19. Transplantation

Potential advantages

• Improved graft survival for high-risk patients

• Onset of first rejection is delayed

• Period of delayed graft function may be foreshortened

• May allow for less aggressive maintenance regimen

Potential disadvantages

• Risk of first-dose reactions

• May prolong hospital stay and increase cost

• Higher incidence of cytomegalovirus infection

• May increase mortality

19.5.3 Maintenance Immunosuppression

Maintaining immunosuppression is intended to prevent acute and chronic immune system-mediated graft injury. Continuous development of immunosuppressive drugs has led to several new options that can further prevent rejection and improve outcomes in the long run. Immunosuppressive drug application requires careful selection and dose titration to balance the risks of rejection and toxicity. Table 19.2 lists maintenance agents used in clinical practice.

Table 19.2

Maintenance agents in renal transplantation [7]

Calcineurin inhibitors

• Cyclosporine

• Tacrolimus

Antimetabolites

• Mycophenolate mofetil

• Azathioprine

mTOR inhibitors

• Sirolimus

• Everolimus

Corticosteroids

Reproduced with permission from Kennedy et al. [7]

The immunosuppressive treatment regimens for transplant centers vary, and the 2009 KDIGO guidelines on maintenance immunosuppression suggest the use of a CNI, antimetabolite, and corticosteroid in combination. This drug selection method also helps to minimize drug-related adverse events [6]. Selecting a suitable immunosuppressive agent should be patient specific. The most important adverse effects of generalized immunosuppression are cancer and infection, including opportunistic infections. Individual drugs have a specific profile of adverse effects.

19.5.4 Monitoring the Levels of Immunosuppressive Drugs

The avoidance of over-immunosuppression and under-immunosuppression is a major challenge in clinical practice. Patients are routinely monitored for signs of drug toxicity by means of serum drug levels including CNI concentrations, mammalian target of rapamycin inhibitor (mTORi) levels, and at certain centers, MMF/MPA concentrations. Nevertheless, extreme drug levels are helpful but not definitive in the diagnostic process. Moreover, dosing of immunosuppressive drugs remains rather empirical, and there is no test for biological activity of the drugs used in transplantation.

19.5.5 Conclusion

Kidney transplantation has greatly evolved and has seen many advances in immunosuppressive therapy, with an increasing number of immunosuppressive agents available for use in various combinations allowing for more options and personalization of immunosuppressive therapy. When selecting an induction immunosuppressive agent, a clinician must carefully consider several factors including immunological risk of the patient, the cumulative immunosuppression burden, concomitant maintenance immunosuppression, and additional patient factors including age and comorbidities such as cardiovascular disease, pulmonary disease, and prior cancer. T-cell-depleting agents such as rabbit ATG or alemtuzumab are associated with lower acute rejection rates but higher rates of leukopenia and infection as compared to basiliximab. An individual patient’s risk of rejection should be carefully weighed against potential complications due to overimmunosuppression and/or drug-related toxicities. Maintenance immunosuppressive therapy has greatly evolved too. Although CNI-based therapy with tacrolimus, mycophenolate, with or without corticosteroids continues to be the standard (most commonly utilized) regimen ensuring low rates of acute rejection, the associated medication-related toxicities continue to contribute to morbidity and mortality.

19.6 Allograft Dysfunction

With a living donor kidney transplant, the graft usually begins to function soon after the vascular anastomosis is complete. Although immunosuppressive agents, surgical techniques, and histocompatibility tests have improved, allograft dysfunction remains the most common complication of renal transplantation [8].

19.6.1 Immediate Posttransplant Period

With a living donor kidney transplant, the graft usually begins to function soon after the vascular anastomosis is complete. Impairment of graft function is suggested by a decrease in urine output and/or a rise in creatinine levels. The definition of DGF varies among transplantation centers, and the most common definition is dialysis that is required within 7 days. On the other hand, the current definition of DGF does not enable clinicians to distinguish the causes of DGF from other types of graft dysfunction and can lead to misclassification of patients. Furthermore, there are different criteria for dialysis prescription among nephrologists. The main causes of DGF are listed in Table 19.3.

Table 19.3

Main causes of DGF

Prerenal

• Hypotension, hypovolemia

• Arterial thrombosis, venous thrombosis

Parenchymal

• Acute tubular necrosis (Ischemia, drug)

• Rejection (hyperacute, acute)

• Thrombotic microangiopathy (CNIs, mTOR inhibitors)

• Recurrence of original disease (FSGS, HUS, primary hyperoxaluria)

Postrenal

• Ureteral obstruction (ureteral kinking, ureteral stenosis, blood clots, lymphocele)

• Urine leakage

• Urine fistula

DGF delayed graft function, CNI calcineurin inhibitor, mTOR mammalian target of rapamycin, FSGS focal segmental glomerulosclerosis, HUS hemolytic uremic syndrome

19.6.2 Management of DGF

Patients with DGF show longer hospitalization and are at a higher risk of occult rejection or other undiagnosed insults to the graft. Most studies suggest that patients with DGF have worse long-term outcomes than patients with immediate function. Great efforts should be made to reduce the damage during the transplantation process; these measures include optimal management of donors, a precise surgical technique, optimizing allograft perfusion, minimizing cold ischemia time, and ensuring adequate preparation of the recipient (Table 19.4).

Table 19.4

Main measures for preventing DGF

Donor

• Normovolemia

• Maintain blood pressure

• Optimize cardiac output

• Adequate kidney perfusion

Kidney perfusion

• Selection of renal preservation solution^a

• The use of pulsatile machine perfusion

Cold ischemia time

• Maintain <12–24 h when possible

Ischemia-reperfusion injury

• Multiple anti-inflammatory and antioxidant therapies^a

Recipient

• Check blood volume

• Low-dose dopamine

• Loop diuretics

DGF delayed graft function

^aRequires more research

19.6.3 Early Posttransplant Period

Early posttransplant allograft dysfunction is often defined as a sustained increase in plasma creatinine concentration, and the reasons are listed in Table 19.5 [9].

Table 19.5

Causes of allograft dysfunction in the early postoperative period

Prerenal

• Transplant artery stenosis

• Hypovolemia/hypotension

• Renal vessel thrombosis

• CNIs

Parenchymal

• Acute thrombotic microangiopathy

• Acute allergic interstitial nephritis

• Recurrence of primary disease

• Acute rejection

• Acute CNI nephrotoxicity

• Toxic/ischemic acute renal tubular necrosis

• Acute pyelonephritis

Postrenal

• Urine leaks

• Urinary tract obstruction

CNI calcineurin inhibitor

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Tags: Chronic Kidney Disease Diagnosis and Treatment

Oct 20, 2020 | Posted by admin in NEPHROLOGY | Comments Off

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