Abstract
A 70-year-old woman with acute kidney injury, a high serum Creatinine (Cr) level (3.91 mg/dL), and proteinuria (protein/Cr ratio 1.59 g/gCr) was admitted. Serum IgG λ-type and urinary λ-type M proteins were observed. A bone marrow examination indicated monoclonal gammopathy of undetermined significance (MGUS). A renal biopsy showed distended proximal tubular cells, and immunofluorescence identified tissue positive for proximal tubular cell λ light chains. Electron microscopy identified fibril-like structures in the lysosomes. The patient was diagnosed with light chain proximal tubulopathy without crystals in IgG λ-type MGUS and treated with bortezomib and dexamethasone therapy, which improved her renal function.
Keywords: light chain proximal tubulopathy without crystals, monoclonal gammopathy of renal significance, monoclonal gammopathy of undetermined significance, paraprotein-related kidney disease
Introduction
Paraprotein-related kidney disease is a renal injury observed in multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS), and light chain cast nephropathy, monoclonal Ig deposition, light chain amyloidosis, and light chain proximal tubulopathy (LCPT) are variations (1).
LCPT is a rare disease that presents with tubular injury induced by the deposition of free light chains in the proximal tubular cell cytoplasm and lysosomes. Clinical symptoms include Fanconi syndrome, renal dysfunction, and proteinuria. Previously, this condition was believed to progress slowly; however, research has recently reported its rapid progression to end-stage renal failure (2).
A treatment for LCPT has not yet been established. Furthermore, LCPT associated with MGUS is not an indication for hematological treatment; therefore, no cases treated using this approach have been reported. Cases of LCPT without crystals in IgG λ-type MGUS treated using chemotherapy are also unknown.
We herein report for the first time the treatment of LCPT without crystals in IgG λ-type MGUS with bortezomib and dexamethasone therapies. The results showed that the treatment improved the renal function and helped avoid end-stage renal failure.
Case Report
The patient was a 70-year-old Japanese woman. She had been diagnosed with type II diabetes and hypertension at 69 years old and was started on sodium-glucose cotransporter 2 inhibitor, dipeptidyl peptidase-4 inhibitor, and angiotensin receptor blocker. She had been experiencing a poor appetite and whole-body malaise for approximately two months. One month before the visit, she consulted another physician and exhibited high levels of creatinine (Cr 2.78 mg/dL), which had worsened (Cr 3.62 mg/dL) by her subsequent visit, so she was referred to our department.
She was 162.5 cm tall and weighed 64.9 kg, and her blood pressure, pulse rate, body temperature, and SpO2 level were 157/84 mmHg, 82/min, 36.7°C, and 98%, respectively. Chest and abdominal examinations showed no abnormalities; no edema was observed on the lower legs. A urinary test revealed proteinemia with a protein/Cr ratio of 1.59 g/gCr but no hematuria. The urine β-2 microglobulin level was 3,008 μg/L. Blood tests indicated renal dysfunction (Blood urea nitrogen 40 mg/dL and Cr 3.91 mg/dL). The serum immunoglobulin (Ig) level was normal, depicting no decrease in serum complement levels. Serum protein electrophoresis showed IgG-λ-type M-proteins and increased free κ and λ light chain levels of 139.3 mg/dL and 162.5 mg/dL, respectively, but the κ/λ ratio was normal (0.86). Urine protein electrophoresis showed positive λ-type Bence Jones proteins (Table 1).
Table 1.
Laboratory Data from Blood and Urine Tests before Chemotherapy.
| <Urinalysis> | <Blood chemistry> | <Serology> | |||||||||||
| pH | 5.0 | TP | 8.0 | g/dL | CRP | 3.69 | mg/dL | ||||||
| Gravity | 1.006 | Alb | 3.6 | g/dL | IgG | 1,658 | mg/dL | ||||||
| Protein | (1+) | AST | 12 | U/L | IgA | 313 | mg/dL | ||||||
| 1.59 | g/gCr | ALT | 12 | U/L | IgM | 78.4 | mg/dL | ||||||
| Occult blood | (1+) | LDH | 152 | U/L | CH50 | 95 | U/mL | ||||||
| Glucose | (3+) | BUN | 40 | mg/dL | C3 | 153.6 | mg/dL | ||||||
| β2MG | 3,008 | ng/mL | Cre | 3.91 | mg/dL | C4 | 85.7 | mg/dL | |||||
| NAG | 9.3 | IU/mL | Na | 138 | mEq/L | ANA | ×40 | ||||||
| WBC | 0-1 | /HPF | K | 4.0 | mEq/L | FLC | |||||||
| RBC | 0-1 | /HPF | Cl | 107 | mEq/L | κ | 139.3 | mg/L | |||||
| Hyaline cast | 0-1 | /HPF | Ca | 9.3 | mg/dL | λ | 162.5 | mg/L | |||||
| Granular cast | 1-4 | /HPF | iP | 4.1 | mg/dL | κ/λ | 0.86 | ||||||
| BJP | Positive | HbA1c | 7.4 | % | |||||||||
| Hyperamino-aciduria | Negative | ||||||||||||
| <Complete blood> | <Venous blood gas> | ||||||||||||
| WBC | 9,890 | /μL | pH | 7.38 | |||||||||
| RBC | 409 | 104/μL | PCO2 | 40 | mmHg | ||||||||
| Hb | 11.6 | g/dL | HCO3- | 22.8 | mEq/L | ||||||||
| Platelets | 41.2 | 104/μL | |||||||||||
BJP: Bence-Jones protein, WBC: white blood cell, RBC: red blood cell, HPF: high-power field, Hb: hemoglobin, TP: total protein, Alb: albumin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, ALP: alkaline phosphatase, LDH: lactate dehydrogenase, BUN: blood urea nitrogen, CRP: C-reactive protein, ANA: antinuclear antibody, FLC: free light chain
A bone marrow examination indicated that plasma cells accounted for 2% of the bone marrow blood, and flow cytometry showed that 76.9% of the CD38-positive cells were λ light chains. We did not identify any signs suggesting MM; thus, the patient was diagnosed with MGUS.
A kidney biopsy was performed, and it identified 20 glomeruli, of which 6 were affected by global glomerulosclerosis. The proximal tubular cells were distended, and proximal tubular cell vacuolation containing granular inclusions were observed, and acute tubular injury were also observed in the periphery. Part of the interstitium was infiltrated by inflammatory cells, indicating interstitial nephritis. Arterioles were mildly sclerotic with hyaline changes (Fig. 1). Immunofluorescence (IF) indicated that the glomerular deposits were negative for IgG, IgA, IgM, C1q, C3, fibrinogen, and κ or λ light chains. At the same time, granular deposits of λ light chains were found on the proximal tubular cell cytoplasm by IF staining of the protease-digested paraffine section (Fig. 2). Electron microscopy findings showed fibril-like structures in the lysosomes of the proximal tubular cells (Fig. 3). We additionally detected κ- or λ-expressing plasma cells using in situ hybridization, which revealed no light chain restriction in the plasma cells.
Figure 1.
Light microscopy findings. (a) Distended proximal tubular cells and infiltration of inflammatory cells in part of the interstitium (PAS stain; ×40). (b) Proximal tubular cell vacuolation containing granular inclusions (PAS stain; ×400). (c) Hematoxylin and Eosin (H&E) staining highlights of the granular inclusions in the proximal tubular cells (H&E staining; ×400). (d) Acute tubular injury with flattened epithelial cells (PAS stain; ×100). PAS: periodic acid Schiff
Figure 2.
Immunofluorescence staining for κ and λ light chains on protease-digested proximal tubules. κ light chains were negative, but λ light chains were positive in the proximal tubules.
Figure 3.
Electron microscopy analysis results. Electron microscopy shows lysosomes, including fibril-like structures, in the proximal tubules (a, b).
The patient was thus diagnosed with LCPT without crystals in IgG λ-type MGUS. Bortezomib 2.1 mg/day (1.3 mg/m2) and dexamethasone 4 mg/day were administered for 5 weeks on days 1, 4, 8, 11, and 22. However, treatment was withdrawn on day 25 owing to bortezomib-induced peripheral neuropathy. On day 29, bortezomib was restarted at 1.1 mg/day (0.7 mg/m2). On day 32, bortezomib was again withdrawn for 10 days and continued for 6 weeks, after which the treatment was continued weekly. Serum Cr levels improved to 1.35 mg/dL and the urinary protein/Cr ratio to 0.82 g/gCr, and serum λ-light chain levels decreased to 29.2 mg/L after 7 months of treatment (Fig. 4).
Figure 4.
Clinical course of the patient. Serum Cr levels improved to 1.35 mg/dL, the urinary protein/Cr ratio improved to 0.82 g/gCr, and serum λ light chain levels decreased to 29.2 mg/L after 7 months of treatment.
Discussion
To date, there have been few reports on the treatment of LCPT with MGUS, and consequently, there are no established effective treatment modalities. Among the subtypes, LCPT without crystals in MGUS is rare. To our knowledge, no existing studies have reported the effectiveness of bortezomib and dexamethasone for LCPT without crystals in IgG λ-type MGUS; hence, this is the first report of its kind.
LCPT is a paraprotein-related kidney disease, accounting for only 4-5% of paraprotein-related kidney diseases (2,3). The underlying hematologic disease, apart from MGUS or MM, can be non-Hodgkin's lymphoma or chronic lymphoid leukemia. Stokes et al. (2) reported 46 cases of LCPT, among which 21 were associated with MGUS, 15 with MM, and 7 with smoldering MM. Vignon et al. (4) reported 49 cases of Fanconi syndrome and M-proteinemia, of which 13 were associated with MGUS, 7 with MM, and 25 with smoldering MM. However, most consisted of κ-type MGUS, including the 21 cases of Stokes et al.'s study mentioned above (2). Messiaen et al. (5) reported 11 cases of LCPT that manifested Fanconi syndrome, 3 of which were κ-type MGUS. LCPT with λ-type MGUS was thus considered extremely rare.
Electron microscopy showed structures of various shapes in the cell interstitium of the proximal tubules and lysosomes. Structures are classified into crystalline and noncrystalline. LCPT without crystals has three morphologic variants (6): 1) No organized structure and appears mottled when viewed with the electron microscope. 2) Amyloid deposits are observed in the proximal tubular cells. 3) The proximal tubular cytoplasm contains large fibrils. Larsen et al. (3) reported 11 cases of λ-type LCPT associated with MM and smoldering MM, all consisting of mottle-shaped structures without crystals. According to Stokes et al. (2), two cases of LCPT without crystals were found to be associated with λ-type MM. Bate et al. (7) reported that LCPT without crystals was associated with λ-type MGUS. Therefore, λ-type LCPT tends to be noncrystalline LCPT. This case was λ-type LCPT and was considered to involve LCPT without crystals, as a large fibril-like structure was observed.
LCPT is thought to occur in two major pathways (8). The first pathway is the excessive production of monoclonal immunoglobulin free light chains (FLCs), such as in multiple myeloma, which cannot be handled in proximal tubular cells, resulting in structural damage to the proximal tubules and infiltration of inflammatory cells. FLCs themselves are also thought to directly damage proximal tubular cells. The second pathway do not require excess FLCs. FLCs resist proteolytic enzymes due to somatic mutations in the variable domains (V domains) and accumulation in proximal tubular cells, causing cell damage. LCPT without crystals is often associated with the first pathway. This case was one of MGUS, and while we believe there was no excessive production of FLCs, noncrystalline structures were observed, suggesting that mutations that tend to adopt an amorphous structure may have occurred.
The detailed treatment methods of LCPT associated with MGUS have not been previously reported. The International Kidney and Monoclonal Gammopathy Research Group defines monoclonal gammopathy of renal significance as a condition that may exhibit renal dysfunction due to MGUS despite having a low degree of hematological malignancy that does not meet the criteria for hematological therapy, which would lead to recommended therapeutic intervention (9). We reviewed PubMed studies investigating LCPT associated with MGUS with or without treatment and identified 27 cases (2,5,7,10-19), of which 13 were treated with chemotherapeutic agents, such as bortezomib or hematopoietic stem cell transplant; in all cases but one, the treatment improved the renal function or prevented end-stage kidney disease. The remaining 14 cases were not treated aggressively or were treated with cyclophosphamide or dexamethasone monotherapy. The renal function worsened in eight cases and required dialysis or resulted in death (Table 2). In one of the two cases of LCPT without crystals in MGUS, a stable renal function and proteinuria were reported; however, chemotherapy was not performed in that patient (7). In the remaining cases, renal function worsened, leading to end-stage renal failure (5). Our present case involved LCPT without crystals in MGUS that exhibited acute renal dysfunction and exacerbation of proteinuria. Aggressive chemotherapy with bortezomib and dexamethasone is effective for such cases; indeed, end-stage renal disease was prevented by this intervention in our case.
Table 2.
Clinical and Morphological Findings in 27 Cases of LCPT with MGUS.
| Reference | EM inclusions | Monoclonal Ig | Treatment | Follow (months) | Renal outcomes | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| (10) | No date | κ | C | 39 | Stable | |||||
| No date | κ | No treatment | 12 | Stable | ||||||
| (11) | Rhomboid, needle | κ | No treatment | 6 | Worsening | |||||
| (12) | No date | κ | No treatment | 24 | Stable | |||||
| (13) | No date | κ | No treatment | 42 | Worsening | |||||
| (7) | Geometric outlines (Noncrystal) | λ | No treatment | 24 | Stable | |||||
| (5) | Crystal | IgAκ | No treatment | 12 | Stable | |||||
| Crystal | IgGκ | No treatment | 72 | Hemodialysis | ||||||
| Noncrystal | κ | No treatment | 72 | Worsening | ||||||
| (14) | Needle, rectangular, rod | IgGκ | L, D | 4 | Improved | |||||
| (2) | Rhomboid | IgAκ | No treatment | 70 | Hemodialysis | |||||
| Rhomboid, lattice | IgGκ | No treatment | 18 | Hemodialysis, died | ||||||
| Rhomboid | Negative | B, D | 39 | Stable, progressed to MM | ||||||
| Rhomboid | κ | D | 19 | Died | ||||||
| Rhomboid | κ | SCT, M | 57 | Improved | ||||||
| Rhomboid | IgGκ | B, D | 39 | Stable | ||||||
| Rhomboid | κ | B | 36 | Worsening | ||||||
| Rhomboid | κ | SCT, L, B, D, M | 14 | Stable | ||||||
| Rhomboid | κ | T, B | 69 | Worsening | ||||||
| Rhomboid | κ | C, B, D | 5 | Stable | ||||||
| Rhomboid | κ | No treatment | 1 | Died | ||||||
| Rhomboid | κ | T | 49 | Improved | ||||||
| (15) | Rhomboid, rod | IgGκ | C, B, D→L, D | 12 | Stable | |||||
| (16) | Club | IgGκ | B, D | 30 | Improved | |||||
| (17) | Needle | IgGκ | C, B, D | 36 | Hemodialysis, progressed to MM | |||||
| (18) | Needle | κ | B, L, D | 12 | Improved | |||||
| (19) | Needle | IgGκ | No treatment | 12 | Stable |
EM: electron microscopy, SCT: stem cell transplantation, C: cyclophosphamide, L: lenalidomide, D: dexamethasone, B: bortezomib, M: melphalan, T: thalidomide
One limitation of this case study was that diabetes mellitus and hypertension were present in the background of renal dysfunction. These factors may have contributed to the rapid worsening of the renal dysfunction, residual renal dysfunction, and proteinuria. In addition, as published reports for LCPT without crystals in MGUS are limited, and there are many unknowns, further research is required to better manage patients with LCPT without crystals in MGUS.
In conclusion, our results suggest that active intervention in conjunction with hematology leads to good outcomes, even for LCPT by MGUS with a poor renal function or proteinuria. Aggressive therapeutic intervention may be effective for LCPT without crystals in MGUS.
Written informed consent was obtained from the patient for publication of this article.
The authors state that they have no Conflict of Interest (COI).
Acknowledgement
The authors wish to thank the patient and the medical staff for their contributions to the case report.
References
- 1.Doshi M, Lahoti A, Danesh FR, Batuman V, Sanders P; the American Society of Nephrology Onco-Nephrology Forum. Paraprotein-related kidney disease: kidney injury from paraproteins - what determines the site of injury? Clin J Am Soc Nephrol 11: 2288-2294, 2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Stokes M, Valeri A, Herlitz L, et al. Light chain proximal tubulopathy: clinical and pathologic characteristics in the modern treatment era. J Am Soc Nephrol 27: 1555-1565, 2016. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Larsen C, Bell J, Harris A, Messias N, Wang Y, Walker P. The morphologic spectrum and clinical significance of light chain proximal tubulopathy with and without crystal formation. Mod Pathol 24: 1462-1469, 2011. [DOI] [PubMed] [Google Scholar]
- 4.Vignon M, Javaugue V, Alexander MP, et al. Current anti-myeloma therapies in renal manifestations of monoclonal light chain associated Fanconi syndrome: retrospective series of 49 patients. Leukemia 31: 123-129, 2017. [DOI] [PubMed] [Google Scholar]
- 5.Messiaen T, Deret S, Mougenot B, et al. Adult Fanconi syndrome secondary to light chain gammopathy: clinicopathologic heterogeneity and unusual features in 11 patients. Medicine 79: 135-154, 2000. [DOI] [PubMed] [Google Scholar]
- 6.Colvin RB, Chang A. Diagnostic Pathology. In: Kidney Diseases. 3rd ed. Elsevier, Philadelphia, 2019: 644-651. [Google Scholar]
- 7.Bate KL, Clouston D, Packham D, Ratnaike S, Ebeling PR. Lambda light chain induced nephropathy: a rare cause of the Fanconi syndrome and severe osteomalacia. Am J Kidney Dis 32: E3, 1998. [DOI] [PubMed] [Google Scholar]
- 8.Christophe S, Vecihi B, Paul WS. The proximal tubule toxicity of immunoglobulin light chains. Kidney Int Rep 6: 1225-1231, 2021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Leung N, Bridoux F, Batuman V, et al. The evaluation of monoclonal gammopathy of renal significance: a consensus report of the international kidney and monoclonal gammopathy research group. Nat Rev Nephrol 15: 45-59, 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Harrison J, Blainey J. Adult Fanconi syndrome with monoclonal abnormality of immunoglobulin light chain. J Clin Pathol 20: 42-48, 1967. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Lee D, Drinkard J, Rosen V, Gonick H. The adult Fanconi syndrome: observations on etiology, morphology, renal function, and mineral metabolism in three patients. Medicine (Baltimore) 51: 107-138, 1972. [PubMed] [Google Scholar]
- 12.Smithline N, Kassirer J, Cohen J. Light-chain nephropathy: renal tubular dysfunction associated with light-chain proteinuria. N Engl J Med 294: 71-74, 1976. [DOI] [PubMed] [Google Scholar]
- 13.Alavi N, Lianos EA, Palant CE, Bentzel CJ. Induction of epithelial tight junctions by a light chain protein isolated from a patient with Fanconi's syndrome. Nephron 35: 130-135, 1983. [DOI] [PubMed] [Google Scholar]
- 14.Elliott M, Cortese C, Moreno-Aspitia A, Dwyer J. Plasma cell dyscrasia causing light chain tubulopathy without Fanconi syndrome. Am J Kidney Dis 55: 1136-1141, 2010. [DOI] [PubMed] [Google Scholar]
- 15.Yu XJ, Zhou XJ, Wang SX, Zhou FD, Zhao MH. Monoclonal light chain crystalline podocytopathy and tubulopathy associated with monoclonal gammopathy of renal significance: a case report and literature review. BMC Nephrol 19: 322, 2018. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Ito K, Hara S, Yamada K, et al. A case report of crystalline light chain inclusion-associated kidney disease affecting podocytes but without Fanconi syndrome. A clonal analysis of pathological monoclonal light chain. Medicine (Baltimore) 98: e13915, 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Patel A, Choi J, Mutter W, Weins A, Riella L. Crystalline light chain proximal tubulopathy and podocytopathy: a case report. J Bras Nefrol 42: 99-105, 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Chopra R, Santana R, Batal I, Batra S, Jim B. Light chain proximal tubulopathy with cast nephropathy in monoclonal gammopathy of renal significance. BMJ Case Rep 13: e234361, 2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Sugimoto Y, Fujimoto M, Machida H, Nagaharu K, Murata T, Tsukada T. Light chain proximal tubulopathy diagnosed solely by electron microscopy of a renal biopsy specimen in a patient with monoclonal gammopathy of undetermined significance. Int J Hematol 114: 303-304, 2021. [DOI] [PubMed] [Google Scholar]