Transplant endocrinology

Abstract

Solid organ transplants and stem cell transplants are becoming more common but a significant proportion of patients are still on waiting lists, awaiting transplants. When endocrinologists treat transplant recipients who have underlying endocrine problems, which might include endocrine emergencies, there are special clinical care considerations to be aware of. The stage of the transplant (pre-transplant, early post-transplant, and chronic post-transplant) must be taken into account. Additionally, it's crucial to be knowledgeable about immunosuppressive medications, their typical adverse effects and drug interactions.

The review article addresses a number of endocrine and metabolic abnormalities that are reported after transplantation.

Introduction

Given the growing number of organ transplants conducted each year, these patients often encounter adverse effects in the endocrine system. Around 144,302 organ transplants took place worldwide in 2021, with 95,532 of those being kidney transplants alone. In decreasing order, the most often transplanted solid organs are the kidney, liver, heart, lung, combined kidney/pancreas, pancreas, intestine, and combined heart/lung. Stem cell transplantation (SCT) is the most widely performed transplant procedure in clinical practice (Table 1).

Table 1.

Endocrine dysfunction in transplant setting.

Endocrine Dysfunction

•Adrenal insufficiency

•Hypothyroidism/Hyperthyroidism

•Hypopituitarism

Metabolic Dysfunction

•New Onset Diabetes mellitus

•Hypoglycemia

•Dyslipidemia

•Bone/Mineral Disorders

•Hypercalcemia/Hypocalcemia

•Hypophosphatemia

•Hyperuricemia

Electrolyte/Acid Base Disturbances

•Hyperkalemia

•Metabolic acidosis

•Hypomagnesemia

Pre-transplant, early post-transplant (within the first year), and chronic post-transplant are the three clinical phases that make up the clinical scenario in which the various effects of transplant need to be seen.

When endocrinologists encounter transplant patients, there are a number of clinical factors that are to be taken into account. The type of transplant, the indication for the transplant, and the patient's present clinical status must be understood. It is also crucial to know about immunosuppressive medications, including their typical side effects and drug interactions. Glucocorticoids and calcineurin inhibitors (cyclosporine and tacrolimus) have adverse skeletal effects and cause diabetes while mTOR inhibitors (sirolimus and everolimus) have adverse lipid effects. These medications are frequently used in conjunction and so should be looked into in detail.

Recipients of solid organ transplants may experience a variety of metabolic and endocrine problems. These disorders are the result of intricate interplay between physiological changes brought on by the transplanted organ, post-transplant lifestyle changes, immunosuppressive drugs, and hereditary vulnerability. They develop on a backdrop of pre-existing co-morbid conditions. In addition to this, chronic kidney disease, which is widespread in solid organ transplant recipients both before and after the procedure, has an impact on endocrine illness and its treatments.

When compared to recipients of solid organ transplants, patients undergoing SCT are typically younger, have a shorter time between diagnosis and transplant, and frequently undergo chemotherapy along with total body irradiation as part of their conditioning regimen. Allogeneic SCT, as opposed to autologous SCT, frequently results in graft versus host disease (GvHD) and may need a high dose of immunosuppressive treatment. SNPs, or single nucleotide polymorphisms, have been connected to specific immunosuppressive drug adverse effects. Identification of genetic variables may improve our comprehension of the causes of metabolic and other side effects of anti-rejection drugs and open the door to the potential for personalized immunosuppression in the future.

The patients need strict observation for a variety of electrolyte disorders in the immediate post-transplant period. These are initially linked to the surgical process, but they quickly give place to illnesses caused by modifications in organ function and the need for immunosuppressive medications that affect electrolytes. There is frequently a need for specific therapy of hyperkalemia, hypercalcemia, hypomagnesemia, and hypophosphatemia. As many as 87% of kidney transplant recipients without a history of diabetes mellitus experience acute hyperglycemia.

In the long run, the metabolic syndrome, which includes diabetes mellitus, hypertension, and dyslipidemia, may be prevalent in at least 40–50% of liver and kidney transplant recipients. Heart transplant and kidney transplant recipients who have the metabolic syndrome are more likely to develop allograft vasculopathy and cardiovascular disease respectively. After kidney and liver transplantation, new-onset diabetes after transplant (NODAT) is linked to graft failure and overall mortality.

Hyperglycemia and diabetes mellitus

The timing and anticipated duration of hyperglycemia post-transplant may vary as per the nature of transplant and immunosuppressive regimen. Due to the stress of surgery and immunosuppression, hyperglycemia can happen right after transplant. Notably, the incidence of NODAT is four times higher in patients with acute hyperglycemia following transplant. Insulin is a favored therapy during the perioperative period because acute hyperglycemia is typically resistant to oral medications and blood glucose levels are unpredictable when immunosuppressant dosage and regimen (particularly corticosteroids) are changed from day to day.

Long-term NODAT incidence across all donated organs could reach as high as 30%, particularly in adult solid organ transplant recipients.¹ In addition to the well-known traditional risk factors (older age, obesity, and ethnicity), hepatitis C infection and exposure to immunosuppression significantly raise the risk.² Direct toxicity to the pancreas cells and enhanced insulin resistance are two key routes that play a role in the complicated pathophysiology of NODAT.² Restoring renal function may “unmask” pre-existing diabetes since the kidneys play a significant role in the removal and breakdown of circulating insulin.

The screening for NODAT should be performed on all non-diabetic solid organ transplant recipients using fasting blood glucose measurements, oral glucose tolerance tests every week for the first four weeks, every three months for the first year, and then once a year after that. HbA1C is helpful for screening, however levels can be affected by hemolysis, erythropoietin administration, blood transfusions, uremia, and other factors.

Although dietary and lifestyle changes are beneficial for managing NODAT, pharmacological therapy is often required for people with persistent hyperglycemia. While there is no one oral hypoglycemic agent that is best, the risks and advantages of each medication should be carefully considered in order to rule out any potential interactions with immunosuppressive medications. For people with insulin resistance and stable renal function,³ metformin seems to be a wise choice but requires to be stopped if acute renal dysfunction gastrointestinal intolerance, severe infections, or tissue hypoxic states like cardiac or respiratory failure.

In the transplant population, insulin secretagogues can be employed, particularly if the main mechanism is thought to be reduced insulin secretion. Depending on the degree of hyperglycemia, a combination therapy including oral antidiabetic drugs from various classes and insulin may be required.⁴

Hypoglycemia

Spontaneous hypoglycemia after liver transplantation indicates a poor liver recovery and suggests primary graft failure with severe graft malfunction. Patients with renal impairment are more susceptible to hypoglycemia from sulphonylurea medications and insulin. Antibiotics like fluoroquinolone and the trimethoprim-sulfamethoxazole combination used after transplantation can result in hypoglycemia, particularly in the context of liver and/or renal impairment.5, 6, 7 Even though it's uncommon, stage 5 chronic kidney disease and liver failure can both lead to spontaneous hypoglycemia. Hepatocellular carcinoma patients in need of liver transplants may have hypoglycemia as the tumor produces insulin like growth factor – 2 (IGF-2).⁸

Dyslipidemia

Over half of those who receive liver, kidney, or heart transplants may have dyslipidemia. Genetic predisposition, obesity, nephrotic syndrome, hypothyroidism, diabetes mellitus, and the use of medications, especially immunosuppressants, are all contributing factors.9, 10, 11

The metabolism of cholesterol is negatively affected by corticosteroids and long-term use of these drugs results in hyperinsulinism and insulin resistance, which raises levels of triglycerides (TG), total cholesterol (TC), and very low-density lipoprotein (VLDL) wGrafthile lowering levels of high-density lipoprotein (HDL). The activity of HMGCoA reductase, acetylcoenzyme A carboxylase and free fatty acid synthetase, is upregulated along with inhibition of lipoprotein lipase and down-regulation of LDL receptor activity.

Cyclosporine causes hyperlipidemia by suppression of the enzyme 26-hydroxylase and the down-regulation of LDL receptors.¹²

The levels of cholesterol and TG are considerably raised by mTOR inhibitors in a dose-dependent manner.¹³ The mechanisms of sirolimus's adverse lipidemic effects are unknown and may be multifactorial including blockage of insulin-stimulated lipoprotein lipase, increased hepatic production of TG and lipoproteins, decreased plasma clearance and cellular transport, and decreased catabolism of apoB100-containing lipoproteins. Azathioprine or mycophenolate mofetil, however, do not result in dyslipidemia.

Fish oil, fibrates, statins, and occasionally niacin formulations are used to treat dyslipidemia. The patients who cannot tolerate statins can be treated with ezetimibe or nicotinic acid alone. It may be required to switch to a different immunosuppressant or reduce the dose of the patient's existing one in severe dyslipidemia that are resistant to pharmaceutical therapy.

The cytochrome P450 3A4 pathway is used in the metabolism of several statins, including simvastatin, atorvastatin, and lovastatin. Concurrent use of these medications with cyclosporine can significantly raise the risks of myopathy since cyclosporine is processed by the same mechanism as these other medications.

Bone and mineral disorders

Solid organ transplant recipients frequently have bones and mineral disorders. Advanced age, pre-existing osteodystrophy, underlying illness causing end-stage organ failure, vitamin D insufficiency, smoking, diabetes, and transplantation-specific medications, especially immunosuppressive drugs, are all contributing factors.^14,15

Within the first 6–12 months following a solid organ transplant, bone loss is very fast and ranges from 0 to 24% at the spine to 2–11% at the hip.^14,16 Reduced immunosuppressive drug dosages and improvements in metabolic/endocrine abnormalities are believed to be the causes of the decreased rates of bone loss in the latter post-transplant period. Accelerated bone loss could result from increasing glucocorticoid dosages to treat rejection or for other causes.

Chronic kidney disease (CKD), which affects numerous facets of mineral metabolism including phosphate retention, hypocalcemia, and impaired vitamin D activation, is a condition that affects only kidney transplant patients.^14,16 Secondary hyperparathyroidism is a result of these effects stimulating the parathyroid glands. These metabolic abnormalities can cause tertiary hyperparathyroidism and parathyroid cell hyperplasia if they are not properly addressed.¹⁷ Many of these anomalies in mineral and bone metabolism are reversed by successful kidney transplantation, but the degree of improvement is typically only partial. In addition to graft micro-calcifications and malfunction, persistent hypercalcemia can also cause soft tissue and vascular calcifications, bone demineralization, renal failure from afferent arteriole vasoconstriction, and an increased fracture rate.¹²

Hypercalcemia

The transplant patients may experience hypercalcemia due to a number of distinct factors. The pre-transplant liver patients may experience non-PTH mediated hypercalcemia with ascites, diuretic usage, and compromised renal function or PTHrP mediated hypercalcemia caused by hepatocellular carcinomas. The chronic kidney disease can have hypercalcemia secondary to factors like tertiary hyperparathyroidism, calcium-containing phosphate binders, vitamin D analogs and impaired renal calcium excretion.¹⁸

Up to 66% of kidney transplant recipients have experienced post-transplantation hypercalcemia, which is most likely caused by persistent or tertiary hyperparathyroidism.¹⁹

Bisphosphonates, which are excreted through the kidneys and used to treat hypercalcemic crises can cause renal toxicity, however Denosumab is a safe therapeutic option.²⁰

Hypocalcemia

Within the first postoperative day, 41% of kidney transplant recipients experience transient hypocalcemia, probably as a result of increased urinary calcium excretion.²¹ Patients at higher risk include those with low pre-transplant PTH and high serum calcium levels. However, by the second week, the serum calcium levels start to rise slowly and then stabilize.²² Subtotal parathyroidectomy or total parathyroidectomy with or without auto-transplantation for tertiary hyperparathyroidism, which can be temporary or persistent, is another cause of hypocalcemia in renal transplantation.

Patients with CKD are more vulnerable to hypocalcemia from antiresorptive osteoporosis treatments that may be used in the transplant scenario, such as denosumab and bisphosphonates.²³ Vitamin D deficiency, especially in chronic liver disease or with malabsorption in conditions like biliary cirrhosis, infiltrative hypoparathyroidism associated with hemochromatosis and Wilson's disease, rapid transfusion with large amounts of citrate-containing blood, and renal failure due to decreased calcitriol production or hyperphosphatemia are additional causes of hypocalcemia that may be seen in pre-transplant and post-transplant patients.¹⁷

Hypophosphatemia

Due to increased renal phosphate loss and decreased calcitriol levels from fibroblast growth factor-23 (FGF-23), hypophosphatemia is frequent in the early stages of kidney transplantation.^24,25 However, phosphate replacement is often only used when blood phosphate levels are below 1–1.5 mg/dL (0.32–0.48 mmol/L) unless patients are experiencing symptoms because, by a year following a kidney transplant, FGF-23 and phosphorus levels usually return to normal.²⁶

Hyperuricemia

Hyperuricemia is frequently encountered in solid organ transplantation.^27,28 The pathogenesis is complicated and connected to pretransplant hyperuricemia, the use of diuretics and immunosuppressive medications, older age at transplant, obesity, metabolic syndrome, and decreased uric acid excretion with lower GFR. Hyperuricemia may be common among kidney transplant recipients (up to 80%, particularly in those taking cyclosporine) and liver transplant recipients (near to 50%). Gout occurs less frequently (6–7%).

Men are more likely to die from cardiovascular disease and other causes when their serum uric acid levels are elevated. Additionally linked to metabolic syndrome and insulin resistance are hyperuricemia and these conditions.²⁹

Hyperuricemia warrants treatment only in presence of gout or uric acid stones. Both the acute inflammatory response linked to gouty flares and hyperuricemia are the targets of therapeutic methods. These include dietary changes such a reduction in alcohol, shellfish, red meat consumption and other dietary modifications.¹⁹

If possible, diuretics should be avoided, and hypertension should be treated with alternate medications.

Short-term corticosteroids can be given for the acute gout flare. Patients with normal renal function may potentially benefit from a brief course of NSAIDS. Patients with eGFR less than 60 mL/min/1.73 m² should refrain from using colchicine for an extended period of time.

Long-term uric acid reducing medication may need to be initiated.³⁰ Although allopurinol is frequently used, kidney disease may require dose decrease and immunosuppression to be adjusted. In transplant recipients, newer hypouricemic medications such febuxostat or pegloticase may be beneficial.^31,32

Electrolyte disturbances and acid base disturbances after transplantation

Hyperkalemia

The most common electrolyte disruption experienced after solid organ transplantation, particularly in the initial weeks, is hyperkalemia.^33,34 Almost typically, many factors, such as increased food intake, redistribution, and decreased renal excretion, are involved in its development. Medications like trimethoprim and CNIs, which are frequently prescribed to transplant patients, raise the risk of hyperkalemia.³⁴ Trimethoprim causes hyperkalemia by preventing potassium excretion in the distal nephron, and people with compromised kidney function are more likely to have this effect.³⁴ Aldosterone synthesis is impaired, as is the renal response to aldosterone, and potassium secretion in the collecting duct is inhibited by CNIs.^35,36

Hypomagnesemia

Hypomagnesemia is fairly prevalent in patients receiving CNIs after solid organ transplantation. It often shows up in the first few weeks and may recur with long-term CNI use. More than 95% of the serum magnesium is reabsorbed throughout the tubules, whereas around 80% is freely filtered in the glomerulus. CNIs increase urine magnesium wasting and inhibit urinary magnesium reabsorption, leading to hypomagnesemia.^35,36

In renal transplant recipients on cyclosporine, serum magnesium levels are linked to a quicker decline in kidney allograft function and higher rates of graft loss. Arrhythmias and seizures may be brought on by severe hypomagnesemia. In kidney transplant recipients, hypomagnesemia is another independent predictor of NODAT.

Metabolic acidosis

Decreased kidney function and CNIs may contribute to metabolic acidosis after solid organ transplant.³⁷ Through the deregulation of important acid-base transporters in the proximal tubule and the distal nephron, it has been demonstrated that CNIs cause metabolic acidosis.^35,36 After receiving a transplant, patients using CNIs may develop type IV renal tubular acidosis (hyperkalemic metabolic acidosis), which is brought on by the collecting duct's suppression of potassium release. Bicarbonate loss in the urine from pancreatic secretions may cause metabolic acidosis in pancreas transplant recipients with bladder-drained pancreas.

Adrenal disease

When corticosteroid therapy is stopped in SCT recipients, secondary adrenal insufficiency is a common issue.³⁸ It can also be a problem in GvHD when high dosage glucocorticoids are used. Patients with immunodeficiency, including those who have undergone transplantation, have been found to experience primary adrenal insufficiency brought on by adrenalitis linked to CMV infections.

Thyroid disease

Because thyroid hormones play a crucial role in the circulatory system, both hypo- and hyperthyroidism can have serious negative effects on people who have had heart transplants.³⁹ Amiodarone-induced thyrotoxicosis (AIT), which is used to treat supraventricular arrhythmias, is a common thyroid emergency among people who have had heart transplants, though any cause of hyperthyroidism can be present.³⁹

Allogenic SCT patients are more vulnerable to endocrinopathies, particularly thyroid illness, than autologous SCT recipients. Nearly 40% of SCT patients have hypothyroidism, although autoimmune hyperthyroidism has also been reported; this may be because donor immune cells were transferred or because of immunological dysregulation and reconstitution brought on by GvHD.⁴⁰

The implications of end-stage renal disease and liver illness on thyroid disease are additional special considerations in the transplant context. In addition, when renal protein loss occurs, as it would in nephrotic syndromes, thyroid hormone requirements are frequently higher due to increased renal protein loss, including thyroid binding globulin. Thyroid hormone has a significant impact on renal hemodynamics, glomerular filtration, and the water and sodium balance. The need for thyroid hormone should diminish after a kidney transplant in nephrotic syndrome patients, necessitating a proactive reduction in thyroid hormone dosage.

Given that thyroid hormone naturally regulates the metabolic rate of hepatocytes and normal liver function, end-stage liver disease and liver transplants may also be impacted by thyroid malfunction. Additionally, the liver plays a significant role in the metabolism of thyroid hormones. In fact, thyroid dysfunction is prevalent in a number of conditions linked to end-stage liver disease, including non-alcoholic fatty liver disease, primary sclerosing cholangitis, and primary biliary cirrhosis. Long-term use of ATD in individuals with underlying liver illness would also be discouraged given the worry with liver damage. If there are limitations to ATD or urgent thyroidectomy is considered, plasmapheresis to eliminate thyroid hormone may also be a consideration in this population, however the advantage is only lasting 1–2 days.

Pituitary disease

After a transplant, hypopituitarism is quite uncommon. According to reports, this can happen when the pituitary is affected by a fungal or bacterial infection as well as a post-transplant lymphoproliferative condition.⁴¹

Conclusions

Patients undergoing SCT and solid organ transplantation frequently have underlying endocrine disorders, which can be connected to both immunosuppressive drugs and the severe underlying organ dysfunction. There are certain clinical considerations that must be taken into account when endocrine disorders happen in this complex group of patients. Pre-transplant, early post-transplant, and chronic post-transplant stages of the patient's transplant also have an impact on the therapy of the endocrine dysfunction. In order to effectively manage endocrine disorders in transplant patients, it is crucial to recognize the most frequent risk factors involved. Additionally, itis important to understand how end organ dysfunction affects the development and treatment of the particular endocrine dysfunction. Effective management of these endocrine manifestations can help improve graft survival, post transplant health of the patients and overall quality of life.

Disclosure of competing interest

All authors have none to declare.