Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (569 page)

   Although 0 HLA-mismatched grafts generally have superior transplant outcomes compared to ≥1 HLA-mismatched grafts, some 0 HLA mismatches may be complicated by acute rejection, possibly due to incompatibilities at other minor HLA loci or the imperfect tissue typing methods used routinely. On the other hand, some ≥1 HLA-mismatched grafts have excellent graft outcomes, suggesting that certain HLA mismatches may be permissible under certain circumstances.

   HLA-DR mismatches are associated with the highest risk of acute rejection after kidney transplantation compared to mismatches at the HLA-A and HLA-B loci. Additionally, HLA mismatches exert their effects at different times posttransplant (e.g., the maximum effect of HLA-DR mismatching occurs within the first 6 months, whereas that of HLA-B mismatching arises 2 years posttransplant).

   The most common form of acute allograft rejection involves activation of recipient T cells directed against donor MHC antigens. Additionally, B cells may play an important role in the immune response to an allograft through the production of antibodies that either mediate acute or chronic rejection of the allograft (antibody-mediated rejection) or, in the case of acute cellular rejection, support recipient T cells.

   Acute renal allograft rejection is associated with acute deterioration in allograft function and specific pathologic changes in the graft. Most episodes of acute rejection occur during the first 6 months after transplantation, with many episodes occurring early after surgery.

   Although most patients who have acute rejection episodes are asymptomatic, some patients occasionally present with fever, malaise, oliguria, hypertension, and graft pain or tenderness. Differential diagnoses in symptomatic patients include viral infection (BK, CMV, and adenovirus), bacterial pyelonephritis, and urinary leak or obstruction.

   An acute rise in serum creatinine level over the patient’s baseline is the main laboratory finding in patients with acute allograft rejection. This finding, however, occurs relatively late in the course of rejection and usually indicates the presence of significant histologic damage. Other laboratory findings reported with acute rejection include decreased urinary output, proteinuria, appearance of urinary cellular or granular casts, decreased urine osmolality, and hyperchloremic renal tubular acidosis.

   Kidney biopsy is the gold standard for diagnosing acute rejection among transplant patients with deteriorating kidney function. The biopsy may show either cellular- or antibody-mediated rejection or both.

   Other noninvasive candidate methods for the diagnosis of acute kidney rejection include

   Sequential measurement of subsets of activated T cells by flow cytometry.

   Measurement of urinary concentration of mRNAs for the cytotoxic proteins perforin, granzyme B, and cyclophilin B by PCR (increased in acute rejection).

   Other biomarker candidates for determining acute rejection have been identified by urinary proteomic analysis by mass spectrometry, and they demonstrate good diagnostic performance.