Providing care for kidney transplant recipients: An overview for generalists

Abstract

Kidney transplantation is the preferred treatment for patients with advanced chronic kidney disease and end-stage kidney disease, offering superior quality of life and survival compared to dialysis. This manuscript provides an updated overview of post-transplant care, highlighting recent advancements and current practices to assist generalists in managing these patients. It covers key areas such as immunosuppression strategies, drug interactions, and the management of transplant-specific acute kidney injury. The focus includes the use of sodium-glucose cotransporter-2 inhibitors and cell-free DNA monitoring for evaluating allograft health and immune-mediated injury. The manuscript reviews the fundamentals of immunosuppression, including both induction and maintenance therapies, and underscores the importance of monitoring kidney function, as well as addressing hypertension, diabetes, and infections. It also provides recommendations for vaccinations and cancer screening tailored to kidney transplant recipients and emphasizes lifestyle management strategies, such as exercise and sodium intake, to reduce post-transplant complications.

Key Words: Kidney transplantation; Clinical practice guidelines; Immunosuppression; Cell-free DNA; Sodium-glucose cotransporter-2 inhibitors; Pregnancy

Core Tip: This updated overview serves as a comprehensive guide for generalists involved in post-kidney transplant care. It covers essential aspects such as the management of immunosuppression, drug interactions, and acute kidney injury, as well as the integration of advanced therapies like sodium-glucose cotransporter-2 inhibitors and cell-free DNA monitoring. In addition to lifestyle management and targeted screening recommendations, we provide guidance on managing pregnancy after a successful kidney transplant. We also highlight when it is appropriate to consult subspecialists for further expertise in managing complex cases or complications, ensuring optimal care for transplant recipients.

INTRODUCTION

Kidney transplantation (KT) is the preferred therapy for patients with advanced chronic kidney disease (CKD) and those on dialysis[1] as it improves the quality of life and overall survival compared to remaining on dialysis[2]. Transplant nephrologists typically handle immediate post-transplant care, which can last from weeks to years, varying by institution and patient factors. Beyond this period, general physicians and nephrologists manage follow-up care. This article aims to update prior narrative reviews with recent evidence, focusing on immunosuppression basics, drug interactions, and transplant-specific acute kidney injury diagnosis, especially post-pandemic. It includes sodium-glucose cotransporter-2 inhibitors (SGLT2i) in kidney transplant recipients (KTR) and explores cell-free DNA for monitoring allograft health and immune-mediated injury investigations.

BASICS OF IMMUNOSUPPRESSION

Understanding the specific immunosuppression protocols used in KTR is crucial to grasp the unique challenges involved in their care. Initially, KTR undergo induction immunosuppression at the time of transplantation, typically with agents like anti-thymocyte globulin or alemtuzumab, which deplete T-lymphocytes, or with an interleukin-2 receptor inhibitor such as Basiliximab[3,4]. Following transplantation, maintenance immunosuppression is initiated during the inpatient period and continues indefinitely to support graft survival[5]. The components of maintenance immunosuppression are designed based on the three-signal model of alloimmune responses[6].

Signal 1 occurs when the antigen on the surface of antigen-presenting cells (monocytes, macrophages, dendritic cells)[7] activates T cells via their respective T cell receptors and transduced through the CD3 complex[4]. Signal 2 involves co-stimulation provided by dendritic cells when CD80 and CD86 engage with T-cell CD28[8]. These signals trigger three transduction pathways: Calcium-calcineurin, rat sarcoma virus-mitogen-activated protein kinase, and nuclear factor kappa B[9]. These pathways activate transcription factors that upregulate molecules and cytokines such as interleukin-2, supporting cell proliferation (signal 3), and activating the mammalian target of rapamycin (mTOR) pathway[10]. This is visualized in Figure 1.

Figure 1 Three signal model of T-cell activation. This figure presents a general overview of the key signaling events linking the production of a T-cell response. Signal 1 occurs when antigen-presenting cells (APCs) such as monocytes, macrophages, dendritic cells present antigen via major histocompatibility complex peptide complex on the APC cell surface to their respective T cell receptors on the surface of T cells and that is transduced through the CD3 complex. For Signal 1 to induce clonal expansion of naive T cells, the costimulatory signal 2 with B.7-1 (CD80) and B.7-2 (CD86) of dendritic cells binding with T-cell CD28 must also occur. Intracellular CD28 signaling also upregulates binding of CD40 by CD40 ligand (CD154) that also activates the APC to secrete proinflammatory molecules/and express B.7 molecules stimulating further T cell proliferation. These signals trigger three transduction pathways: Calcium-calcineurin, rat sarcoma virus-mitogen-activated protein kinase, and protein kinase C-nuclear factor kappa B. These pathways activate transcription factors that upregulate molecules such as interleukin-2 receptor genes and cytokines such as interleukin-2, supporting cell proliferation (signal 3), and activating the mammalian target of rapamycin pathway. Cell images obtained from reactome, an open-source, open access database. TCR: T cell receptor; MHC: Major histocompatibility complex; IL-2: Interleukin-2; mTOR: Mammalian target of rapamycin; NFAT: Nuclear factor of activated T cells; AP-1: Activating protein-1.

The rationale outlined above supports the use of a combination of multiple immunosuppressant agents for long-term maintenance therapy in transplant recipients. The most frequently employed immunosuppression protocol involves a three-drug regimen comprising a calcineurin inhibitor (CNI), typically cyclosporine or tacrolimus, an antimetabolite such as mycophenolate mofetil (MMF) or its active metabolite mycophenolic acid (MPA), and a low-dose corticosteroid. Detailed descriptions of these commonly used immunosuppressant drugs are provided below and summarized in Table 1.

Table 1 Common maintenance immunosuppressants used in kidney transplantation.

Drug name	Mechanism of action	Key interactions	Non-immune toxicities	Additional comments
Tacrolimus and tacrolimus XR	Bind to FKBp12 and the complex inhibits the calcineurin phosphatase and T cell proliferation	Inhibitors and inducers of cytochrome P450 system impact drug levels. Common inhibitors include azole antifungals, nondihydropyridine antihypertensives, protease inhibitors, macrolides and grapefruit juice. Common inducers include rifampin, rifabutin, carbamazepine, and phenobarbital	New onset diabetes after transplant, neurotoxicity, hemolytic uremic syndrome, nephrotoxicity, alopecia. Less likely to cause hypertension, hyperlipidemia, gum hyperplasia than cyclosporine	Trough monitoring required, 12-hour troughs for tacrolimus and 24-hour troughs for tacrolimus XR
Cyclosporine and cyclosporine modified	Binds to cyclophilin and the complex inhibits calcineurin phosphatase and T cell proliferation	Inhibitors and inducers of cytochrome P450 system impact drug levels. Common inhibitors include azole antifungals, nondihydropyridine antihypertensives, protease inhibitors, macrolides and grapefruit juice. Common inducers include rifampin, rifabutin, carbamazepine, and phenobarbital	More likely to cause hypertension, hyperlipidemia, gum hyperplasia than tacrolimus but can also cause hemolytic uremic syndrome, nephrotoxicity and neurotoxicity like tacrolimus	12-hour trough monitoring or checking levels 2 hours after administration required
Sirolimus and everolimus	Binds to FKBP12 and the complex inhibits TOR and IL-2 driven T cell proliferation	Increased toxicity of calcineurin inhibitors when used concurrently	Dyslipidemia, delayed wound healing, delayed graft function, proteinuria, pneumonitis, interstitial lung disease, mouth ulcers	Trough monitoring required, 24-hour troughs for sirolimus and 12-hour troughs, for everolimus. Monitoring of lipids and urine protein required
Mycophenolate mofetil and enteric coated mycophenolic sodium	Inhibits inosine monophosphate dehydrogenase and thus synthesis of guanosine monophosphate nucleotides which prevents proliferation of B cells and T cells	Proton pump inhibitors reduce intestinal absorption of mycophenolate mofetil, and cyclosporine reduces enterohepatic recirculation and drug exposure	Gastrointestinal side effects (nausea, heartburn, and especially diarrhea) and cytopenia	Contraindicated in pregnancy, therapeutic monitoring not required though may be used to improve efficacy/assess for adherence
Azathioprine	Inhibits purine nucleotide synthesis, gene replication, and T cell activation by incorporating itself into cellular DNA	Xanthine oxidase inhibitors such as allopurinol and febuxostat increase azathioprine levels	Bone marrow suppression and liver toxicities	Blood count monitoring required
Corticosteroids	Inhibit NFkB which is a transcription factor to express necessary cytokines for T cell activation	N/A	Osteoporosis, impaired wound healing, dyslipidemias, impaired glucose tolerance, and psychological impacts	Early steroid withdrawal based on recipient factors including low immunological risk (e.g. low calculated panel-reactive antibodies) with a non-immune-mediated cause of end stage renal disease (such as, diabetes mellitus, hypertension, polycystic kidney disease)
Belatacept	Binds to CD80/CD86 on antigen presenting cells blocking the interaction with CD28 on T cells and thus inhibiting costimulatory signal 2	Used in lieu of calcineurin inhibitors and used concomitantly with mycophenolate mofetil/mammalian target of rapamycin inhibitors and steroids	Contraindicated in recipients who are Epstein Barr virus seronegative due to prohibitive risk for post-transplant lymphoproliferative disorder	Monthly infusion in steady state for low immunologic risk recipients with benefits to longitudinal creatinine compared with remaining on calcineurin inhibitors

TOR: Target of rapamycin; IL-2: Interleukin 2; NFkB: Nuclear factor kappa B; N/A: Not applicable.

CNIs used in solid organ transplantation include cyclosporine and tacrolimus inhibit T-cell proliferation and cytokine production[11] as well as subsequent T cell differentiation and activation[12]. Cyclosporine is marketed in formulations such as Sandimmune^® (cyclosporine) and Neoral^® (cyclosporine modified), typically monitored through 12-hour trough levels with therapeutic targets adjusted based on the patient’s post-transplant timeline, whether immediate or long-term. Tacrolimus is available as Prograf^® (twice-daily immediate release) or Envarsus^® (once-daily extended release), monitored with either 12-hour trough levels for Prograf or 24-hour trough levels for Envarsus. Caution is advised when switching between these formulations and drug classes due to differences in bioavailability. Both classes of these immunophilin-binding agents share similar adverse effects, predominantly dose-dependent toxicities linked to their metabolism via the cytochrome P450 system[13]. It is important therefore the be aware of common inducers (e.g. rifampin, carbamazepine, phenobarbital, etc.) and inhibitors (macrolides, azole antifungals, no dihydropyridine antihypertensives, protease inhibitors, etc.) of this cytochrome P450 system for these patients to mitigate drug interactions[14]. Signs and symptoms of CNI toxicities to monitor are numerous including neurotoxicity, tremors, nephrotoxicity, and hemolytic uremic syndrome[4,15].

mTOR inhibitors like sirolimus (once daily) and everolimus (twice daily) are frequently used as alternatives to CNIs to mitigate their associated toxicities[16] and because of their anti-neoplastic properties[10]. mTOR inhibitors require monitoring of target drug levels every 12 hours or 24 hours, depending on the specific formulation used. These agents act by blocking signal 3 and are noted for side effects such as impaired wound healing, delayed recovery from acute tubular necrosis, delayed graft function, dyslipidemias, proteinuria, increased rejection risk in high immunologic risk patients, and heightened overall mortality rates[6,16].

Coming to the antiproliferative drugs MMF and MPA, these agents function by inhibiting the enzyme inosine monophosphate dehydrogenase, thereby blocking the production of guanosine nucleotides[17]. Importantly, MMF interacts with proton pump inhibitors, which decrease its intestinal absorption by reducing gastric acidity, and with cyclosporine, which disrupts the enterohepatic recirculation of MPA, leading to reduced exposure to this active metabolite[5]. Common side effects associated with this class of medications include cytopenias and gastrointestinal (GI) symptoms such as heartburn, nausea, and most frequently, diarrhea[6]. Severe GI symptoms of MPA led to creation of the enteric-coated mycophenolate sodium in an effort to improve its GI tolerance[17,18].

Azathioprine is less frequently used as an antimetabolite immunosuppressant for KTR in current practice given increased rates of steroid-resistant rejection compared to MMF[4,19], This prodrug of 6-mercaptopurine[17] may be considered when patients cannot tolerate the GI side effects of MMF/MPA or when female transplant recipients are planning pregnancy and MMF/MPA is contraindicated[20]. The primary side effects to monitor with this purine analog include bone marrow suppression and, less commonly, liver toxicity, necessitating regular monitoring of hematologic parameters and hepatic function[6]. Special caution is warranted in transplant recipients with gout or hyperuricemia, as azathioprine interacts with xanthine oxidase inhibitors such as allopurinol, potentially causing severe myelosuppression[21].

Belatacept is an intravenously administered immunosuppressant used instead of CNIs in KTR who are at low immunologic risk due to increased risk for acute rejection[22]. This fusion protein binds to CD80/CD86 on antigen-presenting cells, thereby preventing their interaction with CD28 on T cells and inhibiting signal 2. Due to its action on CD28, Belatacept preferentially inhibits de novo T cell responses over memory T cell responses, which reduces the patient’s ability to mount an effective immune response to primary Epstein-Barr Virus (EBV) infection[23]. Because EBV infection is strongly linked to post-transplant lymphoproliferative disorder (PTLD), Belatacept is contraindicated in EBV seronegative recipients due to the significantly increased risk of PTLD associated with its use[23].

Corticosteroids inhibit the transcription factors required to produce several cytokines essential for T-cell activation. In recipients of low immunologic risk and with induction choice with depleting therapies[24], it may be possible to reduce or discontinue corticosteroid use early after transplantation[4,25]. The goal of minimizing or avoiding long-term, high-dose steroid use is due to their well-documented side effects, including osteoporosis, impaired wound healing, dyslipidemias, impaired glucose tolerance, and psychological effects. Early withdrawal of corticosteroids is preferred, as delaying their discontinuation significantly increases the risk of allograft rejection and should be avoided[26].

Monitoring kidney function is crucial for patients with CKD as well as for KTR throughout the lifespan of the allograft. Initially, KTR are monitored closely post-transplantation and on transitions of care to ensure stability[27]. Laboratory testing is performed twice weekly during the first month post-transplant. This frequency gradually decreases to every 1-3 months for stable, long-term patients. Any increase in serum creatinine levels greater than 20% to 25% from the KTR’s baseline warrants further investigation[5].

Before referring to a specialist, initial evaluations should include a comprehensive history and physical examination to check for volume depletion, a kidney transplant ultrasound with Doppler to exclude obstruction and assess vascular flow, and a measurement of tacrolimus or cyclosporine trough levels to detect potential calcineurin toxicity. Additionally, testing for de novo donor-specific antibodies should be conducted to assess for antibody-mediated rejection, and serum BK virus (BKV) polymerase chain reaction (PCR) should be performed. A urinalysis with reflex culture is also important to detect hematuria, proteinuria, and bacteriuria, which can indicate rejection, recurrent or new glomerular diseases, or transplant pyelonephritis[5]. Recently, donor-derived cell-free DNA has been validated as a more reliable biomarker for detecting clinically evident and subclinical antibody-mediated and T cell-mediated rejection compared to traditional markers like serum creatinine[28]. Based on these preliminary findings, specialist care should be pursued, particularly if there are concerns about recurrent or new diseases, BKV nephropathy, or acute rejection, which may require a kidney biopsy to guide treatment.

HYPERTENSION

Managing hypertension in KTRs presents more complexity than in the general CKD population due to the absence of established blood pressure (BP) targets specific to this group, as there are no definitive randomized trials. The 2021 KDIGO Clinical Practice Guidelines recommend a BP target of less than 130/80 mmHg for KTR[29]. This number is higher than the general CKD target of less than 120 mmHg systolic BP. The difference arises from concerns about an increased risk of acute kidney injury and accelerated loss of estimated glomerular filtration rate with lower BP targets[29]. Additionally, there is a focus on prolonging allograft function over mortality risk among stakeholders[30]. With respect to pharmacologic therapy, the current guidelines suggest using either a dihydropyridine calcium channel blocker or an angiotensin receptor blocker (ARB) as first-line treatments, based on their efficacy in reducing graft loss. When selecting antihypertensive agents, considerations should include the presence of proteinuria, as ARBs are preferred for their antiproteinuric effects. However, ARBs are generally avoided in the early post-transplant period due to their potential impact on glomerular filtration rate, which can be confusing. Moreover, ARBs are contraindicated in women who are pregnant, trying to conceive, or breastfeeding due to their known teratogenic effects on the fetus and newborn[29].

POST-TRANSPLANT HYPERGLYCEMIA AND DIABETES MELLITUS

Post-transplant diabetes mellitus (PTDM) is a relatively common complication, especially given that tacrolimus is toxic to pancreatic islet cells (more so compared to cyclosporine)[31]. Additionally, the need for ongoing steroid therapy as part of the immunosuppression regimen can contribute to the development of PTDM[32]. Risk factors for PTDM include obesity, African American and Hispanic ethnicity, and a family history of diabetes[5]. PTDM is particularly concerning as it increases both cardiovascular and infection risks in KTR, potentially impacting patient and graft survival. Therefore, effective management of metabolic disorders in the post-transplant period is crucial for ensuring long-term success of the transplant[32]. Early in the post-transplant period, insulin therapy using basal-bolus regimens is generally recommended. Studies suggest that insulin therapy helps protect pancreatic beta cells and can prevent further damage, thereby reducing the incidence of PTDM in KTR[33]. In the longer term, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists can be beneficial for managing blood glucose levels and improving insulin resistance, with glucagon-like peptide-1 receptor agonists also providing the added benefit of weight loss[32]. After a year post-transplant, when immunosuppression has been reduced, SGLT2i may also be considered, offering additional glycemic benefits as discussed further in this review.

INFECTIOUS ISSUES

Urinary tract infections are a significant issue for KTR, particularly occurring within the first six months post-transplant. These infections can endanger both the graft and the patient due to ongoing immunosuppression, which often includes the antimetabolite mycophenolate, and potential catheterization or existing urinary tract abnormalities related to the transplant[34]. Diagnosing urinary tract infections in this population can be challenging due to the reduced sensitivity of transplanted kidneys and the masking effects of immunosuppressive therapies on clinical and laboratory infection markers[35]. Treatment typically involves antibiotics targeted at the causative organism, most commonly Escherichia coli, and ensuring proper urinary drainage while maintaining fluid balance to prevent acute kidney injury[34]. There is insufficient high-quality evidence to support the routine use of antibiotics for asymptomatic bacteriuria in KTR[36].

BKV viremia and subsequent BKV-associated nephropathy are significant concerns, with monitoring protocols involving periodic BKV PCR screenings during the early post-transplant period, usually up to two years[35]. This double-stranded DNA virus, a polyomavirus, can cause nephropathy in the transplanted kidney either through primary infection or reactivation from latency due to relative or absolute immunodeficiency. BKV nephropathy typically occurs within the first year or following rejection treatment and is diagnosed via kidney histology. The standard treatment protocol involves reducing immunosuppression.

Cytomegalovirus (CMV) is another common viral infection post-transplant. Prophylaxis and monitoring are based on the recipient’s and donor’s serological profiles[5]. CMV infection often presents with symptoms such as leukopenia, diarrhea, fever, malaise, and pulmonary issues[5]. For intermediate-risk KTR (CMV recipient positive) and those at high risk of seroconversion (CMV donor positive and CMV recipient negative), a prophylactic regimen of renally dosed valganciclovir is recommended for 3-6 months post-transplant[37]. Serological screening with CMV serum PCR should follow the completion of prophylaxis, and treatment for positive cases often involves oral valganciclovir or intravenous ganciclovir, depending on resistance[37]. Fungal infections can be particularly challenging in KTRs, often requiring substantial reductions in immunosuppression due to their high morbidity and mortality risk[5]. Antifungal prophylaxis is provided according to protocol: Against Candida for the first month and against Pneumocystis jirovecii pneumonia for approximately six months post-transplant, with special attention to Toxoplasmosis donor-recipient mismatch status[38].

Disseminated fungal infections, such as those caused by Coccidioides, often necessitate prophylactic antifungal treatment, and should involve input from transplant infectious disease specialists. Further discussion of infectious disease management and prophylaxis, including individualized approaches for hepatitis C and hepatitis B donor kidney recipients, falls outside the scope of this brief overview and should involve consultations with transplantation specialists and/or infectious disease experts.

VACCINATIONS

Because of the immunocompromised status, reviewing the vaccination status of KTR is crucial to prevent infections. They face a higher risk of complications from vaccine-preventable illnesses[39]. However, KTR have decreased immunologic responses to vaccination. So, it is generally recommended that they and their close contacts or family members be fully immunized before transplantation. Live vaccines should be administered at least 4 weeks prior, as they can be problematic to give afterward. Most inactivated vaccines can be administered as early as one-month post-transplant. The disease-specific vaccines recommended for KTR align with those recommended for the general population according to local guidelines. This includes influenza vaccines, hepatitis B vaccination with monitoring of titers and revaccination, if necessary, pneumococcal vaccines pneumococcal conjugate vaccine 13 and pneumococcal polysaccharide vaccine 23 with boosters as needed, meningococcal vaccines for patients with risk factors, human papillomavirus vaccination for age-appropriate at-risk recipients, and subunit herpes zoster vaccination for KTRs over the age of 50[39].

SGLT2I

SGLT2i have garnered interest in KTR due to their notable cardiovascular benefits and proven kidney-protective effects, particularly in reducing proteinuria in CKD. Initially developed as antidiabetic agents, recent research has shown that their benefits extend beyond glycemic control to include reductions in proinflammatory reactions associated with glucotoxicity[40]. Moreover, several studies have highlighted the immunomodulatory effects of these medications, particularly through their impact on T cell receptor signaling and effector functions, which leads to decreased production of proinflammatory cytokines and reduced immune activation, at least for canagliflozin in vitro[41]. However, landmark randomized controlled trials, such as the dapagliflozin in Patients with CKD[42], did not include KTR due to concerns that SGLT2i’s mechanism of concentrating glucose in the urine might increase the risk of infections, compromise allograft function[32], or alter immunosuppressant levels[43]. Consequently, there is limited evidence available for this specific population, highlighting the need for further research.

ADVICE ON EXERCISE

Following KT, the recovery period can be particularly challenging. KTR must adapt their lifestyles to accommodate their new transplant, adhere to a rigorous follow-up schedule for health monitoring, and manage medication regimens, all while striving to return to normalcy[44]. An often-overlooked complication of KT is the emergence of lifestyle and non-communicable diseases, such as weight gain, new-onset diabetes, dyslipidemia, and muscle wasting, which can increase the risk of cardiovascular disease[44]. Since cardiovascular disease is the leading cause of death among KTR, it is crucial to implement multidisciplinary care strategies post-transplant to mitigate modifiable risks through diet, pharmacological therapy, and exercise[5,45]. Exercise plays a vital role in the recovery process by enhancing aerobic capacity, strength, graft function, and overall quality of life[44,46]. Healthcare providers must address barriers such as lack of exercise guidance, physical limitations, and concerns about harming the kidney to help KTRs achieve the recommended 150 minutes of activity per week[44,46].

ADVICE ON SODIUM INTAKE

Maintaining a low sodium intake remains important for KTR, both before and after transplantation, though strong evidence supporting this is still lacking[47]. Limited studies suggest that keeping sodium intake to no more than 2.3 g per day can have beneficial or at least non-harmful effects on proteinuria/albuminuria, volume management, graft function, and cardiovascular disease risk[47,48]. This is particularly relevant as low sodium intake combined with antihypertensive therapy has been linked to better hypertension control in KTR[48]. Furthermore, increased salt intake is thought to potentially contribute to kidney allograft dysfunction by modulating the immune system towards a proinflammatory state.

BONE HEALTH

Patients undergoing KT often experience decreased bone strength and a higher fracture risk due to advanced CKD and associated bone mineral disorders, which disrupt calcium, phosphorus, fibroblast growth factor 23, parathyroid hormone, klotho, and vitamin D levels[49]. Moreover, KTR are observed to have increased rates of trabecular bone fractures, likely due to glucocorticoid-induced osteopenia, particularly within the first six months post-transplantation[50]. The initial year to year and a half after transplantation is marked by rapid bone mineral density loss and elevated fracture risk[50]. This can be assessed biochemically through serum levels of phosphorus, vitamin D, calcium, and parathyroid hormone, and with dual X-ray absorptiometry scans, with bone biopsy considered if necessary[49]. Early post-transplant disorders such as hypophosphatemia, hypovitaminosis D, and hyperparathyroidism are common but typically resolve within 1-2 years[49]. Tertiary hyperparathyroidism, characterized by post-transplant hyperparathyroidism with hypercalcemia, is managed with calcimimetics like cinacalcet to enhance the sensitivity of parathyroid calcium-sensing receptors to calcium, thereby suppressing parathyroid hormone secretion and lowering serum calcium levels. Subtotal parathyroidectomy is usually reserved for cases of refractory tertiary hyperparathyroidism[49].

PREGNANCY ADVICE

Fertility often improves in patients with end-stage renal disease who undergo a successful kidney transplant, as the uremia-induced disruptions in the hypothalamic-pituitary-gonadal axis, including hyperprolactinemia, are corrected[51]. However, managing pregnancy in KTR presents significant challenges due to potential adverse maternal events such as preeclampsia, hypertension, acute rejection, or worsening of the allograft[52]. Fetal complications may include being small for gestational age, premature birth, and low birth weight. Additionally, exposure to immunosuppressants, particularly MMF during pregnancy, is associated with a higher incidence of structural malformations in the fetus[20]. Effective contraception is crucial before starting MMF, during therapy, and for six weeks after discontinuation. Additional general advice regarding the criteria for pregnancy after kidney transplant are based on the American Society of Transplantation consensus statement for timing pregnancy at least 1 year after transplant in the setting of stable allograft function with creatinine less than 1.5 mg/dL, in absence of or with minimal proteinuria, without recent rejections and the patient on stable maintenance immunosuppression[53]. Pregnant KTR should be managed by high-risk obstetricians and gynecologists and may need to switch to a less teratogenic immunosuppressant, such as azathioprine, with guidance from a transplantation specialist[5]. The use of donor-derived cell-free DNA for allograft monitoring during pregnancy needs further research as recent large studies excluded pregnant women from analysis as current assays may give inaccurate results in pregnancy[54,55].

CORONAVIRUS DISEASE 2019 PREVENTION

The coronavirus disease 2019 pandemic had a significant global health impact, disproportionately affecting individuals with weakened immune systems, such as KTR, due to their immunosuppressive therapy[56]. Consequently, preventive measures are recommended, and vaccination has been shown to decrease mortality among KTR infected with severe acute respiratory syndrome coronavirus 2[57]. However, KTR generally exhibit a reduced immune response to coronavirus disease 2019 vaccination[58]. Factors contributing to this diminished response include advanced age (over 60 years), diabetes, higher doses of MMF, recent use of high-dose corticosteroids, and recent therapy with B-cell-depleting agents. Social distancing remains advisable, and specific treatments, such as antiviral and monoclonal antibody therapies, are recommended for those who test positive. Care should be taken to avoid the combination of nirmatrelvir/ritonavir (marketed as Paxlovid by Pfizer) due to its well-documented interaction with CNIs. This interaction significantly reduces CNI clearance, leading to an increased risk of adverse events, including acute kidney injury.

CANCER SCREENING

Post-transplant malignancy is a significant concern for KTR and remains a major cause of both morbidity and mortality[59]. The primary risk factor is the ongoing need for immunosuppression, which weakens the immune system. Consequently, unchecked viral replication of oncogenic viruses, reduced immune surveillance of cancer, disruptions in DNA repair mechanisms, and potential direct carcinogenic effects of immunosuppressant medications contribute to this risk[60,61]. Several clinical practice guidelines exist for these patients though the consensus is to follow age-appropriate cancer screenings as per the general population depending on their personal risk factors for cervical cancer, breast cancer, colorectal cancer, prostate, and lung cancer[62]. Specific differences in KTR include monitoring native kidneys for the occurrence of renal cell carcinoma, which is only recommended by the European Best Practice Guidelines every 1-3 years[63]. Further, recommendations for skin cancer screening and PTLD screening are important areas of distinction compared to the general population[62]. Clinical skin exams are recommended for this patient population at least annually[61]. As PTLD is often driven by EBV infection, clinicians should be vigilant, particularly in their EBV non-immune patients for further evaluation of symptoms including low-grade fevers, dyspnea, headaches, or abdominal discomfort with decreased threshold for computed tomography[5,64].

CONCLUSION

In summary, KT remains the preferred treatment for advanced CKD due to its superior outcomes compared to dialysis. Effective post-transplant care requires a nuanced understanding of immunosuppression protocols, monitoring for acute kidney injury, and managing comorbid conditions like hypertension and diabetes. Advances in monitoring tools, such as cell-free DNA, offer promising improvements in detecting graft rejection. The inclusion of SGLT2 inhibitors presents potential benefits for KTR, though further research is needed. Addressing infectious risks, vaccination, and cancer screening are critical components of care. Finally, lifestyle modifications, including exercise and dietary adjustments, are essential to optimize long-term health and graft survival. Continued interdisciplinary collaboration and research will enhance patient outcomes and address emerging challenges in this evolving field.