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Proximal Tubulopathies Associated With Monoclonal Light Chains: The Spectrum of Clinicopathologic Manifestations and Molecular Pathogenesis.

Our understanding of renal lesions occurring in patients with plasma cell dyscrasias has advanced considerably in the last 2 decades. These lesions are classified into specific entities (1-6) that have made possible treatment algorithms addressing each one of them. Renal lesions not previously recognized have been conceptualized, and a rather ample understanding of pathogenesis associated with each one of the entities has been deciphered. Basic science contributions have greatly helped to decipher molecular pathogenetic events responsible for the morphologic manifestations observed in the various lesions. (7,8) In fact, in some instances research efforts have called attention to what was being missed in the diagnostic arena. Information emanating from the laboratory has been ably translated to the clinical practice. Tubular interstitial entities associated with circulating monoclonal light chains are associated with proximal and distal tubular lesions. Distal nephron pathology is a well-recognized pattern referred to as light chain cast nephropathy or in a more generic way as "myeloma kidney" (Figure 1). While some of the information provided in the article has been previously published in the form of few case reports and short series, the complex data that have emerged have never been organized, classified, and conceptualized in a unified manner addressing pathogenesis.

The present series highlights the importance of proximal tubule-centered lesions and discusses challenges and pitfalls in the evaluation of renal biopsies from patients with plasma cell dyscrasias. These lesions do not appear to occur in association with heavy chain diseases, unless they coexist with circulating free light chains (9,10) or truncated heavy chains able to cross the glomerular capillary walls and reach the proximal tubules. The latter has not been described in the literature but could potentially occur if heavy chains are also endocytosed via the same receptors that light chains use and are similarly handled by the endosomal/lysosomal system.

Recently, a case with Waldenstrom macroglobulinemia was reported with a coexistent proximal tubulopathy with crystalline inclusions in the cytoplasm of proximal tubular cells associated with renal Fanconi syndrome. However, this patient also had circulating free [kappa] light chains confirmed by a markedly elevated ratio of [kappa] to [lambda] light chains in the serum and free [kappa] light chains in the urine. (10) This case exemplifies the first situation mentioned.

Proper recognition of these proximal tubulopathies is of utmost importance. The main purpose of this article is to provide specific diagnostic criteria to unequivocally identify and classify these lesions and define molecular mechanisms involved.

MATERIALS AND METHODS

A total of 5410 renal biopsies for medical renal diseases from 2 institutions during a period of 5 years were scrutinized to identify patients with tubular interstitial manifestations associated with plasma cell dyscrasias. Monoclonal or predominant staining for either [kappa] or [lambda] light chains in proximal tubular cells and/or along tubular basement membranes served as one of the main criteria to select these cases.

Specimens were submitted for light microscopy, immunofluorescence, and electron microscopy and handled routinely. Specimens for light microscopy were fixed in 10% formaldehyde (formalin) and embedded in paraffin, sectioned, and stained with hematoxylin-eosin, periodic acid-Schiff, Masson trichrome, and Jones silver methenamine. Specimens were also placed in Michel solution, frozen, sectioned, and stained by using direct immunofluorescence for immunoglobulin (Ig) G, IgM, IgA, C3, C1q, albumin, fibrinogen, [kappa] light chains, and [lambda] light chains. In addition, 1-mm cubes of tissue were fixed in 2.5% glutaraldehyde for electron microscopy, embedded in Epon, sectioned, placed on grids, and stained with lead citrate and uranyl acetate. The cases were viewed with a transmission electron microscope with careful evaluation of glomerular, interstitial, and vascular compartments. Representative digitized photos were obtained and carefully analyzed. Representative cases were immunolabeled primarily to demonstrate localization of light chains in proximal tubules and to understand the pathogenesis of these disorders better, but also to make a definitive diagnosis when immunofluorescence evaluation was unable to prove monoclonality or demonstrate deposition of monotypical light chains in renal tissues. For ultrastructural immunolabeling a postembedding method was used, and immunogold using 10-nm particles was used for labeling. The procedure used has been previously published in detail. (11-13)

Cases with known exposure to nephrotoxins (n = 5) were excluded to eliminate any possibility that the proximal tubulopathies may reflect at least some changes related to these, rather than to the monoclonal light chains.

RESULTS

One hundred and twenty-six renal biopsies with renal lesions associated with monotypical deposition of light and/ or heavy chains (2.5% of all cases) were identified. The overall renal lesions included light/heavy chain deposition diseases, light (AL)/heavy (AH) chain amyloidosis, light chain cast nephropathy, and proximal tubulopathies. Thirty-one were cases of light chain cast nephropathy (also referred to as "myeloma kidney") and they were not further analyzed, as the main purpose of the article is to address proximal nephron-centered lesions.

In all proximal tubulopathies glomerular and vascular compartments were unremarkable, except when other nonrelated lesions were present, such as vascular nephrosclerosis, which was common in the patient population because of age. Five cases also had evidence of diabetic nephropathy, nodular glomerulosclerosis.

A total of 57 cases were proximal tubulopathies (approximately 1.5% of all patients; approximately 46% of all cases with lesions related to plasma cell dyscrasia). Tables 1 through 4 detail the patients' demographics and clinical information, and immunopathologic characteristics of the renal biopsies from patients with the various variants. Comparison of the percentage of light chain cast nephropathy cases (33% of all cases associated with plasma cell dyscrasia) with proximal tubular-centered cases (roughly 46% of all cases with underlying plasma cell dyscrasias) emphasizes that the total number of proximal tubulopathies indeed represents a very significant portion of all lesions observed. All different types of proximal tubulopathies together account for more than all the cases with light chain cast nephropathy (approximately 13% more).

Immunomorphologic Findings in Each Category

Four types of proximal tubulopathy were noted.

Proximal Tubulopathy Without Cytoplasmic Inclusions (Table 1).--Light Microscopy.--Proximal tubular damage was the main finding, though the degree of damage was quite variable. It varied from subtle cytoplasmic vacuolization in proximal tubular cells to frank necrosis (Figure 2). Mitotic figures were identifiable in proximal tubular cells in approximately 45% to 50% of the cases. No significant interstitial inflammation and no tubulitis were evident. No tubular casts were appreciated.

Immunofluorescence.--There was granular monoclonal light-chain staining in the cytoplasm of proximal tubular cells (Figure 3, A and B) with either monoclonal light chains detected in different cases but k predominating overall. In 5 cases both light chains stained positively but the pertinent one was significantly more positive than the other (3+ to 1+ to trace). Two cases required ultrastructural immunolabeling to clarify monoclonality.

Electron Microscopy.--The findings varied, with some tubules showing an abundance of lysosomes in proximal tubular cells and others exhibiting cytoplasmic vacuolization, apical blebbing with numerous lysosomes in the cytoplasmic protrusions, and desquamation and fragmentation of tubular cells, including some with loss of architectural/cellular integrity (frank necrosis) (Figures 4; 5, A and B; 6, A and B; and 7). None of the cases showed punctate, electron-dense material along tubular basement membranes.

Tubulopathy Associated With Interstitial Inflammatory Reaction (Table 2).--Light Microscopy.--The most striking finding in these cases was the interstitial inflammation, which varied from patchy (12 cases) to diffuse (16 cases). The interstitial inflammatory cells included mostly lymphocytes and scattered plasma cells, but also contained eosinophils in most cases, though in variable numbers (Figure 8, A and B). There were no tubular casts. Tubulitis was seen, either focally or rather strikingly.

Immunofluorescence.--The pattern of immunofluorescence staining was similar to the one described above (granular and cytoplasmic); however, linear staining along tubular basement membranes was also a prominent finding in the areas with inflammation (Figure 9, A through C). Though the immunofluorescence findings were more prominent in proximal tubules, some distal tubules also revealed staining along tubular basement membranes for monoclonal light chains but no staining in the cytoplasm of distal tubular cells.

Electron Microscopy.--The tubules also typically contained an abundance of lysosomes and evidence of tubular damage generally associated with areas with inflammation and tubulitis. In 7 cases, there was also focal deposition of punctate electron-dense material along tubular basement membranes, though this finding was usually focal and often unimpressive (Figures 10, A and B; 11; and 12, A and B). Ultrastructural labeling was performed in 3 of these cases.

Proximal Tubulopathy With Cytoplasmic Inclusions (Table 3).--Light Microscopy.--The findings on the hematoxylin-eosin-stained sections were subtle and very easy to miss. Proximal tubular cells appeared swollen. Periodic acid-Schiff stain highlighted empty cleftlike spaces, often with angulated, sharply demarcated borders diffusely present in the cytoplasm of proximal tubular cells (Figure 13). No other tubular interstitial findings were evident.

Immunofluorescence.--Two of the cases revealed monoclonality (1 after pronase digestion of corresponding paraffin-embedded sections) for k light chains. In 1 of the cases the staining revealed rectangular to angulated inclusions in the cytoplasm of proximal tubular cells. The other 2 cases yielded negative results, even after pronase digestion.

Electron Microscopy.--All 4 cases showed characteristic inclusions in the cytoplasm of proximal tubular cells (Figure 14, A and B). The inclusions were crystalline in 3 cases (Figures 14 and 15) and fibrillary in 1 case (Figure 16, A and B). The cytoplasmic inclusions varied in size and shape, most being rectangular or, less commonly, rhomboidal.

Proximal Tubulopathy With Lysosomal Indigestion/ Constipation (Table 4).--Light Microscopy.--The proximal tubular cells were enlarged and with the trichrome stain showed red cytoplasmic granules (Figures 17, A through C).

The tubular cells were sometimes so swollen that the tubular lumina appeared almost completely obliterated.

Immunofluorescence.--There was striking granular positivity for k light chains in the cytoplasm of proximal tubular cells in all cases (Figure 18).

Electron Microscopy.--The proximal tubular cells were markedly enlarged and their cytoplasm was occupied by myriads of lysosomes of various sizes. Some of the lysosomes exhibited atypical morphology (Figures 18; and 19, A and B). Essentially no other organelles could be identified in the cytoplasm of the proximal tubular cells.

Figure 20 is a flowchart that illustrates how to approach the diagnosis of these proximal tubulopathies, with salient immunomorphologic findings typical for each variant noted.

Of the 4 variants, the tubulopathy associated with the interstitial inflammatory reaction (acute tubular interstitial nephritis variant) was the most prevalent (n = 28 or 49% of all cases with proximal tubulopathy; Table 2), followed by the proximal tubulopathy without cytoplasmic inclusions (acute tubular necrosis variant) (n = 22, 39% of all cases; Table 1), proximal tubulopathy with cytoplasmic inclusions in proximal tubular cells (4 cases; approximately 8%; Table 3), and 3 cases (5% of all cases) with the "lysosomal indigestion/constipation" variant (Table 4).

Patients' ages ranged from 42 to 89 years (mean, 68 years) in the interstitial inflammatory variant group of these tubulopathies, and this group included 17 men and 12 women (Table 2). The [kappa] to [lambda] ratio was 16:12. The patients' age range for the proximal tubulopathy without inclusions variant was 42 to 83 years (mean, 70 years), the [kappa] to [lambda] ratio was 16:6 with 12 male and 10 female patients (acute tubular necrosis variant; Table 1). Interestingly, all patients in groups 3 and 4 were [kappa] light chain related (Tables 3 and 4) and their overall age range was lower for group 3 (group 3: mean age, 49 years; and group 4: mean age, 64 years). The male to female ratio was 3:1 in group 3 and 1:2 in group 4.

COMMENT

Most of the early publications dealing with interstitial renal damage in myeloma highlighted the distal tubular obstructive pathologic process that became recognized as "myeloma kidney." (14) Initially it was doubted that light chains could produce proximal tubular injury.

In 1921, Lohlein (15) called attention to the presence of crystalline inclusions in the cytoplasm of proximal tubular cells in a patient with multiple myeloma. In the 1960s and 70s, Costanza and Smoller, (16) as well as Maldonado et al, (17) suggested that proximal tubular damage was an important pathologic finding in some patients with myeloma and renal dysfunction. About the same time, experimental studies (18) performed by using isolated perfused rat kidneys showed that light chains purified from the urine of patients with Bence Jones proteinuria did not alter proximal tubular function; morphologic alterations in proximal tubules were stated to be absent, creating doubts about the ability of light chains to induce proximal tubular damage. Furthermore, in the mid 1970s, Clyne et al (19) demonstrated intracytoplasmic inclusions in proximal tubular cells, but when they injected Bence Jones proteins intraperitoneally, glomerular filtration rate remained normal, further supporting the prevalent belief of the time.

Finally, studies conducted in the mid 1980s clearly and unequivocally showed that some monoclonal light chains isolated from the urine of patients with myeloma, when perfused in rat nephrons, produced proximal tubular damage with features recognized as mimicking acute tubular necrosis, settling the dispute convincingly. (20-22) In 1988, Sanders et al (23) showed morphologic alterations of the proximal tubules in biopsy specimens from patients with light chain-related renal disease, emphasizing that the changes seen in animals in the research laboratory were also observed in humans. In 2000, Pote et al (24) and in 2002, Sengul et al (25) supported the view that proximal tubular damage occurs, associated with some monotypical light chains, with studies using cultured cells. These studies also delineated some of the molecular mechanisms involved in the proximal tubular cell damage.

It took more than 2 decades for this information to be fully integrated into clinical practice and to understand the importance of proximal tubular damage as the main, and in a significant number of the cases as the only, renal pathologic process in some patients with underlying plasma cell dyscrasias.

The diagnosis of proximal tubule-centered lesions requires a high degree of suspicion, coupled with careful evaluation and integration of light microscopic, immunofluorescence, and ultrastructural findings, interpreted in the clinical context of the case in question. Demonstrating monoclonality is very important for linking the pathologic findings with an underlying neoplastic pathologic process responsible for the production of the tubulopathic light chains. Unfortunately, this is not always possible using only immunofluorescence, and careful correlation of the findings emanating from all ancillary diagnostic techniques becomes most important when monoclonality is unclear by immunofluorescence. (26-28) In these cases, serious consideration should be given to using additional immunofluorescence studies, using polyclonal antibodies that may detect other light-chain epitopes or ultrastructural immunolabeling, which is a more sensitive technique, (28) to determine monoclonality. Immunoelectron microscopy also allows precise localization of the monoclonal light chains to different cellular compartments, clarifying the situation in most instances. (28) Some cases in this series were immunolabeled to clarify the pathologic findings and make a definitive diagnosis.

Metabolism of Light Chains in Proximal Tubules/Handling of Physicochemically Abnormal Light Chains

Monoclonal light chains produced by a neoplastic clone of plasma cells circulate as monomers if [kappa] and dimers if [lambda] type, and are freely filtered through the capillary walls and delivered to the proximal tubules. (4,5,29) They are endocytosed in the proximal tubules via the megalin-cubilin receptor. (30-34) Light chains are normally catabolized in the apical portions of the proximal tubules by endosomes. While the primary function of early lysosomes is sorting, late endosomes and lysosomes attempt to digest the internalized light chains. When endosomes encounter physicochemically abnormal light chains, they direct them to the lysosomes, the terminal degradation compartment of the endocytic pathway. The inability of the endosomal system to catabolize abnormal light chains results in pathologic alterations.

After internalization of the megalin-cubilin light chain complex, a vacuolar electrogenic [H.sup.+]-ATPase ([H.sup.+]-adenosine triphosphatase) pump acidifies and facilitates dissociation of the complex within endosomes. The receptor is then recycled to the surface membrane in the microvillous border and the ligand is taken in. (35) The chloride channel ClC-5 has been found to be critical in this process, because it allows chloride entry into endosomes, which in turn shunts the electrical gradient created by the vacuolar [H.sup.+]-ATPase. (35) Internalized light chains are then degraded mainly by late endosomes and, selectively, in combination with early lysosomes. (36)

Endosomes that maintain a stable pH of 6 to 6.2 (37) are recycling and sorting centers from which endocytosed material in polarized epithelial cells can be selectively marshaled into at least 3 appropriate cellular destinations/ compartments as follows: (1) to extracellular compartment (ie, regurgitation or recycling to the cell surface), which occurs with normal light chains; (2) to the lysosomal compartment for further degradation; or (3) to the (opposite) basolateral side by transcytosis. (38) The membranes of the endocytic vesicles are subject to a series of highly complex molecular sorting events resulting in targeting of the endocytosed light chains to specific cellular compartments. (38,39)

A unique cadre of Rab proteins is localized to endosomes, with Rab 4 and 5 being associated with early endosomes and Rab 7 and 9 with late endosomes. Rab proteins play a key role in transporting cargo through the different subcellular regions, especially in the endosomal/lysosomal system. (39)

Cathepsin B and pepsin are the main proteolytic enzymes in lysosomes (which maintain a pH around 4.5-5 (40)) in proximal tubular cells, but many other enzymes are also present. These enzymes when confronted with some abnormal light chains cannot adequately catabolize them owing to their peculiar physicochemical characteristics. (41)

The deeper the internalized light chains traverse into the endocytic/processing pathways in the proximal tubules, the lesser the likelihood that they can be completely catabolized. Thus, light chains delivered to the mature lysosomal compartment in the proximal tubules are essentially nondigestible or, at best, only partially catabolized. The alterations in proximal tubules are different depending predominantly on the light chains involved. Their interactions with mature lysosomes dictate and help explain the morphologic expressions exhibited in the proximal tubules and, ultimately, the clinical consequences.

Ultrastructural labeling has provided an exquisite immunomorphologic representation of the events that lead to the pathologic expressions in the different situations that occur and is instrumental in helping define molecular mechanisms at play in the various situations.

Several publications (42-45) have addressed specifically tubulointerstitial pathology associated with plasma cell dyscrasias, including a recent comprehensive review, (46) but proximal tubulopathies have not been entirely conceptualized, classified into different variants with specific clinicopathologic implications, or defined (understood) in terms of pathogenesis. In addition, the incidence of these conditions in the daily practice of nephropathology has never been analyzed.

The 4 lesions that have been identified are typically associated with characteristic clinical scenarios that can be clearly explained with an understanding of how these light chains have been handled by the lysosomes in the proximal tubules. Two lesions--proximal tubulopathy without cytoplasmic inclusions and the variant associated with the inflammatory interstitial process--are classically associated with either slowly or rapidly deteriorating renal function. The other 2 patterns of proximal tubular damage are characteristically seen in patients with clinical Fanconi syndrome exhibiting type II renal tubular acidosis, phosphaturia, hyperuricemia, aminoaciduria, and glycosuria without hyperglycemia (those associated with cytoplasmic inclusions in proximal tubular cells and those with constipated lysosomes). Batuman et al (47) have demonstrated the direct toxicity of some light chains on proximal tubular cells, inhibiting the transport of phosphate and glucose into tubular cells, providing experimental support for the pathogenesis of these disorders, and activating redoxsensitive pathways that promote apoptosis.

In patients who have tubular manifestations with light microscopic features of acute tubular necrosis (proximal tubulopathy without cytoplasmic inclusions), the endosomes unable to adequately process those peculiar light chains direct them to the lysosomal compartment. In the process of trying to catabolize them, the lysosomes burst and release their hydrolytic enzymes, leading to cytoplasmic vacuolization, apical blebbing, desquamation, and/or frank necrosis of the proximal tubular cells (Figures 3 through 9). The fragments of cytoplasm blebbing from the proximal tubular cells often contain numerous enlarged lysosomes. (26) This process in its various steps can be seen in renal biopsies from these patients. Initially, the proximal tubular cells exhibit an increase in morphologically normal-appearing lysosomes, an indicator that these cells are in the process of attempting to catabolize endocytosed low-molecular-weight proteins that cannot be fully handled by endosomes (Figure 3). In some instances, ultrastructural examination of the lysosomes in proximal tubular cells engaged in this process reveals variable electron densities reflecting the release of their enzymatic contents to the cytosol (Figure 6). Following this finding, changes of cellular damage become apparent as signs of cellular injury occurring as a consequence of the release of the lysosomal enzymes (Figures 5 and 7). The degree of proximal tubular damage can be quite variable, and in some of these cases the morphologic findings at the light microscopic level may be subtle and easy to miss or to disregard as unimportant or nonspecific. The variability in terms of the speed of renal function deterioration depends on the degree of tubular nephrotoxicity inherent to the particular light chain involved. Two series of patients manifesting this pattern of proximal tubulopathy have been published in the literature. (48,49) Although both [kappa] and [lambda] light chains have been documented to occur in association with this variant, a predominance of j light chains has been observed.

Those light chains associated with interstitial inflammatory reactions are also delivered to the lysosomal compartment, and catabolism is also impaired. In this situation, transcytosis of the light chains to the basolateral border occurs (50) (Figure 12) via transcytotic vesicular pathways. The light chains then accumulate in close relationship with the tubular basement membranes, activating cytokines, leading to the recruitment of inflammatory cells including eosinophils (Figure 12). Therefore, this process morphologically mimics an acute tubular interstitial nephritis due to hypersensitivity. Gu and Herrera (51) called attention to this entity in a seminal article published in 2006 and more recently, a similar case (52) has been documented. The deposited light chains are detected usually by immunofluorescence (monotypical linear staining for light chains along tubular basement membranes) and in selected cases, also ultrastructurally (Figure 16, B). However, these findings (even the fluorescence staining) may only be detectable in focal areas of the biopsy sample, typically in the areas with inflammation, tubulitis, and tubular damage. Because of the deposition of monotypical light chains, this variant could be conceptualized as an interstitial form of light chain deposition disease. (52) The main clinical presentation was acute renal failure (40% of these patients). These cases were a combination of k and k light chain-related lesions.

The manifestations associated with unique cytoplasmic inclusions, which are generally crystalline in proximal tubular cells, represent the lesion that has been recognized in the literature as light chain Fanconi syndrome (49,53-57) (Figures 13 through 16). Clinically, it is characterized by progressive renal dysfunction with defects in proximal tubule reabsorption and typically exhibits a rather slow, protracted clinical course. Evaluation of the bone marrows in these patients often reveals low numbers of plasma cells, though monoclonality may be substantiated by using techniques such as immunohistochemistry or flow cytometry.

This type of proximal tubulopathy is typically associated with [kappa] light chains of the kappa ([kappa])I subgroup. In general these patients are younger than those in the other groups. By light microscopy, the proximal tubular cells exhibit empty, cleftlike spaces, some with relatively well-defined, somewhat angulated borders that do not stain with periodic acid-Schiff. The cytoplasmic inclusions are formed in mature lysosomes within the proximal tubular cells, as they try to break down the tubulopathic light chains.

There are cases where staining for both light chains is seen and determination of monoclonality is impossible. In some instances, staining for light chains is entirely negative with routine immunofluorescence, even after pronase digestion. The crystalline appearance of the modified light chains in the proximal tubules may become apparent but this is not always the case. In the study by Nasr et al, (58) however, all cases treated with pronase demonstrated monoclonality, but that has not been the author's experience (unpublished observation). Two cases in this series did not show monoclonality even after pronase treatment of the paraffin-embedded material.

This group of patients includes the youngest patients in all 4 groups. The light chains involved in all the patients in this series were [kappa] type. There are only rare cases with [lambda] monoclonality documented in the literature. (53-57)

An animal model for this variant has shown that the primary structure of the light chains is directly responsible for the pathologic findings observed, and a transgenic model has been created where the disease has been reversed with experimental manipulations. (57,59-61) An incomplete form of this condition has also been reported, (62) emphasizing once more the importance of the physicochemical characteristics of the light chains in producing pathologic processes. Light chains from most of these cases ([kappa] type) exhibit a specific amino acid substitution at position 30, which provides resistance to catabolism, (59-61) promoting the formation of cytoplasmic inclusions.

Finally, the lysosomal indigestion and constipation variant represents the fourth and least common of the manifestations detailed in this article, where the inability to catabolize certain light chains leads to marked lysosomal proliferation, enlargement and formation of atypical, markedly enlarged lysosomes with unusual shapes in proximal tubular cells (Figures 18 and 19). These lysosomes are unable to release their enzymes (burst). The entire cytoplasm of the proximal tubular cells becomes completely filled with lysosomes and virtually no other organelles are left (Figures 18 and 19). This variant is referred to as the lysosomal indigestion/constipation variant to highlight the lysosomal deficiency in catabolizing the light chains and their engorgement resulting from accumulation of monoclonal light chains. All the reabsorptive functions of the proximal tubular cells eventually cease, as the machinery necessary for this is no longer in the proximal tubular cells, creating a clinical picture of Fanconi syndrome similar to that seen in association with those light chains that lead to the formation of intracytoplasmic inclusions. While the immunomorphologic and clinical manifestations of this last variant and the previous one are similar, the ultrastructural findings are different. While crystalline inclusions are readily identified in the former variant, none are seen in the "lysosomal constipation" group. The clinical management of patients with the lysosomal indigestion/constipation variant may require a different type of intervention to unclog the lysosomal compartment (ie, possibly changing the pH of the lysosomes).

The ability of different light chains to be responsible for various lesions depends on their intrinsic amino acid composition and conformation (ie, resulting in the release of lysosomal enzymes into cytosol or difficulty to break them down--proteolytic resistance).

Few immunoglobulin light chains involved in proximal tubulopathies have been analyzed at the molecular level. In addition to the physicochemical alterations in the light chains, there could also be some inherent host factors that may affect the process of catalytic destruction of the light chains in proximal tubules; however, this has not been studied.

Because of the ability of the tubules to regenerate, these patients have the ability to recover, provided that the underlying plasma cell malignancy can be treated effectively and the delivery of tubulopathic light chains to the tubules can be stopped and that the renal parenchyma is not irreversibly damaged.

The renal pathologist must be fully aware and be able to identify these patterns of renal damage associated with an underlying plasma cell dyscrasia by paying special attention to the immunofluorescence (especially [kappa] and [lambda] light-chain stains) and ultrastructural findings that allow more comprehensive characterization of the tubular changes noted at the light microscopic level. Otherwise, while identification of the generic pathologic process present may be accomplished, the important link to an underlying neoplastic process may not be uncovered.

It is of great importance for a number of these patients with lymphoplasmacytic lesions to identify renal pathology resulting from the neoplastic process; otherwise, recognition of the underlying neoplasia and appropriate treatment may be delayed with negative consequences for the patients. Since renal involvement may represent an early manifestation of a plasma cell dyscrasia, renal biopsies are often performed without clinical suspicion of the underlying disorder.

Another area where the renal biopsy may be of value is in patients with monoclonal gammopathy of undetermined significance (MGUS) who develop renal dysfunction. The renal biopsy can identify that the renal problem is due to the circulating monoclonal light chains rather than an unrelated cause. This will automatically indicate end-organ damage and the patient should no longer be considered as having MGUS, but the underlying plasma cell clone or lymphoplasmacytic disorder responsible for the production of the monoclonal light chains should be treated. If tubular interstitial manifestations are not properly diagnosed, a great opportunity is lost to identify the connection with MGUS and, therefore, the patient is denied the opportunity to be treated aggressively to control the plasma cell dyscrasia. Delay in treatment of a patient with myeloma has been shown to result in more rapid deterioration of renal function and decreases survival overall.

Molecular therapy holds great promise for the treatment of selected renal diseases. (63) These tubular interstitial disorders appear to be prime candidates for molecular targeting as a means of therapeutic intervention. Disrupting endocytosis of tubulopathic light chains or intervening in the sorting and delivery mechanisms of light chains to the various proximal tubular compartments, most importantly lysosomes, represents a possible future avenue to prevent progressive and, ultimately, irreversible renal disease in these disorders. Inhibition of internalization of certain light chains by cardiac fibroblasts has been possible experimentally. (64) A similar strategy may work in inhibiting the uptake of tubulopathic light chains into proximal tubules, thus avoiding tubular damage. This, coupled with treatment of the underlying plasma cell-associated process, combined with the regenerative capabilities of proximal tubular cells, provides an excellent avenue to control, ameliorate, and repair the tubular interstitial injury.

The current tendency is for aggressive management of those patients who are able to withstand such treatment, even in cases where the development of the renal damage typically occurs slowly, with the aim not only to avert irreversible renal damage but also to eradicate the underlying plasma cell dyscrasia. Therefore, early depiction of end-organ involvement becomes crucial and it is often in the hands of the nephropathologists, as renal dysfunction is in many instances the initial manifestation of end-organ involvement in either a patient with MGUS, a manifestation of recurrence in a treated patient with myeloma, or the initial presentation in a patient with an underlying plasma cell dyscrasia. A prolonged delay before diagnosis is associated with a significant impact on the clinical course of multiple myeloma. Patients who experienced a delay of more than 6 months before diagnosis were more likely to have complications. (65) This study clearly shows that a prolonged time to diagnosis had a significant effect on disease-free survival and was associated with early mortality. (65)

Please Note: Illustration(s) are not available due to copyright restrictions.

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Guillermo A. Herrera, MD

Accepted for publication December 27, 2013.

From the Department of Pathology, Louisiana State University, Shreveport.

The author has no relevant financial interest in the products or companies described in this article.

This work was presented in part at a platform presentation at the United States and Canadian Academy of Pathology meeting; March 2012; Vancouver, British Columbia, Canada.

Reprints: Guillermo A. Herrera, MD, Department of Pathology, Louisiana State University, 1501 Kings Hwy, Shreveport, LA 71130 (e-mail: gherr1@lsuhsc.edu).

Caption: Figure 1. Tubulopathic light chains can produce damage in proximal tubules in various ways (proximal tubulopathies) and can also be associated with obstructive distal tubulopathy (light chain ["myeloma"] cast nephropathy). Abbreviations: DT, distal tubule; PT, proximal tubule; T-LC, tubulopathic light chain.

Caption: Figure 2. Proximal tubular damage without associated inflammation. Tubular integrity is compromised (hematoxylin-eosin, original magnification X750).

Caption: Figure 3. A and B, Direct immunofluorescence. A, [lambda] Light chains. B, [kappa] Light chains. Granular monoclonal staining in the cytoplasm of proximal tubular cells for [lambda] light chains. Note absent staining for [kappa] light chains (fluorescein thiocyanate, original magnifications X500 [A], X350 [B].

Caption: Figure 4. Transmission electron microscopy. Increased number of lysosomes in cytoplasm of proximal tubular cells and apical cytoplasmic blebbing and fragmentation/desquamation (uranyl acetate and lead citrate, original magnification X8500 [A] and X750 [B]).

Caption: Figure 5. Immunogold labeling for [lambda] light chains, 10-nm gold particles, transmission electron microscopy. A, Lysosomes appear heavily labeled for [kappa] light chains. B, Lysosomes exhibit variable electron densities, indicating that some of their contents have been expelled into the cytoplasmic matrix (uranyl acetate and lead citrate, original magnifications X15 500 [A] and X12 500 [B]).

Caption: Figure 6. Transmission electron microscopy. A, Numerous lysosomes in the cytoplasm of proximal tubular cells. B, Very early cytoplasmic vacuolization is seen. Vacuoles are intimately related to the lysosomes (uranyl acetate and lead citrate, original magnifications X7500 [A] and X8500 [B]).

Caption: Figure 7. Transmission electron microscopy. Marked cytoplasmic vacuolization in proximal tubular cells in severe tubular damage (uranyl acetate and lead citrate, original magnification X9000).

Caption: Figure 8. Interstitial inflammation with focal tubulitis and tubular damage (B) (hematoxylin-eosin, original magnifications X350 [A] and X750 [B]).

Caption: Figure 9. Direct immunofluorescence. A and B, [kappa] Light chains. C, [lambda] Light chains. Granular monoclonal staining in the cytoplasm of proximal tubular cells and linear staining along tubular basement membranes for [kappa] light chains. Note absent staining for [lambda] light chains (fluorescein thiocyanate, original magnifications X500 [A and C], and X750 [B]).

Caption: Figure 10. Immunogold labeling for [lambda] light chains, 10-nm gold particles, transmission electron microscopy. A, Lysosomes are full of monotypical [lambda] light chains and early transcytosis is noted, with some [lambda] light chains starting to deposit on the basolateral border of the proximal tubules. B, Punctate electron-dense material on the outer aspect of the tubular basement membrane (light chain deposits) (uranyl acetate and lead citrate, original magnifications X7500 [A] and X8500 [B]).

Caption: Figure 11. Transmission electron microscopy. Segmental loss of integrity of the proximal tubule with absent microvillous border and cell fragments in the tubular lumen (uranyl acetate and lead citrate, original magnification X7500).

Caption: Figure 12. Transmission electron microscopy, uranyl acetate and lead citrate, [lambda] and B. B, Immunogold labeling for [lambda] light chains, 10 nm gold particles. Interstitial inflammatory infiltrate with eosinophils in A. Lysosomes with monotypical [lambda] light chains (no labeling for [lambda] light chains) and punctate lectron dense material also labeled for [lambda] light chains along the basolateral side of a tubule, indicating the deposition of light chains in that location in B (original magnifications X8500 [A] and X10 500 [B]).

Caption: Figure 13. Empty angulated spaces in the cytoplasm of proximal tubular cells (periodic acid-Schiff, original magnification X500).

Caption: Figure 14. Transmission electron microscopy. A and B, Crystalline inclusions in the cytoplasm of proximal tubular cells. Note variable shapes of crystalline inclusions of cytoplasm of proximal tubular cells (uranyl acetate and lead citrate, original magnifications X8500 [A] and X12 500 [B]).

Caption: Figure 15. Immunogold labeling for [kappa] light chains, 10-nm gold particles, transmission electron microscopy. Crystalline inclusions are labeled for monoclonal [kappa] light chains. No labeling for [lambda] light chains (uranyl acetate and lead citrate, original magnification X9500).

Caption: Figure 16. Transmission electron microscopy. A and B, Cytoplasmic inclusions in proximal tubular cells are fibrillary rather than crystalline (uranyl acetate and lead citrate, original magnifications X8500 [A] and X12 500 [B]).

Caption: Figure 17. A, Swollen proximal tubular cells with granular cytoplasm. B, The enlarged tubular cells exhibit no cytoplasmic staining. C, In trichrome staining the cytoplasm is bright red (hematoxylin-eosin, original magnification X750 [A]; periodic acid-Schiff, original magnification X750 [B]; trichrome, original magnification X750 [C]).

Caption: Figure 18. A, Transmission electron microscopy. The proximal tubular cells are packed full of lysosomes of various sizes and shapes. No other organelles are discernible. B, Direct immunofluorescence. Granular cytoplasmic staining for [kappa] light chains. No staining for [lambda] light chains (uranyl acetate and lead citrate; original magnification X6500 [A]; fluorescein thiocyanate, original magnification X500 [B]).

Caption: Figure 19. Immunogold labeling for [kappa] light chains, 10-nm gold particles, transmission electron microscopy. A, Details of cytoplasm full of lysosomes with various sizes and shapes. Note absence of other organelles. B, Intense labeling of lysosomes in proximal tubular cells for [lambda] light chains. No labeling for [lambda] light chains (uranyl acetate and lead citrate, original magnifications X8500 [A] and X18 500 [B]).

Caption: Figure 20. Flowchart for diagnosis and classification of monoclonal light chain-associated proximal tubulopathies.
Table 1. Proximal Tubulopathy Without Cytoplasmic Inclusions (Acute
Tubular Necrosis Variant)

Case   Age,   Sex   Clinical                              LC
No.    y            Presentation                       Involved

1      63     M     Slowly progressive inc SC          [kappa]
                      BL SC 1.1-2.3
2      74     F     Slowly progressive inc SC 2.73     [kappa]
                      Prot 0.7
3      69     M     SC 2.34                            [kappa]
                      Prot 0.295
4      50     F     SC 2.5                             [kappa]
                      Nonnephrotic range proteinuria
5      79     M     Rapid inc SC 1.35-2.72 in 3 mo     [kappa]
6      83     F     SC 1.9                             [kappa]
7      64     M     Rapid inc SC from 1.1-3.5          [kappa]
8      74     M     SC 2.73                            [kappa]
                      Prot 0.7
9      69     M     SC 2.34                            [kappa]
                      Prot 2.95
10     50     F     SC 1.95                            [kappa]
                      Prot 0.5
11     75     F     SC 1.2                             [kappa]
                      Prot 3.8
12     79     M     Rapid inc SC 2.72                  [kappa]
                      Prot 2.5
13     42     F     ARF; dialysis                      [lambda]
14     86     F     CLL; SC 6.7                        [lambda]
15     68     M     SC 2.4 Prot                        [lambda]
16     56     M     SC 1.6 Prot                        [kappa]
17     64     M     ARF; dialysis                      [kappa]
18     63     F     SC 1.1                             [kappa]
19     46     M     SC 1.1/1.2                         [lambda]
                      Prot 1.3
20     57     M     SC 1.5                             [lambda]
21     73     F     SC 4.1                             [kappa]
22     72     F     ARF; dialysis                      [lambda]

Case              Plasma Cell   Free Light     Serum
No.      MGUS     Dyscrasia     Chains Urine   [kappa]/
                                               [lambda]
       Yes   No   Yes   No      Yes   No       Ratio

1       X               X        X             N/A

2       X               X             X        3

3            X          X        X             N/A

4       X               X        X             2

5       X                        X    X        2.1
6       X               X             X        N/A
7            X          X             X        2.7
8            X          X        X             N/A

9            X     X                  X        3.7

10      X               X        X             N/A

11      X               X        X             N/A

12           X          X        X             6

13      X               X             X        1:3
14           X          X             X        N/A
15           X          X             X        N/A
16           X          X        X             214
17      X               X             X        N/A
18      X          X             X             N/A
19      X               X        X             N/A

20      X               X             X        1.9
21           X          X             X        4
22      X               X             X        N/A

Abbreviations: ARF, acute renal failure; BL, baseline; CLL, chronic
lymphocytic leukemia; inc, increase; LC, light chain; MGUS,
monoclonal gammopathy of undetermined significance; N/A, not
available; Prot, proteinuria (g/d); SC, serum creatinine (mg/dL).

Table 2. Tubulopathy Associated With Inflammatory Reaction (Acute
Tubular Interstitial Nephritis Variant)

Case   y    Sex   Clinical Presentation          LC Involved
No.

1      69   F     ARF; dialysis                    [kappa]

2      61   M     ARF                              [kappa]

3      79   M     Rapid inc SC 4                  [lambda]
                    SC BL 1.5-4.65
4      78   M     ARF; dialysis                   [lambda]
                    Prot 2.1
5      46   M     SC 1.82                         [lambda]
                    Minimal Prot 0.275 g/day
6      61   M     ARF; dialysis                   [lambda]

7      73   F     ARF                              [kappa]
                  SC 4.1
8      67   F     ARF                              [kappa]
                    SC 23
                    Prot 1
9      75   M     ARF                              [kappa]
                    SC 8.3
10     73   F     Rapid inc SC = 5                 [kappa]
                    Prot 2
11     42   M     ARF; dialysis                   [lambda]

12     72   F     ARF; SC 6.1                     [lambda]

13     66   M     ARF                             [lambda]

14     80   M     SC 2                             [kappa]

15     67   F     SC 2.7 BL normal                [lambda]

16     53   M     ARF                             [lambda]
                    SC 5.4
17     52   M     SC 2                             [kappa]
18     53   M     Inc SC from 1.9-2.8             [lambda]
                    in 2 mo
19     80   M     SC 3.8                           [kappa]

20     76   M     ARF; dialysis                    [kappa]
                    SC 6.82
21     70   F     SC 2.23                          [kappa]
                    ARF
22     89   F     ARF                             [lambda]
                    Prot 1.4
23     72   M     SC 3.7                           [kappa]

24     73   F     ARF                              [kappa]
                    SC 4.1
25     74   M     SC 2                             [kappa]
                    Prot 7.78
26     72   F     ARF; dialysis                   [lambda]
                    SC 6.1
27     75   M     SC 2.9                           [kappa]
                    Lymphoplasmacytic lymphoma
28     64   F     ARF                              [kappa]
                    SC 6.4
                    Prot 8

Case   MGUS                  Plasma     Free Light   Serum
No.                          Cell       Chains       [kappa]/
                             Dyscrasi   Urine        [lambda]
                                                     Ratio
       Yes              No   Yes   No   Yes   No

1      X                     X          X
                                                     N/A
2                       X          X    X
                                                     N/A
3      X                           X    X
                                                     N/A
4      X IgA [lambda]              X    X
                                                     1:4 (R)
5      X                     X          X
                                                     N/A
6                                  X    X
                                                     N/A
7                            X
                                                     N/A
8      X (faint              X          X
         monoclonal                           N/A
         spike)
9                            X          X
                                                     6.2
10                      X          X          X
                                                     N/A
11     X                           X    X
                                                     N/A
12     X                     X
                                                     N/A
13                           X          X
                                                     N/A
14     X                           X    X
                                                     N/A
15     X                           X          X
                                                     N/A
16                      X          X    X
                                                     N/A
17                      X          X          X      r
18     X                           X          X      5
                                                     1:2 (R)
19                                 X          X
                                                     N/A
20                                 X          X
                                                     N/A
21     X                           X    X
                                                     N/A
22                                 X    X
                                                     N/A
23     X                           X    X
                                                     2.1
24                           X     X    X
                                                     N/A
25                           X                X
                                                     N/A
26     X (faint IgG)               X          X
                                                     N/A
27                           X                X
                                                     N/A
28                                 X    X
                                                     7.2

Abbreviations: ARF, acute renal failure; BL, baseline; Ig,
immunoglobulin; inc, increase; LC, light chain; MGUS, monoclonal
gammopathy of undetermined significance; N/A, not available; Prot,
proteinuria (g/d); R, reversed ratio; SC, serum creatinine (mg/
dL).

Table 3. Proximal Tubulopathy With Cytoplasmic Inclusions

Case   Age,    Sex    Clinical            LC         MGUS
No.      y            Presentation     Involved

                                                     Yes

1       44      M     SC 1.7           [kappa]
                        Prot 0.8                      X
2       47      M     Glucosuria       [kappa]
                        SC 1.5                        X
                        Prot 1.2
3       56      F     Glucosuria,      [lambda]       X
                        phosphaturia
                        SC 3
                      Prot 5.4
4       48      M     Back pain        [kappa]        X
                        Glucosuria,
                        phosphaturia
                        SC 3
                        Prot 3

Case        Plasma      Free       Serum
No.         Cell        Light      [kappa]/
            Dyscrasia   Chains     [lambda]
                        Urine      Ratio

       No   Yes   No    Yes   No

1           X           X
                                   N/A
2           X           X
                                   1.8

3                 X     X
                                   1:2 (R)

4                 X           X
                                   N/A

Abbreviations: LC, light chain; MGUS, monoclonal gammopathy of
undetermined significance; N/A, not available; Prot, proteinuria (g/
d); R, reversed; SC, serum creatinine (mg/dL).

Table 4. Proximal Tubulopathy With Lysosomal Indigestion/
Constipation

Case   Age,   Sex    Clinical                      LC
No.     y            Presentation               Involved

1       76     F     Glucosuria, phosphaturia   [kappa]
                       SC 2.9
                       Prot 1.2
2       63     F     Glucosuria, phosphaturia   [kappa]
                       SC 3
3       52     M     Phosphaturia               [kappa]
                       SC 2.5

Case     MGUS     Plasma      Free       Serum
No.               Cell        Light      [kappa]/
                  Dyscrasia   Chains     [lambda]
                              Urine      Ratio

       Yes   No   Yes   NO    Yes   No

1       X               X           X    1.7

2       X         X           X          4

3       X         X           X          3.2

Abbreviations: LC, light chain; MGUS, monoclonal gammopathy of
undetermined significance; Prot: proteinuria (g/d); SC, serum
creatinine (mg/dL).
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