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CLINICAL HISTORY

65-year-old male who initially presented to the local hospital after a fall. An imaging study revealed an osteolytic lesion with suspected pathological fracture of C6 vertebral body. Following resection of the lesion, the patient received radiation to the affected area. Pathological examination showed tumor cells positive for CD138 with kappa restriction, consistent with the diagnosis of plasmacytoma. Two and half years later, he was evaluated for elevated creatinine, which increased from a baseline of 1.0 (N = 0.6-1.3) mg/dl to 1.5 mg/dL.  The physical exam was unremarkable.  Comprehensive metabolic panel was also unremarkable.  In addition, there was an elevation of free kappa light chains to 38.09 (0.33-1.94) mg/dL, kappa to lambda ratio of 35.93 (0.26-1.65), serum protein electrophoresis was negative for M-spike and blood immunofixation was positive for IgA kappa monoclonal gammopathy. The urinary protein electrophoresis was negative for M-spike but urine immunofixation was positive for monoclonal free kappa light chain band.  Urinary protein-to-creatinine ratio (UPC) was less than 0.1 and urinalysis was devoid of cells and sediment.  Initially patient was followed conservatively but underwent a kidney biopsy ten months after presentation to the renal clinic because of rising free kappa light chains (84.07 mg/dL) and development of proteinuria with a UPC 0.6. 

BIOPSY FINDINGS

Light microscopy revealed mild ischemic changes in nine out of forty-seven glomeruli (9/47).  The remaining glomeruli were unremarkable. Nearly 30% of the cortical tissue showed tubular atrophy with mild interstitial fibrosis and minimal to sparse chronic interstitial inflammatory infiltrates, composed of lymphocytes admixed with scattered macrophages and occasional plasma cells. Tubular findings are summarized in Figure 1.  

Figure 1: Most of the proximal tubules appear enlarged. The epithelial cells are distended by coarsely granular, eosinophilic material (A) that is PAS-negative (B) and strongly fuchsinophilic on trichrome stain (C). There is an accompanying tubular epithelial injury that ranges from the loss of brush border, karyopyknosis to the loss of cellular cohesion and their subsequent sloughing into the lumen.

IMMUNOFLUORESCENCE MICROSCOPY (IF):

Immunofluorescence microscopy (2 glomeruli), performed on frozen tissue (IF-F), revealed no staining for immunoglobulins IgG, IgA, complement components C3, C1q, kappa and lambda light chains within the glomeruli, tubulointerstitial compartment and arterial vessels. Immunofluorescence, performed on protease digested formalin-fixed paraffin-embedded tissue (IF-P) is shown in Figure 2.

Figure 2: IF-P using FITC-conjugated anti-human kappa and lambda light chains showed a 1-2+ positive staining for kappa light chains mainly within the tubular cells (A). Occasional glomerular epithelial cells positivity was also noted (not shown here). No staining for lambda light chains was noted within the tubular cells (B).

ELECTRON MICROSCOPY (EM):

Figure 3. Proximal tubular epithelial cells were variably swollen containing prominent lysosomes with dark stained inclusions (A; arrow marks tubular basement membrane), some of which had crystalline (B) or myelin body configurations. Several crystals can be seen in the tubular lumen (B).

FINAL DIAGNOSIS

• Light chain proximal tubulopathy, mainly non-crystalline and focal crystalline type, associated with monoclonal kappa light chains with occasional glomerular epithelial involvement.
• Focal tubular atrophy with mild interstitial fibrosis, 30% of the cortex.
• Mild global ischemic changes and global glomerulosclerosis.
• No evidence of concomitant monoclonal immunoglobulin deposition disease or Bence Jones cast nephropathy or amyloidosis.

DISCUSSION

Monoclonal gammopathy is defined as detectable monoclonal heavy chain, heavy and light chains or kappa or lambda light chain alone in the circulation. This is as a consequence of an abnormal production of monoclonal immunoglobulins or their components. The source of monoclonal proteins (paraproteins) ranges from indolent B-cell lymphomas to plasma cell neoplasms.  The spectrum of clinical presentation also varies – from low-grade entities that do not require treatment (MGUS) to progressive diseases with poor prognosis. These paraproteins can deposit in various organs, causing tissue damage. Pertaining to the kidney, the term monoclonal gammopathy of renal significance (MGRS) was introduced to highlight the evidence of kidney damage related to monoclonal paraproteinemia despite the absence of diagnostic criteria for a hematologic neoplasm [1]. It was shown that renal disease in patients with monoclonal gammopathy or multiple myeloma is associated with worse prognosis [2], which can be improved by timely chemotherapeutic reduction of light chains (LCs) by controlling the neoplastic clone [3].

Renal lesions under the MGRS commonly include AL amyloidosis or monoclonal immunoglobulin deposition disease amongst others, which also involve the tubulo-interstitium and vasculature. Light chain proximal tubulopathy (LCPT) is an uncommon representative of this group, accounting for 4-5% of MGRS (Table 1) [4, 5]. A typical clinical presentation of LCPT is non-nephrotic proteinuria with median protein of 1.5-2.5 g/day or mild CKD (median creatinine of 1.9–2.0 mg/dl) [6]. Complete or incomplete Fanconi’s syndrome is detected in approximately 40% of the cases [4]. Bence Jones proteinuria is almost always present.

Several morphologic forms of LCPT are described, however, it is commonly divided into crystalline and non-crystalline types [5, 7]. Crystalline type is characterized by intracellular crystalline inclusions of a variety of sizes and shapes - rectangular, rhomboid, needle shaped etc. They tend to accumulate in the lysosomes of the proximal tubular epithelium, causing cellular injury and interfering with their function. Monoclonal light chains are freely filtered through the glomerulus and reabsorbed by the proximal tubular epithelial cells via the megalin/cubilin scavenger receptor, followed by their intralysosomal degradation. In LCPT, however, abnormal light chains possess a hydrophobic amino acid side chains due to mutations in the variable domain of the immunoglobulin molecule that confer the ability to resist lysosomal enzyme and protease degradation. Such light-chain crystals or inclusions disrupt lysosomal function, inducing cellular injury, impairing reabsorption, which results in light-chain proximal tubulopathy [8]. More than 90% of the LCs causing LCPT belong to the subgroup 1 of kappa variable domain. In contrast, most cases of lambda LCPT are of non-crystalline type because lambda LCs lack the capability to spontaneously crystallize [9]. Podocytes can sometimes exhibit an accumulation of crystalline inclusions in cases of crystalline type LCPT, leading to nephrotic-range proteinuria [4]. No crystalline podocyte structures were identified in our case. The significance of electron dense podocyte vacuoles that we encountered is unknown. They can either represent a non-specific finding that reflects a low-level proteinuria or be related to the monoclonal protein.

LCPT is a diagnostic challenge provided its rarity and only a fraction of patients having a detectable diagnosis of related hematologic disorder at initial presentation. Only 15% to 50% of the patients had a known MGRS-associated hematologic entity by the time of the renal biopsy [4, 5, 10]. Another challenge is a frequent false-negative light chain immunostaining, when performed on frozen tissue. An antigen retrieval step using enzyme digestion may be required to expose the specific epitopes to achieve a positive staining [11]. The sensitivity of IF-F and IF-P for detection of LCPT was 35% (15/43) and 97% (37/38), respectively. Interestingly, IF-F was significantly better for detecting noncrystalline LCPT than crystalline LCPT [4].

While crystalline and non-crystalline monoclonal light chain deposits can co-exist, crystalline deposits can often be recognized only on ultrastructural examination, with light microscopy showing mostly coarsely granular material in the proximal tubules and failing to show clear crystalline structures [4]. This is demonstrated in the case presented here (see above light and electron microscopy findings). However, a doubt is raised about whether non-crystalline type of LCPT represents a truly independent disease process or is just a physiologic trafficking of light chains [5, 12]. The focal crystal formation in our case does not reflect the extent or severity of tubular damage that is seen by light microscopy and corroborated by the laboratory data. This suggests that non-crystalline component of LCPT is accountable for much of the proximal tubular epithelial dysfunction leading to acute kidney injury (AKI).

The mainstay of MGRS treatment is controlling the neoplastic clone with chemotherapy or stem cell transplantation - approaches that were earlier utilized only in patients with an established diagnosis of hematologic malignancy. Free light chain reduction in patients with monoclonal gammopathies is associated with better renal recovery, resulting in improved patient survival [13].

Table 1. A summary of common MGRS as well as some non-MGRS related renal lesions primarity affecting the tubulo-interstitium (adapted with modifications from [6] and [9]).

References

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