Caring for children after a kidney transplant

You are working in the paediatric emergency department of a busy District General Hospital. The triage nurse wants you to see the next patient, a young person who has had a kidney transplant.

How does your differential diagnosis change? What about your diagnostic workup? Do you need to consult Paediatric Nephrology, and if so, do you need to call them overnight? What will they want to know?

This article will go over some specific considerations when managing a child with a kidney transplant.

How common are kidney transplants in kids?

Approximately 650 children and young people have kidney transplants in the UK. Around two-thirds received a living donor transplant, and one-third received a deceased donor transplant.

The commonest reasons for needing a transplant are 49% tubulointerstitial disease, mainly Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), 17% familial/hereditary nephropathies, 15% glomerular disease, 14% miscellaneous renal disorders and 5% systemic diseases.

The UK has thirteen paediatric kidney centres, and ten perform kidney transplants. These centres have a close relationship with their patients, but this does not mean they may not turn up at your emergency department!

Acute issues in the child with a kidney transplant

Children with kidney transplants suffer from routine illnesses, too, but remember that they are immunosuppressed. Low exposure to immunosuppressants, often due to nonadherence, can lead to allograft rejection, whereas exposure to agents such as tacrolimus can increase the incidence of infections, toxicity, and malignancies.

Infections are the most common reason for hospitalisation within the first two years of transplant and are much more likely than rejection. 

History

• Try to find any recent clinic letters for background information, if available.
• When did the symptoms start? What is the history of the presenting complaint and the patient’s background? Have there been any previous episodes of hospitalisation since receiving the transplant? 
• Evaluate the recommended and actual fluid intake in children who have undergone renal transplantation. Are they achieving their daily hydration goals? Inadequate fluid intake, combined with factors such as hot weather or strenuous physical activity, can lead to gradual dehydration with cumulative effects.
• Have there been any recent changes in medication, such as adjustments in type, dose, or frequency? Are there any missed doses to note? Consider any side effects or adverse events from medication. Be vigilant for new medications, including over-the-counter options and grapefruit juice, as these can interact with existing treatments.
• Any evidence of infection, such as fever, cough, coryza, diarrhoea, vomiting or urinary symptoms? Any contacts with chickenpox or cold sores?
• Any changes in urinary output, colour or dysuria? Ask about the frequency of intermittent catheterisation, if applicable. 
• Any history of injury? Have a low threshold to investigate with appropriate imaging. Kidney transplant recipients have a higher risk of fractures.

Examination

Assessing hydration status is notoriously challenging due to significant variability between observers and even within the same observer. Clinical examination, such as checking for peripheral oedema and differences in core and extremity temperatures, vital signs, weight trends, fluid balance, and blood tests (including creatinine, urea, sodium, and haematocrit levels), can provide valuable insights.

The renal graft is most commonly transplanted into the right lower quadrant of the abdomen. Assess for any pain on palpation (suggestive of pyelonephritis or rejection) and listen for a bruit (indicative of vascular stenosis or arteriovenous fistula).

In the case of associated urological problems, children may also have stomas (e.g., Mitrofanoff stoma, ureterostomy, nephrostomy), indwelling devices (e.g., suprapubic catheters, gastrostomy tubes, haemodialysis or peritoneal dialysis lines, which may have been left in situ in the initial post-operative period), and central venous catheters. 

Depending on the underlying diagnosis, the child’s native kidneys may have been removed. Look for scars indicating previous central lines, peritoneal dialysis catheters, or surgical procedures. If in doubt, ask. Most parents/carers will be happy to explain, and do not expect every doctor to be an expert in their child!

First-line investigations

• FBC, U&Es, Bone profile, CRP, LFTs
• Tacrolimus trough levels (ideally 12 hours after dose/immediately pre-dose) **
• Urinalysis, Urine microscopy, culture, and sensitivities

**Tacrolimus concentration caveat: 

TAC binds to erythrocytes, and the unbound fraction in blood is < 1%.

Total TAC concentrations are measured in whole blood, while the unbound fraction exerts pharmacological effects. An increase in total TAC concentration following a rise in Haematocrit (Hct) does not increase the drug’s unbound fraction.

Changes in TAC concentrations related to changes in haematocrit should not lead to a prompt dose adjustment.  

Second-line investigations

• Blood culture (if suspecting severe infection or sepsis)
• Respiratory viral PCR 
• Blood viral PCR or serology – commonly nucleic acid amplification testing (NAT) for CMV, EBV, BK-polyoma virus (BKpV)
• Urine BKpV NAT (has a nearly 100% negative predictive value for BKpV viraemia/nephropathy however many centres prefer BK PCR in blood)

• PTH, vitamin D, lipid profile, HbA1C, uric acid
• Specific blood tests if suspecting recurrence of primary disease
• Graft Doppler ultrasound

How do we assess kidney function? 

Creatinine is the primary biochemical marker for assessing renal function. Various equations have been developed to estimate renal function using the Glomerular Filtration Rate (GFR) for different patient groups, including children and adults. Biomarkers such as cystatin C have been introduced to improve the correlation between biomarker levels and estimated GFR (eGFR). They are particularly useful in certain patient cohorts, such as those with low muscle mass.

It’s important to look at creatinine in the context of previous results. Creatinine varies with age, height/weight, muscle mass, gender, and the size of the transplanted organ.

A single creatinine measurement may fall within the reference range provided by the biochemistry laboratory (note the units: mg/dL or µmol/L). Still, it could be significantly higher than the baseline level for a child with a kidney transplant. This is particularly crucial in younger children who have received a large adult kidney and typically have relatively low creatinine levels when stable and well.

In contrast, teenage kidney transplant recipients may have a baseline creatinine level slightly above the laboratory’s reference range. Additionally, any child with a kidney transplant might have some degree of chronic kidney disease (CKD).

The priority is to monitor the trend in creatinine levels. Variations of less than 10% are considered acceptable for any patient.

Higher than normal creatinine?

Often, kidney transplant recipients will present with a creatinine level higher than their baseline. Adopt a wide differential diagnosis.

But keep in mind the mnemonic DDIOR (Dehydration, Drugs, Infection, Obstruction and Rejection) for the most common causes of graft dysfunction.

Differential Diagnosis of Acute Issues

Dehydration

Each child will have a minimum daily fluid intake goal. Rehydration with oral or intravenous fluids is often sufficient to return creatinine levels to baseline.

Drugs

All immunosuppressants increase the risk of infection and malignancy, and certain medications, such as tacrolimus, can be nephrotoxic. 

Glucocorticoids	hypertension, fluid retention, hyperlipidaemia, diabetes, gastric ulcers, growth impairment, Cushing syndrome, osteoporosis, fractures, aseptic bone necrosis, cataracts, poor wound healing, acne, psychological effects
Mycophenolate	abdominal pain, diarrhoea, vomiting, neutropenia, thrombocytopenia, anaemia
Calcineurin Inhibitors Tacrolimus and Cyclosporine	nephrotoxicity, hypertension, hyperkalaemia, hypomagnesemia, NODAT, dyslipidaemia, neurotoxicity, alopecia, pruritus
	gingival hyperplasia, hirsutism, hepatotoxicity
Calcineurin Inhibitors: Tacrolimus and Cyclosporine	dose-dependent leucopenia, anaemia, thrombocytopenia, pancreatitis, hepatotoxicity, alopecia, skin cancer
MTOR inhibitors Sirolimus and everolimus	hyperlipidemia, proteinuria, delayed wound healing, aphthous ulcers, interstitial pneumonia, myelosuppression

Infection

• Do they look unwell? Consider sepsis and treat it accordingly.
• Urinary tract infection (UTI): more likely in cases of urologic comorbidities and operations (e.g. CAKUT, catheterisation requirement). Lower urinary tract dysfunction increases the chances of post-transplantation UTI.
• Viral illnesses: common things are common. Could it just be a mild viral URTI?
• Ask about recent exposure to chickenpox or HSV (herpes simplex virus). Enquire about the child’s vaccination status. One study found that only 8% of paediatric kidney transplant recipients had completed their vaccinations. Induction treatment may significantly reduce immunoglobulin titers.
• Consider CMV, EBV, and BK polyomavirus infections: patients are often on prophylaxis for variable durations, with varying outcomes.
  
  CMV can present as a nonspecific viral illness or tissue-invasive CMV disease. Symptoms can include fever, leukopenia, thrombocytopenia, allograft dysfunction, pneumonitis, hepatitis, and encephalitis.
  
  EBV infects 90% of children before age 5. It is strongly associated with post-transplantation lymphoproliferative disease and is identified in >90% of early B-cell PTLD within the first post-transplant year.
  
  BK-polyoma virus (BKpV) has a seroprevalence of >90% by four years, and its peak age is 2-5 years. It can present with flu-like symptoms and may establish a non-replicative, latent infection in renal tubular epithelial cells and uroepithelium. BKpV nephropathy occurs in 2-8% of paediatric renal transplant recipients, and in 95% of cases, it presents in the first 2 years after kidney transplantation.
• Consider varicella: a non-immune paediatric transplant recipient should receive post-exposure prophylaxis within 72 hours of exposure. If symptomatic, they require intravenous acyclovir and adjustment of immunosuppressants.
• Gastroenteritis (caveat): tacrolimus levels may be increased due to the destruction of P-glycoprotein-carrying epithelial cells in diarrhoea/enterocolitis (14).
• Other considerations are pneumocystis pneumonia, candidiasis, and donor-derived infections.

Obstruction

Obstruction of urinary flow can occur at various levels within the urinary tract. Issues related to the kidney graft vessels or ureters, such as mechanical obstruction of the anastomosis, are more likely to arise in the immediate postoperative period. During this time, patients are closely monitored by their tertiary centre. An ultrasound scan of the graft is usually sufficient to rule out these complications.

Rejection

Presentations can be non-specific. Classic symptoms such as fever and graft tenderness are uncommon. These complications can be categorised as immediate, early, late acute, and late chronic.

Non-adherence is the leading cause of rejection in young transplant recipients. It increases the risk of acute rejection, and one study concluded that these barriers are potentially modifiable therapeutic targets. Rejection is diagnosed via kidney biopsy and is classified as acute cell-mediated and/or antibody-mediated rejection.

Primary Disease recurrence

What caused the need for transplantation?

Differential Diagnosis of Chronic Issues

Hypertension (HTN)

Hypertension is a risk factor for graft loss, cardiovascular morbidity, and mortality. The prevalence of post-transplant hypertension ranges from 60 to 90%. It may be related to residual chronic native kidney disease, medications, or chronic allograft dysfunction. Ambulatory blood pressure monitoring is the gold standard.

The recommended target is the same as for healthy children, i.e., below the 95th percentile. It remains unclear whether post-transplant hypertension is a cause or an effect of kidney dysfunction.

Haemo-oncological problems

Anaemia: Post-transplant anaemia is common, with a prevalence ranging from 22-85%.

Early anaemia, occurring within six months of transplantation, is often due to surgical blood loss and iron deficiency.

Late anaemia is associated with graft dysfunction, iron deficiency, drug toxicity, and post-transplant inflammation. Studies suggest that post-transplant anaemia may increase the risk of graft failure or combined graft failure and death. Renal centres usually limit transfusions to minimise the risk of allosensitization. Instead, they use treatments like iron supplements and erythropoiesis-stimulating agents to raise haemoglobin levels.

Post-transplant lymphoproliferative disease (PTLD): Patients with post-transplant lymphoproliferative disorder (PTLD) typically show symptoms such as swollen lymph nodes, tonsillitis, enlarged liver or spleen, neurological or gastrointestinal issues, and prolonged fever without specific signs.

Most PTLD cases occur within the first year after transplant, during the period of intensive T-cell immunosuppression. Diagnosis is based on Epstein–Barr virus (EBV) in the blood, radiologic findings, and biopsy results. Management involves reducing the immunosuppressive regimen and starting specific treatments.

Metabolic problems

Diabetes: Early post-transplant hyperglycaemia has been shown to increase the risk of rejection and infection. New Onset Diabetes After Transplantation (NODAT) affects 7-11% of paediatric renal transplant recipients.

Obesity: Obesity, whether before or after transplant, is linked to worse outcomes. A systematic review and meta-analysis found that patients with a BMI over 30, classified as obese, have a higher risk of acute rejection, delayed graft function, graft loss, and death. There is increasing interest in the use of SGLT-2 inhibitors, a class of medications that may confer cardiovascular benefits in these patients.

Growth problems

Renal osteodystrophy: A study found that post-transplant hyperparathyroidism was associated with an increased risk of all-cause mortality and graft loss. (20). Kidney transplant recipients are at higher risk of rickets and fractures. (13) A study found that the incidence of all fractures was sixfold higher, and the incidence of vertebral fractures was 160‑fold higher in children and adolescents who had undergone solid organ transplantation than in the general population. 

Short stature

Delayed puberty and development

When should you contact Paediatric Nephrology?

The Paediatric Nephrology team often requests patient transfer to their hospital for closer monitoring. They will want to know:-

• Height, weight, BMI – trend and centiles
• Vital signs – trend and BP centiles
• Do they still have indwelling catheters/devices (e.g. HD lines, PD lines, suprapubic catheters etc)
• Results of the first line of investigations
• Working diagnosis and ongoing management

When to call (and how quickly)?

It is worth noting that patients will be well known to the paediatric nephrology team and will often be their first point of contact.

When in doubt, call the team. 

Call that shift

• Raised creatinine – if creatinine > 10% from baseline
• Dehydration – if requiring hospitalisation or creatinine > 10% 
• Sepsis – after stabilisation 
• UTI – if upper UTI or lower UTI is not responding to antibiotics
• Symptomatic Hypertension 
• Symptomatic Anaemia 
• Abdominal trauma with possible injury to graft 

Call during office hours

• Exposure to varicella or measles in non-immune transplant recipients – involve local paediatric infectious disease team.
• Asymptomatic hypertension
• Other systemic illness impacting upon fluid intake, medication and renal transplant function (e.g. acute appendicitis, need for NBM/surgery)
• Complications of immunosuppression such as non-acute Infections, NODAT, unexplained lymphadenopathy, and asymptomatic anaemia 

Ensure that they have a follow-up with the kidney team on discharge.

Prescribing for Kidney Transplant Patients

• Always check and adjust the doses of newly prescribed medications for kidney transplant recipients based on their kidney function. If needed, consult Pharmacy or the paediatric nephrology team.
• Monitor creatinine and tacrolimus levels regularly in unwell patients.
• Avoid potentially nephrotoxic medications (e.g. NSAIDs, aminoglycosides).
• Therapeutic drug monitoring if the use of vancomycin or aminoglycosides is unavoidable.
• Be mindful / avoid interactions with ongoing medications (especially immunosuppressive medications) – BNF provides a helpful interaction checker.

Drug interactions

Agents that decrease blood levels include anticonvulsants (barbiturates, carbamazepine, phenytoin) and antituberculous agents (isoniazid, rifampicin).

Agents that increase blood levels of tacrolimus and cyclosporine: Calcium channel blockers (amlodipine, verapamil, diltiazem, nicardipine), antifungal agents (ketoconazole, itraconazole, fluconazole), antibiotics (erythromycin, clarithromycin), grapefruit juice

Many thanks to the great Paediatric Nephrology team at Alder Hey Children’s Hospital for their teaching and feedback and for always answering my countless questions with a smile.

References

UK Renal Registry (2023) UK Renal Registry 25th Annual Report – data to 31/12/2021, Bristol, UK. Available from https://ukkidney.org/audit-research/annual-report

ISN-KDIGO Webinar: Management of the failing kidney allograft, 19/09/2023

Acott, P.D. and Hirsch, H.H., 2007. BK virus infection, replication, and diseases in pediatric kidney transplantation. Pediatric nephrology, 22(9), pp.1243-1250.

Peruzzi, L., Amore, A. and Coppo, R., 2014. Challenges in pediatric renal transplantation. World journal of transplantation, 4(4), p.222.

Prytuła, A. and van Gelder, T., 2019. Clinical aspects of tacrolimus use in paediatric renal transplant recipients. Pediatric Nephrology, 34(1), pp.31-43.

Hebert MF et Al (2013) Interpreting tacrolimus concentrations during pregnancy and postpartum.Transplantation 95:908–915

Liverman, R., Chandran, M.M. and Crowther, B., 2021. Considerations and controversies of pharmacologic management of the pediatric kidney transplant recipient. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 41(1), pp.77-102.

Sherwin CM et al. The evolution of population pharmacokinetic models to describe the enterohepatic recycling of mycophenolic acid in solid organ transplantation and autoimmune disease. Clin Pharmacokinet. 2011;50(1):1-24.

Aki, F.T., Aydin, A.M., Dogan, H.S., Donmez, M.I., Erkan, I., Duzova, A., Topaloglu, R.E.Z.A.N. and Tekgul, S.E.R.D.A.R., 2015, May. Does lower urinary tract status affect renal transplantation outcomes in children?. In Transplantation proceedings (Vol. 47, No. 4, pp. 1114-1116). Elsevier.

Chatani, B., Glaberson, W., Nemeth, Z., Tamariz, L. and Gonzalez, I.A., 2019. GCV/VCVG prophylaxis against CMV DNAemia in pediatric renal transplant patients: A systematic review and meta‐analysis. Pediatric transplantation, 23(6), p.e13514.

Seeman, T., Myette, R.L. and Feber, J., 2023. Hypertension in pediatric kidney transplantation. Pediatric Transplantation, 27(5), p.e14522.

Varnell, C.D., Rich, K.L., Zhang, B., Carle, A.C., Pai, A.L., Modi, A.C. and Hooper, D.K., 2021. Predicting acute rejection in children, adolescents, and young adults with a kidney transplant by assessing barriers to taking medication. Pediatric Nephrology, 36, pp.2453-2461.

Helenius, I., Remes, V., Salminen, S., Valta, H., Mäkitie, O., Holmberg, C., Palmu, P., Tervahartiala, P., Sarna, S., Helenius, M. and Peltonen, J., 2006. Incidence and predictors of fractures in children after solid organ transplantation: a 5‐year prospective, population‐based study. Journal of Bone and Mineral Research, 21(3), pp.380-387.

Balani, S.S., Jensen, C.J., Kouri, A.M. and Kizilbash, S.J., 2021. Induction and maintenance immunosuppression in pediatric kidney transplantation—Advances and controversies. Pediatric transplantation, 25(7), p.e14077.

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