malignancy after transplantation: impaired immune surveillance secondary to immunosuppression; carcinogenic factors like sun exposure; and host factors such as genetic predisposition to cancer, presence of oncogenic viral infection and prolonged dialysis.

How does a viral infection may increase the risk of malignancy?

Certain virus like EBV, HHV-8 and HPV carry viral oncogenes in their genome, which directly affect cell-cycle and apoptosis regulation. For example, HPV has the E6 oncogene that produces a protein that binds to p53, a major regulator of cell growth and tumor suppressor protein. Following E6 binding of p53, p53 is degraded, allowing unchecked cellular cycling and accumulation of chromosomal mutations without DNA repair.

Do different immunosuppressive drugs vary in their risk of post-transplant malignancy?

In general, the intensity and duration of immunosuppression therapy plays a major role in determining this risk of malignancy, since it severely disrupts the immune surveillance of cancers cells and dampen anti-viral immunity. Moreover, certain specific drugs like azathioprine and cyclosporine have been shown to directly lower the repair rate of DNA damage induced by solar UV radiation. In contrary, mTOR inhibitors have been shown to inhibit tumor growth mediated by both blockade of the PI3K-Akt-mTOR pathway, which is frequently activated in cancer, and by angiogenesis inhibition.

Compared to the general population, are there special screenings required for the kidney transplant recipient?

Since skin cancer is one of the most prevalent malignancies, recipients should be educated about their increased risk and recommended to reduce levels of sun exposure (especially between 10am and 4pm), wear protective clothing and apply sunscreen to sun-exposed areas, perform self-examinations and annual skin examinations by qualified health professional. For non-skin cancers, the KDIGO guidelines recommend solely reinforcement of the regular cancer screenings performed in the general population.

If a malignancy arise, what is the ideal approach?

The cancer should be managed with specific therapies for the particular tumor type associated with reduction and/or conversion to a mTOR inhibitor. The conversion to mTOR inhibitors have been successful in inducing complete regression of Kaposi’s sarcoma (figure) and decreasing the recurrence of skin cancers. General contraindications for conversion in kidney transplant recipients are proteinuria greater than 500mg/day and GFR less than 40 ml/min.

Gap in knowledge: we still need some prospective trials in order to determine if further cancer screening exams would be warranted in the transplant population that carries other competing risks like cardiovascular disease and infection.

Monday, April 25, 2011

Thirst and xerostomia

One of the major problems we struggle with in haemodialysis patients is excess, volume, inter-dialytic weight gain and ultrafiltration. Despite constant reminders by nursing staff, physicians and nutritionists, patients seem to find it extremely hard to restrict their fluid intake to what we’d like it to be.

The reasons for this are variable and include social and cultural differences, habit, psychological diagnoses, medications and likely the very dialysis procedure itself by means of salt-loading. One of the clinical manifestations that is important to differentiate from thirst (a central mechanism driven by tonicity) is xerostomia (dry-mouth).

Xerostomia has a broad differential of possible causes and includes medications (particularly those with anti-cholinergic effects), anxiety, radiation therapy, connective tissue disease and rarely, autonomic disease. It is important to examine the long list of medications prescribed to our patients for possible culprits contributing to dry mouth and the excessive fluid intake that results from it.

I came across a small study of 43 HD patients followed for two years in Holland (not the most robust study, but interesting nonetheless). Unstimulated and chewing-stimulated 5 minute saliva collections were performed at baseline and at 2 years, along with a formal xerostomia inventory and thirst questionnaires. Then a formal dental examination was performed on each patient examining for decay, oral hygiene and periodontal disease.

Twenty patients were transplanted during follow-up. The most interesting finding was that those who were transplanted experienced an increase in salivary flow rate from 0.3ml/min to 0.44ml/min (p=0.002) and a decrease in thirst score from 10.6 to 8.1 (p=0.02); there were no significant changes over the 2 years for those who remained on dialysis. Also, there were no detectable differences in oral health between the 2 groups and the 2 time-points.

It’s possible that there is something peculiar about the state of ESKD that alters salivation and contributes to the symptom of dry mouth (supported by the observation of improvement after renal transplantation). Perhaps attention to the medication history and trying to distinguish the symptoms of thirst from dry-mouth may help us to help our patients in their ongoing battle with inter-dialytic weight gain.

Wednesday, April 20, 2011

Are we finally getting thE kNaCk of edema in nephrosis?

Mechanisms of edema formation in nephrotic syndrome (NS) are controversial. The traditional underfill hypothesis has come under heavy fire, and there are now many clinical and experimental observations that contradict it. The overfill hypothesis has now captured the zeitgeist. It postulates that sodium retention in many patients with NS is caused by an intrinsic renal defect in sodium excretion, which in turn causes an expansion of plasma volume. However, the exact mechanism of sodium retention has not been clearly elucidated and many renal sodium transporters have been implicated.

One recent paper by Svenningsen et al suggests that the epithelial sodium channel (ENaC) might be strongly implicated. Most of our understanding of the molecular mechanisms of sodium retention in NS is derived from the puromycin aminonucleoside (PAN) mouse model, which resembles minimal change disease. They found that urine of PAN nephrotic rats increased ENaC currents and amiloride abolished them. Proteolytic cleavage has a major role in regulating the activity of these channels by increasing their open probability. Specific proteases have been shown to activate ENaC by cleaving different channel subunits at specific sites within their extracellular domains. They found that plasminogen and/or plasmin were the serine proteases responsible for ENaC activation in nephrotic urine. The urine of nephrotic rats contained both substances, but the plasma from these animals only contained plasminogen, suggesting that plasmin was formed in the urine in situ and was not filtered out of the plasma. Svenningsen et al also observed that cortical collecting duct cells of nephrotic rats had urokinase activity which was directly responsible for the conversion of filtered plasminogen into plasmin. Another important observation was that amiloride not only blocks ENaC but also inhibits urokinase. Significantly, Svenningsen et al were able to reproduce all of the previously described experiments with urine from patients with NS.

These findings suggest a novel mechanism of edema in NS: plasminogen present in plasma is filtered through the defective glomerular barrier of NS and it is then converted into plasmin by the action of urokinase present in the cortical collecting duct. Plasmin then activates ENaC by proteolysis, resulting in sodium retention with the subsequent appearance of edema. More studies are needed, but this could be an important breakthrough.

Helbert Rondon, MD, FASN, FACP

Tuesday, April 19, 2011

Webinar: FHN Daily Trial and NxStage Freedom Study

The recent publication of the landmark FHN Daily Trial was a step forward in our understanding of dialysis care.

One of the authors, Dr. Brent Miller from Washington University School of Medicine in Saint Louis, is giving a free webinar entitled The Clinical Impact of More Frequent and Home Hemodialysis: Results of the Frequent Hemodialysis Network Daily Trial, the NxStage FREEDOM Study and other data.

It's running Tuesday, April 19th at 12:00 pm ET and Wednesday, April 20th at 1:00 pm ET.

Monday, April 18, 2011

Doc, this itching is making me crazy

Nearly every time I walk through the dialysis unit at the VA, at least one patient calls me over to tell me that their itchy skin is driving them crazy. Pruritus is a torment to many dialysis patients, and the best I’ve been able to offer to patients as far as management is: come to dialysis, stay the whole time, and watch your phosphorus intake. That’s pretty dissatisfying to many patients, especially when they are already doing all of those things.

More than half of all patients undergoing dialysis complain of pruritus, and the mechanism isn’t really very well understood. Some studies have found no significant difference in serum levels of creatinine, BUN, calcium, phosphorus, alkaline phosphatase, PTH, and hematocrit in patients with pruritus vs without, but the general recommendation is to keep phosphorus and PTH under good control. One study did find a significant difference in the frequency of neuropathy in patients with pruritus, and another found an association with hemoglobin A1c.

Trials investigating treatment options have not yielded a cure, but treatments are out there, and include topical therapies such as emollients, capsaicin, gamma-linolenic acid, and tacrolimus, systemic therapies such as activated charcoal, gabapentin, pentoxyfilline, and thalidomide, and physical therapies like UV phototherapy, electroacupuncture, and renal transplantation. First and foremost, management involves ensuring the patient is adequately dialyzed and their calcium/phosphorus and PTH levels are well controlled. A flow chart (I love flow charts) is found in this article.

In the patient with severe refractory itching, a diagnosis to consider is Kyrle’s disease, or perforating folliculitis. Kyrle’s disease is associated with diabetes and CKD/ESRD- one series found 9 cases in 200 dialysis patients, and is an odd disorder wherein keratin, collagen, and elastic fibers migrate transepidermally. The lesions are small papules that are flesh colored or slightly hyperpigmented. They slowly enlarge with time and each one contains a central, keratotic, slightly depressed core. This core contains a plug filled with keratin, parakeratotic scale, and basophilic debris. The epidermis around the core is thinned, and the plugs can contact the dermis and become inflamed. Treatment is difficult, but some success has been noted with tretinoin creams (though these should be used with caution in dialysis patients due to risk of high vitamin A levels), avoidance of trauma and scratching- ie wearing gloves, trimming fingernails, and transcutanous nerve stimulators. Large lesions can be excised, and phototherapy has been particularly successful for dialysis patients. Occasionally, patients are cured with renal transplantation. I had a patient recently who was severely affected by pruritus and had been treated for everything from scabies to psychiatric disease. We diagnosed her with Kyrle's disease after a skin biopsy, and although the therapies were not immediately effective in eliminating the itching, it was some relief to her to put a name to her symptoms.

Friday, April 15, 2011

Linked: Sodium and Potassium

Emily mentioned in her recent post on the Rule of 6s that potassium administration needs to be taken into account when correcting the plasma sodium in cases of hyponatremia.

Why is this the case?

When potassium is given most of it will move into to cells (remember that 98% of total body potassium resides here.) As this occurs, electroneutrality is maintained in three ways, all of which act to raise the plasma sodium concentration.

1. Intracellular sodium exits cells directly increasing the plasma sodium concentration.

2. Extracellular Cl will enter cells along with potassium. The addition of intracellular KCl raises intracellular osmolality causing water to move into cells. The loss of extracellular water causes the plasma sodium concentration to rise.

3. Intracellular protons exit cells as potassium enters. Proton movement is osmotically neutral as they combine both intra and extracellularly with buffers. This is in contrast to potassium, which raises intracellular osmolality and causes water to move into cells. This loss of extracellular water again causes the plasma sodium concentration to rise.

The Practical Point: If solute is part of your hyponatremia treatment plan and you need to additionally replete potassium remember that each mEq of potassium given will act on the plasma sodium like a mEq of sodium.

Thursday, April 14, 2011

Sodium – interpretation of measurements Part II

Ok, so here is the brief review of the various clinical methods of detecting sodium concentration (as I understand it):

Flame photometer
The older flame photometer method measured the concentration of sodium in plasma. The preparation of the sample involved dilution of the plasma, and assumed that plasma water was 93% of total plasma.

Imagine that the lab reports a sodium concentration of 143mmol/L. Assume that the plasma water is 93% of total plasma - then the sodium concentration in plasma water would be 143/0.93 = 154mmol/L. Let’s take this as ‘normal plasma water sodium’.

Now imagine that the sodium measurement in another patient came back from the lab at 120mmol/L:
- if plasma water is 93% of total plasma, then the sodium in plasma water is 120/0.93 = 129mmol/L – true hyponatraemia
- if plasma water is only 80% of total plasma, then the sodium in plasma water is 120/0.8 = 150mmol/L. This is closer to what we’d expect in normal circumstances, and so we can call this pseudohyponatraemia.

Indirect Ion Selective Electrode
Ion-selective electrodes (ISEs) only measure free sodium ions in a solution; not the volume in which they are dissolved.

The indirect method involves a dilution of the acquired total plasma sample– and again, the lab assumes that plasma water is 93% of total plasma. Therefore the potential for pseudohyponatraemia unfortunately still exists if your lab performs these types of measurements.

Direct Ion Selective Electrode
The direct method of ISE measurement does not use a dilution step and has no assumptions regarding the percentage plasma water of total plasma. Direct measurements are most commonly used in blood gas analyzers. Remember, that direct ISEs measure activity.

Entropy suggests that as energy is introduced to a system, it will be dispersed in a uniform pattern to allow a state of maximal disorder (the lowest energy state). Introduction of sodium (solute) to a solution (blood) does not follow this classic law, as the sodium can interact with water molecules and other ions. Therefore, not all sodium ions are free to enter a reaction, which explains why the concentration of sodium is different than the measured activity. Biochemists multiply the absolute concentration by an activity coefficient (around 0.93 for sodium) to determine the actual activity of sodium.

The direct ISE will only measure free sodium ions, which are limited to the plasma water fraction. From our assumptions above, we noted that a ‘normal person’ had a plasma water sodium concentration of 154mmol/L. But, because not all these sodium ions are free to react, then the measured activity of sodium in plasma water will be around 143mEq/L. This corresponds almost perfectly with the figure obtained by multiplying the sodium concentration in plasma water by the activity coefficient of sodium (154 x 0.93 = 143mEq/L). Note that this 0.93 comes from the activity coefficient of sodium, not the plasma water fraction – it just so happens that they are similar.
Because the direct ISE does not make any assumptions about the plasma water content, it is immune from the concept of pseudohyponatraemia.

Finally, back to our patient with the lab reported sodium of 120mmol/L, who has 93% plasma water, and from our earlier calculations had a plasma water sodium of 129mmol/L. If we measure the sodium activity using direct ISE, we would find that the sodium activity equals the plasma water sodium multiplied by the activity coefficient (129 x 0.93) = 120mmol/L – again true hyponatraemia.

Wednesday, April 13, 2011

Vaccines 101 in Kidney Transplant Recipients

One of my transplant patients came to clinic last week excited about his trip to Tanzania. He had undergone kidney transplantation three years ago and has had an uneventful course.

As a transplant nephrologist, you kind of become a PCP for your patients and travel medicine advice must be an integral part of the visit. On a recent survey, more than 35% of transplant patients have reported recent travel outside Canada and USA. 63% of these patients had traveled to endemic areas of hepatitis A but only 5% did receive vaccination. An unacceptable ratio, especially since immunosuppressed patients are increasingly susceptible to enteric, vector-borne or bloodborne infections. Below, some pearls about vaccination/travel medicine in kidney transplant recipients:

Which vaccines are safe for transplant recipients?

  • Inactivated vaccines are generally safe and do not seem to increase the risk of rejection, however transplant recipients have a lower rate of seroconversion.
  • Live vaccines are contraindicated in transplant recipients – those include MMR, Varicella, Yellow fever and BCG.

What are the routine vaccines for adult transplant recipients?

  • Influenza yearly (2011 flu vaccine will protect against H1N1)
  • Pneumococcus every 5 years
  • Tetanus every 10 years

Which vaccines should be tested for seroconversion?

  • Hepatitis A, hepatitis B and pneumococcal vaccines. Seroconversion is defined as a 4-fold increase in titers over 4 weeks after vaccination.

When is it safe to give an inactivated vaccine after transplantation?

When is it safe to travel abroad after transplantation?

  • In general, traveling to ‘high risk’ areas should be avoided on the first year after transplantation or during the treatment of a rejection episode.

Your patient is heading to Tanzania. What should be your recommendations?

  • The CDC Yellow book is a terrific site to obtain information and updates about travel destinations.
  • For example in Tanzania, the general recommended vaccinations include hepA, hepB, typhoid, polio and yellow fever. The latter should not be given since it is a live attenuated vaccine. For polio, the inactivated Salk should be used and the TyphimVi (Aventis) for typhoid. On this case, it is worth a visit to a travel clinic in order to get all the required vaccinations (find one close to you here).
  • This patient will also require anti-malarial drugs, since malaria is endemic in Tanzania – it is worth noting that most anti-malarial drugs may increase CNI level or increase toxicity of bactrim.

** Finally, Traveler's diarrhea (TD) is the most common illness of travelers, affecting 10-60% of travelers to developing regions. TD may be life threatening in kidney recipients. In addition to food and water precautions, a five day prescription of Ciprofloxacin 500mg BID should be given to the patient. Threshold to self-treatment include more than 4 unformed stools/day, fever, blood, pus or mucus in the stool.

Kidney transplantation opens up the world to kidney patients but safety precautions should not be overlooked! Have a safe travel!

Picture: Wildbeest migration in Tanzani, one of the most spectacular wildlife events on Earth, when wildebeest and zebras migrate to greener pastures as the seasons change and predators follow them closely.

Posted by Leonardo Riella M.D.

Tuesday, April 12, 2011

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.

Monday, April 11, 2011

Cisplatin nephrotoxicity

Cisplatin was discovered more than 40 years ago, and is still widely used in chemotherapy regimens for many different types of cancer. Its wider use has been limited by toxicities, one of which is nephrotoxicity. Nate Hellman also wrote about cisplatin nephrotoxicity here.
I was recently consulted on an oncology patient with suspected cisplatin nephrotoxicity. The patient had hematuria with dysmorphic red blood cells on microscopy, and I wondered whether this could be a manifestation of cisplatin toxicity. The answer I found was: maybe.
Early clinical manifestations of the renal effects of cisplatin include a uniformly present polyuria. There is early polyuria at about 24-48 hours, which resolves, but is followed by a late phase between 72 and 96 hours after administration. Hypomagnesemia is a common complication and is likely due to a renal defect in magnesium reabsorption. Hypomagnesemia results in secondary hypocalcemia and hypokalemia. An incomplete distal RTA can also occur. The fall in GFR accompanying cisplatin nephrotoxicity is usually seen about 10 days after administration. A nice review of nephrotoxicity is here.
Preexisting kidney disease predisposes patients to nephrotoxicity because about 50% of cisplatin is excreted in the urine 24 hours after administration. Most of that actually appears in the first hour. Platinum is extensively protein-bound, and free platinum is freely filtered at the glomerulus and excreted unchanged in the urine. However, uptake of platinum does occur, primarily in the proximal tubule. When it enters the tubular cell it undergoes biotransformation and leads to apoptosis. The mechanism of renal damage is complex and multifactorial and due to activation of pathways that lead to production of TNF- α and subsequent inflammation. A review of these complex pathways is found here. The proximal tubular damage can result in glucosuria and amino aciduria. The glucosuria may also occur with cisplatin induced glucose intolerance. Salt wasting has also been reported with cisplatin.
Pre-hydration with saline for a goal urine output of 3 to 4L per day, drug dosage decrease (toxicity is generally dose-related), and screening for renal abnormalities are the most accepted ways to prevent nephrotoxicity. Mannitol and furosemide have been studied as preventative agents, but results have not been uniformly promising. Sodium thiosulphate is another potential protective agent, however there is some concern that it may affect the antitumor activity of cisplatin. Liposomal preparations of cisplatin are being studied and may be less nephrotoxic than the original preparations.
Proximal tubular damage, however, doesn’t explain my patient’s dysmorphic red blood cells. Cisplatin has also rarely been associated with a thrombotic microangiopathy that could possibly explain them. TMA is more commonly seen with cisplatin in combination with bleomycin and gemcitabine, but has occurred with cisplatin alone or with other drugs. He did not have schistocytes on peripheral smear and renal dysfunction was mild, so pheresis was not considered. It is possible that he had an underlying glomerulonephritis that was not previously recognized, but given his platelets of 17 and a single kidney on imaging, we didn’t plan to biopsy to find out. He did not receive any further cisplatin.
Emily Petersen, MD

Thursday, April 7, 2011

Pitfalls with paraproteins

We were recently consulted on a patient with a history of multiple myeloma who had developed severe hypercalcemia and acute renal failure. The calcium on admission was 15mg/dl (albumin 2.6) and the patient was treated aggressively with IV fluids, diuretics, bisphosphonates and calcitonin. Despite this, the calcium remained elevated and the patients renal function continued to deteriorate. The patient was discharged from the hospital on iv diuretics but returned a few days later with bleeding gums and loose teeth. At this stage, the creatinine was 4mg/dl and his calcium was 11mg/dl.  Paraprotein levels were extremely high at 9g/dl and it was felt that the patient might have a hyperviscosity syndrome so was started on plasmapheresis. The morning after the plasmapheresis, the calcium dropped to 6mg/dl. What could explain this dramatic fall?
It turns out that his calcium was never truly elevated. The ionized calcium was not checked during his first admission but just before starting plasmapheresis it came back low at 1.0mmol/l. It turns out that this is just one of the many artifactual results produced by paraproteins in the serum. Some IgG paraproteins can bind calcium in a similar manner to albumin. While the total calcium is elevated, the ionized calcium remains normal and so treating this hypercalcemia is inappropriate. Obviously, most hypercalcemia related to MM is real and related to the disease itself – this demonstrates the importance of checking the ionized calcium in these cases.
There are a number of ways in which paraproteins interfere with lab assays:
- By interfering with the lab assay in vitro
- By interaction with a specific target in vivo
Increased sample viscosity:
This is usually due to an IgM paraprotein and its effect on an assay depends on whether the turbidity related to the paraprotein dissipates early or late in the processing and can lead to artificially high (PO4, GGT, Bili, CRP) or low (HDL, Glucose, Paracetamol) results. It can be prevented by pre-dilution of the sample and these results are not usually reported as most lab analyzers will detect that there is something amiss with the reaction kinetics and report and error.
Reaction with the assay:
Pseudohypocreatininemia has been reported due to IgG paraproteins interfering with the Jaffe reaction. Similarly, as reported in an earlier post, pseudohypercreatininemia has been seen in some patients with Waldenstrom’s Macroglobulinemia due to interference by the IgM paraprotein with the enzymatic method for measuring creatinine. Binding of paraproteins to the assay constituents can also lead to falsely low TSH and CRP levels. These errors are not easily picked up and are usually detected because they do not correlate with the clinical picture.
This is a well-described consequence of high paraprotein levels. It has been mentioned in previous blog posts and is due to the reduction in the plasma water fraction because of the increased total protein concentration. This can be detected by directly measuring the serum sodium concentration on a blood gas analyzer.
Binding to cations and anions:
Along with calcium, some paraproteins can bind copper or phosphate, raising the total blood levels without altering the free levels. Depending on the substance, they may or may not be biologically active. Similarly, paraproteins can bind hormones such as T4 or insulin (leading to increased insulin requirements, or delayed hypoglycemia if the insulin is slowly released from the paraprotein).
Finally, paraproteins can interfere with the anion gap. IgG paraproteins act as cations at physiological pH leading to retention on chloride and a reduction in the anion gap. In contrast, IgA paraproteins act as anions at the same pH and as a result will cause an increase in the anion gap.

Wednesday, April 6, 2011

Hyponatremia correction; rule of 6s

Profound hyponatremia of around 100mEq/L or less is a double-edged sword- it’s got to be treated but can be terrifying to treat. The University of Rochester shared their protocol for controlled correction of severe hyponatremia with AJKD in October of 2010.
Hyponatremia with neurologic symptoms needs to be treated promptly but cautiously to avoid overcorrection with associated risk of osmotic demyelination. The most efficient and rapid way to raise sodium levels is to use 3% saline, but this carries a high risk of overcorrection.
The cause of hyponatremia and its reversibility must also be considered when deciding a course of action. In hypovolemia-induced hyponatremia, vasopressin levels decline and sodium levels rise as volume status is restored to normal. When medications such as thiazides and SSRI are discontinued, their effect on sodium levels goes away and sodium levels will begin to rise as the medications are cleared from the body. Similarly, in patients with beer potomania, sodium levels will rise as they begin to take in increased concentrations of solutes.
As reversible causes of hyponatremia are eliminated, vasopressin levels rapidly fall to undetectable levels- causing polyuria. Patients can excrete massive quantities of maximally dilute urine that can increase sodium levels at an unsafe rate of up to 2mEq/L/h. Most patients who present with profoundly low sodium are at higher risk of osmotic demyelination- chronic hyponatremia, sodium less than 105mEq/L, hypokalemia, alcoholism, malnutrition and liver disease all place patients in danger of this complication.
Desmopressin administered q6-8 hours has been shown by this same Rochester group to be effective and more practical than hypotonic fluids in preventing overcorrection of hyponatremia. They administer desmopressin immediately without waiting for the onset of water diuresis, and concurrently administer 3% saline solution. The goal of the use of desmopressin is to maintain constant antidiuresis and a more predictable response to 3% saline. The downside is that it takes longer to correct sodium, leaving the patient on hypertonic saline for a longer time. During this time, water intake needs to be restricted to avoid decreasing serum sodium concentrations. Desmopressin has also been used in a few cases to re-decrease serum sodium concentrations after neurologic symptoms have developed, which was effective in reversing the symptoms.
They recommend correction of no faster than 6mEq/day for patients with severe chronic hyponatremia, with 6mEq in 6 hours on the first day if symptoms are severe. This has led to the rule of 6s.
  • 6 a day makes sense for safety
  • 6 in 6 hours for severe symptoms and stop (no more correction that first 24 hours)
Also remember:
Potassium administration also has to be taken into account when correcting sodium with the formula:
Serum [Na+] = {Total body exchangeable (Na+ + K+)} / total body water
* Solve for {Total body exchangeable (Na+ + K+)} by multiplying total body water by serum sodium.
* Determine the amount of solute to give to correct to a goal serum sodium level by solving for the goal serum [Na+]
For example:
Current serum Na+ = 100 mEq/L
Goal serum Na+ = 105 mEq/L
Total body water = 50L
100 mEq/L=5000 mEq/ 50L
105 mEq/L= ? mEq/ 50L
105 mEq/L= 5250 mEq/ 50L
To correct sodium to 105mEq/L, 250mEq of combined sodium and potassium should be administered over an appropriate time period (6 or 24 hours based on the rule of sixes above)
Emily Petersen, MD

Tuesday, April 5, 2011

Sepsis & AKI - an insoluble problem?

I expect very few medical users of this website went into nephrology to manage acute kidney injury (AKI) in the context of sepsis. It is hard to avoid pessimism when considering the state of play in this condition: 65% of patients with septic shock develop AKI; this AKI is an independent risk factor for death and up to 75% of patients with AKI and severe sepsis die.

It is, therefore, not surprising that research into this area continues. Much of which has focussed on the use of extra-corporeal blood purification techniques (EBP) to improve outcomes via immune modulation by removal of circulating inflammatory mediators (summarised in this recent review by Ricci et al.).

The most familiar EBP technique is standard CVVH delivered at high doses. Indeed, when I was training in ICU in 2008 we would regularly use high volume CVVH (often seeking treatments of up to 6 L/hr) in patients with co-existent severe sepsis and AKI. Although both the ATN and RENAL trials failed to demonstrate any benefit of this tactic in the management of severe AKI, many feel that the ‘high intensity’ groups in these trials were simply not high intensity enough to demonstrate a treatment effect in septic patients. This feeling largely stems from a favourable body of evidence (summarised in this review) from animal studies and small trials with soft end-points using CVVH doses of 45-115ml/kg/hr (in contrast to the ATN and RENAL CVVH doses of 35-40ml/kg/hr). The completed but unpublished IVOIRE trial prospectively randomised 139 patients with septic shock and AKI to 70ml/kg/hr or 35ml/kg/hr with a primary outcome of all-cause mortality and may help to settle this argument.

The counter view is that dose approaches are bound to fail because whilst inflammatory mediators are water-soluble, their molecular weight means that they are unlikely to be maximally cleared by standard haemofilters. This can be attacked in two ways: high-cut off membranes or haemadsorption.

High-cut off membranes have been evaluated in small studies and demonstrated reduction in vasopressor requirements in septic patients. However, when used in continuous treatments these filters are associated with a very large obligate loss of albumin, leading some to suggest such filters should only be used in intermittent treatments (i.e. dialysis; similar to strategies used in myeloma).

Haemadsorption passes blood across broadly interacting sorbents to attract larger molecules, which exceed the cut off of standard membranes, thus making this an attractive technique for EBP in sepsis. Use of this technology had previously been limited by poor biocompatibility and resultant haematological abnormalities but recent advances have eliminated this problem. The commonest sorbent is polymyxin B, a systemically toxic antibiotic which can bind lipopolysaccharide and damage gram-negative bacteria. Although a number of studies have evaluated polymyxin B haemadsorption significant further work is required to make a compelling case for this treatment (excellently summarised by Ricci et al.)

Furthermore, coupled plasma filtration and adsorption has been trialled. This allows initial separation of plasma from blood, followed by selective passage of the plasma across the sorbent and has demonstrated some efficacy in small initial studies.

I find it hard to see where this field is going to end up; only high volume haemofiltration strategies seem to have a consensus behind them and these will always now be open to the charge that randomised controlled trials have shown them to be ineffective. Adsorptive techniques are currently relatively heterogeneous and therefore, the large multicentre trials required to demonstrate their applicability seem a long way off. It appears that septic AKI may continue to be a feared condition for some time yet.

Saturday, April 2, 2011

ASN In-Training Exam: ASN and RFN Review Material

I took the MCAT with pencil and paper. Over 500 nervous sweaty pre-meds in one giant auditorium. Everyone was so tense I'm surprised there wasn't a spontaneous combustion. Ever since, it's been electronic standardized testing were you often find yourself sitting next to a random guy taking the food handling safety exam. Just not as dramatic.

This coming Thursday April 7th and Friday April 8th are the dates for the ASN In-Training Exam for Fellows. It's usually administered at your home institution so we'll probably avoid the food safety guy. If you're interested, there's a brief practice test on the ASN site along with the NephSap core knowledge questions for review.

From RFN, below are links to previously posted review questions.

Question: Water-1 (answer choices are at the top of the "Answer")
Answer: Water-1

Question: PD-1
Answer: PD-1

Question: Transplant-1
Answer: Transplant-1

Question: Hypertension-1
Answer: Hypertension-1

Question/Answer: Pregnancy
Question/Answer: Transplant

If anyone has any other useful online review sources share the wealth in the comments.