In the USA and Europe, AL amyloidosis is currently the most prevalent type of systemic amyloidosis, but ALECT2 and hereditary amyloidoses are being diagnosed with increasing frequency [1, 13–16, 37, 38]. The incidence of AA, however, appears to be declining. In North America, AL contributes 85 % of cases, and worldwide >90 % of renal amyloids are of the AL/AA type with marked regional differences concerning the incidence of AA ([13, 14, 37, 38], please see also Chap. 20). Thus, while, in North America, AA is diagnosed in 3.5–7 % of kidney biopsies, in one large European series the incidence was reported to be 40 % [13, 14, 16, 38], although more recent studies report a declining rate of AA in European patients [39]. Thus, in the kidney, with a declining rate of AA in North America in particular, the non-AL/AA amyloidoses are collectively becoming the second most prominent group of amyloidoses. Discovered in 2008, ALECT2 has emerged as the third most common type of renal amyloidosis in the USA ([14, 19–21, 40], please see also Chaps. 4 and 5). ALECT2 is also systemic and the second most common type of amyloidosis in the liver [41]. Although individual types are rather rare, collectively, the hereditary amyloidoses constitute a significant proportion of patients with systemic amyloidosis, currently estimated at approximately 10 % in the USA (and they may still be underdiagnosed) [37]. While several of the familial disorders are distinctly neuropathic or cardiopathic, virtually all of them can affect the kidneys, although, in some of these amyloidoses, renal deposits may be clinically silent [1]. In the USA, among patients with hereditary amyloidoses, 85 % are diagnosed with ATTR and 5 % with AFib [1, 14, 17, 37, 42, 43] (Fig. 28.2). In contrast, in the United Kingdom, AFib is the most frequent hereditary amyloidosis [42]. Although rare, these forms need to be properly recognized because of the implications for patient management (please see also Chap. 5 and Part VI—Chaps. 36, 37). Amyloid derived from apolipoprotein AIV (AApolipo AIV), apparently not associated with a mutation, was also recently reported in the kidney [32]. Rare patients with mixed renal amyloid deposits have also been reported (AL + AA, AA + ATTR, AL + ATTR) [13].

AL amyloidosis has been extensively discussed in Chaps. 2, 20, and Part VI—Chap. 36. Significant progress has been achieved in the treatment of AL with chemotherapy and stem cell rescue [25]. Thus, the main issue now centers on early and correct diagnosis of AL and distinguishing it from other types of amyloidosis, which require different treatments. Immunoglobulin heavy chain amyloidosis, AH, is a rare, poorly recognized disease with very few cases thus far reported. It often poses a diagnostic dilemma [22, 43, 44] since immunohistochemistry may be negative and more sophisticated studies are needed for diagnosis. In some patients, the heavy chain may be associated with the light chain [22–24]. The treatment regimen of these immunoglobulin component-derived amyloidoses is similar [25, 26].

AA amyloidosis is discussed extensively in Chap. 3. It usually arises in the context of an acute phase response such as that seen in the inflammatory arthritides, periodic fevers, chronic infections, and malignancies, including renal cell carcinoma [1]. Significant proteinuria and nephrotic syndrome are the most common presenting symptoms, diagnosed in 97 % of patients in one recent large series [45]. Occasional patients may present with renal failure without significant proteinuria. These patients have deposits that are limited to the interstitium and affect predominantly the medulla or tubules. Less commonly, crescentic glomerulonephritis may be seen [29, 30]. Rare instances, where AA co-deposits with AL in the kidney, have been reported [1]. Interestingly, while patients with Waldenstrom’s macroglobulinemia typically develop AL, instances of AA amyloidosis were also reported in these patients [1]. Familial AA amyloidoses develop in the context of mutations in genes for non-amyloid fibril proteins that play a permissive role in the development of amyloid (please see Chap. 3 and Figs. 3.​2 and 3.​3). Amyloid deposits in familial Mediterranean fever (FMF) are distributed throughout the body in small vessels with primarily glomerular involvement. While proteinuria is presumptive evidence of amyloidosis, other renal pathologies should also be considered, in particular, in patients treated with colchicine [1]. Also, an increased incidence of vasculitides and Henoch–Schoenlein disease has been reported in patients suffering from FMF. Since albuminuria is an early finding in FMF amyloidosis, patients should undergo periodic urinalyses, especially those who are at high risk.

ALECT2 amyloidosis (amyloid derived from leukocyte chemotactic factor 2) is the latest type of systemic amyloidosis to be described [14, 19–21, 40]. It was first reported in patients with renal failure; subsequently, some patients with proteinuria/nephrotic syndrome were also reported. Typically, there is amyloid deposition in the cortical interstitium with sparing of the medullary interstitium. However, in at least some patients, glomeruli and extraglomerular renal vessels are also involved (please see also Chaps. 4 and 5 and Fig. 5.​18). It is postulated that ALECT2 represents a unique and perhaps not uncommon disease entity, which shows a predilection for certain ethnic groups, most notably Mexican Americans. Based on two large recently published series, it represents 3–10 % of renal amyloidoses in the USA [14, 19, 20]. However, there are big regional differences. Thus, in the US South-West, where there is a high concentration of Mexican Americans, ALECT2 amyloidosis accounts for 54 % of renal amyloidosis cases [20]. Other ethnic groups affected by ALECT2 include First Nation people in Canada and Punjabi people in a UK series ([19, 20, 46], see also Chaps. 4 and 5). There is no clear evidence, as yet, whether ALECT2 represents a hereditary amyloidosis, since no mutation has been documented. Interestingly, however, two brothers affected by ALECT2 were recently reported [20].

At present, there is no specific treatment available. Hence, it is important not to misdiagnose ALECT2 as AL, or other type, where a specific treatment may be available ([21], please see also Chap. 20, Fig. 20.​3).

The hereditary amyloidoses are described in Chap. 5. Here, they are discussed in connection with their pertinence to the kidney.

AFib (amyloid derived from a mutant fibrinogen A-α chain) primarily causes renal amyloidosis, but, increasingly, evidence is emerging that the disease is systemic [27, 28, 47–49]. There is variable penetrance, and de novo mutation has been documented [32]. Clinically, there is a rapid deterioration in kidney function from initial presentation (proteinuria, hypertension, mild renal impairment) to end-stage renal failure, leading to dialysis dependence within 1–5 years [27, 28, 47, 48]. AFib shows a remarkable tropism for the kidney, with a very characteristic histology (Fig. 28.2, please see also Chap. 5 and Fig. 5.​12 and Chap. 20 and Fig. 20.​2). There is near replacement of the glomeruli by amyloid, without any interstitial or vascular involvement. Deposits stain specifically with antibodies to fibrinogen [27, 28, 47–49].

ATTR (amyloid derived from various mutants of transthyretin) is typically associated with polyneuropathy (with progressive peripheral and autonomic neuropathy) and cardiomyopathy. However, nephropathic and lower genitourinary system deposits have also been found associated with certain mutations [1, 7, 17]. In the kidney, typically, medullary deposits of amyloid are present, but, in some mutations, significant glomerular deposits can also be seen (please see Chap. 5 and Fig. 5.​3). Despite being inherited, the disease is not clinically apparent until middle or later life. In general, there is a low penetrance in carriers of the mutation, and, hence, a family history may be absent. In elderly patients, even wild-type transthyretin may form amyloid, which typically shows a cardiac tropism but may also be associated with clinically silent renal interstitial and lower genitourinary tract deposits (please see also Chaps. 5 and 7).

AApoAI (amyloid derived from various mutants of apolipoprotein AI) amyloidosis is due to germline mutations in the APOA1 gene ([4, 50, 51], please see also Chap. 5). Replacement of the leucine residue at position 75 by proline (Leu75Pro) leads to a new hereditary systemic amyloidosis, involving mostly the liver, kidney, and testis [4, 51]. Interestingly, an incidental mutation in the APOA1 gene, in a patient with systemic AL amyloidosis, was also recently documented [51]. Renal amyloid deposition differs, depending on the mutation. In many patients, amyloid deposits are small and limited to large arteries while the glomeruli are generally spared (please see also Chap. 5 and Fig. 5.​6). However, other patients also showed glomerular deposits [50]. AApo AII (amyloid derived from various mutants of apolipoprotein AII) amyloidosis is characterized by slowly progressing renal disease with glomerular, interstitial, and vascular deposits (please see also Chap. 5 and Figs. 5.​15–5.​17).

AGel (amyloid derived from a mutant gelsolin gene) is associated with severe nephrotic syndrome in homozygotic patients and it may be the presenting feature of this disease in young, homozygotic patients when other manifestations are minimal [52]. ALys (amyloid derived from lysozyme) is relatively rare and characterized by nephropathy (with glomerular and vascular deposits), dermal petechiae, gastrointestinal involvement with bleeding, hepatic involvement, and ocular or oral sicca syndrome ([53], please see Chap. 5 and Fig. 5.​14). ACys (amyloid derived from cystatin C) is associated with familial cerebral congophilic angiopathy. However, systemic deposits of amyloid were also reported in the kidneys and lower genitourinary tract, where the deposits are clinically silent [54].

This systemic amyloidosis develops in patients with chronic renal failure undergoing long-term dialysis (please see Chap. 6). For this reason, it is frequently referred to as dialysis-related amyloidosis. Aβ2M (amyloid derived from β2-microglobulin) is deposited in end-stage kidneys, but this has no clinical significance. At autopsy, Mazanec et al. [55] detected amyloid within the stroma of the kidney in one patient with a 15-year history of dialysis, together with foci of calcification. Recently, an autosomal dominant hereditary Aβ2M was reported in individuals with normal kidney function and normal levels of circulating β2M. These individuals were shown to have an inherited mutation together with extrarenal and extra-osteoarticular deposits of amyloid (please see Chap. 6).

Amyloidosis of the genitourinary tract, outside the kidney parenchyma, is uncommonly reported [1, 8–12, 55–76]. This involvement may be part of a systemic amyloidosis or represent a localized process and this subject will be presented here accordingly.