I. Problem/Challenge.

The prevalence of individuals who have received a renal transplant is rising due to both increased rates of renal transplantation and increasing survival. Transplantation has become more predictable than it was 20-30 years ago and advances and innovations have led to dramatic improvements in morbidity and mortality rates. As of 2008, approximately 30% of the population with end-stage renal disease (ESRD) had functioning renal transplants. Given the increasing number of patients with ESRD and the excellent results seen with renal transplantation, a key challenge is to increase the rate of transplantation. As the number of post-transplant patients increases, hospitalists will increasingly take care of this patient population.

In the immediate post-operative period (within three months), these patients should be cared for by the transplant surgeons at one’s own institution, preferably at the hospital where the transplant was performed. After that time, hospitalists may play a much larger role in the care of these patients. In many cases, these patients have the same medical issues that caused renal failure in the first place, i.e., diabetes and hypertension, in addition to issues specific to organ transplantation, i.e., altered anatomy and immunosuppression.

In addition, hospitalists see many patients in whom renal transplantation should be considered. Some of the diseases we used to treat have diminished, such as analgesic nephropathy, but the incidence of diabetic and hypertensive nephropathy in older patients has exponentially risen. Hospitalists should refer patients with chronic kidney disease (stage 4 or 5) to a nephrologist to discuss pre-dialysis access and/or transplantation. For patients already on dialysis, renal transplantation may offer a more cost-effective alternative to dialysis, in addition to a morbidity and mortality benefit. Absolute contraindications to transplantation include active malignancy, chronic diseases with a markedly reduced life expectancy, and poorly controlled mental illness or substance abuse.

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The causes of death after transplantation have been changing slowly over the past decades and vary with the time passed since transplantation. Infection, cardiovascular disease, and malignancy remain the three most important causes of death. Improvement of immunosuppression potentially through individualized regimens is also paramount. Another challenge is to reduce the rate of graft loss by understanding the role of antibodies to donor HLA antigens, and by improving the way in which nephrotoxic drugs are used in the short-term given their long-term disadvantages.

A long-term challenge is to reduce the mortality rate after kidney transplantation through the improvement of cardiovascular health, reduction of infection risks, and early detection and treatment of cancer. In addition, the challenge to prevent CKD and slow progression to ESRD among patients with various comorbidities remains a priority.

II. Identify the Goal Behavior

The most common medical problem of renal transplant patients managed by hospitalists is acute kidney injury. It is important to note that acute kidney injury in renal transplant patients is defined as a 20% rise in serum creatinine over baseline, lower than the 50% rise in non-transplant patients. Another goal is to increase familiarity with management of chronic immunosuppressive medications. Hospitalists also manage the same co-morbidities that patients have before their renal transplant.

III. Describe a Step-by-Step approach/method to this problem.

The history is an important aspect of determining the etiology of acute kidney injury. History of diarrhea, vomiting, or reduced oral intake should be sought. In addition, patients should also be asked about their recent medication history, including over-the counter medication, new medications, and adherence to an immunosuppressive regimen.

For post-transplant patients with acute kidney injury, the most common cause is volume depletion. A trial of fluid is given in case volume depletion is partially or wholly responsible for the increase in creatinine.

Blood levels of immunosuppressive medications, i.e., calcineurin inhibitors cyclosporine and tacrolimus, should be measured early in the admission. An elevated level is suggestive of calcineurin inhibitor toxicity, and a low level is supportive of rejection. A urinalysis, with new or increased protein levels is also suggestive of rejection. Leukocytes are suggestive of infection or acute interstitial nephritis. Transplant patients can also have renal dysfunction due to rhabdomyolysis at much lower creatinine kinase level than non-transplant patients.

Other causes that can be evaluated include blood clots in the vessels of the transplanted kidney. Infections can also occur and can lead to detrimental problems if not detected and treated early. Although it is not very common, it is possible for the disease that damaged the original kidneys to recur and cause injury to the transplanted kidney.

If these results are negative or equivocal, the patient may require a biopsy of the transplanted kidney to evaluate for rejection and confirm other diagnoses.

IV. Common Pitfalls.

Hospitalists may be less familiar with the calcineurin inhibitors (cyclosporine or tacrolimus) that form the mainstay of immunosuppressive regimens. Every hospitalized patient with a renal transplant should have their drug levels checked.

Typically, cyclosporine and tacrolimus are measured in trough samples. The goal range of these medications can vary by clinician practice as well as patient characteristics (time since transplant and previous rejection episodes). Usually, for patients more than 1 year post-transplant, a desirable cyclosporine trough is 100-150 micrograms/L and tacrolimus trough is 8-10 micrograms/L.

A significantly higher level (cyclosporine >300 and tacrolimus >20) are nephrotoxic because they cause vasoconstriction and renal ischemia. Levels that are significantly lower than the desired range predispose patients to rejection. Low levels point to patient non-adherence, inappropriately prescribed dose or drug-drug interaction.

In addition, cyclosporine has many significant drug-drug interactions that must be taken into account when prescribing a new medication or evaluating the current medication list. Earlier generation calcium channel blockers (diltiazem, verapamil etc.) should be avoided because they increase levels of cyclosporine and predispose to nephrotoxicity. Certain antibiotics (nafcillin, cotrimoxazole, isoniazid and rifampin) can decrease levels of cyclosporine, as can anti-convulsants (phenytoin, phenobarbital, and carbamazepine).

There is a need to recognize early changes in creatinine. A sudden rise in serum creatinine levels at the lower end of the range is far more serious than a rise when the creatinine is already at higher levels. Simply looking at serum creatinine level is not sufficient; it is important to calculate the glomerular filtration rate (GFR) which is essential for purposes of appropriate drug dosing. When ordering diagnostic procedures, it is also imperative to consider if iodinated contrast is necessary as this can be damaging to the kidneys. Excessive use of nonsteroidal anti-inflammatory drugs should also be avoided in renal transplant patients.

V. National Standards, Core Indicators and Quality Measures.

No national standards/benchmarks established yet.

What's the Evidence?

Braun, WE, Johnson, RD. “The Medical Management of Renal Transplant Recipients”. Comprehensive Clinical Nephrology. 2003. pp. 1105-1123.

Chapman, J. “What are the key challenges we face in kidney transplantation today?”. Transplantation Research. vol. 2. 2013. pp. S1

Formica, RN. “Long-Term Medical Management for Patients with Kidney Transplants”. Hospital Physician. vol. 38. 2002. pp. 27-35.

Kasiske, BL, Snyder, JJ, Gilbertson, D, Matas, AJ. “Diabetes Mellitus after Kidney Transplantation in the United States”. Am J Transplant. vol. 3. 2003. pp. 178-185.

Magee, CC, Pascual, M. “Update in renal transplantation”. Arch Intern Med. vol. 164. 2004. pp. 1373-88.

Nankivell, BJ, Alexander, SI. “Rejection of the kidney allograft”. N Engl J Med. vol. 363. 2010. pp. 1451-62.

Ponticelli, C. “Renal Transplantation Strengths and Shortcomings”. J Nephrol. vol. 14. 2001. pp. S1-6.