Most of the data regarding pathophysiology of early stages of radiation nephropathy are derived from animal studies as human data are only available in late-stage disease . Identification of target cells susceptible to radiation damage is somewhat difficult in the kidneys as there are a number of different cell types that vary in their ability to proliferate and regenerate after initial insult. Studies showed early damage to glomerular and juxtaglomerular cells with glomerular thrombosis indicating that glomerulus is an important target of radiation [5]. Electron microscopy of porcine model revealed that 3 weeks after 9.8 Gy single dose radiation exposure, there was glomerular endothelial disruption and leukocyte adherence followed by subendothelial expansion with electron-lucent material [6]. There is also activation of renal plasminogen activator inhibitor-1 (PAI-1) localized to the glomerulus. PAI-1-increase likely leads to impaired fibrinolysis and increased thrombosis as well as fibrosis via attenuation of plasmin-mediated matrix degradation. Mesangial cells are also involved in radiation nephropathy with mesangiolysis evident in murine models as well as human studies [6] . Vasculature was also noted to be affected by radiation. In canine model, the vascular damage occurs as early as 3 weeks after single 15 Gy dose exposure with arterioles and small arteries most affected. The changes are characterized by hyalinization of intima, endothelial swelling and/or proliferation, and hypertrophy and/or proliferation of smooth muscle. By 24 weeks the changes are more consistent with fibrinoid necrosis and fibrosis of the vessel walls. Authors also identified tubular damage in their model. By 9 weeks, there was significant parenchymal loss and tubular atrophy, however, a number of cells showed evidence of regeneration and by week 11 there was significant improvement in volume and function of tubular epithelium. However, between weeks 13 and 24 there was a second wave of tubular atrophy believed to be secondary to vascular damage [7].

The role of renin angiotensin system (RAS) in radiation nephropathy is suggested by a number of animal studies which showed mitigation of the severity of the disease with administration of angiotensin converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB). However, there is no evidence of activation of RAS per se. In both pig and murine models blood renin levels were low or normal [8] .

Prior exposure to certain chemotherapy agents can potentiate radiation damage to the kidney. In a rat model of TBI (17 Gy) followed by bone marrow transplant, the renal function decreased in the dose-dependent fashion in the animals exposed to cisplatin or carmustine 3 months prior to TBI [9]. Busulfan, high dose cyclophosphamide, and fludarabine have also been reported as risk factors for TA-TMA [4, 10].

The pathological findings on kidney biopsies done in patients with radiation nephropathy reveal evidence of TMA including vascular endothelial damage with endothelial cell dropout, subendothelial widening, and double contours of the glomerular basement membrane. There is also mesangiolysis, platelet aggregation in capillary loops, glomerular capillary thrombi, red cell fragmentation, thickening of glomerular arteriolar intimal layer as well as tubular atrophy [11, 12]. The precipitating event is believed to be endothelial damage leading to dysregulated interaction between platelets and glomerular endothelium resulting in microthrombi and ischemic end organ damage. Another hypothesis was proposed to explain multi-target nature of radiation injury. Glomerular radiation injury may lead to egress of pathologic mediators into urinary space and this leakage might produce parenchymal fibrosis if tubular denudation is present [6] .

The renal tolerance to radiation therapy is largely determined by the use of either whole field (bilateral kidney irradiation) or partial field (unilateral uniform or unilateral segmental kidney radiation). The whole field radiation patients are further divided into subgroup of patients receiving TBI .

In the whole field radiation (excluding TBI), total dose associated with 5 % probability of renal dysfunction after 5 year (TD 5/5) range from 14 Gy delivered in two fractions to 23 Gy delivered over 5 weeks. TD 50/5 (50 % probability of renal dysfunction after 5 year) was 28 Gy [13].

TBI radiation tolerance data are somewhat complicated by the fact that the patients in this group are generally sicker and exposed to a number of nephrotoxic therapeutic and chemotherapeutic agents. Multivariate analysis of 12 studies reporting on nephrotoxicity (elevated creatinine or development of TMA) in a mixed pediatric and adult patient population undergoing TBI showed that the dose associated with 5 % risk of renal dysfunction was 9.8 Gy regardless of fractionation schedule (median dose 12 Gy; range 75–14; median fractions 6, range 1–11, delivered once or twice daily) [1]. In addition to the radiation dose, prior exposure to fludarabine, cyclosporine, and teniposide has also been shown to increase the risk of renal dysfunction after TBI [1]. Partial kidney irradiation also carries the risk of renal dysfunction. It has been shown that doses of 26–30 Gy delivered unilaterally are likely to eliminate functions in the irradiated kidney [5]. Treatment of one kidney and its renal artery may produce renal artery narrowing leading to renal artery stenosis and high renin HTN . This side effect is more common in infants and children and should be distinguished from other causes of radiation associated HTN. Both vascular surgery approach and nephrectomy have been used to address this phenomenon [5] .

Radiation nephropathy is characterized by late onset and generally manifests 6–12 months after exposure to radiation . The clinical features include worsening renal function, edema, new or worsening HTN, and microangiopathic hemolytic anemia (MAHA) . Renal dysfunction is generally gradual in onset and after a period of rising serum creatinine most patients enter a more stable state. However, some patients may progress to end stage kidney disease (ESKD) [4]. Evidence of hemolysis with anemia disproportionate to the degree of chronic kidney disease (CKD), thrombocytopenia, elevated serum lactate dehydrogenase levels, low serum haptoglobin, and schistocytes on peripheral smear may support the diagnosis of MAHA . However, not all patients develop MAHA. Some patients have kidney limited TMA with renal dysfunction, edema, and HTN as the only manifestations [14]. In patients with no evidence of MAHA the diagnosis of TA-TMA could be made clinically due to high degree of clinical suspicion or by renal biopsy. Recently, two working groups’ guidelines and one validation study were published to address noninvasive diagnostic criteria for TA-TMA [4]. Unfortunately, all three guidelines rely on laboratory hematologic parameters of MAHA and are likely to miss patients with isolated renal TMA.

Most patients undergoing TBI in conjunction with HSCT also are treated with calcineurin inhibitors (CNI) to prevent or treat graft versus host disease (GVHD). CNI are well documented to cause both renal dysfunction and TMA [15]. Therefore it is often difficult to distinguish the causative agent of TMA. In a classic review, Pettitt and Clark proposed four distinct but overlapping subtypes of TA-TMA [16]. First is an early onset (20–100 days post HSCT) type which occurs in patients receiving CNI. The risk factors included GVHD, CMV infections, and intense pre-transplant conditioning . The course is rapidly progressing and commonly fatal. This type was termed fulminant, multifactorial TMA. In the second, late onset (> 6 months), type the manifestations are predominantly renal with HTN, edema, and renal failure in association with MAHA but with minimal systemic manifestations and absence of significant GVHD. TBI is noted as a predisposing factor particularly if unfractionated or given with multiple chemotherapeutic agents. This type was named conditioning associated TMA. The remaining two subtypes are strongly associated with CNI use and manifest as either nephrotoxicity or neurotoxicity of these agents with clinical improvements after CNI discontinuation .