Indian Journal of Transplantation

REVIEW ARTICLE
Year
: 2019  |  Volume : 13  |  Issue : 4  |  Page : 240--251

Comprehensive management of the renal-transplant recipient


Praveen Kumar Etta 
 Department of Nephrology and Renal Transplantation, Virinchi Hospitals, Hyderabad, Telangana, India

Correspondence Address:
Dr. Praveen Kumar Etta
Department of Nephrology and Renal Transplantation, Virinchi Hospitals, Hyderabad - 500 034, Telangana
India

Abstract

Renal transplantation (RT) is the current treatment of choice for patients with end-stage renal disease (ESRD). Innovations in RT and immunosuppressive regimens have greatly improved both the patient and graft survival. A successful RT offers enhanced quality and duration of life and is more effective (medically and economically) than long-term dialysis therapy for patients with ESRD. Close follow-up and monitoring treatment are the important part of the management of RT recipients (RTRs). Cardiovascular disease, infections, and drug toxicity play a key role in the long-term morbidity and mortality of this patient population. As RTRs survive for longer periods of time with functioning allografts, physicians will likely become more involved in their management, mandating at least a basic understanding of management of an adult RTR.



How to cite this article:
Etta PK. Comprehensive management of the renal-transplant recipient.Indian J Transplant 2019;13:240-251


How to cite this URL:
Etta PK. Comprehensive management of the renal-transplant recipient. Indian J Transplant [serial online] 2019 [cited 2020 Mar 31 ];13:240-251
Available from: http://www.ijtonline.in/text.asp?2019/13/4/240/274604


Full Text



 Introduction



Renal transplantation (RT) is the optimal treatment of choice for patients with end-stage renal disease (ESRD). A successful RT improves the quality of life and reduces the mortality risk for most patients with ESRD when compared with long-term dialysis. However, patients require close follow-up after RT since they are on complex regimen of immunosuppression (IS) and other drugs that render them susceptible to various complications and to preserve graft function. Since most RT recipients (RTRs) can be classified as having chronic kidney disease (CKD) by Kidney Disease: Improving Global Outcomes definition, they are inherently at risk of CKD-related complications.[1] At the same level of kidney function, death rates are higher in RTRs compared with nontransplant patients with CKD.

With the use of potent IS therapy, improvement in surgical techniques, and post-RT care, patient and graft survival rates have improved dramatically. With constraints on the RT centers, limited availability of nephrologists, patient considerations of finance, and geography, it is recognized that primary care physicians (PCPs) will play an ever-increasing role in the care of the RTRs. Hence, it is imperative that the PCPs have an understanding of the complex and interacting medical issues these patients face. This topic addresses the immediate post-RT care, long-term follow-up, and management of adult RTRs, with emphasis on monitoring allograft function and minimizing the risk of complications in a PCP perspective.

 Phase-Based Management



An interdisciplinary approach that includes urologists, nephrologists, intensivists, PCPs, infectious disease specialists, and specialized nurses is required to provide close follow-up and to prevent and treat the potential complications in RTRs. The management of an RTR can be divided into three phases depending on the time since RT [Table 1]:{Table 1}

Peri- and immediate post-RT period (up to 1 month after RT) includes RT surgery, initiation of IS, and postoperative careEarly post-RT period (1–6 months after RT) includes optimization of IS and graft function, prevention of acute rejection, and prevention of opportunistic infectionsLate post-RT period (after 6 months of RT) includes preservation of graft function and prevention of long-term consequences of IS, including drug toxicity.

 Immediate and Early Posttransplant Management



During the early post-RT period, the patient remains under close observation with monitoring of vital data and clinical status. It is preferred to keep the patient slightly hypervolemic (about 1 kg above their dry weight) at the time of RT surgery to decrease the risk for hypotension intraoperatively. Fluid and electrolyte replacement during the post-RT period aims to maintain an adequate intravascular volume to ensure renal perfusion so that immediate graft function is optimized.

Initially, urine output (U/O) is recorded hourly and replaced with the same volume of crystalloids. Ensure that U/O should at least be greater than 0.5 ml/kg/h and patient's native kidney (pretransplant) U/O should be known when assessing U/O adequacy. Conventionally, normal saline (NS) has been chosen during the perioperative period of RT as it does not contain potassium. However, large-volume administration of NS may itself result in hyperchloremic metabolic acidosis, and hyperkalemia may result due to transcellular movement. Half NS can be used for replacement fluid as urinary sodium after RT initially tends to be between 60 and 80 mEq/L. Several studies conducted during the last few years comparing the use of NS and balanced crystalloid solution (BCS; Ringer's lactate or isolyte) during the perioperative period of RT concluded that BCS is relatively safe in this aspect.[2],[3],[4],[5],[6] The relative hypotonicity of BCS causes inhibition of antidiuretic hormone, and the water diuresis occurs earlier and more satisfactory than with NS.[7] Clinical examination for volume status and close monitoring of serum electrolytes (4–6 hourly initially) remain a cornerstone of care for guiding fluid therapy. Fluid replacement is also guided by hemodynamic parameters such as central venous and mean arterial pressures. Maintenance fluids should also account for insensible losses and any other body fluid losses. Overzealous fluid administration should also be avoided. Because of high urinary volume in this post-RT period, calcium, magnesium, potassium, and phosphate levels must be monitored (6 hourly) and replaced. The initial fluid management varies among centers; our institute's protocol is presented here [Table 2].{Table 2}

Dihydropyridine calcium channel blockers (DHP CCBs) are safe and effective for blood pressure (BP) control, as they can reverse the vasoconstrictive effect of calcineurin inhibitors (CNIs). Thrombotic prophylaxis with heparin is recommended in the immediate post-RT period for patients at risk of thrombosis. Routine, periodic postoperative ultrasound (USG) and Doppler are required to identify urinary obstruction, pyelonephritis, fluid collections – urinoma, hematoma, lymphocele, or abscess and vascular thrombosis. The renal allograft generally is placed in the right or left iliac fossa in an extraperitoneal position and is most often anastomosed to the internal or external iliac artery. Graft tenderness and swelling are often observed in cases of acute rejection, outflow obstruction, pyelonephritis, or renal vein occlusion. In general, abdominal drains and bladder catheters are left in place for at least 3–7 days. An increase in the drain output can indicate urinary fistula, lymphorrhea, or bleeding. Foley catheter ensures that the bladder is well drained and reduces strain on the ureter anastomosis. If inserted, double–J stent is removed after 2–4 weeks of RT.

Allograft dysfunction and rejection may occur in this period. Hyperacute rejection occurs within few minutes to hours of the RT due to the presence of preformed donor-specific antibodies (DSAs) in the recipient.[8] This typically involves complement activation, vascular endothelial necrosis, and thrombosis. Nephrectomy is indicated in most of these cases. Improvements in the detection of DSAs and cross-match techniques have largely eliminated this complication. Acute rejection can occur at any time which can be cellular or antibody mediated. The significant risk factors for acute rejection are greater number of human leukocyte antigen (HLA) mismatches, younger recipient age, older donor age, African-American ethnicity, panel-reactive antibody >30%, presence of DSAs, blood group incompatibility, delayed graft function (DGF), and cold ischemia time (CIT) >24 h.

Immunosuppression

IS must begin before or at the time of the RT. The IS protocols may differ among RT centers. It can be divided into induction and maintenance regimens.[9] Induction therapy administered at or around the time of RT typically consists of biologic antibodies. Patient's risk is determined by the presence of DSAs, sensitization status, age and race, type of transplant (kidney vs. kidney–pancreas), and HLA matching. In patients with low immunological risks, interleukin-2 receptor antagonist (basiliximab) is generally used for induction, whereas, in patients with high immunological risks, T-cell-depleting antibodies are recommended (rabbit antithymocyte globulin [ATG]). The maintenance therapy is continued for the life of the allograft; the typical triple IS therapy consists of a CNI (tacrolimus or cyclosporine [CsA]), an antimetabolite (mycophenolate mofetil [MMF] or azathioprine [AZA]), and glucocorticoids. Mammalian (mechanistic) target of rapamycin inhibitors (mTORi, sirolimus, or everolimus) is used in few patients. CNIs and mTORi blood concentrations are monitored regularly following RT.[10]

Antimicrobial prophylaxis

Antibiotics are routinely administered during the perioperative period to prevent wound infections. Antimicrobial/antiviral prophylaxis for the first 6 months to 1 year after RT is routinely administered as these are at high risk of life-threatening infections. Trimethoprim-sulfamethoxazole (TMP-SMX) is initiated to prevent Pneumocystis jiroveci pneumonia (PJP), but it is also effective against Nocardia and urinary tract infections (UTIs). Dapsone, atovaquone, and pentamidine are alternative agents that may be used in the case of sulfa allergy. Anti-Cytomegalovirus (CMV) prophylaxis is recommended based on the donor and receptor CMV serological status and the IS regimen. CMV-seronegative recipients (R−) receiving organ from CMV-positive donors (D+) and those who received ATG are at highest risk for CMV disease. Based on the results of the Improved Protection Against CMV in Transplant trial, patients deemed highest risk (D+/R−) should receive 6 months of prophylaxis.[11] Oral or topical antifungal agents such as clotrimazole or nystatin are used for fungal prophylaxis. The role of isoniazid prophylaxis for tuberculosis is not clear, but it can be considered in patients at greater risk in endemic regions.

Delayed graft function and slow graft function

DGF is most commonly used to describe the failure of the allograft to function promptly, requiring dialysis within 1 week after RT. It is usually a form of AKI affecting renal allografts.[12] It occurs in up to 5% of living donor (LD) recipients and 20% of deceased donor (DD) recipients. When the serum creatinine (Scr) is very slow to decrease and not requiring dialysis, that is defined as having slow graft function (SGF). LD kidneys may be from a related, unrelated, or swap donor. DDs broadly are of two types: i. e., donation after brain death (DBD) and donation after circulatory death (DCD). DBD donors can be a standard criteria donor (SCD) or expanded criteria donor (ECD). The risk of DGF is highest with DCD and ECD, followed by SCD, and least with LDs. Due to increased acceptance of ECDs and DCDs, the incidence of DGF and SGF has increased in recent years. Other risk factors include age >60 years, CIT >24 h, warm ischemia time >45 min, no induction given, maintenance hemodialysis before RT, obesity, diabetes, male gender, African-American race, small-for-size organ, and prior immune-sensitizing events such as blood transfusions, pregnancy, and previous transplant. Optimal fluid therapy has been shown to decrease DGF after RT. Machine perfusion technique for the preservation of graft also seems to decrease the risk for DGF in ECD kidneys. When the transplanted kidney is not functioning, it is critical to exclude arterial or venous occlusion and urinary obstruction or leak. DGF immediately after RT is usually due to acute tubular necrosis of allograft. DGF also increases the risk of graft rejection and ultimately decreases the long-term graft survival.[13]

 Long-Term Management



Outpatient follow-up

RTRs are followed very closely for at least first 3–6 months following RT. The frequency of follow-up varies among centers and depends upon the stability of the patient, but usually, this involves twice weekly for the first 2–4 weeks, then weekly for 1–2 months, then every 2 weeks for another 1–2 months, and then every 1–3 months for the 1st year after RT.[1] IS therapy is gradually reduced during the first 3–6 months to avoid adverse medication effects while still preventing rejection. RTRs continue to require close monitoring lifelong to ensure that the graft is functioning optimally and to assess for infections and other complications.

Maintenance immunosuppression

Maintenance IS initiated at the time of RT is continued long term for the duration of the allograft. Both CNIs bind to specific cytoplasmic receptors and inhibit calcineurin and the expression of IL-2 and other cytokines that are integral for T-cell proliferation. Among CNIs, tacrolimus is more commonly used as it is associated with reduced acute rejection rates and graft loss.[13] Numerous classes of drugs interact with CNIs due to their effect on the hepatic cytochrome P450 (CYP) system. Rifampin/rifabutin, barbiturates, phenytoin, and carbamazepine induce CYP; non-DHP CCBs (verapamil and diltiazem), azole antifungals, macrolides, protease inhibitors, and grapefruit (furanocoumarins) inhibit CYP. Corticosteroids inhibit nuclear factor κB (NFκB), a transcription factor necessary for the expression of several cytokines involved in T-cell activation. MMF is a prodrug, and after conversion to active metabolite mycophenolic acid (MPA), it inhibits enzyme inosine monophosphate dehydrogenase involved in de novo purine synthesis. MPA specifically inhibits T-cell proliferation due to the absence of salvage pathway for the production of guanosine nucleotides. CsA inhibits enterohepatic recirculation of MMF reducing its level, an effect that is not seen with tacrolimus. MMF absorption is inhibited by coadministration with other drugs, such as proton pump inhibitors and oral iron. AZA is a purine analog, inhibits nucleotide synthesis, and inhibits ultimately T-cell activation. It is useful when patients cannot tolerate MMF or as an alternative in anticipation of pregnancy. As it is metabolized by xanthine oxidase (XO), concomitant use with allopurinol or febuxostat should be avoided. mTORi binds to the same cytosolic protein as does tacrolimus but instead inhibits the TOR rather than calcineurin, inhibiting cytokine-dependent activation of the cell cycle. Sirolimus has a longer half-life than everolimus. Belatacept is a fusion protein that binds to CD80/CD86 on antigen-presenting cells, blocking the interaction with CD28 on T-cells (costimulatory signal). It is typically used to prevent long-term toxicity associated with CNIs and is used in combination with MMF or mTORi and steroids. It is contraindicated in patients who are Epstein–Barr virus (EBV) seronegative as it is associated with increased incidence of posttransplantation lymphoproliferative disease (PTLD). Several IS agents have a narrow therapeutic window necessitating close monitoring of drug levels. Target levels are influenced by side effects, infectious and malignancy complications, underlying kidney disease, and duration since RT. Whole-blood concentrations of CNIs and mTORi are routinely monitored among RTRs to achieve proper dosing and to avoid drug toxicity [Table 3]. MMF, tacrolimus, and mTORi can cause diarrhea. Diarrhea can be associated with increased paracellular absorption of tacrolimus, resulting in a further increase in tacrolimus levels.{Table 3}

Laboratory monitoring

RTRs are monitored very closely, and few laboratory tests are recommended at particular intervals to assess the functioning graft and to monitor patient's health status. The commonly followed protocol is shown in [Table 4].[1]{Table 4}

Allograft monitoring

Regular monitoring of allograft function is required throughout the life of the transplanted kidney; this typically involves monitoring the renal function tests and urine examination. In general, a 20%–25% increase in Scr concentration above baseline warrants attention. In cases of acute illness such as a viral illness or UTI, it is important to check the Scr level because a generalized immune response can trigger rejection.[13] USG and Doppler studies should be performed in all cases of graft dysfunction [Table 5]. Most of the RTRs require a renal biopsy, the gold standard test to determine the cause of graft dysfunction. Some centers perform surveillance biopsies on all RTRs at regular intervals, whereas others do surveillance biopsies on all high-risk RTRs, such as those with a history of BK virus, those at higher risk for recurrent disease or rejection, or highly sensitized patients. The threshold for allograft biopsy should be kept low since the procedure is relatively safe and pathological diagnosis and further management often help in the preservation of graft function. Renal pathological diseases are graded based on severity, typically using Banff criteria. The important causes of chronic allograft dysfunction include chronic allograft nephropathy (CAN), CNI nephrotoxicity, chronic rejection, and recurrent or de novo glomerulonephritis (GN) [Table 5]. CAN is defined as a condition of renal allograft dysfunction occurring at least 3 months after RT without evidence of active rejection, drug toxicity, or other diseases. In the Banff 2007 scheme, the term CAN has been replaced by interstitial fibrosis/tubular atrophy (IFTA).{Table 5}

Cellular rejection

It usually occurs in the early post-RT period although it can manifest later, especially if IS is reduced. It commonly presents as an asymptomatic increase in Scr level. Uncommonly, it may present with fever, graft tenderness, oliguria, and hypertension (HTN). Histologically, it is characterized by tubulitis (t), interstitial infiltration (i), and intimal or transmural arteritis (v) [Table 6].[14] It is usually treated with glucocorticoids (pulse intravenous [iv] methylprednisolone); if refractory, lymphocyte-depleting agents (ATG) are used.{Table 6}

Antibody-mediated or humoral rejection

Acute antibody-mediated rejection (ABMR) occurs within the first few weeks to years after RT. It is due to an anamnestic antibody response that results from prior antigenic exposure such as pregnancy, blood transfusions, or prior transplants. It can be complement dependent or independent. Histologically, it is characterized by microvascular inflammation (MVI) (glomerulitis [g] or peritubular capillaritis [ptc]), acute tubular injury, thrombotic microangiopathy (TMA), or intimal or transmural arteritis; evidence of complement activation by C4d deposition in the peritubular capillaries; and presence of DSAs [Table 6].[14] Chronic ABMR is one of the most common causes of graft failure. Histologically, it is characterized by transplant glomerulopathy (TG), severe peritubular capillary basement membrane multilayering (on EM), or intimal arterial fibrosis. ABMR is treated with plasma exchange (PLEX); iv immunoglobulin (IVIG); rituximab, bortezomib, and eculizumab alone; or in various combinations.[15]

Calcineurin inhibitor nephrotoxicity

CNI nephrotoxicity plays a significant role in progressive graft dysfunction with most allografts showing histopathologic signs of CNI toxicity by 10 years. CNIs can mediate acute nephrotoxicity via reversible afferent arteriolar vasoconstriction, leading to transient increase in Scr. They can cause TMA, arteriolar hyalinosis, and IFTA. A number of approaches such as CNI avoidance, withdrawal, and minimization have been attempted to reduce their toxicity.

Recurrent and de novo glomerulonephritis

Various forms of GN either recurrent or de novo can affect the renal allografts. The rate of recurrence varies based on underlying type of GN. Focal and segmental glomerulosclerosis (FSGS), membranoproliferative glomerulonephritis (MPGN), hemolytic–uremic syndrome (HUS), and membranous glomerulonephritis (MGN) are more likely to recur within the 1st year post-RT, whereas pauci-immune GN, IgA nephropathy (IgAN), fibrillary GN, lupus nephritis, and diabetic nephropathy recur typically after the 1st year.[16] FSGS, MPGN, and HUS are the disorders known to be most aggressive when they recur and lead to rapid graft loss. The risk for recurrence typically increases with the number of transplants.[17] Principal causes of de novo GN in renal allografts include MGN (most common), MPGN, and HUS.

About 30% of idiopathic FSGS will recur after RT. It can recur very rapidly, even within few hours to days. The risk factors for recurrent FSGS include younger age, male sex, European ancestry, mesangial hypercellularity of native kidneys, rapid progression to ESRD, nephrotic-range proteinuria at time of RT, and history of previous graft failure due to recurrence. Treatment options include PLEX, high-dose CNIs, rituximab, and angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs).[18] Idiopathic MGN recurs in up to 40%–50% of cases after RT and 10%–15% develop graft failure after 10 years. MGN is also the most common form of de novo GN post-RT. Patients with anti-phospholipase A2 receptors antibodies pretransplantation have a 60%–80% risk for histologic recurrence.[19] CNIs, steroids, and alkylating agents such as cyclophosphamide (CYC) and rituximab are useful in the treatment of recurrent MGN. Histologic recurrence of idiopathic IgAN has been reported in 50%–60% of patients, though clinically significant recurrence is far less and the estimated 10-year incidence of graft loss due to recurrent IgAN is about 10%. MPGN type II (complement-mediated MPGN; now termed as C3 glomerulopathy) recurs in up to 80%–100% (especially dense deposit disease) and MPGN type I (immune complex-mediated MPGN) recurs in 20%–50% of allografts. The overall graft loss at 10 years due to recurrence is about 15%.

Proteinuria

Proteinuria from the native kidneys normally resolves by 4 weeks (2–10 weeks) post-RT. The common causes of proteinuria in RTRs include TG (chronic ABMR), recurrent and de novo GN, CAN (IFTA), and drug-related nephrotoxicity. It is an independent risk factor for disease progression, graft failure, and patient death. Strict BP control is beneficial; ACEIs and ARBs are beneficial in prolonging allograft survival, but these agents may result in acute graft dysfunction, posttransplant anemia (PTA), and hyperkalemia. They should be avoided in RTRs with suspected transplant renal artery stenosis (TRAS).

Infections

Infections remain the second most common cause of death in RTRs and probably the most common cause in developing countries like India.[20] The risk of a particular infection is related to several factors including the net state of IS. UTIs are among the most common bacterial infections occurring in the RTRs.[21] The opportunistic infections such as CMV, EBV, Polyomavirus (BK virus), and PJP can occur in over-immunosuppressed patients.[22] Rubin initially proposed a “time pattern” of infections in RTRs, which has been modified later [Table 7].[20],[23],[24] Patients with recurrent UTIs should be evaluated for bladder dysfunction, bladder outlet obstruction, bladder diverticula, calculi, reflux, long-standing Foley catheters, or ureteral stents.[25]{Table 7}

CMV disease is common in RTRs. It often presents with fever, malaise, cytopenia, and diarrhea but can also present with other organ specific symptoms. The treatment includes oral valganciclovir or iv ganciclovir for tissue-invasive disease.[26] BK virus, a human polyoma virus, has specific tropism for the genitourinary tract. About 20% of RTRs develop BK viremia post-RT and few of them end up with nephropathy and graft loss. It often presents with unexplained rise in Scr, asymptomatic hematuria, and rarely ureteral stenosis. Diagnosis can be made by biopsy and urine cytology with the presence of characteristic cytopathologic changes. Reduction in IS is the most effective therapy. The uses of IVIG, cidofovir, fluoroquinolone, and leflunomide are not proven.[27] Fungal and tuberculosis infections are also prevalent in RTRs.[28]

Vaccinations

Inactivated vaccines are generally considered to be safe following RT. Vaccination should be restarted approximately 6 months after RT, and efficacy should be documented by serologic assays when available. However, patients should not be given any live or live-attenuated vaccines after RT [Table 8]. It is advisable to avoid direct contact with anyone who has received a live vaccine for a minimum of 1–2 weeks. Close contacts (such as family members) of RTRs should also be fully immunized.[29]{Table 8}

Cardiovascular disease

Death from cardiovascular disease (CVD) remains the leading cause of mortality and graft loss. The strongest risk factor for cardiac risk is pre-existing CVD before RT. Most of the “traditional risk factors” in the general population, including diabetes, HTN, smoking, and dyslipidemia, are also risk factors for CVD in RTRs. These are also the risk factors for CKD and graft failure. Nontraditional risk factors include IS drugs, inflammation, oxidative stress, hyperhomocysteinemia, hyperuricemia, hyperparathyroidism (HPTH), PTA, proteinuria, and graft dysfunction.[30] High-dose folic acid as well as Vitamin B6 and B12 may effectively reduce homocysteine levels, but their effect in mitigating CVD is not clear.

Hypertension

Chronic HTN is a risk factor for CVD and affects graft survival in the long term. In the era of CNIs, about 60%–90% of RTRs seem to be afflicted with HTN. Both CNIs and glucocorticoids contribute to HTN. It is associated with worse long-term graft outcomes. Diet and lifestyle changes should be part of the therapy including sodium restriction (<2.4 g/day), Dietary Approaches to Stop Hypertension eating plan, weight loss if BMI >25 kg/m2, regular exercise, moderate alcohol intake, and smoking cessation. The target BP of ≤130/80 mmHg with lower BP levels (≤125/75 mmHg) if proteinuria >1 g/day is recommended. Ambulatory BP monitoring may show nocturnal “nondipping” pattern; such patients might require higher doses of anti-hypertensives in the evenings. DHP CCBs are generally considered as the first-line therapy, but they may cause edema and gingival hyperplasia (especially in combination with CsA). ACEIs/ARBs can be used 6–12 weeks after RT. If the patient has proteinuria, ACEIs/ARBs can be used as long as the reduction in GFR is <30% from baseline. They can be used even in cases of CVD, CKD, and posttransplant erythrocytosis (PTE). Beta-blockers are preferred if underlying CVD exists. Non-DHP CCBs have significant interactions with CNIs and raise their blood levels. Diuretics may result in hypercalcemia, hyponatremia, hyperuricemia, and impaired glucose/lipid metabolism. TRAS is a rare cause of HTN; it should be suspected when BP is persistently elevated despite multiple drugs. It usually occurs 3 months to 2 years after RT.

Posttransplant diabetes mellitus

Posttransplant diabetes mellitus (PTDM) or new-onset diabetes after transplantation most commonly develops within the first few months after RT.[31] The risk factors for PTDM include increased age, obesity or other component of metabolic syndrome, African-American race, Hispanic ethnicity, family history of diabetes, gestational diabetes, pretransplant impaired fasting glucose or impaired glucose tolerance, polycystic kidney disease, increased HLA mismatches, DD allografts, history of acute rejection, hepatitis C virus (HCV) and CMV infections, and use of IS drugs such as glucocorticoids, CNIs, mTORi, and diuretics.[32],[33] Insulin therapy is preferred during first few weeks after RT, and one study suggested intensified early treatment with regimens that include basal insulin significantly reduce risk of PTDM after 1 year, presumably via insulin-mediated protection of β-cells.[34] The oral hypoglycemic agents such as sulfonylureas, metformin (biguanide), meglitinides, dipeptidyl peptidase-4 inhibitors or gliptins, and thiazolidinediones are the approved therapies for use in PTDM. Meglitinides are short acting, have lesser risk of side effects compared to sulfonylureas, and preferred agents for patients with postprandial hyperglycemia along with α-glucosidase inhibitors. Incretin mimetics – exenatide, liraglutide, and lixisenatide – and sodium-glucose co-transporter 2 inhibitors – canagliflozin, dapagliflozin, and empagliflozin – have not yet been validated for use in PTDM.

Dyslipidemia

Dyslipidemia occurs in 60%–80% of RTRs and is a major risk factor for both CVD and reduced renal allograft survival; it is associated with mTORi, CNIs (particularly CsA), and glucocorticoids. Other risk factors include obesity, diabetes, hypothyroidism, proteinuria, and diuretic use. National Cholesterol Education Program III clinical practice guidelines with target total cholesterol, non-HDL cholesterol, low-density lipoprotein (LDL), and triglyceride values of <200, 130, 100, and 150 mg/dl, respectively, are the usual therapeutic targets.[35] Statins (fluvastatin and pravastatin are preferred), fibrates (gemfibrozil is preferred), and ezetimibe may be used but avoid bile acid sequestrants as they interfere with absorption of CNIs. CNIs also interact with statins and fibrates and precipitate their toxicity. Niacin and omega-3 fish oils may be used instead of fibrates for hypertriglyceridemia. The Assessment of Lescol in Renal Transplant trial, a randomized controlled trial, demonstrated significant reduction in LDL cholesterol, incidence of myocardial infarction, and cardiac death in patients randomized to fluvastatin.[36]

Obesity

Weight gain and obesity are common post-RT and also contribute to CVD.[30] Patients can gain an additional 5–10 kg by 1-year post-RT. Its etiology is multifactorial related to improved appetite, a more liberal diet, lack of regular exercise, and effect of steroids. Obesity contributes to dyslipidemia, HTN, CVD, and PTDM in RTRs. Obesity is also a risk factor for DGF and surgical complications, including wound infections, delayed wound healing, lymphoceles, and perinephric hematomas. A healthy diet, nutritional counseling, and regular exercise may keep body weight under control. Orlistat should not be given with CNIs (especially CsA) as it interferes with its bioavailability and absorption. Absorption and metabolism of IS medications may be altered after gastric bypass, which also increases risk for hyperoxaluria and oxalate nephropathy.

Mineral bone disease

Bone and mineral disorders are common among patients with CKD, often persist following RT, and are associated with a high risk of fracture, morbidity, and mortality. There is a broad spectrum of often overlapping bone diseases seen after RT, including osteoporosis, as well as persisting high- or low-turnover bone disease. It results from a complex interplay of factors, including pre-existing renal osteodystrophy and bone loss related to a variety of causes, such as IS (glucocorticoids, CNIs), hypogonadism, metabolic acidosis, and alterations in the parathyroid hormone (PTH)-vitamin D-fibroblast growth factor 23 (FGF23) axis and changes in mineral metabolism.[37] The spectrum of bone diseases includes renal osteodystrophy, osteoporosis, bone fracture, and avascular necrosis. Post-RT hypercalcemia can be due to tertiary HPTH, which may require treatment with calcimimetic agent, cinacalcet, and rarely surgical parathyroidectomy.[38]

Osteoporosis

Osteoporosis is defined as a reduction in bone mass with microarchitectural deterioration of bone tissue and subsequent increase in bone fragility and susceptibility to fracture. RTRs should undergo bone mineral density (BMD) assessment (at least annually) to screen for osteoporosis as it may be detected as early as 3–6 months after RT.[39] A t-score of ≤−2.5 as measured by dual X-ray absorptiometry (i.e., ≥2.5 standard deviations below the mean BMD of a normal young–adult reference population) is indicative of osteoporosis. The risk factors for osteoporosis that are specific to RTRs include the long-term use of glucocorticoids, CNIs, and persistent HPTH. There is rapid loss of bone mass in the early post-RT period that frequently affects trabecular bone because of decreased bone formation as a result of steroid therapy. They induce a net loss of BMD by reduction in bone formation and bone density, especially in the trabecular bone of the axial skeleton. Most of the fractures occur primarily in the appendicular skeleton, particularly the feet. CNIs have been shown to increase PTH and decrease magnesium. The increase in PTH results in an increase in osteoclastic activity, which may further increase the risk of osteoporosis. In contrast, in CKD patients before RT, bone loss preferentially affects the cortical bone mainly because of secondary HPTH. The use of bisphosphonates, Vitamin D analogs, calcitonin, and hormone replacement therapy was associated with an improvement in BMD as well as a reduction in fracture risk.[40] Bisphosphonates can be used in RTRs with estimated GFR >30 mL/min/1.73 m2 and low BMD, but they are associated with risk of adynamic bone disease.[41] Denosumab, a monoclonal antibody that targets receptor activator of NFκB ligand, may be a viable therapeutic option for transplanted patients with osteoporosis, especially in those with CKD or bisphosphonate intolerance.[42]

Hematological disorders

The blood disorders typically associated with RT mainly include PTA and other cytopenias (leukopenia/neutropenia, thrombocytopenia, and pancytopenia), PTE, PTLD, and TMA. The IS drugs and viral infections could be the two major contributors to most of these blood disorders. At the time of RT, nearly all patients have anemia due to reduced endogenous erythropoietin (EPO) production and iron deficiency that is associated with CKD. The American Society of Transplantation defines PTA as hemoglobin (Hb) <13 mg/dl for men and <12 mg/dl for women. PTA typically resolves within 3–6 months after RT. However, PTA may redevelop late in the post-RT period in association with decreased allograft function, infections, or the use of drugs (IS drugs, ACEIs, ARBs, ganciclovir, TMP-SMX) [Table 9].[43] In patients with PTA, initial testing should include basic tests such as iron studies, red blood cell indices, reticulocyte count, and stool for occult blood. Avoid liberal use of recombinant EPO due to possible increased risk of thrombotic and vascular events. TMA can result from recurrent or de novo HUS, ABMR, or CNI toxicity. It may manifest either as renal/allograft limited TMA or with evidence of systemic hemolysis, such as increased lactate dehydrogenase, thrombocytopenia, increased indirect bilirubin, low haptoglobin, and increased reticulocyte index, with evidence of fragmented RBCs on the peripheral smear. PTE is defined as persistently elevated Hb (>17 g/dL) and hematocrit (>51%) levels that occur after RT, persists for more than 6 months, and occurs in the absence of another underlying cause. The pathogenesis of PTE involves growth factors such as EPO, insulin-like growth factor-1, stem cell factor, angiotensin II, and androgens. ACEIs or ARBs are recommended for the initial treatment of PTE, and refractory cases may require phlebotomy.[43] Leukopenia is a common occurrence following RT and may be associated with lymphocytopenia, neutropenia, or both. It is frequently related to medications, such as ATG, MMF, AZA, and mTORi. In addition, viral infections such as CMV, EBV, and parvovirus B19 can also cause leukopenia.[44]{Table 9}

Malignancy

RTRs are more likely to develop cancers than the general population, and it is the third most common cause of death in them. The relative risk depends on the type of malignancy. The risk is 2–3 folds for common malignancies such as lung, prostate, breast, and colon and up to 100 folds for entities such as Kaposi's sarcoma, PTLD, and skin cancers. The most common malignancies are PTLD (early after RT) and skin carcinomas, especially nonmelanoma skin cancers (late after RT). IS drugs and infections (EBV, human papilloma virus, hepatitis B virus, HCV, human herpes virus-8) play a key role.[45] IS therapy used in RTRs can cause malignancy by supporting oncogenesis caused by certain viruses or by impairing immune surveillance, thereby enabling faster tumor growth.[46] Previous use of cytotoxic drugs (e.g. CYC) and history of analgesic abuse are additional risk factors. Some evidence suggests that mTORi have some antitumor activity, and hence, these drugs might be useful in patients who develop malignancy after RT and switching from CNIs to mTORi may be helpful in modifying the course of the malignancy.[47] Squamous cell skin cancers do not typically metastasize, but if untreated, metastasis can occur. RTRs should undergo an annual skin exam and be counseled regarding sun-protective measures. The majority of PTLD cases are driven by an EBV infection. Age-appropriate cancer screening should be performed as indicated.

Electrolyte and acid–base disturbances

The most frequent electrolyte and acid–base disturbances in RTRs are hyperkalemia, metabolic acidosis, hypercalcemia, hypomagnesemia, and hypophosphatemia.[48] Hypomagnesemia thought to be due to CNIs; it may play a role in the development of PTDM and CNI nephrotoxicity. The incidence of hypomagnesemia and of PTDM is reported to be higher among patients using tacrolimus than those on CsA. Hyperkalemia can result from impaired allograft function and the concomitant use of medications, such as CNIs, ACEIs, ARBs, beta-blockers, and TMP-SMX. Hypercalcemia and hypophosphatemia are the results of persistent HPTH. FGF23 and PTH are found to be at elevated levels in CKD and ESRD patients in response to elevated phosphate levels. After successful RT, elevated FGF23 levels and other phosphatonins might take some time to come down and this persistent elevation is considered to play a key causative role in the phosphaturia and hypophosphatemia seen in the RTRs. Tacrolimus also increases renal phosphate wasting. Metabolic acidosis is also common, and it is predominantly of the normal anion gap variant. Both proximal and distal (including type 4) renal tubular acidosis can be seen. Factors such as suboptimal allograft function, donor age, DD RT, graft rejection, HPTH, and the use of CNIs have been associated with post-RT acidosis.

Hyperuricemia and gout

Gout is a common problem among RTRs with a prevalence of 2%–13%. Hyperuricemia is even more common. Reduced uric acid excretion leads to hyperuricemia in most of them. It can occur due to effect of CNIs (especially CsA), loop/thiazide diuretics, and renal impairment; other comorbidities such as HTN, diabetes mellitus, obesity, and CVD may also contribute to the increased risk of gout in this population.[49] Colchicine can be used to treat acute gout, with appropriate dose reduction for decreased kidney function, as myopathy and neuropathy may develop as adverse reaction. XO inhibitors should be avoided in patients receiving AZA.

Pregnancy

RT offers best hope to women with ESRD who wish to become pregnant. Despite the return of fertility after RT, the rates of successful pregnancy remain far lower than in the general population. Pregnancy in RTRs continues to remain challenging due to the side effects of IS medication, risk of deterioration of allograft function, risk of adverse maternal complications of preeclampsia and HTN, and risk of adverse fetal outcomes of premature birth, low birth weight, and small-for-gestational age infants.[50] mTORi use in men can result in oligospermia and reduced testosterone levels, which can contribute to infertility and erectile dysfunction. The International Transplant Pregnancy Registry has been established, and it is a good resource for information regarding pregnancy after organ transplantation.[51]

The factors associated with poor pregnancy outcomes include presence of HTN, Scr >1.5 mg/dL, and proteinuria. About 30% of pregnancies in RTRs experience pregnancy-induced HTN. Methyldopa, hydralazine, and labetalol can be safely used to treat HTN; ACEIs and ARBs are contraindicated during pregnancy. Modification of the maintenance IS regimen is frequently necessary before conception. The recommended maintenance IS in pregnant women is combination of CNIs, AZA, and low-dose prednisone.[52] CNI levels need to be monitored closely because its metabolism by the placenta and dilution by an increased volume of distribution can result in subtherapeutic levels. The placenta also metabolizes prednisone to prednisolone; therefore, only low levels have been detected in the fetal circulation. Rejection if occurs during pregnancy, it is difficult to diagnose based on Scr level, given hyperfiltration during pregnancy. The use of MMF and mTORi should be avoided starting 6 weeks before conception as they are teratogenic [Table 10]. Breast-feeding is not contraindicated and should not be discouraged.{Table 10}

 Conclusions



RT is the treatment of choice for patients with ESRD. Optimal fluid therapy immediately after RT has been shown to decrease DGF and its long-term effects. Patients require close follow-up after RT since they are on IS regimens that render them susceptible to infection, malignancy, and CVD. RTRs present with a unique and complex set of medical issues. As patients survive longer with functioning allografts, the responsibility for their care will become increasingly dependent on the PCPs. It is crucial that PCPs have the necessary skills and knowledge to provide appropriate care to them, ensuring optimum health. PCPs can play a crucial role in improving long-term patient and graft survivals by taking an active part in the management of these high-risk patients. Collaboration and communication between nephrologists and PCPs are vital to ensure quality medical care of RTRs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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