The most common donor-related histological abnormalities are secondary to long-standing arterial hypertension [17]. The large and small arteries show sclerosis and sclerosis with hyalinosis, respectively, leading to various degrees of luminal narrowing (Fig. 31.3). The interstitium shows increased fibrosis and there is corresponding atrophy of the tubular components. Subcapsular ischemic scars as well as a significant number of scattered obsolescent glomeruli are also indicative of chronic hypertension (nephrosclerosis). The Maryland aggregate pathology index (MAPI) is a histological scoring system based on the presence or absence of five morphological features associated with hypertensive/chronic ischemic renal parenchymal injury (hyalinosis of glomerular-size arterioles, >15 % global glomerulosclerosis, significant arterial sclerosis, periglomerular fibrosis, and cortical scar) which are assigned scores according to their relative significance. The MAPI has been shown to be predictive of post-transplant graft survival or failure [16].

Approximately 4 % of all kidney transplants in the United States are derived from diabetic donors [17, 18]. Identification of fully developed nodular diabetic glomerulosclerosis in a donor kidney biopsy is a contraindication for transplantation; however, milder diabetic glomerular involvement is compatible with acceptable outcomes [18, 19].

With the increased utilization of organs from older donors there has been an increase in the identification of renal cell carcinomas both in deceased and living donors (≈1 %). Organs with small, completely resected, low grade tumors are now routinely utilized for transplantation with excellent outcomes [20]. Frozen section evaluation is required for rapid histological characterization diagnosis of any donor mass. In this setting, the two most common lesions are small renal cell carcinomas and angiomyolipomas. The latter are benign connective tissue tumors that do not pose any risk to the recipient irrespective of their size [21].

A variety of other processes can be identified in pretransplant donor biopsies, one of the most common being mesangial IgA deposition and membranous nephropathy, both of which appear not to have a negative post-transplantation impact. Similarly, other forms of mild glomerulonephritis can resolve after transplantation [22]. In addition, we have seen successful outcomes after transplantation of kidneys with mild sarcoidosis and eclampsia-related glomerular injury. The decision about transplanting organs with known pathological processes is made after careful consideration, on a case-by-case basis.

Biopsies from patients with delayed graft function (DGF) in the early post-transplant period usually show acute tubular necrosis (ATN). This injury is presumed to be ischemic in nature as a result of the organ procurement procedures and reperfusion injury. Tubular injury can be subtle, consisting only of cytoplasmic vacuolization, loss of brush border, and isolated cell necrosis or apoptosis. In more pronounced cases there is frank disintegration and sloughing of the tubular cells that can accumulate as debris in the tubular lumina. When there is pronounced tubular cell loss there is flattening of the remaining tubular lining and partial denudation of the basement membranes. Tubular calcifications are common in areas of previous tubular injury (Fig. 31.4). Interstitial edema and mild interstitial inflammation, often including some eosinophils, can be present in ATN. If the inflammation is significant and there is tubulitis, a concurrent acute cellular rejection should be suspected. The presence of multifocal neutrophilic capillaritis and/or microscopic thrombi requires correlation with the C4d stain and DSA studies to rule out ATN associated with early acute AMR.

Severe ischemic injury often secondary to hemodynamic issues or surgical complications may result in focal of diffuse parenchymal necrosis. Localized infarcts are often unsuspected clinically and may become evident only in a needle biopsy for evaluation of DGF. Identification of infarction in core biopsies is usually associated with significant ischemic injury and always leads to subsequent fibrous scarring of the infarcted areas (Fig. 31.5). Therefore, depending on the extent of parenchyma involved, infarcts may be associated with poor graft function or primary non-function.

In patients with DGF, glomerular endothelial cell swelling and microthrombi that may mimic early acute AMR may result from ischemic injury to endothelial cells [25, 26] (Fig. 31.6). These changes are usually reversible unless the ischemic process has also led to multifocal areas of infarction. In patients with microvascular changes suspected to represent ischemic endothelial injury, examination of a C4d stain and serological studies to document the absence of DSA are necessary to confirm the purely ischemic nature of the injury.

Prolonged DGF or poor renal function may be the result of suboptimal perfusion of the graft due to preexisting vascular sclerosis (narrowing) [16]. In addition to the donor-related vascular sclerosis these biopsies may show frank ATN or milder forms of tubular injury (Fig. 31.4).

The most characteristic lesions of early acute AMR result from lytic endothelial cell graft injury due to damage by alloantibodies (i.e., anti-HLA DSA).

Specifically, circulating DSA in conjunction with complement activation leads to endothelial cell swelling and necrosis with superimposed formation of microthrombi. Accumulation of inflammatory cells (neutrophils and macrophages) in glomerular and PTC appearing as glomerulitis and capillaritis is also a common feature of acute AMR [4].

Early acute AMR develops in a proportion of pre-sensitized patients despite conditioning protocols and may also occur in the early post-transplantation period in patients with no apparent risk for AMR [30].

In contrast to milder forms of early acute AMR which are characterized by attenuated endothelial injury that may even resemble bland ATN, in hyperacute rejection, the most severe form of AMR, there are abundant preformed circulating antibodies leading to diffuse arterial and venous necrosis with secondary thrombosis and parenchymal infarction [4]. A diagnosis of pure acute AMR requires exclusion of features of T-cell-mediated rejection (CMR).

The current Banff classification of acute AMR is based on the combination of (1) C4d+, (2) the presence of circulating antidonor antibodies, and (3) morphologic evidence of acute tissue injury (see Table 31.3 [4, 31]). Acute AMR is categorized in types or grades I, II, or III (I. ATN-like minimal inflammation, II. capillary and or glomerular inflammation and/or thromboses, and III. arterial necrosis). In essence, the Banff Category I (C4d+ and ATN-like changes only) represents a milder form of Category II (characterized additionally by microvascular inflammation and microthrombi). Category III is defined by arterial fibrinoid necrosis resembling lesions seen in hyperacute rejection and therefore represents a more severe form of AMR in comparison to Categories I and II.

Differential diagnosis of acute AMR: The most important differential diagnosis of early acute AMR is ischemic injury leading to microvascular thrombosis [25, 26] (Fig. 31.6). History of prolonged cold ischemia time and/or surgical complications may support the impression of ischemic graft injury; however, evaluation of C4d staining and DSA studies are essential to rule out a concurrent component of acute AMR. In our experience some degree of C4d staining may be present in early biopsies with ischemic injury, but this typically resolves in subsequent biopsies. Renal function recovers in most patients with ischemic endothelial injury, unless there is very extensive microvascular thrombosis or infarcts which would eventually lead to diffuse glomerular sclerosis and formation of scars. TMA of other etiologies—including CNI toxicity—may also require differentiation from acute AMR (see section “Thrombotic Microangiopathy”).

Acute CMR is characterized by interstitial T-cell and macrophage infiltrates, tubular inflammation (tubulitis), and inflammation of the arterial endothelium (intimal arteritis). A diagnosis of pure acute CMR requires exclusion of AMR (evaluation of C4d stain and negative DSA studies).

The current Banff classification of acute CMR uses the following categories: Borderline—suspicious, Type I (A and B), Type II (A and B), and Type III (see Table 31.3).

Borderline changes: “Suspicious” for acute CMR is used when no intimal arteritis is present, but there are foci of tubulitis with minor interstitial infiltration or interstitial infiltration with only mild tubulitis.

On the other hand, Types I–III are considered diagnostic of acute CMR. In essence, Type I rejection is defined by tubulitis (Fig. 31.9), Type II is defined by arterial inflammation without necrosis (intimal arteritis, endarteritis) (Fig. 31.10), and Type III is characterized by arterial necrosis and accompanying lymphocytic inflammation (Fig. 31.11). Whereas Type II CMR (intimal arteritis) is the most diagnostic form, Type I requires differentiation from other causes of graft inflammation (i.e., PVN, infections, nonspecific inflammation) and Type III requires differentiation from AMR due to overlap of necrotizing vascular lesions in the severe forms of CMR and AMR.