Discussion and conclusions
LCCN is the most common MM-related renal disease. According to a Mayo Clinic report, LCCN accounts for 33% of all cases of MM-related kidney diseases [
1]. However, LCAC nephropathy and LCCC nephropathy are very rare variants. We used Medline and EMBASE database retrieval and manual retrieval to collect articles and case reports of LCAC and LCCC nephropathy written in English for literature review. Abstracts of conference proceedings that were not published in full were not included (Supplementary file
2).
In 1962, when Vassar et al. [
7] and Azzopardi et al. [
8] first reported LCACs when they observed these unique morphological casts in autopsies of patients with MM. From 1962 to 1980, LCACs were found in approximately 55 autopsy patients with MM, and in about 2/3 of these patients, amyloid casts were diagnosed only by methyl violet staining and/or thiocyanin T staining [
7‐
12]. From 1980 to 2020, only 25 patients with LCACs caused by MM were identified (renal biopsy in 24 cases and autopsy in 1 case), and the diagnosis of amyloid casts in these patients was based on Congo red staining and/or electron microscopy [
6,
13‐
21] (Table
1). In addition, in three other papers the authors mentioned that they also observed LCACs in some patients with renal damage caused by MM, but they did not provide a detailed description [
22‐
24].
Table 1
Light chain amyloid in tubular casts and other tissues in multiple myeloma
| 1962 | 33a | ND | Rimmed Laminated | ND | PTC cytoplasm in several cases | ND |
| 1962 | 1a | Distal | Laminated | ND | No | No |
| 1966 | 1a | ND | Rimmed Laminated | ND | No | Yes in skin and Pericardium, etc. |
| 1970 | 1a | Distal | Laminated | ND | No | Yes in tumour, No in other organs |
| 1973 | 15a | convoluted tubules, loops of Henle, etc. | Rimmed | ND | PTC cytoplasm in 3 cases | No c |
| 1980 | 4a | ND | Rimmed Laminated Homogeneous | ND | No | No |
| 2007 | 1b | ND | Rimmed | λ | PTC cytoplasm | Yes in BM and joint |
| 2008 | 1b | ND | Rimmed | λ | No | ND |
| 2009 | 1b | ND | Rimmed | λ | No | No in BM |
| 2014 | 1b | ND | Rimmed | λ | No | No in BM |
| 2015 | 1b | Distal | Rimmed Laminated Homogeneous | λ | No | ND |
| 2016 | 1b | Many segments | Homogeneous | λ | PTC cytoplasm | ND |
| 2018 | 1b | ND | Rimmed Homogeneous | λ | PTC cytoplasm | ND |
| 2018 | 16b | ND | Rimmed Laminated Homogeneous | λ△ in 13 cases | PTC cytoplasm in 4 cases | Yes in 5 cases |
| 2018 | 1b | Distal | Laminated | λ | No | No in BM and salivary gland |
| 2020 | 1a | ND | Laminated | λ | PTC cytoplasm | Yes in lungs and heart |
Our case | | 1b | Distal | Rimmed | κ | No | No in BM and arterioles |
Unlike the ordinary light chain protein cast, LCAC has a unique shape. In most cases, it has a lightly stained central area and a deeplystained burr-like edge, which is black, blue and fuchsia with PASM, Masson trichrome and PAS staining, respectively. Positive Congo red staining and electron microscopy can confirm its amyloid properties [
15,
16,
18,
19]. Under polarized light microscopy, ordinary light microscopy and fluorescence microscopy, Congo red staining exhibits apple green double refraction, brick red and bright red, respectively [
19]. In addition to the abovementioned typical pattern, the amyloid deposits also have other distribution forms in the cast, such as lamination form, which can present as two or more layers, and sometimes in a tree-ring shape [
6‐
10,
12,
19‐
21], and homogeneous form, which is composed of clumped homogeneous deposits distributed in the whole cast [
6,
12,
17,
19]. Electron microscopy shows numerous randomly arranged unbranched fibrils with a diameter of 8–12 nm in the amyloid structures of the casts [
6,
13,
15‐
17,
19,
21]. Immunofluorescence or immunohistochemical examination reveals that the light chain in the cast has monoclonal properties, that is, only λ or κ light chain is present [
6,
13‐
16,
18‐
21]. The morphological characteristics of the casts in Case 1 of this paper are completely consistent with those of LCAC above. Furthermore, in LCAC nephropathy, the amyloid casts usually coexist with the ordinary light chain protein casts. Gibier et al. [
19] reported 17 cases of LCAC nephropathy, of which 16 cases were caused by MM. Among these cases, the proportion of amyloid casts in the total casts was < 5% in 9 cases, 5–25% in 3 cases and > 25% in 5 cases. In Case 1 of this paper, the amyloid casts accounted for 65% of all the casts.
The mechanism of LCAC formation remains unclear. It is known that the free light chains with a low molecular weight (approximately 20–25 kDa) can pass through the glomerular filtration membrane, while the amyloid fibrils with larger size cannot. Therefore, it can be inferred that the LCACs are formed in the tubules [
15,
17,
18]. There are two hypotheses. One possible mechanism is that the light chain proteins filtered into Bowman’s space or the renal tubular lumen are affected by some environmental factors (such as the pH value of the filtrate and high concentration urea) to change their conformation and become amyloid proteins with β-fibril structure, and then aggregate to form LCACs in the distal tubules [
6,
15,
17,
19,
20]. Another explanation is that the filtered light chain proteins are endocytosed by proximal tubular epithelial cells, undergo a conformational change under the action of lysosomal enzymes and obtain the properties of amyloid; these altered proteins are then discharged from the cells into the lumen to form the LCAC in the distal tubules [
11,
15,
18‐
20]. The later hypothesis is supported by the fact that LCACs often coexist with amyloid light chain-mediated proximal tubulopathy [
11,
13,
17‐
19].
Many patients with LCAC nephropathy do not have amyloid deposits in the glomeruli, tubular epithelial cells, renal small arteries and renal interstitium [
6,
8‐
10,
12,
14‐
16,
20], nor amyloidosis of extrarenal organs [
8,
11,
12,
15,
16,
20]. Even in some autopsy cases, no amyloid lesions in the above sites can be found [
8,
12]. The same is true for the patient described in Case 1 of this paper, whose renal parenchyma and bone marrow were negative for Congo red staining. Therefore, a question is raised; is there a link between LCAC and systemic amyloidosis? In 2018, a retrospective large sample study published by Gibier et al. [
19] brought the answer to this question to light. After careful and systematic examinations of the tissues of the extrarenal organs (including biopsy tissues and surgical specimens) of patients with LCAC nephropathy caused by MM, the authors did observe amyloid deposits in some extrarenal organs and found that the formation of intratubular LCACs occurred earlier than extrarenal organ amyloidosis. Thus, that study suggests that LCAC may be a precursor of systemic amyloidosis. Based on the findings by Gibier et al. [
19], we believe that all patients with LCAC should be carefully examined for the existence of systemic amyloidosis, and if not, a long term follow-up should be performed.
In the literature, only Gibier et al. [
19] implemented a controlled cohort study of small samples that compared the response to treatment between the LCCN patients with and without amyloid casts. After treatment with bortezomib and immunomodulatory drug (lenalidomide or thalidomide)-based regimens, the hematological response (at least partial response) and renal response (defined by estimated glomerular filtration rate ≥ 30 ml/min/1.73 m
2 and/or independence from dialysis at 3 months) were achieved in 68 and 32% of patients, respectively. The hematological and renal responses were not significantly different between the two groups. In addition, there were 3 case reports that described the renal response of patients with LCAC nephropathy after treatment. None of these patients exhibited significant improvement of renal function [
13,
18,
20]. In Case 1 of this paper, MM achieved partial remission after 4 courses of chemotherapy, but renal function did not improve concomitantly. The poor renal response of this patient may be caused by two factors: the response to therapy of LCAC nephropathy itself is not good, and the AKI of this patient occurred on the basis of chronic kidney disease (benign hypertensive nephrosclerosis with chronic renal insufficiency). Taken together, the response to therapy of LCAC nephropathy need to be further observed by expanding the number of cases.
Regarding LCCC caused by MM, the earliest data we retrieved were two individual case reports published by Silk [
25] and Neumann [
26] in 1949, respectively. However, it is said that LCCC was first reported by Löhlein in 1921 and published in a journal of pathology written in German [
25]. In the published English literature, we retrieved 12 cases of LCCC confirmed by autopsy from 1949 to 1989 (one of the patients underwent renal biopsy before death) [
25‐
30] and 27 cases of LCCC diagnosed by renal biopsy from 1987 to 2020 [
31‐
43] (Table
2). Moreover, in two other papers, the authors mentioned that they also observed LCCC, but they did not provide detailed descriptions [
44,
45].
Table 2
Light chain crystals in tubular casts and other tissues in multiple myeloma
| 1949 | 1a | Distal | ND | PTC cytoplasm | NPC in medulla of the kidney |
| 1949 | 1a | All segments | ND | Bowman’s capsule Interstitial cells | Bone marrow, NPC in tumour area |
| 1972 | 7a | Distal | ND | PTC cytoplasm Interstitium | Bone marrow |
| 1983 | 1ba | ND | λ | No | Lung |
| 1985 | 1a | ND | λ | Bowman’s capsule Blood vessel | Interstitial tissue of the heart |
| 1989 | 1a | Distal | κ | PTC cytoplasm Glomerulus NPC in interstitium | No |
| 1987 | 14bc | Distal | κ or λ | PTC or DTC cytoplasm (5 cases) | ND |
| 2001 | 1b | ND | λ? | Bowman’s capsule | Bone marrow |
| 2003 | 1b | ND | λ | PTC cytoplasm | ND |
| 2005 | 1b | ND | λ | Glomerulus, Blood vessel, Interstitium | Bone marrow |
| 2011 | 1b | ND | λ | PTC cytoplasm Bowman’s capsule | Bone marrow |
| 2014 | 1b | Distal | λ | No | ND |
| 2014 | 1b | ND | λ | No | ND |
| | 1b | Distal and Proximal | κ | PTC cytoplasm | ND |
| 2016 | 1b | ND | λ | No | ND |
| 2016 | 1b | Proximal | λ | No | ND |
| 2020 | 1b | Distal | κ | PTC cytoplasm | ND |
| 2020 | 1b | Distal | κ | Glomerulus, Interlobular arteries | ND |
| 2020 | 1b | Distal | λ | No | No in bone marrow |
| 2020 | 1b | Distal | λ | No | ND |
Our case | | 1b | Distal | λ | No | No in bone marrow |
The crystals in LCCC vary in size and shape. These crystals can appear as needle-shaped, bar-shaped, spindle-shaped, diamond-shaped, triangle, rectangle, pentagon, hexagon and other geometric shapes [
25‐
43]. Some LCCCs are also surrounded by cellular reactions [
25,
26,
28,
31,
32,
37]. LCCCs are usually formed in the distal tubules, but occasionally can also form in the proximal tubules [
26,
37,
39]. The staining properties of the crystalline casts are the same as those of ordinary light chain protein casts, appearing eosinophilic by HE staining, polychromatic (mixed red and blue) or fuschinophilic by Masson trichrome staining, pale by PAS staining and lack argyrophilic by PASM staining [
38,
39,
42,
46,
47]. If toluidine blue is used to stain semi-thin sections, the crystals appear blue with the best recognition effect [
31]. Electron microscopy is also important for identifying and further confirming the crystalline casts. In addition, it has been reported in 3 articles that different shapes of crystals or/and crystalline casts were observed in the urinary sediment of patients with LCCC nephropathy [
33,
37,
40]. Luciano et al. [
37] believe that urinary sediment microscopy should be performed in all patients with monoclonal light chain-related nephropathy caused by MM, and this approach may provide important clues for the discovery of LCCC nephropathy. The histopathological features of the patient described in Case 2 in this paper are consistent with the LCCC nephropathy described above, and crystals were also found in the urine of this patient.
The mechanism of LCCC formation in patients with MM is still not well understood. There are several hypotheses. First, some light chain proteins more easily form crystals due to their individual characteristics (such as isoelectric point, glycosylation and amino acid sequence). When they are filtered from the glomerulus to the tubular lumen and reach a higher concentration in the tubule fluid, crystals may form under the action of certain local factors (such as a decreased pH value and a slower flow rate of the tubule fluid) [
31,
34,
35]. Second, after the filtered light chain proteins are reabsorbed by proximal tubular epithelial cells, if the amount of lysosomal enzymes in the cytoplasm is insufficient, the function of lysosomal enzymes is deficient, or some light chain proteins (such as the κ light chain belonging to the VκI subclass) are resistant to lysosomal enzymes, these light chains will accumulate in the lysosomes, and undergo homogenous polymerization to form crystals [
3,
31,
44,
48]. Then, these crystals fall off of the apical surface of the damaged epithelial cells into the tubular lumen, forming LCCCs [
45]. Third, LCCC formation may be related with crystalglobulinemia. In this case, monoclonal globulins, or occasionally monoclonal light chains in the systemic vasculature can spontaneously form microcrystals and result in multiple organ embolism [
41,
47,
49]. If the microcrystals embolize the glomerular capillaries and cause their destruction, the crystals in the circulation enter Bowman’s space and the tubular lumen and then form crystalline casts in the distal tubules. In the literatures, LCCCs can appear in three states: LCCCs existing alone [
36‐
39,
42,
43], LCCCs coexisting with light chain crystal deposits of the proximal tubular epithelial cells [
25,
27,
31,
33,
40], and in a few cases, LCCCs coexisting with light chain crystal deposits of the renal small vessels, glomerular capillaries, Bowman’s space and even extrarenal tissues [
26,
29,
30,
32,
34,
35,
41]. These three states may provide some circumstantial evidence for the above three LCCC formation mechanisms. Case 2 in our paper should belong to the first state.
LCCN usually causes AKI clinically, and severe cases often require dialysis treatment. LCCC nephropathy is no exception. Is there any difference in the response to treatment between LCCC nephropathy and ordinary LCCN? To date, too few cases of LCCC nephropathy have been treated, so it is impossible to draw a conclusion. In the literature, Haider et al. [
36] and Kumakura et al. [
39] each reported one patient with LCCC nephropathy; both patients developed AKI, and one patient underwent hemodialysis. After treatment with bortezomib-dexamethasone regimen, the MM of the patients achieved complete remission or good partial remission, respectively, the elevated serum creatinine levels returned to normal and the hemodialysis was stopped. Chou et al. [
41] reported another patient with LCCC nephropathy with AKI undergoing dialysis. After receiving plasma-pheresis and 11 courses of the combined therapy of bortezomib, dexamethasone and cyclophosphamide, her MM achieved complete remission, renal function returned to nearly normal and hemodialysis was no longer needed. The patient described in Case 2 in this paper also obtained the same effects as above after treatment. Therefore, we believe that patients with LCCC nephropathy should not cease treatment for MM, even if they have received dialysis. The prognosis of treated MM and secondary AKI in these patients may still be very good and may be similar to those of ordinary LCCN. Of course, this view needs to be verified by a large number of treatment cases in the future.
In summary, LCAC nephropathy and LCCC nephropathy caused by MM are two rare types of LCCN, and both have their own unique morphological characteristics. LCAC nephropathy may or may not be accompany with systemic light chain amyloidosis. LCCC nephropathy can exist alone or can coexist with crystalline LCPT or crystalglobu-linemia. In the urine of some patients with LCCC nephropathy, crystals may also be detected. The mechanisms of LCAC and LCCC formation are unclear. Is the response to treatment of LCAC nephropathy without systemic light chain amyloidosis better than that of treating LCAC nephropathy with systemic light chain amyloidosis? Is the response to treatment of LCCC nephropathy similar to that of ordinary LCCN? Both questions require further studies.