1. Kidney transplantation in children and its etiology
Kidney transplants in which the recipient is under 18 years of age are called pediatric kidney transplants. Because they are still in the process of physical and psychological development, children with uremia have a more active immune system, delayed development and immature cognitive function. Compared to kidney transplantation in adult patients, kidney transplantation in children has its own characteristics.
Common causes of end-stage renal disease in children include primary glomerulonephritis (about 30%), congenital, hereditary, or cystic renal disease (about 26%), interstitial renal disease (about 9%), collagen vascular disease (about 9%), and hypertensive renal damage (about 5%). Urological diseases are usually congenital if the patient is younger than 5 years old, and acquired or hereditary diseases after 5 years old. Uremia caused by kidney stones is rare.
2. Implementation of kidney transplantation in children
2.1 Donor selection Donor sources include relative donor kidney and cadaver donor kidney. Because of the more active immune status of children, the matching requirements are higher, especially for the DR locus. The requirements for donor age and donor volume are also more stringent than those for adults.
2.2 Recipient selection Since pediatric patients are less tolerant to uremia than adults, the laboratory indexes of the indications are appropriately relaxed compared to adults. However, the actual work should be determined with reference to age, primary disease species, donor kidney and other specific circumstances.
2.3 Pre-transplantation dialysis treatment Direct kidney transplantation without dialysis treatment before transplantation has many advantages, such as higher quality of life for the child, no delay in growth and development, and avoidance of dialysis and the resulting complications. However, when the child has refractory hypertension, severe proteinuria or uncontrollable urinary tract infection, the original kidney needs to be removed, and these children need dialysis to wait for a donor kidney source; some children with oliguric renal failure need immediate dialysis treatment; and some special primary diseases need a certain stage of dialysis treatment as preparation before kidney transplantation.
2.4 Kidney transplantation In children with adult donor kidney, it is advisable to choose a larger vascular anastomosis to ensure adequate blood supply to the transplanted kidney after opening. The main sites of arteriovenous anastomosis of the transplanted kidney in the recipient are the abdominal aorta/vein, common iliac artery/vein, external iliac artery/vein and internal iliac artery/vein. The anastomosis of the transplanted renal artery to the recipient internal iliac artery has the potential for distant anastomotic stenosis as the recipient’s vessels grow, so an end-to-end anastomosis to the external iliac artery may be more appropriate. There are two types of surgical approaches: transabdominal and extraperitoneal. The transabdominal approach is required for anastomosis with the main/inferior abdominal vessels, with the transplanted kidney placed intraperitoneally or retroperitoneally, and is mainly used in younger children. As the age of the recipient decreases, the surgical technique becomes more difficult, and kidney transplantation in recipients under 2 years of age is the most difficult, with a high postoperative mortality rate. If the cause of renal failure is a congenital malformation of the urinary tract, the urinary tract malformation should be treated before or at the same time of transplantation to restore normal urethral anatomy and function. Related approaches include ureteral reimplantation to correct reflux and bladder enlargement or modification. Lower urinary tract anomalies are not contraindications to transplantation, but should be detected and treated promptly, such as neurogenic bladder, bladder dystocia, urethral stricture, etc.
3. Management of renal transplantation in children
3.1 Perioperative management Children have relatively low effective blood volume, while the volume and capacity of the donor kidney are relatively large. After opening the blood flow during surgery, hemodynamic changes may occur suddenly due to insufficient blood volume, resulting in hypotension and delayed recovery of graft function. In infants and children receiving adult donor kidneys, a large amount of blood flowing into the relatively large transplanted kidney after opening the circulation may cause sudden hypovolemia, resulting in a drop in blood pressure and even shock and cardiac arrest. Hemodynamic monitoring should be performed before opening the blood flow, and crystalloids and colloids can be appropriately presupplemented. In the early postoperative polyuria period, fluid rehydration therapy needs to be more delicate to control the balance of inlet and outlet. Children weighing more than 30 kg are basically similar to adults.
3.2 Immunosuppressive therapy The immune system of children is rich in initial T cells and has a stronger cellular immune defense, which makes them more susceptible to acute rejection. Children with active hepatic cytochrome P450 enzyme metabolism and rapid drug metabolism are sensitive to drug therapy. Immunosuppressive therapy after transplantation needs to take these characteristics into account.
FK506 is the first-line and basic drug for post-transplantation, including tacrolimus (FK506) and cyclosporine (CsA), which can rapidly reach therapeutic window concentration, has relatively low hepatic and renal toxicity, and is effective in refractory rejection. The main adverse effects of CsA are nephrotoxicity and hypertension, but other adverse effects such as hirsutism, gingival hyperplasia, skin roughness and other cosmetic changes are more prominent. In adolescents, especially girls, it can cause severe emotional depression and even severe noncompliance. Switching to FK506 may improve these adverse effects. There was no significant difference in the nephrotoxic reactions caused by the two drugs.
There are no reports on the safety and efficacy of rapamycin in children.
Immunoinduction therapy with OKT3 or anti-thymocyte globulin is not significantly different in children and adults. Anti-CD25 monoclonal antibodies are effective, easy to use, and more suitable for children. In pediatric cadaveric kidney transplantation, the 5-year graft survival rate is 10% higher and acute rejection is 30% less and occurs later in those who use antibody induction.
Long-term hormone administration will cause side effects such as hypertension, aseptic osteonecrosis and osteoporosis. The importance of hormones in maintenance therapy has diminished with the use of potent immunosuppressive combinations such as CNI+MMF. The complete discontinuation of hormones after renal transplantation in children is still highly controversial. However, it is generally believed that measures such as accelerated reduction of hormone dosage, low maintenance dose or even complete discontinuation can be taken according to the treatment plan and the response of the child recipient.
4. Growth and development after transplantation
Growth retardation can occur early in children with renal insufficiency. The average hospital stay and death rate of children with growth retardation are significantly higher than those with near-normal growth, suggesting that kidney transplantation should be performed as early as possible, rather than waiting until severe growth retardation occurs.
An important indicator of the long-term function of the transplanted kidney is the ability of the child to reach his or her expected adult height. Children who receive a kidney transplant before the age of 6 years may have significantly faster growth in the first 3-4 years after transplantation; however, most children who receive a kidney transplant after the age of 6 years have limited or sometimes negative height growth. Recombinant human growth hormone (rhGH) helps to increase the growth rate of children, but it is controversial whether it increases the incidence of acute rejection and chronic rejection. A multicenter randomized controlled trial conducted by the North American Pediatric Renal Transplantation Society (NAPRTCS) showed that rhGH significantly increased the growth rate of children after kidney transplantation, and no rejection was observed during the first few years of treatment; at 5-year follow-up, growth was better in children under 10 years of age treated with rhGH than in children over 10 years of age, and final adult height after rhGH treatment was significantly better than in controls. No increase in the incidence of dysfunction and other side effects of the transplanted kidney was observed after rhGH treatment, indicating that rhGH can effectively prevent and treat growth delay after kidney transplantation in children.
5. Factors affecting survival
With the maturation of renal transplantation techniques, the application of new immunosuppressive agents, and advances in donor-recipient matching techniques and requirements, both short- and long-term survival rates of transplanted kidneys have improved significantly. nAPRTCS reported 6500 cases [Microsoft User 2] of children who received renal transplants, and the primary cause of graft failure was chronic rejection (31%), and other causes included: thrombosis (12%), recurrence of primary disease (6%), and Other causes included: thrombosis (12%), recurrence of primary disease (6%), non-compliance of the child (3%), graft non-function, infection, tumor and other causes. Infections accounted for 35% of deaths, while other causes of death included cardiopulmonary disease (16%), tumors (11%), and comorbidities from dialysis use after graft failure (14%). Forty-five percent of the children who died had good graft function.
5.1 Source of donor kidney The survival rates at 1 and 5 years were 92.9% and 81.4% for patients who received living kidney transplants and 84.9% and 66.6% for those who received cadaveric kidney transplants, respectively. The survival rates were 97%, 96% and 94% at 1, 2 and 5 years, respectively, and 98%, 97% and 95% at 1, 2 and 5 years, respectively, for those who received a living kidney donor. The cold and heat ischemia time should be shortened as much as possible for both living and cadaveric kidney donations.
5.2 Age of the recipient Age is one of the most important factors affecting the survival of kidney transplantation in children. The survival rate of transplanted kidneys in children younger than 6 years of age is significantly lower, especially in those who receive cadaveric donor kidneys. Graft survival was lowest in children younger than 2 years of age, with 5-year survival rates of 81.6% and 52.7% for living and cadaveric kidney transplants, respectively, and this difference is due to the stronger immune response in infants and children and the relatively higher chance of surgical complications.
5.3 Preoperative Dialysis and Transfusion The 7-year survival rate of transplanted kidneys after transplantation in children on dialysis before transplantation was nearly 20% less than in those transplanted directly without dialysis treatment. Receiving more than 5 transfusions before surgery also decreases kidney survival, and repeated transfusions expose the recipient to a variety of HLA antigens, increasing the chance of rejection.
5.4 Recipient body mass index Obese children with a body mass index greater than 30 have a lower survival rate of the transplanted kidney at 1 and 5 years. Obese children, especially those aged 6 to 12 years, are more likely to have thrombosis, leading to loss of the transplanted kidney.
5.4 Multiple transplantation The 5-year survival rates for those with a history of kidney transplantation were 76.4% and 53.4%, respectively.
5.5 Nonadherence After transplantation, at least half of the children who receive a cadaveric kidney source experience significant nonadherence, up to 60% in adolescents, which can be partial or total. Partial nonadherence may be manifested by intermittent missed or excessive medications, due to forgetfulness, misunderstandings, changes in treatment dosage, or events that cause the child to lose confidence in the medication. Complete noncompliance in children is usually caused by emotional or psychologically or socially stressful stimuli.
5.6 Malignancies Children receiving immunosuppressive therapy after renal transplantation have an increased chance of complicating malignancies. The most common tumor in pediatric kidney transplant recipients is lymphoma. Other common tumors include skin cancer, liver cancer, sarcoma, thyroid cancer, Kaposi’s sarcoma, cervical cancer, head and neck cancer, ovarian cancer, and kidney cancer.
5.7 Size of transplant centers Large pediatric kidney transplant centers have higher success rates than smaller centers.
6. Current Focus of Attention
The focus of research on pediatric kidney transplantation has gradually shifted from ischemia-reperfusion injury and rejection to issues related to long-term survival. 95% of children survive into adulthood. In addition to infection, tumors, drug side effects, and poor compliance, the high incidence of cardiovascular disease and mortality have become important issues in long-term survival. Statistical tables show that 11% of transplanted children die from cardiovascular disease. The occurrence of cardiovascular disease is closely related to hypertension, diabetes mellitus, elevated LDL levels, and postoperative obesity is also an important influencing factor. The younger the age of renal failure, the higher the rate of vascular calcification and the higher the rate of death from cardiovascular disease. Hypertension resulting from a decrease in the number of kidney units in the transplanted kidney may be the highest risk factor for the development of cardiovascular disease.
Chronic kidney disease (CKD) in transplanted kidneys is an important problem after kidney transplantation in children. complications associated with CKD include hypertension, anemia, hypercholesterolemia, metabolic bone disease, etc. CKD is also an important cause of cardiovascular disease. CKD is also associated with immunosuppressant nephrotoxicity, hypertension, lipid metabolism disorders, diabetes mellitus, hepatitis C infection, etc. Close monitoring of renal function is an important tool for early detection of CKD, and early use of low nephrotoxicity drugs to control rejection and infection can help protect renal function.
7. The future of kidney transplantation in children
At this stage, the short-term and long-term survival rates of kidney transplantation in children and adults are not significantly different, and kidney transplantation is recognized as one of the best ways to treat end-stage renal disease in children. In the next 5-10 years, more efficient and less toxic immunosuppressive agents are expected to be developed and used in the clinic; hormone-free and CNI-free immunosuppressive regimens are expected to be introduced in children with kidney transplantation. Stem cell transplantation to modulate immune response and repair transplanted kidney injury also shows good application prospects.