Does this patient have early graft dysfunction related to intrinsic causes?

What is early graft dysfunction?

Kidney transplantation is the preferred mode of renal replacement therapy for end stage renal disease, with dramatic improvements in patient and graft survival over the last 50 years. In the modern era of immunosuppression, 1-year patient survival is close to 98%, and 1-year allograft survival rates have improved to 90% for deceased donor kidney transplants and 95 % for living donor kidney transplants with some inter-center variability. Fluctuations in serum creatinine, which is the primary method for monitoring graft function, are frequent, particularly in the first year of transplantation.

Definition: early graft dysfunction

A rise in serum creatinine of 15% or more above baseline defines allograft dysfunction. Urine output, especially in the first few days of transplantation, may also be monitored and a decline to levels of oliguria or anuria may also define early graft dysfunction.

What causes early graft dysfunction?

Early graft dysfunction can be divided into three categories based on the different risk factors:

(1) immediate post-operative graft dysfunction (within the first week after transplantation) (Figure 1)

(2) graft dysfunction in the first 3 months after transplantation (Figure 2)

(3) graft dysfunction more than 3 months after transplantation.

Similarly to acute kidney injury, acute allograft dysfunction can be divided in three categories, based on pre-renal, post-renal and intrinsic-renal etiologies. Differential diagnosis is impacted based on the timing postoperatively. This chapter focuses on intrinsic-renal allograft etiologies.

Delayed Graft Function

The term delayed graft function (DGF) is often used interchangeably with acute tubular necrosis (ATN) in literature. DGF is a clinical diagnosis, which is defined as need for dialysis within the first week after transplant. ATN is the most common cause of DGF, and is either a histological diagnosis, or a clinical diagnosis after other causes of DGF have been excluded. It is most commonly the result of ischemia- reperfusion injury.

What is the incidence of DGF?

The incidence of DGF in recipients of deceased donor kidneys varies between 17%, when the donor is 15-20 years old, and 40%, when the donor is over 65 years old (adapted from UNOS 1998).
What is the prognosis of DGF?

The impact of DGF is significant and is associated with reduced 1-year graft survival rates of at least 10% and a reduction in allograft half-life by 2 years.
Risk factors for DGF include: prolonged cold ischemic time, older donor age, donor history of hypertension, kidney donor profile index (KDPI, which is an estimation of the organ quality based on donor’s characteristics), donation after cardiac death, exposure to nephrotoxins, recipient volume depletion, decreased cardiac output, pre-transplant dialysis, atherosclerosis of recipient vessels, preformed donor specific antibodies.
Prevention and Management of DGF

Modification of pre-engraftment factors may reduce the rate of DGF. Euvolemic or hypervolemic state in the recipient should be maintained after engraftment to ensure adequate perfusion to the allograft. Prolonged warm and cold ischemic time, hypotension and vessel injury during procurement surgery predispose the kidney to tubular injury; hence, many centers utilize hypothermic machine perfusion, which has been shown to decrease the rate of DGF and is associated with improved graft survival at 1 year over static cold storage.

Duplex ultrasonography, or rarely renal nuclear imaging, should be done at regular intervals to rule out thrombosis, urinary obstruction or urine leak in oliguric patients. Core renal biopsy may be performed on day 7 – 14 to rule out acute rejection (Figure 1).

Acute Tubular necrosis

ATN is the most common cause of DGF and is usually the result of ischemia- reperfusion injury. It is a histological diagnosis, or a clinical diagnosis of exclusion after ruling out other causes of DGF by renal imaging (Figure 1). Even if diagnosed clinically, an allograft biopsy may be necessary to guide management, particularly in scenarios of DGF lasting more than one week.

At a cellular level, following the period of ischemia, the allograft adapts to anaerobic metabolism. At the time of reperfusion, excess availability of oxygen leads to macrophage activation and formation of superoxide radicals/reactive oxygen species which then begins a cascade of events leading to parenchymal and endothelial injury. The innate immune response is activated. This may cause increased expression of histocompatibility antigens, adhesion molecules, cytokines and growth factors leading to an inflammatory response causing further injury.

Some centers delay the use of calcineurin inhibitors (CNI) in patients with DGF, as CNIs may contribute to renal ischemia. Sirolimus delays the recovery from ATN, and is usually not a valid alternative. The majority of transplant centers advocate the use of depletional induction therapy with polyclonal anti-thymocyte globulin when DGF is anticipated. Oxygen scavengers, I CAM 1, monoclonal antibody and pentoxiphylline have not been beneficial so far. Finally, the oliguric phase of injury is typically followed by a diuretic phase and adequate volume repletion in the recipient is mandated to avoid volume contraction and hypotension, which can prolong injury in the recovering allograft.

Hyperacute Rejection

Definition:

Hyperacute rejection is the result of preformed cytotoxic donor-specific antibodies, such as anti- HLA antibodies, anti-endothelial antibody or ABO isoagglutinins. It results in early acute graft loss due to the overwhelming injury that is uncontrollable by standard immunosuppression. With the advent of crossmatch screening (crossmatch test between donor’s lymphocytes and prospective recipient’s serum to detect pre-existing donor specific antibodies) prior to transplant and use of ABO compatible transplants, hyperacute rejection is an extremely rare event.

Presentation and evaluation

Clinical presentation may occur as soon as the vascular anastomosis of the allograft is established in the operating room. The allograft can become cyanotic and mottled as a result of severe endothelial injury from deposition of preformed cytotoxic donor specific antibodies leading to intravascular coagulation and vascular thrombi and hence no blood flow. In this setting, the patient may be oliguric or anuric, and there is no uptake of the radiotracer on the renal scan with lack of blood flow to the kidney on duplex ultrasonography. Biopsy may show widespread vascular thrombi especially involving arteries, arterioles, capillaries and glomeruli, polymorphonuclear leukocytes infiltration.

Immunofluorescence staining may demonstrate deposition of IgG, IgM, C3 and fibrin in capillaries and arterioles. C4d staining, a detection of complement activation in peritubular capillaries that is diagnostic of antibody mediated rejection, may be widespread. Electron microscopy, if performed, shows endothelial swelling and injury and necrosis.

The differential diagnosis includes renal artery or vein thrombosis, urinoma, volume depletion, thrombotic microangiopathy (Figure 1).

Treatment:

Immediate surgical exploration of the allograft and intra-operative biopsy are performed to determine the viability of tissue. In the context of preformed antibody, salvage may be impossible and transplant nephrectomy may be undertaken.

Acute Antibody mediated rejection (AMR)

Acute antibody mediated rejection (also referred to as humoral rejection) is a result of activation of the immune system with endothelial injury from either pre-existing or de novo donor specific antibodies (DSA), which can be anti- HLA or non- HLA antibodies. The estimated rate of AMR is 5-10% in the first year of kidney transplantation.

Diagnosis of AMR

The diagnosis of acute AMR is based on three criteria (Banff 2013):

Pathology evidence of tissue injury (glomerulitis, peritubular capillaritis, intimal arteritis, thrombotic microangiopathy, or ATN).
Signs of interaction between antibodies and endothelium (mostly represented by the presence of C4d deposition in the peri-tubular capillaries. C4d is a degradation product of complement activation).
The detection of circulating DSA (typically HLA antibody).

This diagnosis is usually made in the context of allograft dysfunction. More recently, with the advent of protocol (surveillance) biopsies, pathological abnormalities may be found consistent with this entity without allograft dysfunction.

Risk factors for AMR

Major risk factors for the development of AMR include:

– Pre-existing immune sensitization/donor specific antibody

– ABO-incompatible transplantation

– Insufficient immunosuppression/poor medication adherence

Treatment of AMR

Main goals of treatment of AMR are:

To remove the circulating DSA
To suppress the formation of new DSA
To deplete the B memory and naïve cells
To suppress the T-cell dependent antibody injury
To remove antibody-producing plasma cells
To block the activation of complement
To increase the overall immunosuppression

Role of plasmapheresis

Plasmapheresis and immunoadsorption are both known to remove donor specific antibodies and reduce the titers of circulating antibody in the blood. However, when used by themselves as a treatment of AMR, they do not improve graft survival, due to the continuous production of antibodies. Many groups have successfully treated acute humoral rejection with combination therapy including plasmapheresis and intravenous gammaglobulin with/without rituximab (anti-CD20 antibody against B cells), and other immuno-modulators as a combined therapy.

Intravenously administered immunoglobulin (IVIG)

IVIG has played an important role in many autoimmune disorders and has become invaluable by itself or in combination with other treatments in transplant medicine. Immunoglobulin is a product of B cells (plasma cells). There are 5 types of immunoglobulin – M, A, G, E, D – and all of them have their individual role as defense mechanism in the human body. IVIG preparations are made from pooled plasma from blood donors and can be unselected, or selected with high antibody titers against a particular antigen.

Various mechanisms of actions have been identified both in vivo and in vitro, which may explain the immune-modulatory and anti- inflammatory effects of IVIG in solid organ transplant. The mechanisms include:

Inhibition of complement activation and complement mediated inflammation
Suppression of cell mediated immunity, both B and T cell.
Modulation of the innate response by action on dendritic cells
Inhibition of the production of pro-inflammatory cytokines and adhesion molecules from monocytes and macrophages
Promotion of excretion of antibody by the kidney

Various centers have used IVIG in conjunction with plasmapheresis with/without rituximab. Most protocols describe using 100 mg/kg of IVIG after each session of alternate day plasmapheresis, followed by 2 g/kg of IVIG (usually divided in 2 or 3 doses) at the end of plasmapheresis cycle, followed by rituximab. Some centers give 2- 4 high doses of IVIG, 3-4 weeks apart after completion of initial treatment. These protocols are not standardized and should only be used by centers with experience. High dose IVIG is associated with some serious complications such as sucrose induced osmotic nephropathy, thrombotic complications, hemolysis, and headaches. When ordering IVIG, a sucrose-free brand should be chosen.

Rituximab – chimeric anti-CD20 (anti B cell) monoclonal antibody

Rituximab is a chimeric monoclonal antibody that is specific for the CD20 cell surface protein expressed on circulating B cells. As such, infusion depletes circulating B cells (CD20 cells) as well as those residing in lymph node and spleen. It modestly reduces circulating antibody levels, despite the lack of action on mature plasma cells, which are CD20 negative and primarily are responsible for antibody production. B cell elimination is rapid, usually within 1- 3 days and the effect lasts usually 1- 2 years.

Other effects include depriving T cells of antigen presenting cell activity provided by antigen- specific B cells thus altering the T-cell effector mechanism. Rituximab is currently approved for CD20 positive lymphoma and rheumatoid arthritis, but it has found wide application in the treatment of autoimmune disorders, vasculitis, and post transplant lymphoproliferative disorder (PTLD). It has found its role as a combination therapy with plasmapheresis and IVIG in treatment of acute antibody mediated rejection and in desensitization protocols. Small studies have shown that patients with AMR treated with plasmapheresis, IVIG, and Rituximab as a combination therapy have better graft survival than patients treated with high dose IVIG alone or the combination of IVIG and plasmapheresis. Rituximab is given as an intravenous infusion, at a dose of 375 mg/m2 (or alternatively 1 g) for 2 infusions, but the dose and number of infusions are variable and center dependent. Common side effects are infusion reaction and hypotension. Complications include bacterial and fungal infections, leukopenia. Rituximab can cause fulminant hepatitis in patients who are positive for hepatitis B, and hepatitis testing should be performed and reviewed before administration of this medication.

Evolving Approaches to AMR

Bortezomib- proteasome inhibitor

Bortezomib is a modified dipeptidyl boronic acid analog that binds to 26 s proteasome, present in cytoplasm and nucleus of cells, selectively and reversibly. Inhibition of this proteasome leads to alteration of multiple signaling pathways, which then ultimately leads to cell apoptosis (programmed cell death). Bortezomib causes plasma cell apoptosis in the bone marrow with subsequent inhibition of antibody production. Small single center studies have shown 1) reversal of cell mediated as well as antibody mediated rejection, 2) significant reduction of anti- HLA antibodies specifically donor specific antibody, and 3) improved renal allograft function. The effect lasted for at least a few months. Side effect profile includes fatigue, weakness, anorexia, gastro-intestinal toxicity, paresthesias, peripheral neuropathy, thrombocytopenia, neutropenia and psychiatric disorders.

Long-term efficacy and safety profile still need to be established, but some preliminary results have been promising. Further studies are underway in recipients of kidney transplants as well as other sensitized solid organ recipients.

Eculizumab

This biologic agent (biologic agents are nonchemical in nature and include antibodies, fusion proteins, cytokines and chemokines and their antagonists) is a humanized monoclonal antibody against complement C5 and ultimately prevents the formation of C5-9 membrane attack complex. This is a critical part of injury mediated by antibody. Eculizumab prevents completion of complement activation cycle and hence halts the injury caused by antibody activation. Preliminary studies of this agent in humans demonstrate reduced intensity of antibody injury. High HLA risk patients treated with eculizumab, in combination with plasmapheresis and IVIG, have been reported experiencing decreased rates of AMR. Further multicenter studies are underway to demonstrate the safety and efficacy of this therapy.

Eculizumab use is associated with increased risk of meningococcal infection, and patients should be vaccinated before receiving Eculizumab. If Eculizumab is needed before a vaccination can be done, patients should receive prophylaxis therapy until they can receive a vaccination and the vaccination is believed to be effective.

Splenectomy

Splenectomy has been used by few centers as a rescue therapy for severe AMR that failed to respond to plasmapheresis and IVIG. Splenectomy could help in decreasing the levels of antibody producing plasma cells, which are not responsive to anti-CD20 cell therapy, and activated B cells, hence reducing the antibody titers. Splenectomy is associated with risk of surgical procedure plus increased susceptibility to serious infection.

Acute Cellular Rejection

Cellular rejection is a process of immune mediated injury of the kidney. It is identified by mononuclear cell, eosinophil and plasma cell infiltration of interstitium and tubules of a renal allograft, and is associated with infiltration of the vessels, arteritis, in severe cases. The histological classification is based on the degree and extent of mononuclear inflammation and the degree of vascular involvement on the allograft biopsy. Many transplant centers utilize the Banff biopsy classification scheme (Table I). Of note, interstitial inflammation and tubulitis is not exclusive of T cell mediated rejection and are seen in viral nephritis (e.g., polyoma nephropathy, CMV nephritis) and in post transplant lymphoproliferative disorder (PTLD).

Clinical Manifestation

Patients may be asymptomatic and are found to have rapidly rising creatinine; in severe cases cell mediated rejection may present with fever, malaise, decreased urine output and allograft tenderness.

Diagnosis

Diagnosis is made by the renal allograft biopsy in an appropriate clinical setting. In the setting of adequate immunosuppression, viral nephritis, bacterial infection and drug induced interstitial nephritis should also be considered in the differential diagnosis and need to be ruled out.

Treatment

Treatment of T-cell mediated rejection is dependent on the biopsy finding. When the suspicion for cellular rejection is high, treatment with intravenous methylprednisone, 500 mg daily for 3 consecutive days, may be started even before the biopsy results are known. Patient with only tubulointerstitial inflammation (borderline, 1a, 1b) may respond to steroids with improvement in urine output and serum creatinine. If there is an inadequate response to steroids, or if the rejection is an aggressive 1b, then a T- cell depleting agents should be considered. Vascular rejection (Banff 2, 3) is typically refractory to steroids and requires treatment with a T cell depleting agent (intravenous anti-thymocyte globulin 1-1.5 mg/kg for 5 -10 days, or alemtuzumab, anti CD 52 agent, 30-60 mg for 2 doses). OKT-3 is not available in the US anymore, due to severe toxicity.

Patients on cyclosporine-based regimen are usually switched to tacrolimus. Patients who are on azathioprine as anti-metabolite are switched to mycophenolate mofetil or mycophenolate sodium. If a patient is already on these agents, they are usually up-titrated to full dose. Prednisone is usually added to patients who are on a steroid free regimen. If T cell depletion is used, center-specific prophylaxis for opportunistic infections should be followed.

Prognosis

Outcomes vary depending on baseline renal function and the extent of injury. A good prognostic feature is renal function that returns to baseline after treatment. Poor prognostic features are: mixed antibody mediated and cellular rejections, the presence of hemorrhage and fibrinoid necrosis with vascular injury, as well a persistently elevated serum creatinine. A biopsy after treatment course may be indicated if allograft function remains elevated. Concurrent AMR should be excluded with an assessment of donor specific antibodies.

Recurrent Glomerular Disease

Certain glomerular diseases such as primary focal segmental glomerulosclerosis (FSGS), IgA nephropathy, hemolytic uremic syndrome (HUS) and pauci immune glomerulonephritis can recur after transplant and can lead to significant graft dysfunction.

Recurrent FSGS

The reported rate of recurrence of FSGS is 15%-30 % in renal allografts. The true incidence of recurrent primary FSGS may be underestimated because of the heterogeneity of the disease and lack of biopsy in many patients. Non-white ethnicity, rapid progression of the disease with need for dialysis within 6 months from the diagnosis, young age, or recurrence in previous transplant are some of the risk factors associated with recurrent FSGS. Living donor source has been reported to be associated with increased risk of recurrent FSGS. However, graft survival in recipients who received a kidney from a living donor is still higher compared to recipients who received a kidney from a deceased donor.
Clinical presentation

Early recurrent FSGS typically presents with nephrotic range proteinuria, which can happen even just minutes after the reperfusion of the allograft; some patients present with full-blown nephrotic syndrome – proteinuria, hypo-albuminemia, hypercholesterolemia and edema. Late recurrence is usually insidious and develops gradually over months or years.
Diagnostic studies

A baseline spot urine protein/creatinine ratio in all patients with suspected or proven FSGS should be obtained prior to transplant, if they are still making urine from their native kidneys. Patients with history of primary FSGS should undergo monitoring for proteinuria in the immediate post transplant period. If there is native function prior to transplantation, native kidney proteinuria usually typically resolves in 2 – 8 weeks. If there is an increase in baseline proteinuria or new onset proteinuria, a kidney transplant biopsy should be performed.

De novo FSGS should also be considered in the differential diagnosis in the presence of proteinuria after transplantation. Viral infection such as hepatitis C, HIV, and rarely parvovirus, or EBV can also cause collapsing FSGS and cause significant proteinuria.
Histology

There are many histological variants of FSGS that can be seen on biopsy. The diagnosis of FSGS may be difficult to make when disease is detected at its earliest stages, as the biopsy might only show diffuse foot process effacement by electron microscopy, without any changes on light microscopy. Multiple thin cut sections should be performed through the glomeruli to look for any sclerotic lesion.
Treatment

In patients who are at high risk of recurrence (rapid progression of the disease with need for dialysis within 6 months from the diagnosis, young age, or recurrence in previous transplant), institution of plasmapheresis before the transplant can reduce the risk of recurrence. We start plasmapheresis three days before the transplant, and repeat the day before the transplant, and continue twice from the day after the transplant. This can be done only if the transplant is from a living donor. We perform plasmapheresis with plasma instead of albumin to reduce the risk of bleeding related to the removal of clotting factors with plasmapheresis. Recurrent FSGS can still happen after prophylactic plasmapheresis. Although there is not a commonly accepted and widely demonstrated successful way of treating early recurrent FSGS, many transplant centers use plasmapheresis (some transplant centers use immunoadsorption), IVIG, high dose steroids, cyclosporine and rituximab in various combinations. Some centers use Cytoxan. Recently ACTH (Acthar®) has been reported to be useful in the treatment of recurrent FSGS, but more data is needed. Various protocols are available for treatment, but none has been standardized or validated. ACE inhibitors and ARBs can be used as antiproteinuric agents if tolerated. Statins should be prescribed in patients with hypercholesterolemia.

Recurrent IgA Nephropathy

Although IgA Nephropathy can recur any time after transplant, it is more often considered a later recurrent disease, and will not be discussed in this section. Note that increasing evidence suggests that steroid cessation after transplant is a risk factor for recurrent IgA nephropathy. We routinely continue steroid treatment as part of the maintenance immunosuppression therapy in every patient with history of IgA nephropathy.

Recurrent Hemolytic uremic syndrome

After renal transplantation, hemolytic uremic syndrome (HUS) can occur as both de-novo, or recurrent disease. Recurrent HUS is very uncommon in patients who developed HUS due to diarrheal illness from Shiga-like toxin or Escherichia coli toxin. The underlying genetic defect usually determines the risk of recurrence in patients with atypical HUS. It ranges from 15% to 20% in patients with mutations in the gene that encodes membrane cofactor protein, which exists on endothelial cells, and from 50% to 100% in patients with mutations in the genes that encode circulating regulators of complement, such as factor H and Factor I, which are normally produced by the liver.

Clinical presentation

HUS can present as early as few days after transplant with severe hypertension and rapid allograft dysfunction. Recurrence may be triggered by viral, bacterial infection, immunization or ischemia reperfusion injury resulting in activation of the complement system. The recurrence can be catastrophic for the new allograft depending on the kind of mutation. Differential diagnosis includes CNI induced thrombotic microangiopathy, and acute antibody mediated rejection.

Diagnosis

Rapid allograft dysfunction should trigger a biopsy in patients with history of HUS. Patients can present with urinary abnormalities of hematuria and proteinuria. Elevated LDH, low platelet count, hemolytic anemia, and schistocytes on peripheral smear all support the diagnosis of HUS, but hematological abnormalities have been reported in less than half the patients.

Histology

Light microscopy reveals thrombi in the lumen of arterioles and glomerular capillaries. In severe cases, histologic signs of necrosis can be present, and progression to cortical necrosis is described. Pronounced intimal changes may be present in the interlobular arteries more often in cases of recurrent disease. C4d stain and measurement of circulating DSA should be performed to differentiate between recurrent disease and acute AMR.

Treatment

Eculizumab: This humanized monoclonal antibody against complement C5 ultimately prevents the formation of C5-9 membrane attack complex and generation of prothrombotic C5a.

Plasma exchange: Plasma exchange can be used to remove the mutated protein and replace them with normal proteins in patients who do not respond to Eculizumab. Transplant patients with auto-antibodies against complement factor H have been successfully treated with plasma- exchange, rituximab and high dose steroids.

Liver- kidney transplantation: There have been some case reports of combined liver and kidney transplantation, which has been successful in treating HUS in patients with complement factor H mutation.

It is important to identify the gene mutation that led to atypical HUS in every patient who is evaluated for kidney transplantation and has a history of atypical HUS, in order to estimate the risk of recurrence and plan eventual prevention therapy. The knowledge of the mutation would also allow appropriate counselling, which should happen before transplantation.

De novo thrombotic microangiopathy

De novo thrombotic microangiopathy (TMA) may be caused by medications, and is mostly associated with cyclosporine and tacrolimus. Cases of TMA associated with the use of OKT3, which is not used in the US anymore, sirolimus, and leflunomide have been reported. The other factors that have been associated with de-novo TMA are antibody mediated rejection, prolonged warm ischemia time, kidney transplant from donor who died with cardiac death, anti-phospholipid syndrome, antibodies against Von-Willebrand factor, HIV, mutation in complement regulators, malignancy.

Patients may present with isolated renal allograft TMA, characterized by arteriolopathy and intravascular thrombi on transplant biopsy, or with full-blown HUS with micro-angiopathic hemolytic anemia, thrombocytopenia and rapid allograft failure.

The graft prognosis is poor unless the insulting agent is removed. Plasmapheresis is usually reserved for patients who do not improve after cessation of the medication or treatment of the disease that caused TMA.

Recurrent Oxalosis

Patients with primary hyper-oxaluria are deficient in hepatic enzyme alanine glycoxylate aminotransferase (type 1), or glyoxylate reductase/hydroxypyruvate reductase (type 2) enzymes responsible for oxalate metabolism, leading to oxalate deposition in many organs. Clinical history, elevated urine oxalate levels, detection of enzyme defect in liver biopsy, molecular testing to detect mutation in the gene encoding for the enzyme, and oxalate deposition on the renal biopsy are used to make the diagnosis.

Recurrent oxalate deposition can occur very rapidly after transplant in patients with primary hyper-oxaluria and can lead to acute tubular necrosis and graft failure.

High dose pyridoxine converts glycoxylate to glycine instead of oxalate and can be effective in preventing further deposition. Liver- kidney transplant substitutes the missing enzyme in type 1 primary hyper-oxaluria. Patients with liver-kidney transplants have better kidney allograft survival than patients who undergo kidney alone transplantation in type 1 primary hyper-oxaluria. Patients with type 2 primary hyper-oxaluria, who undergo kidney alone transplantation have a good prognosis since the enzyme is present in both liver and other tissues.

Secondary oxalosis is usually intestinal in origin and is seen in patients with inflammatory bowel disease and intestinal bypass. Gastric bypass should be reversed prior to proceeding with transplant, if possible. Patients need to be on therapy for hyper-oxaluria post transplantation to prevent deposition.

Infections

Kidney transplant recipients are extremely vulnerable to hospital acquired bacterial infections, pyelonephritis, viral infections (BK virus, CMV, adenovirus, JC virus) in the immediate post transplant period. Sepsis and infections can lead to development of acute tubular injury and graft dysfunction. By far the most common viral cause of allograft dysfunction is BK virus infection.

BK virus infection

BK virus is a human double stranded DNA virus, belonging to the family polyomaviridae. In healthy humans, the peak incidence of primary infection is in childhood at an age of 2 to 5 years, after which it lies latent in the genitourinary tract. Reactivation of this virus occurs in the setting of immunosuppression. Approximately 10 to 40% of kidney transplant recipients develop BK viruria, 10-20% develop BK viremia, and 2-5 % progress to develop BK nephropathy. Over-immunosuppression has been implicated in the reactivation and development of this disease. The prevalence has increased over the last decade in part due to better diagnostic recognition but also due to the overall increased potency of immunosuppression.

Clinical presentation

Patients usually are asymptomatic. Sometimes they can have microscopic hematuria, pyuria, cellular casts, hemorrhagic cystitis or acute allograft dysfunction. Some patients can have ureteral stenosis. BK virus infection can present as early as in the first few weeks after transplant, has its peak during the first year and is rarely seen more than 2 years after surgery, although it has been reported as far as 5 years after transplant.

Diagnosis

Routine regular screening for BK virus infection has become standard of care after transplantation by blood or urine polymerase chain reaction (PCR). As a consequence, BK virus infection is usually detected before it causes nephropathy. Urine cytology can show large decoy cells (cell with enlarged nuclei with a single large basophilic intra- nuclear inclusion body; see Figure 3), but decoy cells are not specific for BK virus, can be seen in other viral infections, and are not used anymore by the vast majority of transplant centers at the present time to diagnose BK infection.

BK nephropathy can be a presumptive diagnosis when BK viremia is positive in the setting of allograft dysfunction, or, better, a more definitive diagnosis can be made by renal biopsy.

Allograft biopsy in patients with BK nephropathy resembles acute cell mediated rejection with focal areas of tubulo-interstitial inflammation. Large intra-nuclear inclusion bodies can be seen in the nucleus of tubular epithelium. Immunohistochemistry using an antibody against SV40 can detect viral infection. Other techniques that can be used include electron microscopy and in situ hybridization. Drachenberg et al have proposed a staging scheme to assess the extent of infection (a) mild, viral cytopathic/cytolytic changes, with absent or minimal inflammation involving isolated tubules; (b) moderate and severe, cytopathic/cytolytic changes associated with patchy or diffuse tubulo-interstitial inflammation and atrophy; (c) advanced, graft sclerosis with rare or absent viral cytopathic changes, indistinguishable from chronic allograft nephropathy.

Treatment

The main goal of the treatment is to reduce overall immunosuppression in patients with BK viremia with or without nephropathy. Most transplant centers have instituted a variety of protocols for reducing immunosuppression.

There are currently no approved anti-viral agents which are effective against this virus. Some centers have used cidofovir in the past, but this medication is highly nephrotoxic. Leflunomide has not been clearly demonstrated to be useful in BK nephropathy, and its use has steadily decreased over time. Quinolones, initially thought to have an effect against viral replication, have been proven not to be useful and should not be used for the purpose of treating BK infection.

IVIG has been used and may have beneficial effects on BK viral infection. Although clear data on efficacy of IVIG in BK infection are still lacking, based on the relative low side effects of this medication, we currently use it in cases of BK viremia/nephropathy not responding to reduction of immunosuppression.

Pulse of intravenous methylprednisolone at a dose of 250 mg daily for three days, not followed by tapering steroid therapy, and concomitant reduction of overall immunosuppression, usually reduction of CNI or antimetabolite dose, has been proposed in cases of severe inflammation present at the biopsy, in order to reduce the evolution toward interstitial fibrosis and tubular atrophy, but further validation of this approach is needed.

Prognosis

Thirty to sixty percent of patients with BK nephropathy progress to develop persistent and significant allograft dysfunction. Biopsy may show advanced fibrosis and tubular loss. To improve outcomes, most transplant centers have developed protocols to monitor for BK infection in order to intervene early.

What tests to perform?

Renal function measurements should be obtained daily. Urine output and extent of volume overload should be monitored, like other patients with acute kidney injury (AKI). Urine protein/creatinine ratio and urinalysis should be obtained to determine the extent of proteinuria, if any. A measure of donor specific antibody should be obtained in the context of suspected AMR.

Renal ultrasound should be obtained to rule out obstruction or other post renal causes. See management in prerenal and post renal causes.

Allograft biopsy is the “gold standard” to assist in diagnosis and prognosis of intrinsic causes. Pathology should be processed for light microscopy and should include immunostaining for C4d (to help with the diagnosis of AMR) and SV40 antigen (to diagnose BK nephropathy). Biopsy pathology should be analyzed and a diagnosis should be given using Banff criteria. In the setting of acute recurrent disease, electron microscopy may be warranted.

How should patients with early graft dysfunction related to intrinsic causes be managed?

Delayed graft function

Modification of pre-engraftment factors may reduce the rate of DGF. Euvolemic or hypervolemic state in the recipient should be maintained after engraftment to ensure adequate perfusion to the allograft. Prolonged warm and cold ischemic time, hypotension and vessel injury during procurement surgery predispose the kidney to tubular injury; hence, many centers utilize hypothermic machine perfusion, which has been shown to decrease the rate of DGF and is associated with improved graft survival at 1 year over static cold storage.

Duplex ultrasonography or renal nuclear imaging should be done at regular intervals to rule out thrombosis, urinary obstruction or urine leak in oliguric patients. Core renal biopsy may be performed in case of persistent DGF on day 7 – 14 to rule out acute rejection (Figure 1). Some centers delay the use of CNI in patients with DGF. Some centers also advocate the use of depletional induction therapy with polyclonal anti-thymocyte globulin when DGF is anticipated. Sirolimus delays the recovery from ATN. CNIs may contribute to renal ischemia. Oxygen scavengers, I CAM 1, monoclonal antibody and pentoxiphylline have not been beneficial so far. Finally, the oliguric phase of injury is typically followed by a diuretic phase and adequate volume repletion in the recipient is mandated to avoid volume contraction and hypotension, CNI, which can prolong injury in the recovering allograft.

Antibody mediated rejection (AMR)

There are several goals of treatment of AMR:

To remove the cytotoxic donor- specific antibody
To suppress the formation of antibody
To deplete the B memory and naïve cells
To suppress the T-cell dependent antibody injury
To remove antibody producing plasma cells
To block the activation of complement
To increase the overall immunosuppression

Role of plasmapheresis

Intravenously administered immunoglobulin (IVIG)

Inhibition of complement activation and complement mediated inflammation
Suppression of cell mediated immunity, both B and T cell.
Modulation of the innate response by action on dendritic cells
Inhibition of the production of pro-inflammatory cytokines and adhesion molecules from monocytes and macrophages
Promotion of excretion of antibody by the kidney

Rituximab – chimeric anti-CD20 (anti B cell) monoclonal antibody

Other effects include depriving T cells of antigen presenting cell activity provided by antigen- specific B cells thus altering the T-cell effector mechanism. Rituximab is currently approved for CD20 positive lymphoma and rheumatoid arthritis, but it has found wide application in the treatment of autoimmune disorders, vasculitis, and post transplant lymphoproliferative disorder (PTLD). It has found its role as a combination therapy with plasmapheresis and IVIG in treatment of acute antibody mediated rejection and in desensitization protocols. There are a large number of small studies which have shown that patients with AMR treated with plasmapheresis, IVIG, and Rituximab as a combination therapy have better graft survival than patients treated with high dose IVIG alone or the combination of IVIG and plasmapheresis. Rituximab is given as an intravenous infusion, at a dose of 375 mg/m2, or 1 g for 2 infusions, but the dose and number of infusions are variable and center dependent. Common side effects are infusion reaction and hypotension. Complications include bacterial and fungal infections, leucopenia. Rituximab can cause fulminant hepatitis in patients who are positive for hepatitis B, and hepatitis testing should be performed and reviewed before administration of this medication.

Evolving Approaches to AMR

Bortezomib- proteasome inhibitor

Bortezomib is a modified dipeptidyl boronic acid analog that binds to 26 s proteasome, present in cytoplasm and nucleus of cells, selectively and reversibly. Inhibition of this proteasome leads to alteration of multiple signaling pathways, which then ultimately leads to cell apoptosis (programmed cell death). Bortezomib causes plasma cell apoptosis in the bone marrow with subsequent inhibition of antibody production. Small single center studies have shown: 1) reversal of cell mediated as well as antibody mediated rejection; 2) significant reduction of anti- HLA antibodies specifically donor specific antibody; and 3) improved renal allograft function. The effect lasted for at least a few months. Side effect profile includes fatigue, weakness, anorexia, gastro-intestinal toxicity, paresthesias, peripheral neuropathy, thrombocytopenia, neutropenia and psychiatric disorders.

Eculizumab

Splenectomy

Acute cellular rejection

Treatment of T-cell mediated rejection is dependent on the biopsy finding. When the suspicion for cellular rejection is high, treatment with intravenous methylprednisone, 500 mg daily for 3 consecutive days, may be started even before the biopsy results are known. Patients with only tubulointerstitial inflammation (borderline, 1a, 1b) may respond to steroids with improvement in urine output and serum creatinine. If there is an inadequate response to steroids, or if the rejection is an aggressive 1b, then a T- cell depleting agents should be considered. Vascular rejection (Banff 2, 3) is typically refractory to steroids and requires treatment with a T cell depleting agent (intravenous anti-thymocyte globulin 1-1.5 mg/kg for 5 -10 days, or alemtuzumab, anti CD 52 agent, 30-60 mg for 2 doses). OKT-3 is not available in the US anymore, due to severe toxicity.

Recurrent focal segmental glomerulosclerosis

In patients who are at high risk of recurrence (rapid progression of the disease with need for dialysis within 6 months from the diagnosis, young age, or recurrence in previous transplant), institution of plasmapheresis before the transplant can reduce the risk of recurrence. We start plasmapheresis three days before the transplant, and repeat the day before the transplant, and continue twice from the day after the transplant. This can be done only if the transplant is from a living donor. We perform plasmapheresis with plasma instead of albumin to reduce the risk of bleeding related to the removal of clotting factors with plasmapheresis. Recurrent FSGS can still happen after prophylactic plasmapheresis. Although there is not a commonly accepted and widely demonstrated successful way of treating early recurrent FSGS, many transplant centers use plasmapheresis (some transplant centers use immunoadsorption), IVIG, high dose steroids, cyclosporine and rituximab in various combinations. Some centers use Cytoxan. Recently rACTH (Acthar®) has been reported to be useful in the treatment of recurrent FSGS, but more data is needed. Various protocols are available for treatment, but none has been standardized or validated. ACE inhibitors and ARBs can be used as antiproteinuric agents if tolerated. Statins should be prescribed in patients with hypercholesterolemia.

Recurrent hemolytic uremic syndrome (HUS)

Eculizumab: This humanized monoclonal antibody against complement C5 ultimately prevents the formation of C5-9 membrane attack complex and generation of prothrombotic C5a.

Liver- kidney transplantation: There have been some case reports of combined liver and kidney transplantation, which has been successful in treating HUS in patients with complement factor H mutation.

BK virus infection

The main goal of the treatment is to reduce overall immunosuppression in patients with BK viremia with or without nephropathy. Most transplant centers have instituted a variety of protocols for reducing immunosuppression.

There are currently no approved anti-virals agents which are effective against this virus. Some centers have used cidofovir in the past, but this medication is highly nephrotoxic. Leflunomide has not been clearly demonstrated to be useful in BK nephropathy, and its use has steadily decreased over time. Quinolones, initially thought to have an effect against viral replication, have been proven not to be useful and should not be used for the purpose of treating BK infection.

IVIG has been used and may have beneficial effects on BK viral infection. Although clear data on efficacy of IVIG in BK infection are still lacking, based on the relative low side effects of this medication, we currently use it in cases of BK viremia/nephropathy not responding to reduction of immunosuppression.

Pulse of intravenous methylprednisolone at a dose of 250 mg daily for three days, not followed by tapering steroid therapy, and concomitant reduction of overall immunosuppression, usually reduction of CNI or antimetabolite dose, has been proposed in cases of severe inflammation present at the biopsy, in order to reduce the evolution toward interstitial fibrosis and tubular atrophy, but further validation of this approach is needed.

What happens to patients with early graft dysfunction related to intrinsic causes?

Outcome depends on diagnosis and timely intervention.

– Delayed graft function

ATN usually resolves without intervention other than supportive measures. It may take 4-6 weeks to see a full resolution. The impact of delayed graft function (DGF) is significant and is associated with reduced 1-year graft survival rates of at least 10% and a reduction in allograft half-life by 2 years.

– Antibody mediated rejection

Acute AMR, when treated appropriately, may resolve in 2-4 weeks, depending on treatment response. Prognosis of AMR is variable, but in general allograft survival rate is worse after AMR, as therapy may not cause resolution of the process.

– Acute cellular rejection

Outcomes vary depending on baseline renal function and the extent of injury. Acute cellular rejection of mild or moderate grades should resolve in the first week after successful treatment. More severe episodes may require supportive dialysis. A good prognostic feature is renal function that returns to baseline after treatment. Poor prognostic features are mixed antibody/cellular rejections, the presence of hemorrhage and fibrinoid necrosis with vascular injury, as well as serum creatinine that remains elevated. A biopsy after treatment course may be indicated if allograft function remains elevated. Concurrent AMR should be excluded with an assessment of donor specific antibodies.

Biopsy interpretation may highlight more than one diagnosis present at the same time, such as cellular and antibody mediated rejection. Each has its own management strategy and both should be addressed simultaneously to insure return of renal function to baseline.

– De novo thrombotic microangiopathy

The graft prognosis is poor unless the insulting agent is removed promptly, and plasmapheresis is instituted early on if the patient does not respond to removal of the agent causing TMA.

– BK virus infection

Thirty to sixty percent of patients with BK nephropathy progress to develop persistent and significant allograft dysfunction. Biopsy may show advanced fibrosis and tubular loss. To improve outcomes, most transplant centers have developed protocols to monitor for BK infection in order to intervene early.

How to utilize team care?

Involvement of the transplant medical and surgical teams, as well as transplant pharmacy is appropriate. Consultation with the plasmapheresis team is needed to coordinate timing of treatment and infusion of appropriate biologics.

Are there clinical practice guidelines to help with the decision-making process?

There are two clinical practice guidelines published but both focus on later post transplant management. Nevertheless, they do provide some context for early management.

Other considerations

ICD-10 codes specific for transplant

Kidney transplant status – Z94.0

Kidney transplant rejection – T86.11

Other complication of kidney transplant – T86.19

Encounter for aftercare following kidney transplant – Z48.22

ICD-10 codes not specific for transplant

Acute kidney injury, unspecified N17.9

Acute kidney injury with ATN N17.0

Unspecified nephritic syndrome with focal and segmental glomerular lesions – N05.1

Adverse effect of antineoplastic and immunosuppressive drugs, initial encounter – T45.1X5A

Thrombotic microangiopathy – M31.1

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Nephrology Hypertension

Kidney Transplantation: Diagnosis and Management of Early Graft Dysfunction – Intrinsic Causes and Treatments