MGRS is a group of clonal hematologic disorders that result in kidney injury but do not satisfy the definition of multiple myeloma or malignant lymphoma. Many kidney diseases/lesions have been identified to be associated with MGRS. These kidney diseases are typically refractory to immunosuppressive therapies and have a high rate of relapse after kidney transplantation. Typically, clone-directed therapy is required to achieve a deep hematologic response, such as very good partial response or complete response in order to induce a renal response for preservation of kidney function. Successful treatment of the MGRS also significantly reduces the risk of recurrence after kidney transplantation.

The most common cause of acute kidney injury (AKI) in patients with multiple myeloma is cast nephropathy. Patients with light chain cast nephropathy typically present with AKI that is rapid in onset and can result in acute renal failure. This lesion is characterized by light chain–Tamm-Horsfall protein casts that obstruct post–loop of Henle tubules, resulting in acute tubular injury, inflammation, and subsequently fibrosis. These casts appear fractured with sharp edges, stain PAS negative, and exhibit light chain restriction on immunofluorescence. The casts are often associated with mononuclear and giant cell reactions. Crystalline and amyloidogenic variants of light chain cast nephropathy exist. In addition, multiple myeloma patients can also have any of the kidney lesions that patients with MGRS may have but only light chain cast nephropathy is considered a myeloma-defining event. Patients with other kidney lesions cannot be diagnosed with multiple myeloma unless another myeloma-defining event (e.g., lytic bone lesions, hypercalcemia, and anemia) is present. Finally, AKI can also result from plasma cell infiltration and extramedullary hematopoiesis as a result of overcrowding in the bone marrow.

For light chain cast formation to occur, it requires a high serum-free light chain level (a minimum of 50 mg/dL of monoclonal free light chain, but the majority of patients have a serum concentration >150 mg/dL) and Bence-Jones proteinuria. The Bence-Jones proteinuria is often > 200 mg/day. The high concentration of monoclonal free light chain overwhelms the resorptive capability of the proximal tubules thus allowing large amounts of free light chain to enter the loop of Henle. There, the monoclonal free light chain binds and precipitate with Tamm Horsfall protein to form casts. It is important to note that light chain cast nephropathy can be precipitated by dehydration caused by hypercalcemia, vomiting and diarrhea, ACE inhibitors, and nonsteroidal antiinflammatory drugs, etc.

Treatment required elimination of the potential causes and rapid reduction of the monoclonal free light chain concentration. The monoclonal free light chain should be reduced by 50% to 60% rapidly and to <50 mg/dL by the end of cycle 1 of chemotherapy. Prompt initiation of chemotherapy is the key. Currently, a three-drug regimen containing bortezomib is the standard. The addition of daratumumab, an anti-CD38 antibody, has been shown to improve hematologic response and progression-free survival but has not been tested in patients with AKI. Extracorporeal methods of removing monoclonal light chains have been employed most notably with plasmapheresis and high cutoff dialyzers. Unfortunately, clinical trials have produced mixed results; thus neither modality has become standard therapy. ^, Patients who recover kidney function have a prognosis like patients who never developed AKI. Overall survival is inferior in patients with persistent renal dysfunction, especially those on dialysis.

Immunotactoid glomerulopathy (ITG) is a rare glomerular disease accounting for 0.06% of kidney biopsies. Unlike other MGRS-associated kidney diseases in which plasma cell clones make up the majority of the pathologic clones, lymphocytic clones, particularly chronic lymphocytic leukemia clones, which include small lymphocytic lymphoma and some monoclonal B cell lymphocytosis, are the majority in ITG. One series from France found 60% of the clones were lymphocytic in origin with 48% belonging to the chronic lymphocytic leukemia/small lymphocytic lymphoma lineage. Another series from the Mayo Clinic and Columbia University reported 76% of the clones were either lymphoma, chronic lymphocytic leukemia, or monoclonal B-cell lymphocytosis. Multiple myeloma made up only 4% of the clones while 15% were MGRS. Not all cases of ITG are secondary to a monoclonal gammopathy. Polyclonal immunoglobulin deposits were found in 33% of cases in one series (polytypic variant of ITG). Patients with polyclonal variants of ITG were more commonly found with an autoimmune disease (e.g., psoriasis, ulcerative colitis, systemic lupus erythematosus, rheumatoid arthritis, polymyositis, and multiple sclerosis) than in patients with the monoclonal variant (25% vs. 8%, P = 0.07). Positive antinuclear antibody was also more common in polyclonal than monoclonal ITG patients (35% vs. 17%, P = 0.13). Less than half of the patients are hypocomplementemic (either low C3 or C4). Median age at presentation is 61 years with a slight male predominance (47%–67%). Patients with ITG present with heavy proteinuria typically >6 g/day, hypertension, and moderate renal impairment. Extrarenal manifestations have not been reported.

ITG is defined by glomerular immunoglobulin deposits that organize into parallel microtubules with a distinct hollow core in the absence of a clinicopathologic diagnosis of cryoglobulinemic glomerulonephritis or lupus nephritis. ^, The glomerular pattern of injury on light microscopy (LM) is heterogenous and varies from predominantly membranous nephropathy (29%–59%) to membranoproliferative glomerulonephritis (MPGN) (29%–41%) to endocapillary proliferative GN (35%, Fig. 35.1A–35.1C ). It is not uncommon to see a mixture of these patterns in the same biopsy. Pure mesangial proliferative and diffuse sclerosing patterns are rare (<10%), whereas focal crescents are present in less than a quarter of cases. Occasionally, large, glassy, PAS-positive, and silver-negative subendothelial immune deposits are seen. Cases associated with chronic lymphocytic leukemia/small lymphocytic lymphoma commonly exhibit direct interstitial infiltration by neoplastic B cells. ^,

Pathology of immunotactoid glomerulopathy and cryoglobulinemic glomerulonephritis type 2 associated with dysproteinemias.

(A–C) Monotypic immunotactoid glomerulopathy. (A) A glomerulus exhibits a membranous nephropathy pattern of injury with diffuse thickening and vacuolization of the glomerular basement membrane. There is also mild mesangial hypercellularity (periodic acid–Schiff, ×400). (B) A high-power electron microscopy image shows the deposits to be composed of large microtubules with parallel alignment (×40,000). (C) On immunofluorescence, the glomerulus exhibits 3+ granular global mesangial and glomerular basement membrane staining for IgG (×400) and λ (not shown) with negative staining for κ (not shown). (D–F) Cryoglobulinemic glomerulonephritis type II. (D) Numerous macrophages infiltrating the glomerular capillaries. Trichrome-red intraluminal pseudothrombi (arrows) are present in some glomerular capillaries (×400). (E) On electron microscopy, some of the subendothelial deposits exhibit a substructure characterized by cylinders and short microtubules (×49,000). (F) On immunofluorescence, the glomerulus exhibits 3+ granular global mesangial and glomerular basement membrane staining for IgM (×400). The glomeruli also exhibited 2+ staining for IgG and κ with 1+ staining for λ (not shown).

On immunofluorescence (IF), most cases exhibit dominant staining for IgG with co-deposition of C3 (90%) and C1q (65%). However, exceptional cases of ITG of the IgA class or IgM class ^, and, more recently, a light chain–only variant of ITG have been reported. Two-thirds of ITG cases exhibit immunoglobulin light chain isotype restriction (κ in two-thirds) with IgG subclass restriction (IgG1 in 67% and IgG2 in 27%) defining the monoclonal variant of ITG. The remaining one-third of cases show polytypic deposits consistent with the polyclonal variant of ITG.

On electron microscopy (EM), the deposits in ITG show microtubular substructure with a hollow center at magnification <50,000 and range in thickness from 10 to 60 nm. The deposits have well-defined borders and localize to the subepithelial zone (70%–100%), mesangium (84%), and/or subendothelial zone (75%). Some cases, especially those associated with chronic lymphocytic leukemia/small lymphocytic lymphoma, show smaller microtubules (<20 nm) comparable in size with fibrils of fibrillary glomerulonephritis (FGN). However, contrary to FGN, the microtubules do not permeate the mesangium or GBMs, and are DNAJB9 negative. ^, Intracytoplasmic microtubular inclusions can be seen in peripheral, bone marrow, and renal interstitial infiltrating chronic lymphocytic leukemia/small lymphocytic lymphoma cells.

The pathogenesis of ITG is not fully understood. In monoclonal ITG, the deposits are composed of intact monoclonal immunoglobulin and complement components. The microtubular organization could be influenced by the molecular structure and physicochemical properties of the secreted monoclonal immunoglobulin, such as amino acid substitutions in the hypervariable region of the light chain or alterations in the charge and hydrophobicity of the variable regions of both heavy and light chains. While some investigators proposed that ITG could result from glomerular deposition of low-level circulating cryoglobulins, the vast majority of ITG patients do not have any serologic evidence or systemic manifestations of cryoglobulinemia. There are also notable pathologic differences between these diseases (e.g., contrary to cryoglobulinemic glomerulonephritis [CryoGN]), ITG cases do not exhibit abundant intracapillary infiltrating macrophages or intracapillary pseudothrombi), rendering this proposition unlikely. ^, The pathogenesis of the polyclonal variant could involve glomerular deposition of an unknown protein with intrinsic property of polymerization into microtubules, which then leads to autoimmune response. The IF findings of C3 and C1q glomerular deposition and glomerular proteomic findings of abundant peptide spectra for C3, C1q, C4, C5, C8, and C9 favor activation of the classical and terminal pathway of complement, which in turn triggers glomerular inflammation.

In the largest series of ITG, rituximab-based therapy was used in 43% of monoclonal ITG versus 23% of polyclonal ITG patients. Another 32% of monoclonal ITG patients recieved chemotherapy versus 8% of polyclonal ITG patients. For the chronic lymphocytic leukemia and B cell clones, this was often accomplished with rituximab-based therapy. Approximately 25% of patients progressed to end-stage renal disease, which was more common in the polyclonal immunoglobulin deposits in patients (53% polyclonal vs. 11% monoclonal, P < 0.01).

Of the three types of cryoglobulins, only two are involved with monoclonal gammopathy. All type I cryoglobulins are composed of monoclonal immunoglobulin, which can be IgM, IgG, or IgA. Type II cryoglobulins are mixed, typically involving a monoclonal IgM κ (a rheumatoid factor) against polyclonal IgG, but not all type II cryoglobulins are the result of a lymphoproliferative or plasma cell proliferative disorder. The rest of the type II and type III cryoglobulins are usually secondary to infection, particularly from hepatitis C or autoimmune diseases. However, patients with hepatitis C who develop cryoglobulinemia do have a 35-fold increase in risk of developing non-Hodgkin lymphoma. The median time for non-Hodgkin lymphoma development is 6.3 years. It is important to note that circulating cryoglobulins can be difficult to detect, so the absence of cryoglobulinemia does not rule out CryoGN. ^, Unlike ITG, extrarenal manifestations are common in CryoGN: hypertension; skin (rashes, purpura, digital necrosis); nerve (peripheral neuropathy); joint (arthralgia); vasomotor (Raynaud phenomenon); and others (abdominal pain, hemorrhage, and thrombosis). ^, Renal manifestations are variable with microscopic hematuria, and proteinuria (subnephrotic to nephrotic range) with or without renal impairment. Hypertension is usually severe. Renal failure is uncommon, occurring in 10% to 15% of patients. ^, Hypertension is not a risk factor for ESRD but is associated with cardiovascular death.

LM in CryoGN exhibits macrophage-rich endocapillary proliferative GN or MPGN (see Fig. 35.1D–35.1F ) . Intracapillary pseudothrombi are seen in about 80% of cases. On IF in type I CryoGN, glomeruli stain for one immunoglobulin class (IgG or IgM) and one Ig light chain isotype (κ or λ). In type II CryoGN, there is usually glomerular staining for IgM, IgG, κ, and λ, with more intense staining for IgM than IgG and for κ than λ. On EM, the glomerular electron-dense deposits are subendothelial, mesangial, and intraluminal, whereas subepithelial deposits are uncommon. The deposits in three-quarters of cases exhibit organized substructure, most commonly short cylindrical/microtubular bodies. This substructure is more common in type II than type I CryoGN. CryoGN type I may show a variety of other substructures, such as lattice-like substructure or long straight microtubules with parallel alignment mimicking ITG.

The clones responsible for majority of the monoclonal cryoglobulinemia cases are of B cell origin, particularly the lymphoplasmacytic clone responsible for Waldenstrom macroglobulinemia, which accounts for 21% to 57% of cases in different series. Plasma cell clones are most commonly responsible for type I cryoglobulinemia and are rare in type II cryoglobulinemia.

Use of corticosteroids is an effective initial therapy, especially if life-threatening complications exist. Plasmapheresis should also be considered in rapidly progressive cases. Steroid-sparing agents, such as alkylating agents like cyclophosphamide and rituximab, have a similar response rate of around 67% as frontline agents. Clinicians should be cautious of cryoglobulin flares that occur if rituximab is used initially without an alkylating agent and which may also occur in patients with Waldenstrom macroglobulinemia. For plasma cell clones and lymphoplasmacytic lymphoma, bortezomib-based therapy can also be used. Relapse rates are high with 5- and 10-year event-free survival rates of 26.5% and 20.8%, respectively. Patients with renal involvement and IgG type I cryoglobulinemia were at higher risk of relapse. Overall survival at 5 and 10 years were 77.0% and 52.5%, respectively. The most common causes of death were infection, hematologic progression, and heart failure.

One of the rarest and most severe complications of MGRS and MM is crystalglobulinemia. This entity is characterized by crystallization of monoclonal immunoglobulin intravascularly. These crystals can sometimes precipitate in colder temperatures, and the condition is referred to as cryocrystalglobulinemia. Despite this property, cryoglobulin testing is often negative. ^, Kidney involvement in this syndrome is referred to as “crystalglobulin-induced nephropathy” (CIN). Crystallization of monoclonal immunoglobulin in the renal microvasculature typically results in acute oliguric renal failure. Most patients have mild proteinuria (range 0.6–1.1 g/day). Nephrotic syndrome is not a feature. Hematuria is present in just over half of patients. In the limbs, monoclonal immunoglobulin crystals can result in purpura, hemorrhagic bullae skin necrosis, and in severe cases digit infarct and gangrene. Crystallization in large visceral vessels results in organ infarcts and often death. Corneal and fundi deposits have also been reported. One study found only 4 women out of 17 patients. The median age was 55 years. Most of the patients had multiple myeloma, but more recent reports are in patients with MGRS. ^{, ,} In most patients, the diagnosis of CIN leads to discovery of an underlying plasma cell dyscrasia. Serum protein electrophoresis with immunofixation (SPEP/SIFE) is positive for M-spike in all patients, which is most commonly IgGκ and only rarely IgGλ or IgAk. ^, Urine protein electrophoresis with immunofixation (UPEP/UIFE) was positive for M-spike, and the serum free light chain (sFLC) ratio was abnormal in 50% and 56%, respectively, of reported patients with biopsy-confirmed CIN. ^, The nephropathic clone (typically plasma cell clone) is detected in the bone marrow in 70% of patients with CIN. While anemia, thrombocytopenia, elevated LDH, and low haptoglobin are frequent, peripheral smear schistocytes are not usually observed. Two-thirds of CIN patients have hypocomplementemia.

Histologically, CIN is characterized by the presence of monoclonal immunoglobulin crystalline precipitates within the renal microvasculature (glomerular capillaries and vascular lumina), frequently causing occlusive thrombi, without associated immune-mediated glomerulonephritis. ^, The monoclonal immunoglobulin crystals appear hypereosinophilic on hematoxylin-eosin, trichrome-red, and silver-negative stains ( Fig. 35.2E–35.2F ). Occasionally, the crystals are accompanied by neutrophils, but glomeruli without crystals typically appear nonproliferative, without mesangial hypercellularity or leukocyte infiltration. Secondary glomerular and/or vascular thrombosis as a reaction to the intraluminal crystal precipitation and endothelial cell injury is common, and thus CIN can be misdiagnosed as thrombotic microangiopathy (TMA). Similar crystals can be seen in distal tubule lumina, which are generally rare and not associated with cellular reactions. Tubules typically show acute injury.

On IF, the crystalline deposits most commonly stain with IgG and κ and only rarely with IgA and κ. Analogous to light chain proximal tubulopathy (LCPT) and light chain crystalline podocytopathy, standard immunofluorescence on frozen tissue (IF-F) often fails to show the composition of crystals. In these cases, IF on paraffin tissue sections after antigen retrieval with a protease (IF-P), immunoperoxidase immunohistochemistry, or immunoEM can be revealing.

Ultrastructurally, the electron-dense crystals appear rectangular, rhomboidal, needle shaped, or rod shaped, and on high magnification they usually show parallel linear arrays with a reported thickness of 4 to 6 nm and periodicity of 9 to 20 nm. ^, Neither intracellular crystals nor mesangial, subendothelial, or subepithelial granular or organized electron-dense deposits are features of CIN, distinguishing it from crystal cryoglobulinemic glomerulonephritis type 1.

The pathomechanisms of crystalglobulinemia remain unknown. Intravascular crystallization may occur due to Fc–Fc interactions of the monoclonal immunoglobulin, possibly owing to abnormal glycosylation of the light chain portion of monoclonal immunoglobulin or the presence of unusual hydrophobic amino acids at the variable domain of immunoglobulin heavy or light chains, or through interactions with albumin. ^, The accumulation of crystalglobulins in the microvasculature potentially leads to endothelial cell injury and activation of coagulation cascade, resulting in thrombosis, occlusive changes, and subsequent ischemic injury to the kidney and other organs.

Prompt initiation of antiplasma cell therapy is crucial in the management of patients with crystalglobulinemia. Plasmapheresis can reduce the monoclonal immunoglobulin load and prevent further crystallization into microvasculature, and high-dose corticosteroids serve as bridging therapy until response to treatment of the underlying hematologic condition is achieved. Bortezomib-based regimens (e.g., CyBorD) appear to be effective in inducing complete or partial renal recovery and improvement of extrarenal manifestations in most patients when coupled with bridging plasmapheresis and high-dose corticosteroids. ^, While most patients treated with these regimens come off dialysis, relapses are common and could lead to irreversible kidney failure. ^,

LCPT is found in 1% of kidney biopsies. It accounts for 0.5% of the kidney biopsies from multiple myeloma patients and 5% of patients with monoclonal gammopathies. ^, While LCPT is more common in patients with MGRS, the disease is more severe in patients with multiple myeloma. ^, Nearly two-thirds of the patients are male, and they typically present in their late 50s. ^, Clinically, LCPT presents with renal impairment usually indolent with low-grade proteinuria, although AKI can occur. Patients often have Fanconi syndrome characterized by potassium, phosphorus and uric acid wasting, normoglycemic glucosuria, and aminoaciduria. Phosphorus wasting can result in osteomalacia and stress fractures. It is important to note that the electrolyte wasting often resolves as kidney function declines, but aminoaciduria will persist. The noncrystalline variant of LCPT is less likely to exhibit Fanconi syndrome.

Two morphologic variants of LCPT exist: a crystalline variant (86%) characterized by proximal tubular crystals and a noncrystalline variant (14%) characterized by light chain inclusions without crystal formation. ^, On LM, crystalline inclusions usually appear eosinophilic on hematoxylin-eosin and PAS-weak or negative, but they may appear optically clear. Acute tubular injury (ATI) is frequent, whereas interstitial inflammation is usually inconspicuous unless accompanied by light chain cast nephropathy.

With rare exceptions, crystalline LCPT is associated with κ light chain ( Fig. 35.2 A–35.2B ) while noncrystalline LCPT can be associated with either κ or λ light chains. ^, Importantly, due to the highly crystallized structure of monoclonal immunoglobulin light chain and intracellular localization, which could render the antigenic sites inaccessible to antibody binding, standard IF-F is insensitive (35%) for demonstrating light chain restriction of crystals. IF-P, which potentially denatures cell membranes and reveals the antigenic epitopes sequestered within the crystalline lattice, is much more sensitive (97%) and should be performed on cases with negative results on IF-F. ^, ImmunoEM is also sensitive, but this technique is only available in a few selected centers. In contrast, noncrystalline LCPT can readily be diagnosed on IF-F.

Pathology of light chain proximal tubulopathy, light chain crystalline podocytopathy, and crystalglobulin-induced nephropathy.

(A and B) Light chain proximal tubulopathy: (A) Immunofluorescence performed on paraffin tissue after pronase digestion reveals strong staining of proximal tubular cell crystals for κ (×400). The crystals were negative for λ (not shown). (B) Numerous rhomboidal and rod-shaped electron-dense crystals are present within proximal tubular cytoplasm (electron microscopy, ×2700). (C and D) Light chain crystalline podocytopathy. (C) The glomerulus exhibits collapsing features with retraction of the glomerular tuft and podocyte hypertrophy and hyperplasia (trichrome stain, ×400). (D) Highly electron-dense crystals with various geometric shapes are present in podocyte, within lysosomes, or free in the cytosol (×8000). (E and F) Crystalglobulin-induced nephropathy. (E) The glomerular capillaries are narrowed or occluded by numerous trichrome-red crystalline deposits (×200). (F) An electron microscopy image showing large mildly electron-dense crystalline deposits within glomerular capillaries (×5000).

On EM, proximal tubule crystals appear electron dense, needle shaped, rodlike, rhomboidal, or rectangular. They are present within phagolysosomes or lie free in the cytosol. In noncrystalline LCPT, proximal tubular cells contain electron-dense droplets or vacuoles. In some cases, the cells appear markedly extended by intralysosomal indigested light chains (referred to as “lysosomal indigestion with constipation syndrome.”) A subset of cases of LCPT show concurrent monoclonal immunoglobulin lesions including light chain cast nephropathy, crystal-storing histiocytosis (CSH), light chain crystalline podocytopathy, AL amyloidosis, or light chain deposition disease. CSH is somewhat similar to LCPT in that it is also characterized by light chain crystals, κ light chain predominance, and Fanconi syndrome. Crystals in LCPT are present predominantly in proximal tubular cells and limited to the kidneys, whereas crystals in CSH are predominantly present in interstitial histiocytes in the kidney and other tissues throughout the body including bone marrow and cornea leading to keratopathy.

LCPT results from inability of the proximal tubule lysosomal system to degrade an overload of structurally abnormal filtered light chains. There is a notable homogeneity in the characteristics of light chains responsible for crystalline LCPT Fanconi syndrome. The majority belong to the Vκ1 variability subgroup and are derived from two germline gene segments, IGKV1-33 and IGKV1-39, and exhibit somatic hypermutations in complementarity-determining regions, which expose hydrophobic amino acid residues, making them resistant to degradation by lysosomal enzymes. This favors intralysosomal crystallization, lysosomal dysfunction, cell toxicity, and proximal tubule dysfunction. ^,

LCPT has a relatively indolent course. ESRD occurs in approximately 20% of the patients and is more often in patients with AKI or multiple myeloma. This, coupled with an observed low efficacy of conventional chemotherapy with alkylating agents and their frequent side effects (particularly myelotoxicity), led early reports to suggest deferring chemotherapy if there is no progression in the underlying hematologic condition or kidney dysfunction. However, more recent studies using stem cell transplant and/or new generation of antimyeloma drugs (such as bortezomib-based therapy) demonstrated that achieving hematologic complete response (CR) or very good partial response (VGPR) is associated with stabilization or improvement of kidney function. In one study on LCPT Fanconi syndrome, ESRD developed in only 12% of treated patients versus 50% of untreated patients. Thus effective chemotherapy could delay progression to ESRD in LCPT. Recurrence after kidney transplantation occurs rapidly within weeks to months.

Light chain crystalline podocytopathy is one of the newest kidney disorders recognized to be associated with MGRS. Most patients present with proteinuria (median 3.4 g/day) and CKD (median eGFR at presentation is 35 mL/min/1.73 m ² but ranges from 4 to 113 mL/min/1.73 m ² , median serum creatinine at diagnosis is 1.9 mg/dL). Full nephrotic syndrome is present in 28% to 35%. Hematuria and HTN are present in 26% to 38% and 50% of patients. Overt Fanconi syndrome is uncommon (10%) and, when present, associated with concomitant LCPT. Extrarenal manifestation with crystalline keratopathy is reported in 22%. ^, The underlying hematologic condition in light chain crystalline podocytopathy is most commonly MGRS, less commonly symptomatic multiple myeloma, and only rarely marginal cell lymphoma, which is diagnosed concomitantly with light chain crystalline podocytopathy in most patients, whereas a minority of patients have a known history of monoclonal gammopathy before presentation with light chain crystalline podocytopathy. SPEP/SIFE and UPEP/UIFE are positive for M-spike in all patients, most commonly IgGκ and only rarely IgAk or IgGλ. sFLC is abnormal in 62% to 83% of patients (median dFLC 17 mg/dL). The nephropathic plasma cell clone is detected in the bone marrow in 91% to 100% of patients (median % of monoclonal plasma cells 20%).

On LM, two-thirds of cases exhibit focal segmental glomerulosclerosis (FSGS), which is of the collapsing variant in 67% ( Fig. 35.2 C and 35.2D ) , non–otherwise specified (NOS) in 27% and tip in 7%. ^{, ,} The FSGS pattern is likely secondary to podocyte injury from the extensive intracytoplasmic crystalline inclusions. Misdiagnosis of light chain crystalline podocytopathy as primary or secondary FSGS is not infrequent if IF-P or EM is not performed. In some cases glomeruli appear unremarkable on LM, whereas in others PAS-negative podocytes inclusions/crystals are visible and appear osmophilic on toluidine-blue stained semithin sections.

The defining feature of light chain crystalline podocytopathy is the presence of monoclonal immunoglobulin crystals within podocytes by EM, which are usually numerous and appear highly electron dense with various shapes (rod shaped, needle like, polygonal, rhomboidal, rectangular, or hexagonal) and membrane bound (intralysosomal) or free in the cytosol. On high magnification, they may exhibit a lamellated substructure characterized by parallel linear arrays with a reported periodicity of 4.4 nm. In most light chain crystalline podocytopathy cases, similar crystals are seen in other renal cell types, most commonly within proximal tubule cells (80%, consistent with concomitant LCPT) and interstitial histiocytes (36%, consistent with concurrent CSH), and rarely in endothelial cells and mesangial cells. ^, Podocytes in most cases exhibit global foot process effacement. Podocyte crystals are of κ isotype in 92% and of λ in 8%. As in LCPT, IF-F is insensitive (12%) for demonstrating light chain restriction of podocyte crystals, whereas IF-P (77%), immunoperoxidase immunohistochemistry (83%), and immunoEM (100%) are more sensitive.

In light chain crystalline podocytopathy, the circulating free light chains potentially are endocytosed by podocytes and then crystallize inside lysosomes, leading to podocyte dysfunction, depletion, secondary FSGS, and albuminuria. Few studies have demonstrated that podocytes express megalin and CUBAM (cubilin-amnionless) complex (the receptors for albumin and light chain endocytosis by proximal tubule cells), but this has not been confirmed by others. As in LCPT and CSH, light chains responsible for light chain crystalline podocytopathy are usually κ light chain, and the majority are derived from germline genes IGKV1-33 and IGKV1-39 and exhibit hydrophobic amino acid substitutions in positions 32 or 30, respectively, ^, which could render them resistant to degradation by lysosomal proteases.

Mean ESRD-free survival time in patients with light chain crystalline podocytopathy is 58 months. Kidney response to plasma cell–directed therapy (typically bortezomib-based therapy) depends on achieving hematologic response. In one study, kidney response occurred in 80% of patients who had hematologic CR or VGPR but in only 13% of those with hematologic partial response (PR) or no response (NR). In this study, progression to ESRD was observed only in patients with FSGS (particularly the collapsing type). Thus early diagnosis and prompt initiation of plasma cell–targeted chemotherapy before development of FSGS is important.

On LM, the most common pathologic pattern is mesangial proliferative/sclerosing glomerulonephritis, followed by a membranoproliferative glomerulonephritis pattern. Segmental membranous nephropathy features can be present in some cases. Endocapillary hypercellularity with leukocyte infiltration causing luminal occlusion has also been described, as well as crescents, which can occur in 17% of cases. On IF, most cases show strong smudgy staining for IgG while IgA and IgM can be seen in 28% and 47% of cases, respectively. C3 co-deposition is almost universally present, while C1q deposition is less common. Fibrils typically permeate the mesangial and lamina densa and subepithelial zone of the GBMs. These fibrils are solid and average around 18 nm in diameter. Fibrillary glomerulonephritis typically does not stain with Congo red, although a weakly Congo red–positive variant has been described. Currently, the sine que non-characteristic of fibrillary glomerulonephritis characteristics is the positive staining for DNAJB9, which was first discovered at the Mayo Clinic. When limiting fibrillary glomerulonephritis to positive staining with DNAJB9, the percentage of patients who has a MGRS dropped to <1% with the exception of heavy chain variant of fibrillary glomerulonephritis in which the IgG is monoclonal. ^,

The pathogenesis of fibrillary glomerulonephritis is not well understood. Whereas DNAJB9 has been proven to be an excellent tissue biomarker of the disease, a pathogenetic role in FGN and how it interacts with IgG remain unclear. In addition, how malignancy, autoimmune diseases, and hepatitis infection tie into DNAJB9 is also unanswered.