Nephrology Hypertension

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

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. However, 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 of transplantation) (Figure 1)

Figure 1.

Management of oliguria/anuria after transplant.

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

Figure 2.

Management of elevated serum creatinine in early pre-transplant period (1 week-12 weeks).

(3) graft dysfunction after 3 months of transplantation.

Much like the causes of acute kidney injury, allograft dysfunction can be considered using the pre-renal, post-renal and intrinsic-renal etiologies. Differential diagnosis is impacted based on the timing postoperatively. This chapter focuses on intrinsic-renal 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 in first week post transplant. ATN is the most common cause of DGF. ATN is a histological diagnosis characterized by oliguric acute renal failure and is a result of ischemia- reperfusion injury.

  • What is the incidence of DGF?

    The incidence of DGF in recipients of deceased donor kidneys varies from increased from 17% in donors ages 15-20 to 40% when the donor was over 65 (adapted from UNOS 1998).

  • What is 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: older donor age, hypertension, volume contraction, decreased cardiac output, pre-transplant dialysis, atherosclerosis of recipient vessels and preformed donor specific antibodies, brain death of donor, and exposure to nephrotoxins.

  • 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 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 – 10 to rule out acute rejection (Figure 1).

Acute Tubular necrosis

  • ATN is the most common cause of DGF. ATN is a histological diagnosis characterized by oliguric acute renal failure and is a result of ischemia- reperfusion injury. ATN is clinically a diagnosis of exclusion after ruling out other causes of DGF or a histological diagnosis.

  • 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 leads 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.

  • ATN is a diagnosis of exclusion after other catastrophic causes (Figure 1) have been ruled out by renal imaging. It is typically a clinical diagnosis, but allograft biopsy may be necessary to guide management, particularly in scenarios of DGF lasting weeks.

  • 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 globluin in cases where 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, which can prolong injury in the recovering allograft.

“Hyperacute” Antibody Mediated Rejection

Definition:

Previously called “hyperacute rejection,” accelerated rejection of the kidney allograft was seen in the first 72 hrs of transplantation and is typically a result of preformed cytotoxic donor-specific antibodies, such as anti- HLA antibodies, anti-endothelial antibody or ABO isoagluttinins. This response may result 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 a rare event.

Presentation and evaluation

Clinical presentation may occur as soon as the vascular anastamosis 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 HLA 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 leucocytes infiltration especially in thrombi.

Immunoflorescence 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.

Differential diagnosis includes renal artery or vein thrombosis, thrombotic microangiopathy or recurrent HUS.

Treatment:

Immediate surgical exploration of the allograft and and intra-operative biopsy 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 preexisting donor specific antibodies (DSA) or de novo antibody formation (anti- HLA or non- HLA antibodies). The estimated rate of AMR is 5-10% in the first year of kidney transplantation.

Diagnosis of AMR is based on three criteria

  1. The detection of donor specific antibody (typically HLA antibody)

  2. The presence of C4d deposition (degradation product of complement activation) in the peri-tubular capillaries on kidney allograft biopsy

  3. Pathological findings of tissue injury

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

There are three major risk factors for the development of AMR. They include:

- Immune sensitization prior or after transplant

- Pre-existing donor specific antibody

- ABO incompatible transplantation

Treatment of AMR

There are several goals in treating AMR:

  1. To remove the cytotoxic donor- specific antibody

  2. To suppress the formation of antibody

  3. To deplete the B memory and naïve cells

  4. To suppress the T-cell dependent antibody injury

  5. To remove antibody producing plasma cells

  6. 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). They are 5 types of immunoglobulin – M, A, G, E, D - and all of them have their individual defense mechanism in the 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 to understand the immune-modulatory and anti- inflammatory effects of IVIG in solid organ transplant. The mechanisms include:

  1. Inhibition of complement activation and complement mediated inflammation

  2. Suppression of cell mediated immunity, both B and T cell.

  3. Modulation of the innate response by its action on dendritic cells

  4. Inhibits the production of pro-inflammatory cytokines and adhesion molecules from monocytes and macrophages

  5. Promotes excretion of antibody by the kidney

Various centers have used IVIG in conjunction with plasmapheresis with/without rituximab. Most protocols describe using 100mg/kg of IVIG after each session of alternate day plasmapheresis, followed by 2 gm/kg of IVIG at the end of plasmapheresis, 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).

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) which 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. There are a large number of small studies which have shown that patients with AMR treated with PP/IVIG /Rituximab as a combination therapy have better graft survival than patients treated with high dose IVIG alone or IVIG/PP combination.Rituximab is given at a dose of 375 mg/m2, intravenous infusion per session with a total of 1 to 4 doses, which is again center dependent. Common side effects are infusion reaction and hypotension. Complications include bacterial and fungal infections, leucopenia.

Evolving Approaches to AMR

Bortezomib- proteosome inhibitor

Bortezomib is a modified depeptidyl boronic acid analog that binds to 26 s proteosome, present in cytoplasm and nucleus of cells, selectively and reversibly. Inhibition of this proteosome leads to alteration of multiple signaling pathways which then ultimately leads to cell apoptosis. Bortezomib causes plasma cell apoptosis (programmed cell death) in bone marrow that can inhibit 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 needs to be established, but the results so far have been promising. Further studies are underway in recipients of kidney transplants as well as other sensitized solid organ recipients.

Eculizumab

This biologic agent (a 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 ameliorates the injury of antibody activation. Preliminary studies of this agent in humans demonstrate reduced intensity of antibody injury decreased rates of AMR in 10 patients when treated with eculizumab in combination with PP/IVIG. No adverse effects were reported. Further multicenter studies are underway to demonstrate the safety and efficacy of this therapy.

Splenectomy

Splenectomy has been used by few centers as a rescue therapy for severe AMR that failed to respond to plasmapheresis and IVIG. Patients usually develop high levels of donor specific antibody titers immediately after transplantation and splenectomy helps 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 the process of immune mediated injury of the kidney. It is identified by mononuclear cell, eosinophil and plasma cell infiltration of interstitium of the kidney and tubules of a renal allograft, and is associated with endothelitis in severe cases. The histological classification is based on the degree and extent of mononuclear inflammation, 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 (polyoma nephropathy, CMV nephritis etc) and in post transplant lymphoproliferative disorder (PTLD).

Table I.

Banff Classification for T-Cell Mediated Rejection

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, decrease 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, one should rule out viral nephritis by checking viral titers and viral stain on the allograft biopsy, bacterial infection and drug induced hypersensitivity interstitial nephritis.

Treatment

Treatment of T-cell mediated rejection is dependent on the biopsy finding and steroid responsiveness. When the suspicion is high, one can start treatment with intravenous methylprednisone, 3-5 mg/kg for 3-5 consecutive days even before the biopsy results. 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, then consider treating with a T- cell depleting agents. Vascular rejection (Banff 2, 3) is typically refractory to steroids and requires treatment with a T cell depleting agent (anti-thymocyte globulin 1-1.5 mg/kg iv for 7 -1 4 days, OKT-3, 5 mg/kg iv for 7-14 days, or alemtuzumab –anti CD 52 agent, 30-60 mg for 2 doses).

Patients on cyclosporine based regimen are usually switched to tacrolimus and low dose prednisone should be added to patients on 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 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.

Recurrent Disease

  • Certain glomerular diseases such as primary focal segmental glomerulosclerosis (FSGS), hemolytic uremic syndrome (HUS) and pauci immune glomerulonephritis have been reported to recur in immediate post transplant period and can lead to significant graft dysfunction.

Recurrent FSGS

  • The reported rate of recurrence of FSGS is 20%- 30 % in renal allografts. The true incidence of recurrent primary FSGS is underestimated because of the heterogeneity of the disease and lack of biopsy in many patients. White and hispanic ethnicities, rapid progression of disease, young age or recurrence in previous transplant are some of the risk factors associated with recurrent FSGS. The rate of recurrence may be higher in patients with primary FSGS.

  • Clinical presentation

    Early recurrent FSGS typically presents with nephrotic range proteinuria; some patients present with full-blown nephrotic syndrome- proteinuria, hypo-albuminemia, hypercholesterolemia and edema. Late recurrence is usually insidious and develops gradually over the 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 6 – 8 weeks. A biopsy should be performed, if there is an increase in baseline proteinuria or new onset proteinuria.

    De novo FSGS should also be considered in differential of proteinuria after transplantation. Viral infection such as parvovius, EBV, hepatitis C and HIV 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 and the absence of any changes on light microscopy. Multiple thin cut sections should be performed through the glomeruli to look for any sclerotic lesion.

  • Treatment

    Recurrent early FSGS has been successfully treated by some groups by plasmapheresis /immunoadsorption, IVIG, high dose steroids, cytoxan, cyclosporine and rituximab in various combinations. Various protocols are available for treatment, but none have been standardized so far. ACE inhibitors and ARBs should be used as antiproteinuric agents if tolerated. Statins should be prescribed in patients with hypercholesterolemia.

Recurrent Hemolytic uremic syndrome(HUS)

After renal transplantation, HUS can occur as both de-novo disease 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 liver.

Clinical presentation

HUS can present as early as few days with severe hypertension and rapid allograft dysfunction. Recurrence may be triggered by viral, bacterial infection, immunization or ischemia reperfusion injury resulting in activation of complements. The recurrence can be catastrophic for the new allograft depending on the kind of mutation. Differential diagnosis includes CNI induced thrombotic micro-angiopathy, 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

On light microscopy one can see thrombi present in the lumen of arterioles and glomerular capillaries. In severe cases it can lead to tissue necrosis, which may progress to cortical necrosis. Pronounced intimal changes are present in the interlobular arteries in the case of recurrent disease which is not seen in cases of CNI induced thrombotic microangiopathy. A C4d stain should be performed to differentiate between recurrent disease and acute vascular rejection.

Treatment

Plasma exchange: Large volumes of plasma exchange pre and post transplant to remove the mutated protein and replace them with normal proteins have been attempted with equivocal results. Patients with auto-antibodies against complement factor H have been successfully transplanted with plasma- exchange, rituximab and high dose steroids.

Eculizumab: This humanized monoclonal antibody against complement C5 ultimately prevents the formation of C5-9 membrane attack complex and generation of prothrombotic C5a. There are case reports of using eculizumab successfully as a treatment for recurrent HUS in combination with plasmapheresis.

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

It is important to know the kind of mutation in patients with atypical HUS prior to listing them on the transplant list and all patients should be counseled.

De novo thrombotic microangiopathy (TMA)

De novo TMA is associated with both cyclosporine and tacrolimus. There are cases of TMA associated with high dose OKT3 (10mg/kg) and use of sirolimus, as well as leflunomide. The other factors that have been associated with de-novo TMA are prolonged warm ischemia time, kidney transplant from donor who died with cardiac death, antibody mediated rejection, anti-phospholipid syndrome, antibodies against von-willebrand factor, HIV infection, mutation in complement regulators and de-novo carcinoma. The incidence for de-novo HUS – TTP is reported to be in 3-15 % of cases.

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

The graft prognosis is very poor unless the insulting agent is removed and plasmapheresis is instituted early on.

Recurrent Glomerulonephritis

There are case reports of recurrence of anti- GBM disease, membranous nephropathy, MPGN, pauci-immune vasculitis soon after renal transplantation.

Recurrent Oxalosis

Recurrent oxalate deposition can occur very rapidly in children with primary hyper-oxaluria and can lead to acute tubular necrosis and graft failure. In cases of primary hyper-oxaluria, patients are deficient in hepatic enzyme alanine glycoxylate aminotransferase (type 1) or glyoxylate reductase/hydroxypyruvate reductase (type 2) responsible for oxalate metabolism, leading to oxalate deposition in all the body parts. Clinical history, elevated urine oxalate levels, detection of enzyme defect in liver, molecular testing to detect mutation in the gene encoding for the enzyme, and oxalate deposition on the renal allograft biopsy are used to make the diagnosis of recurrent oxalosis in the transplant allograft.

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 underwent 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. One should reverse the bypass prior to proceeding with transplant if possible. Patients need to be on preventive 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.

  • BK virus infection

    BK virus is a human double stranded DNA virus, belonging to the family of papoviridae. 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 potency of immunosuppression.

  • Clinical presentation

    Patients can be asymptomatic. It can present with microscopic hematuria, pyuria, cellular casts, hemorrhagic cystitis or acute allograft dysfunction. It can present as early as first week and has been seen up to 5 years after transplant.

  • Diagnosis

    A number of methods can be used for diagnosis. Urine cytology can show large decoy cells-(cell with enlarged nuclei with a single large basophilic intra- nuclear inclusion body; see Figure 3). Decoy cells are not specific for BK virus and can be seen in other viral infections. Patients with high levels of viruria may develop viremia which can be measured in the serum by polymerase chain reaction (PCR). Prolonged BK viremia usually precedes the BK nephropathy.

Figure 3.

Urine decoy cells. Upper panel shows low power view of spun urine stained with Sedi-Stain demonstrating hematuria and large cells with dense nuclei, some undergoing division. Lower panel with high power view of decoy cells.

Allograft biopsy in patients with BK nephropathy resembles acute cell mediated rejection with focal areas tubulo-interstitial inflammation at the site of viral infection. Importantly, large intra-nuclear inclusion bodies can be seen in nucleus of tubular epithelium and sometimes in the parietal wall of the glomeruli. Immunohistochemistry using an antibody against the cross-reacting SV40 large-T antigen in BK and other polyoma viruses can detect viral infection. Other techniques used may 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. Most transplant centers have instituted a variety of protocols for reducing immunosuppression. There are no currently approved anti-virals effective against this virus. Some centers have used leflunomide or cidofovir (which is highly nephrotoxic). Adjunctive therapies used based on small studies include IVIg, and quinolones which block DNA gyrase and therefore viral replication. However, these therapies have not been tested in larger, randomized clinical trials.

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 and with rapidly rising serum creatinine, twice daily to monitoring potassium and pH. Urine output and extent of volume overload should be monitored, much like other patients with AKI (please refer to the AKI management chapter). Urine protein and creatinine rato 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 cause. Typically, these studies may be peformed in the global context of understanding the loss of renal function. 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 and SV40 antigen to rule out BK infection. Biospy pathology may be analyzed using Banff allograft criteria (REF). In the setting of acute recurrent disease, electron microscopy may be additive.

Outcome is dependent on diagnosis. ATN usually resolves, and may take an additional 4-6 weeks to see full resolution. Acute cellular rejection of moderate grades when treated should resolve in the first week, and more severe episodes may require supportive dialysis. Similarly antibody mediated rejection may resolve in 1-2 weeks, depending on treatment response.

Biopsy interpretation may highlight superimposed diagnoses, 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.

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 on day 7 – 10 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 globluin in cases where 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,. which can prolong injury in the recovering allograft.

Hyperacute anitbody mediated rejection

There are several goals in treating AMR:

  1. To remove the cytotoxic donor- specific antibody

  2. To suppress the formation of antibody

  3. To deplete the B memory and naïve cells

  4. To suppress the T-cell dependent antibody injury

  5. To remove antibody producing plasma cells

  6. To increase the overall immunosuppression

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). They are 5 types of immunoglobulin – M, A, G, E, D - and all of them have their individual defense mechanism in the 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 action have been identified both in vivo and in vitro to understand 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 its action on dendritic cells

Inhibits the production of pro-inflammatory cytokines and adhesion molecules from monocytes and macrophages

Promotes excretion of antibody by the kidney

Various centers have used IVIG in conjunction with plasmapheresis with/without rituximab. Most protocols describe using 100mg/kg of IVIG after each session of alternate day plasmapheresis, followed by 2 gm/kg of IVIG at the end of plasmapheresis, 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.

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) which 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. There are a large number of small studies which have shown that patients with AMR treated with PP/IVIG /Rituximab as a combination therapy have better graft survival than patients treated with high dose IVIG alone or IVIG/PP combination.

Rituximab is given at a dose of 375 mg/m2, intravenous infusion per session with a total of 1 to 4 doses, which is again center dependent. Common side effects are infusion reaction and hypotension. Complications include bacterial and fungal infections, leucopenia.

Evolving Approaches to AMR

Bortezomib- proteosome inhibitor

Bortezomib is a modified depeptidyl boronic acid analog that binds to 26 s proteosome, present in cytoplasm and nucleus of cells, selectively and reversibly. Inhibition of this proteosome leads to alteration of multiple signaling pathways which then ultimately leads to cell apoptosis. Bortezomib causes plasma cell apoptosis (programmed cell death) in bone marrow that can inhibit 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 needs to be established, but the results so far have been promising. Further studies are underway in recipients of kidney transplants as well as other sensitized solid organ recipients.

Eculizumab

This biologic agent (a 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 ameliorates the injury of antibody activation. Preliminary studies of this agent in humans demonstrate reduced intensity of antibody injury decreased rates of AMR in 10 patients when treated with eculizumab in combination with PP/IVIG. No adverse effects were reported. Further multicenter studies are underway to demonstrate the safety and efficacy of this therapy.

Splenectomy

Splenectomy has been used by few centers as a rescue therapy for severe AMR that failed to respond to plasmapheresis and IVIG. Patients usually develop high levels of donor specific antibody titers immediately after transplantation and splenectomy helps 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

Treatment of T-cell mediated rejection is dependent on the biopsy finding and steroid responsiveness. When the suspicion is high, one can start treatment with intravenous methylprednisone, 3-5 mg/kg for 3-5 consecutive days even before the biopsy results. Patient with only tubulointersitial inflammation (borderline, 1a, 1b) may respond to steroids with improvement in urine output and serum creatinine. If there is an inadequate response to steroids, then consider treating with a T- cell depleting agents. Vascular rejection (Banff 2, 3) is typically refractory to steroids and requires treatment with a T cell depleting agent (anti-thymocyte globulin 1-1.5 mg/kg iv for 7 -1 4 days, OKT-3, 5 mg/kg iv for 7-14 days, or alemtuzumab –anti CD 52 agent, 30-60 mg for 2 doses).

Patients on cyclosporine based regimen are usually switched to tacrolimus and low dose prednisone should be added to patients on steroid free regimen. If T cell depletion is used, center-specific prophylaxis for opportunistic infections should be followed.

Recurrent focal segmental glomerulosclerosis

Recurrent early FSGS has been successfully treated by some groups by plasmapheresis /immunoadsorption, IVIG, high dose steroids, cytoxan, cyclosporine and rituximab in various combinations. Various protocols are available for treatment, but none have been standardized so far. ACE inhibitors and ARBs should be used as antiproteinuric agents if tolerated. Statins should be prescribed in patients with hypercholesterolemia.

Recurrent hemolytic uremic syndrome (HUS)

Plasma exchange

Large volumes of plasma exchange pre and post transplant to remove the mutated protein and replace them with normal proteins have been attempted with equivocal results. Patients with auto-antibodies against complement factor H have been successfully transplanted with plasma- exchange, rituximab and high dose steroids.

Eculizumab

This humanized monoclonal antibody against complement C5 ultimately prevents the formation of C5-9 membrane attack complex and generation of prothrombotic C5a. There are case reports of using eculizumab successfully as a treatment for recurrent HUS in combination with plasmapheresis.

Liver- kidney transplantation

There have been some case reports in which liver transplantation in conjunction with kidney transplantation have been successful in treating HUS in patients complement factor H mutation.

It is important to know the kind of mutation in patients with atypical HUS prior to listing them on the transplant list and all patients should be counseled.

BK virus infection

The main goal of the treatment is to reduce overall immunosuppression in patients with BK viremia. Most transplant centers have instituted a variety of protocols for reducing immunosuppression. There are no currently approved anti-virals effective against this virus. Some centers have used leflunomide or cidofovir (which is highly nephrotoxic). Adjunctive therapies used based on small studies include IVIg, and quinolones which block DNA gyrase and therefore viral replication. However, these therapies have not been tested in larger, randomized clinical trials.

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

Delayed graft function

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.

Acute cellular rejection

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/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.

De novo thrombotic angiopathy

The graft prognosis is very poor unless the insulting agent is removed and plasmapheresis is instituted early on.

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 is appropriate. Consultation with the plasmapharesis team is needed to coordinate timing of treatment and infusion of appropriate biologics.

Are there clinical practice guidelines to inform decision making?

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

Typical lengths of stay--2-5 days depending on diagnosis. Outpatient management utizling plasmapharesis may be available at your center. Patients require daily laboratory monitoring.

What is the evidence?

Solez, K, Colvin, RB, Racusen, LC, Sis, B, Halloran, PF, Birk, PE. "Banff '05 Meeting Report: differential diagnosis of chronic allograft injury and elimination of chronic allograft nephropathy ('CAN')". Am J Transplant. vol. 7. 2007. pp. 518-526.

Racusen, LC, Colvin, RB, Solez, K, Mihatsch, MJ, Halloran, PF, Campbell, PM. "Antibody-mediated rejection criteria - an addition to the Banff 97 classification of renal allograft rejection". Am J Transplant. vol. 3. 2003. pp. 708-714.

Racusen, LC, Solez, K, Colvin, RB, Bonsib, SM, Castro, MC, Cavallo, T. "The Banff 97 working classification of renal allograft pathology". Kidney Int.. vol. 55. 1999. pp. 713-723.

Stegall, MD, Gloor, JM. "Deciphering antibody-mediated rejection: new insights into mechanisms and treatment". Curr Opin Organ Transplant. vol. 15. 2010. pp. 8-10.

"KDIGO clinical practice guideline for the care of kidney transplant recipients". Am J Transplant. vol. 9. 2009. pp. S1-D155.

Kasiske, BL, Vazquez, MA, Harmon, WE, Brown, RS, Danovitch, GM, Gaston, RS, Roth, D, Scandling, JD, Singer, GG. "Recommendations for the outpatient surveillance of renal transplant recipients. American Society of Transplantation". J Am Soc Nephrol. vol. 11. 2000. pp. S1-S86.

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