Help with transplant immunosuppressant maintenance regimens

Immunosuppressants aim to prevent this from happening:

Screen Shot 2017-01-29 at 3.52.15 PM.png
Organ rejection.

But too much immunosuppression can cause this:

Screen Shot 2017-01-29 at 7.16.22 PM.png
Drug toxicity and dead fish.

That’s why people can’t just be on ONE immunosuppressant after transplant: the doses required would be too toxic, so the effect is spread out over 2-3 medications.

Considering that the historical option was total body irradiation, we’ve come a long way. Azathioprine was the first chemical immunosuppressant, but cyclosporine, which came onto the scene in the 1970s, revolutionized kidney transplant survival rates.

***One of my chiefs last year made an amazing figure on maintenance transplant immunosuppression. It is worth this whole post and I highly encourage you to take a look!***

For us peons, what are the commonly used immunosuppressants? 

Mechanism of Action Starting doses Monitoring required Side effects
Tacrolimus (Prograf) Calcineurin inhibitor (CNI) 0.075-0.2 mg/kg/day Cr, drug trough Neurotoxicity, nephrotoxicity, diabetes, alopecia *many drug interactions
Cyclosporine (Neoral) Calcineurin inhibitor (CNI) 2-6 mg/kg/day Cr, drug level Neurotoxicity, nephrotoxicity, diabetes, hypertrichosis, gingival hypertrophy
Mycophenolate mofetil ## (CellCept, MMF) Purine analogue, prevents T cell proliferation 500-1000 mg daily CBC, drug trough GI/diarrhea, myelosuppression, lymphoid neoplasm *many drug interactions, needs dose adjusted for renal failure
Azathioprine (Imuran) Purine analogue, prevents T cell proliferation 1-3 mg/kg/day (maintenance) CBC, LFTs, Cr, check TPMT Nausea/vomiting, myalgias, leukopenia, transaminitis
Sirolimus (Rapamycin) mTOR inhibitor Weight based; 1-5 mg/day (maintenance) Drug level Pneumonitis, arthralgias, edema, hypertension, bone marrow suppression, hyperlipidemia
Everolimus (Afinitor) mTOR inhibitor 0.75-1 mg twice daily Drug level arthralgias, edema, hypertension, bone marrow suppression, hyperlipidemia
Prednisone The dozens of things steroids do Varies widely, minimum 7.5 mg every other day or 5 mg daily n/a Osteopenia, diabetes, headache, Cushing’s, weight, cataracts, psychosis (and many others)

## Mycophenolate can be either mycophenolate mofetil vs. sodium. The difference is that the sodium formulation (Myfortic) is an enteric capsule that may prevent some GI effects like diarrhea(?) but the jury is still out.

What are the major side effects of immunosuppression?

screen-shot-2017-01-29-at-7-04-46-pm
From the National Kidney Foundation

What is the underlying biology? ***This is a gross oversimplification.

Normally, T cells go scouting and if they encounter an antigen-presenting cell with foreign material on it, a chain reaction of events is started: calcineurin is activated, leading to a surge of IL-2 and its receptor, IL-2R, which upregulates the mTOR pathway, which leads to DNA nucleotide synthesis so that the T cell can multiply and generate an immune response.

Notice that the bolded words are the targets of the 6 immunosuppresants in the chart above.

Transplant pharmacology is REALLY COMPLICATED and you can do an entire fellowship training program for this. This is an excellent, but 100-page document from a Canadian transplant website. Here are two organ-specific guides/reviews regarding immunosuppression:

What is the bicarbonate deficit and why does it matter?

The time will come when you have a patient whose serum bicarbonate level is 7 (normal is 24). Usually, this happens in acute renal failure or septic shock associated with a serious metabolic acidosis.

First question: how does bicarb become low? One way is through renal/GI losses of bicarb. There are also types of metabolic acidosis that are associated with decreased bicarb–DKA and lactic acidosis (ketones and lactate that could be converted back into bicarb but are excreted instead). There is also iatrogenic bicarb loss, such as when you give a patient with already low bicarb huge boluses of normal saline. This causes a hyperchloremia that further depletes the organic anions that could have been converted back to bicarb. A more chronic problem is the inability of the kidneys to generate bicarb. This review from CKJ gives a great overview of non-gap metabolic acidosis.

Second question: when should you give oral or IV bicarbonate? Oral bicarbonate is more appropriate for patients who will continue to lose bicarb in the oupatient setting–chronic diarrhea or RTA, for instance. The inpatient setting is more opinion-driven, but what I’ve seen is consistent with this paper on bicarb supplementation, which says to give IV bicarb at an arterial blood pH of ≤7.0. The amount given should be what is calculated to bring the pH up to 7.2.

The reason why it’s important to not give IV bicarbonate liberally is because it is actually associated with higher mortality. Shifts in calcium, increase in extracellular potassium that can cause arrhythmia, hypernatremia and volume expansion (causing flash pulmonary edema) may result. You may also see a paradoxical worsening of acidosis because bicarb is converted to CO2!

How is hemodialysis ordered?

There are multiple components to hemodialysis, and each session of dialysis must be tailored to an individual patient’s needs. For example, do they need more fluid taken off because they have heart failure? Do they need more potassium in the diasylate because they are persistently hypokalemic? Here are some words that you may see in a renal fellow’s note about the components of dialysis and a brief description of what they mean. If you have a LOT of time on your hands, check out these EBPG guidelines published in 2007.

  • Dialyzer: not actually part of the dialysis rx, but I wanted to include it to help you understand the machinery of receiving dialysis. Here is a helpful overview for patients from Davita about the plastic tube that actually does the work of dialyzing.
  • Duration: how long is the dialysis session? Different patients may only be able to tolerate so much, or they may need longer sessions to filter the fluid more slowly. There is no conclusive evidence that longer dialysis time reduces mortality.
  • Ultrafiltration goal: This refers to how much “excess water” is taken off at each session. It is based on that patient’s estimated dry weight (EDW), although the EDW may be difficult to determine at first. There is no recommendation for an UF goal in the US, but based on observational studies, some countries recommend an arbitrary goal of 750-1000 mL/day in anuric patients.
  • Diasylate solution:
      • Sodium: low sodium concentration may exacerbate hypotension, but high sodium may exacerbate volume overload
      • Potassium: In general, one can expect only up to 70 to 90 mEq of potassium to be removed during a typical dialysis session.
      • Calcium: patients with a low concentration of calcium in their bath may not experience as much intra-dialysis hypotension, gain higher vitamin D levels, and can use more phos binders containing calcium to lower phos levels
      • Bicarbonate: usually adjusted to maintain a serum bicarbonate >23. This is important for reducing acidosis.
  • ultra-coefficient: referred to as KUF, has to do with the amount of fluid crossing the diasyler membrane with regards to time and pressure.  I don’t have enough physics know-how to fully analyze its value, but these people seem to.
  • Diasylate temperature: It is thought that lowering the diasylate temperature makes dialysis easier to tolerate and improves symptoms of fatigue/post-dialysis syndrome. Why? Kind of unclear.

 

A few aspects of managing your patients on dialysis

When you encounter a patient who has end-stage renal disease and is on dialysis, there are a few questions you should make sure to answer that will help in your management:

  • What is their dialysis schedule? Have they missed any sessions recently?
  • Does the patient have anemia? Many dialysis patients have anemia of chronic disease due to decreased EPO production. Do they receive EPO during their dialysis sessions?
  • Does the patient have hypertension? If so, is this because they are volume-overloaded? Excess fluid can be removed in dialysis as tolerated. In the meantime, you should make sure to keep their blood pressures carefully controlled (and not too low).
  • Do they have evidence of bone disease? Many patients with ESRD have tertiary hyperparathyroidism (click on the link for a brief pathophys reminder). They may be on cinacalcet (calcimimetic that decreases calcium and phos levels) or sevelamer (phos binder).
  • Are their medications renally dosed? It seems like a no-brainer, but you’d be surprised. Also, are there specific medications that they do receive during dialysis? This is especially important for timing of medications like antibiotics.
  • What is their access? Where is their fistula? Or do they have a tunneled cath? They cannot have IVs in the same arm as a fistula.
  • Nutrition: one of the areas that we as clinicians tend to gloss over, but is extremely important to our patients (have you ever ordered from the renal menu? It SUCKS). Make sure they are on a low K/phos/sodium diet; patient should also be taking nephrocaps (vitamin B and C).

 

dialysis in the ICU

Up to 70% of patients require renal replacement therapy or dialysis. Dialysis is renal therapy via diffusion of small solutes, whereas filtration is the convection of large solutes. Early treatment is better, obviously…

  1. intermittent hemodialysis: is easier to implement, more practical, better solute clearance and fewer bleeding complications
  2. continuous dialysis: better for hemodynamically unstable patients, if have renal and hepatic failure, or acute brain injury
    1. requires continuous anticoagulation with heparin or UFH
    2. citrate may cause electrolyte issues (chelates ionized Ca)
    3. CVVHDF=continuous venovenous hemodiafiltration=dialysis +filtration. The #1 modality in the ICU. Large volume, requires fluid replacement.
    4. CAVHD or AVHDF requires arterial cannulation, and is unreliable in pts with low BP, PVD. More risky.
  3. peritoneal dialysis
  4. SLEDD (hybrid of intermittent and continuous): more flexible than continuous, less need for anticoagulation, but has the same efficacy as continuous

The urine doesn’t lie: understanding the urinanalysis

 

If you’ve ever wondered about how to differentiate sediment on a urinanalysis (you’d have to be a med student!), check out this Renal Fellow Network post about acanthocytes and other abnormal RBCs It’s a helpful starting point. For a more detailed and thorough reference for a differential of urinanalysis findings, I’d refer to this Access Medicine page. It has a neat graphic that helps to conceptualize a lot of the possible crystal findings:

Screen Shot 2016-01-01 at 8.17.46 PM.png

Urinanalysis is a fundamental diagnostic test that can tell us tons about kidney function. For example, red blood cells in the urine, depending on what shape they are, how many of them, etc., may indicate glomerular disease (nephritis, I’m looking at you). “Muddy brown” casts, on the other hand, are a sign of acute tubular necrosis. And in the case of UTIs and pyelonephritis, you can sometimes see the actual bacteria on the slide.

Before microscopes and special stains, though, there was uroscopy–the art of diagnosis through examination of the urine, by looking, smelling, and yes, tasting, of urine. Hippocrates devoted an entire section to it in his Book of Prognostics. Boiling urine, adding components to it…physicians were inventive. Uroscopy was not only a way for physicians to evaluate patients, but a way for patients to evaluate the competence of their doctors, as this description from Wonders and Marvels shows.

what’s the difference between a perm-a-cath and a tunneled line?

There are several types of venous access available for dialysis:

  • AV fistula: ideal because blood vessels have had time to heal and scar over.
  • AV graft: less mature than a fistula, but still pretty good
  • Dialysis catheter: any one of various tubing used to establish venous access
    • tunneled line (Hickman):  as the name implies, tunnels under the skin to the subclavian and can last for months to years
    • Perm-a-cath (vascath): fancy name for a central line. This is probably the least favorable option because it may work for several months before failing and is associated with higher rates of infection

As a reference, here is this handy, concise guide on catheters from the ACP.