Pediatrics

Renal transplant dysfunction

OVERVIEW: What every practitioner needs to know

A kidney transplant represents a life-saving procedure for a patient with end-stage kidney failure. However, it is NOT a cure, with most transplants surviving a finite amount of time only.

The transplant can be subject to several insults that lead to dysfunction and can further shorten transplant organ life. The causes are varied and the treatments cover a broad spectrum of possibilities, some the opposite of each other. Therefore, early detection of dysfunction, early diagnosis of cause and specific appropriate therapy are key points in maintaining graft health.

Are you sure your patient has renal transplant dysfunction? What are the typical findings for this disease?

  1. Kidney transplant health is monitored by a variety of clinical and laboratory criteria, such as urine output, blood pressure, presence or absence of edema, serum creatinine, and urine protein levels.

  2. In a transplant setting, many of the above features may not become abnormal at any point or until late in the process, so that serum creatinine is by far the most commonly used marker. Most patients in fact remain asymptomatic.

What other disease/condition shares some of these symptoms?

This condition is easy to define since the patient has a known history of a kidney transplant. The causes for transplant dysfunction (defined as serum creatinine elevated above the patient’s baseline) are provided below.

What caused this disease to develop at this time?

The typical causes for needing a kidney transplant in children can include:

  • Congenital urinary tract abnormalities such as posterior urethral valves, renal hypoplasia/dysplasia, prune belly syndrome.

  • Acquired renal glomerular diseases such as focal segmental glomerulosclerosis, systemic lupus erythematosus, IgA nephropathy.

  • Acquired infections that leave lasting damage, such as multiple episodes of pyelonephritis, shiga toxin-associated hemolytic uremic syndrome.

  • Genetic inheritable conditions such as cystinosis, oxalosis, genetic forms of hemolytic-uremic syndrome (HUS), congenital nephrotic syndrome, Polycystic kidney disease.

Typical causes for DYSFUNCTION in a renal transplant include:

  • Acute rejection, which can be acute cellular rejection or acute antibody-mediated rejection or both.

  • Acute infection within the graft, such as acute bacterial pyelonephritis or BK virus infection/nephropathy.

  • Drug toxicity, such as high blood tacrolimus trough levels.

  • Obstruction to urinary flow, such as with urinary stones or in a neurogenic bladder that has not been catheterized for a while.

  • Dehydration and hypovolemia.

  • Acute ischemic injury, known more commonly by the term acute tubular necrosis, although ischemia is not restricted to tubules, and reversible cell swelling is much more common than irreversible cell necrosis.

  • Chronic rejection, a slower and more gradual process than acute rejection, associated with a slower "creeping" creatinine.

  • Recurrence of primary kidney disease, which occurs with certain primary diseases (focal segmental glomerulosclerosis, atypical hemolytic-uremic syndrome).

  • Thrombosis in the vessels leading to and from the kidney (usually a very early event, thankfully rare nowadays, but terminal for the graft when it does occur). Thrombosis is not covered in detail in this chapter because it is such a different entity.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

  • Urinalysis, urine protein, and serum chemistry panel (electrolytes, BUN, serum creatinine) and blood trough tacrolimus levels are obtained at each visit and represent the first tests used to evaluate kidney transplant health or dysfunction. Serum creatinine elevation is typically considered significant if more than 20% above previous value. However, in very young children who received an adult kidney, the renal reserve in the allograft may be so high that serum creatinine may not elevate as much. Conversely, in children with some chronic damage to the kidney allograft, serum creatinine may fluctuate within a range at visits without representing acute rejection.

Would imaging studies be helpful? If so, which ones?

  • A renal ultrasound will show if hydronephrosis or stones are present. Parenchymal vascular resistive indices are often calculated by radiologists but are not very helpful. Where acute tubular necrosis (ATN) is suspected, a nuclear medicine scan (typically MAG-3) can determine if renal blood flow is present. The same scan is used in the rare situations where thrombosis is suspected. DMSA (technetium dimercaptosuccinic acid) scans may be used to diagnose acute pyelonephritis.

  • CT scans are rarely used but can also show acute pyelonephritis, stones, hydronephrosis, extrarenal fluid collections.

  • Generally, renal ultrasound is the least invasive, has no radiation, is relatively inexpensive, and covers most of the etiologies.

  • If a renal biopsy is performed, it is typically ultrasound-guided since the transplanted kidney typically sits anteriorly and above the peritoneum in the right or left lower abdominal quadrant in most (but not all) children. Ultrasound provides the best localization. An exception is the small child in whom the kidney is placed intraperitoneally. Performing a biopsy on such a kidney may need CT guidance since the kidney may float around in the abdomen and bowel may overlie the anterior path to the kidney.

Confirming the diagnosis

  • See accompanying algorithm chart (Figure 1).

  • This author's practice is to first determine if the patient's transplant status is "early" (within 6 months post-transplant) or later (more than 6 months). If the latter, the first question to ask is if the patient is known to have chronic allograft nephropathy (CAN) on biopsy. This term implies biopsy evidence of chronic scarring, such as interstitial fibrosis or tubular atrophy. Many patients with CAN have fluctuations in serum creatinine that do not need a biopsy each time. Also, these patients may have reached a point where the allograft is wearing out steadily, such that repeat biopsy is not needed.

  • The next step, if CAN is not known to exist, is to assess if patient had fever at time of testing. Fever in the presence of urinary symptoms such as dysuria and if the urinalysis showed possible bacterial infection (typically the presence of large leucocyte esterase and nitrites on urine dipstick in the presence of dysuria), then UTI should be suspected. Fever does not have to be present. In pediatric kidney transplant patients, all UTI is assumed to be pyelonephritis, not cystitis, unless otherwise proven.

  • Next, this author assesses if the patient was dehydrated at time of blood draw or if the 12-hour trough tacrolimus level was high.

  • If the patient has a setup for urinary obstruction, rule that out. Typically, patients with posterior urethral valves or spina bifida have abnormal bladder function. Many need to be chronically catheterized to keep the urinary bladder empty. Patients who are not compliant with frequent daily catheterization can manifest with elevated serum creatinine from urinary stasis or obstruction.

  • In patients who are still early post-transplant, acute rejection has to always remain high on the differential diagnosis list. They may have no symptoms. Fever can occasionally be an isolated symptom of acute rejection. The diagnosis of acute rejection is by kidney biopsy histology. The diagnostic criteria are called Banff criteria, and the latest versions are available on PubMed.

  • The biopsy can also show if BK virus nephropathy is present.

  • Concomitant tests with biopsy that help solidify the diagnosis include serum testing for the presence of anti-HLA antibodies (especially against donor HLA antigens, for diagnosis of acute antibody-mediated rejection) and BK virus copies in blood by quantitative PCR testing.

Algorithm for clinical decision-making in renal transplant dysfunction

If you are able to confirm that the patient has renal transplant dysfunction, what treatment should be initiated?

  • If dehydration is suspected, ask the patient to hydrate well and repeat blood tests in 4-6 days. Severe dehydration can be treated with intravenous fluids.

  • If the tacrolimus level is high, then reduce the dose and repeat a drug level and serum creatinine in 1-2 weeks.

  • If pyelonephritis is suspected, send urine for culture, initiate antibiotics (PO or IV depending on clinical severity). Adjust antibiotics based on culture results and confirm that serum creatinine is coming down with treatment.

  • If acute rejection is found on biopsy, the treatment is based on the type and severity of acute rejection. See Table I.

Table I.

Treatment options for acute rejection
Medications Acute Cellular Rejection Acute Antibody-Mediated Rejection
Intravenous steroids (methylprednisolone) 10 mg/kg IV once daily for 3-6 doses; initial treatment and may suffice alone for mild cases May be used initially, but not the mainstay of treatment
Rabbit anti-thymocyte immunoglobulin 1 mg/kg/dose once daily IV up to maximum 7.5/10 mg/kg/dose; typically used in Grade 1B or grade 2 rejection Adjunctive therapy in mixed cases
Rituximab Not typically used in pure cellular rejection 375 mg/m2 IV once weekly for 1-4 doses
Intravenous immunoglobulin (IVIG) Rarely used for cellular rejection Dose range 400 mg/kg/day for several doses, to 2 gm/kg as a single dose
Plasmapheresis Not typically used Varying regimens used, typically daily for 3 consecutive days, then more sessions less frequently, as needed; total number of sessions usually 6-8

Treatment options for BK virus (BKV) nephropathy are controversial. Reduction of immunosuppression is the usual initial intervention. The way to reduce is also controversial, with some centers preferring calcineurin inhibitor (tacrolimus, cyclosporine) reduction/stoppage and other centers preferring antimetabolite agent (mycophenolate/azathioprine) reduction/stoppage. Additional BKV specific agents such as IV cidofovir or oral leflunomide have been tried. Case series suggest efficacy, but no prospective control groups were used in these studies.

The initial relief of obstruction is usually by placement of an indwelling urinary bladder catheter or a diversion stoma from the renal pelvis, depending upon the level of obstruction.

  • What about longer term treatment? So far there is no treatment for chronic rejection. Patients with frequent urinary tract infections may need long-term antibiotic prophylaxis. Long-term obstruction relief may require initiation of a chronic catheterization program or creation of vesicostomy or an appendicovesical conduit (Mitrofanoff procedure).

What are the adverse effects associated with each treatment option?

Any intensification of immunosuppression can lead to more infections. This author's practice is to restart 6 months of antimicrobial prophylaxis with valganciclovir (activity against CMV and Epstein-Barr viruses) and trimethoprim-sulfa (for Pneumocystis prevention).

Steroids can aggravate hypertension, mood swings, obesity, and hyperlipidemia.

Rabbit anti-thymocyte globulin can be associated with infusion reactions and requires pre-medication.

IVIG can lead to acute renal failure, especially if sucrose-containing hyperosmolar preparations are used.

Rituximab has a black box warning about potential increased risk for progressive multifocal leukoencephalopathy, a rare degenerative disease caused by JC virus.

What are the possible outcomes of renal transplant dysfunction?

If the dysfunction and its cause are picked up early, the dysfunction can be fully reversed with appropriate treatment. Untreated renal transplant dysfunction, either from obstruction, infection or acute rejection, can lead to complete failure of the renal allograft.

The family should be informed that prognosis depends on cause of dysfunction and stage at which it is picked up.

Given that a kidney transplant is a life-saving treatment, the risk/benefit ratio generally tends to favor aggressive attempts to salvage the renal allograft, unless the graft is deemed too far gone.

What causes this disease and how frequent is it?

  • Acute rejection rates in the first year post-transplant have declined with each more recent era. Current rates are approximately 15-20% of all transplant recipients. However, late acute rejection rates remain unchanged. See Figure 2, taken from the North American Pediatric Renal Transplant Cooperative Studies (NAPRTCS) registry 2010 annual report.

  • BK virus nephropathy emerged in the late 1990s as a new opportunistic infection, temporally associated with more potent immunosuppression being introduced. The incidence appears to highest in the first year post-transplant but additional cases may appear in subsequent years, as shown in Figure 3 from a UNOS database analysis by this author. Most people are exposed to this virus in childhood; it then establishes a long-lived latency in uroepithelium, including the donor ureter, which is transplanted into the recipient along with the transplant kidney. The virus first replicates in urine, known as viruria, seen in approximately 40% of transplant recipients. However, only 15% go on to experience viral replication in blood (viremia) and only 2%-5% go on to experience nephropathy (virus in renal parenchymal tissue plus evidence of dysfunction or tissue inflammation).

  • Urinary tract infection is the most common infection in kidney transplant recipients of any age, experienced by approximately 35%-40% of all recipients in the first year post-transplant. The risk is higher in children with abnormal bladder function. The most common causative organisms are the same as in native-kidney UTI, such as E. coli and Klebsiella. Transmission is usually from the urogenital route below, although hematogenous entry is also possible.

Incidence of acute rejection in different era cohorts. Source: North American Pediatric Renal Transplant Cooperative Studies 2010 annual report

Incidence of treatment for BK virus in transplant recipients. Source: Dharnidharka VR, Cherikh WS, Abbott KC. An OPTN analysis of national registry data on treatment of BK virus allograft nephropathy in the United States. Transplantation 2009;87(7):1019-26.

How do these pathogens/genes/exposures cause the disease?

N/A

Other clinical manifestations that might help with diagnosis and management

N/A

What complications might you expect from the disease or treatment of the disease?

As already stated above, the treatment of acute rejection involves an intensification of immunosuppression, which in turn raises the risk for subsequent major life- or graft-threatening infections such as cytomegalovirus (CMV) or Pneumocystis infection. Making the right diagnosis in critically important. BK virus nephropathy is also an important cause of renal transplant dysfunction. Yet, its treatment is the exact opposite of the treatment for acute rejection. For BK virus nephropathy, reduction of immunosuppression is important, which in turn can raise the risk of subsequent acute rejection. The wrong diagnosis can lead to the wrong treatment, which can exacerbate the primary cause of dysfunction. Transplant professionals therefore have to tread a delicate balance.

Are additional laboratory studies available; even some that are not widely available?

More recently, several molecular or gene expression-based biomarker panels that can predict acute rejection prior to elevation in serum creatinine have been published and are now commercially available. They may become more widely used in future.

How can renal transplant dysfunction be prevented?

Acute rejection episodes are prevented by extrinsic immunosuppression agents, both induction and maintenance.

Induction agents are usually intravenous and administered at the time of transplantation (e.g., rabbit antithymocyte globulin, basiliximab, alemtuzumab).

Maintenance agents are mostly oral, started right after transplantation, but continued lifelong on a daily basis. Examples include calcineurin inhibitors (tacrolimus, cyclosporine), DNA cell synthesis inhibitors (mycophenolate, azathioprine), mTOR inhibitors (sirolimus, everolimus), and prednisone. A newer monthly injectable maintenance agent belatacept is now approved.

Acute herpesvirus infections are prevented by use of ganciclovir or valganciclovir, for variable lengths of time post-transplant, typically 3-6 months. Pneumocystis infections are prevented by use of oral trimethoprim-sulfa, typically on a M-W-F basis. Using the same total dose but on a daily basis can also prevent frequent urinary tract infections. No preventive strategy for BK virus is established, although one study suggested that ciprofloxacin prophylaxis might be useful.

Teenage patients have a higher incidence of medication non-adherence, which increases the risk of acute rejection episodes. Non-adherence with chronic catheterization schedules increases the risk for urinary tract infections or obstruction.

What is the Evidence?

Annotated Bibliography:

For general management:

Dharnidharka, VR, Fiorina, P, Harmon, WE.. "Kidney transplantation in children". New Engl J Med. vol. 371. 2014. pp. 549-558.

Harmon, WE., Himmelfarb, J, Sayegh, MH. "Pediatric renal transplantation". Chronic kidney disease, dialysis and transplantation. Elsevier. 2010. pp. 591-608.

Harmon, WE., Avner, ED, Harmon, WE, Niaudet, P, Yoshikawa, N. "Pediatric kidney transplantation". Pediatric nephrology. vol. 2. Springer-Verlag. 2009. pp. 1867-1902.

For acute rejection biology and incidence:

Ingulli, E, Alexander, SI, Briscoe, DM., Avner, ED, Harmon, WE, Niaudet, P, Yoshikawa, N. "Transplantation immunobiology". Pediatric nephrology. vol. 2. Springer-Verlag. 2009. pp. 1835-1866.

Nankivell, BJ, Alexander, SI.. "Rejection of the kidney allograft". N Engl J Med. vol. 363. 2010. pp. 1451-62.

For acute rejection management:

Smith, JM, Nemeth, TL, McDonald, RA., Avner, ED, Harmon, WE, Niaudet, P, Yoshikawa, N. "Immunosuppression in pediatric renal transplantation". Pediatric nephrology. vol. 2. Springer-Verlag. 2009. pp. 1903-1918.

For BK virus infection incidence:

Hirsch, HH, Knowles, W, Dickenmann, M. "Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients". N Engl J Med. vol. 347. 2002. pp. 488-96.

Dharnidharka, VR, Abdulnour, HA, Araya, CE.. "The BK virus in renal transplant recipients-review of pathogenesis, diagnosis, and treatment". Pediatr Nephrol. vol. 26. 2011. pp. 1763-4.

For BK virus treatment and prevention:

Hilton, R, Tong, CY.. "Antiviral therapy for polyomavirus-associated nephropathy after renal transplantation". J Antimicrob Chemother. vol. 62. 2008. pp. 855-9.

Dharnidharka, VR, Abdulnour, HA, Araya, CE.. "The BK virus in renal transplant recipients-review of pathogenesis, diagnosis, and treatment". Pediatr Nephrol. vol. 26. 2011. pp. 1763-4.

For obstruction treatment:

Mitchell, ME, Balcom, AH., Avner, ED, Harmon, WE, Niaudet, P, Yoshikawa, N. "Bladder dysfunction in children". Pediatric nephrology. vol. 2. Springer-Verlag. 2009. pp. 1379-1404.

For urinary tract infection risk:

Dharnidharka, VR, Agodoa, LY, Abbott, KC.. "Effects of urinary tract infection on outcomes after renal transplantation in children". Clin J Am Soc Nephrol. vol. 2. 2007. pp. 100-6.

For newer molecular and gene expression-based biomarker panels for acute rejection:

Li, L, Khatri, P, Sigdel, T, Tran, T. "A peripheral blood diagnostic test for acute rejection in renal transplantation". Am J Transplant. vol. 12. 2012. pp. 2710-2718.

(This NIH-funded multicenter prospective study in children showed that a peripheral blood gene panel could diagnose acute rejection in pediatric kidney transplant recipients.)

Suthanthiran, M, Schwartz, JE, Ding, R, Abecassis, M. "Urinary-cell mRNA profile and acute cellular rejection in kidney allografts". N Engl J Med.. vol. 369. 2013 Jul 4. pp. 20-31.

(This very large NIH-funded, multicenter, prospective trial showed that a urinary mRNA biomarker panel could predict imminent acute rejection in adult kidney transplant recipients.)

Hricik, DE, Nickerson, P, Formica, RN, Poggio, ED. "Multicenter validation of urinary CXCL9 as a risk-stratifying biomarker for kidney transplant injury". Am J Transplant. vol. 13. 2013 Oct. pp. 2634-44.

(This other NIH-funded, multicenter, prospective study showed that a urinary chemokine could predict imminent acute rejection in adult and pediatric kidney transplant recipients.)

For antibody-mediated rejection therapies:

Ng, YW, Singh, M, Sarwal, MM.. "Antibody-mediated rejection in pediatric kidney transplantation: pathophysiology, diagnosis, and management". Drugs. vol. 75. 2015 Apr. pp. 455-72.

References alphabetically:

Araya, CE, Garin, EH, Meoberger, RE, Jarmodjarla, VR.. "Leflunomide therapy for BK virus allograft nephropathy in pediatric and young adult kidney transplant recipients". Pediatr Transplant. vol. 14. 2010. pp. 145-50.

(This study found that leflunomide use in a select group of patients is well tolerated and may provide an alternative for treatment of BKVAN in pediatric patients.)

Araya, CE, Lew, JF, Fennell, RS. "Intermediate-dose cidofovir without probenecid in the treatment of BK virus allograft nephropathy". Pediatr Transplant. vol. 10. 2006. pp. 32-7.

(The authors state that, in their experience, intermediate-dose cidofovir without probenecid, used judiciously, is not associated with additional nephrotoxicity and may provide an additional alternative for treatment.)

Araya, CE, Lew, JF, Fennell, RS. "Intermediate dose cidofovir does not cause additive nephrotoxicity in BK virus allograft nephropathy". Pediatr Transplant. vol. 12. 2008. pp. 790-5.

(This larger series with extended follow up showed that intermediate dose cidofovir without probenecid for the treatment of BKVAN continues to show stabilization of renal function without progression to renal failure.)

Dharnidharka, VR, Abdulnour, HA, Araya, CE.. "The BK virus in renal transplant recipients-review of pathogenesis, diagnosis, and treatment". Pediatr Nephrol. vol. 26. 2011. pp. 1763-4.

(The authors review the current strategies of screening, diagnosis, and possible treatment, and also review the amount and quality of evidence in favor or against. Similarities and differences between cytomegalovirus, Epstein-Barr virus, and BV virus, the three major viral infections in kidney transplantation, are highlighted.)

Dharnidharka, VR, Agodoa, LY, Abbott, KC.. "Effects of urinary tract infection on outcomes after renal transplantation in children". Clin J Am Soc Nephrol. vol. 2. 2007. pp. 100-6.

Dharnidharka, VR, Cherikh, WS, Abbptt, LC.. "An OPTN analysis of national registry data on treatment of BK virus allograft nephropathy in the United States". Transplantation. vol. 87. 2009. pp. 1019-26.

(This study concluded that higher center volume and living kidney donation exerted a protective effect against BK virus allograft nephropathy. Of concern, rates of treatment of BK virus (TBKV) were significantly higher in more recent transplant years. TBKV report was associated with higher risk of subsequent graft loss (adjusted hazard ratio=1.69, P<0.001).)

Gabardi, S, Waikar, SS, Martin, S. "Evaluation of fluoroquinolones for the prevention of BK viremia after renal transplantation". Clin J Am Soc Nephrol. vol. 5. 2010. pp. 1298-304.

(This analysis demonstrated that fluoroquinolones are effective at preventing BK viremia after renal transplantation.)

Hilton, R, Tong, CY.. "Antiviral therapy for polyomavirus-associated nephropathy after renal transplantation". J Antimicrob Chemother. vol. 62. 2008. pp. 855-9.

(Pooled data from various small case series did not show significant differences in outcome. Prospective randomized studies with a standardized protocol are urgently required.)

Hirsch, HH, Knowles, W, Dickenmann, M. "Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients". N Engl J Med. vol. 347. 2002. pp. 488-96.

(This study concluded that BKV nephropathy in renal-transplant recipients represents a secondary infection associated with rejection and its treatment in most cases and could be monitored by measuring the viral load in plasma.)

Nankivell, BJ, Alexander, SI.. "Rejection of the kidney allograft". N Engl J Med. vol. 363. 2010. pp. 1451-62.

Puliyanda, DP, Toyoda, M, Traum, AZ. "Outcome of management strategies for BK virus replication in pediatric renal transplant recipients". Pediatr Transplant. vol. 12. 2008. pp. 180-6.

(The results of this study showed that with viruria alone no treatment is necessary; with viremia and stable GFR, reduced immunosuppression decreases viremia and maintains GFR. With viremia and reduced GFR, immunosuppression reduction with or without cidofovir decreases viremia and stabilizes GFR in most patients. Greater than 50% reduction in GFR at BKVAN diagnosis correlates with risk for graft loss. Serial monitoring of BKV viremia with early intervention may prevent BKVAN graft loss in children.)

Smith, JM, VDharnidharka, VR, Talley, L. "BK virus nephropathy in pediatric renal transplant recipients: an analysis of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry". Clin J Am Soc Nephrol. vol. 2. 2007. pp. 1037-42.

(This first multicenter, retrospective, cohort study of BK virus nephropathy in pediatric renal transplant recipients found a BK virus nephropathy incidence of 4.6% and identified polyclonal induction and zero HLA DR mismatch as significant risk factors for BK virus nephropathy.)

Ongoing controversies regarding etiology, diagnosis, treatment

Many aspects of etiology, diagnosis, and treatment are controversial. The relative contributions of the different components of the immune system (T cells, B cells, immunoglobulins, complement, NK cells) to acute and chronic rejection are constantly being revised and paradigms are being revisited.

The use of serum creatinine as the main screening test to detect early graft dysfunction secondary to acute rejection is also being challenged.

Research studies that are nearing the clinical arena suggest that molecular signals from effector and regulatory T cells can be elevated in serum or urine much earlier, thereby providing a potential opportunity for earlier intervention.

Kidney biopsy, while referred to as the gold standard for diagnosis of acute rejection, is not 100% sensitive nor 100% specific. Protocol surveillance biopsies at fixed time points to diagnose subclinical acute rejection are performed in a few centers, with growing literature for their support, but this practice is still not routine at most centers.

The optimal treatment for recurrent focal segmental glomerulosclerosis (FSGS) is controversial and no consensus exists.

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