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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
CASE REPORT  
Year : 2017  |  Volume : 28  |  Issue : 4  |  Page : 937-941
Immunoglobulin A nephropathy in a patient with IgG kappa light-chain myeloma


1 Department of Nephrology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Nephrology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India
3 Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

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Date of Web Publication21-Jul-2017
 

   Abstract 


Paraproteins can cause a variable set of pathologic changes in the kidney. The introduction of novel anti-plasma cell agents capable of reversing renal failure have revolutionized the management of paraprotein-mediated kidney injury. Activation of the transcription factor nuclear factor kB (NF-kB) has been shown to be involved in the development of human glomerulonephritis (GN). Inhibitors of NF-kB may provide potential agents for treatment of immune complex GN. In this paper, we report a patient with IgA nephropathy and IgG kappa myeloma, who responded dramatically to chemotherapy targeted toward myeloma. Our findings support the idea that drugs modulating NF-kB may add another dimension to the management of IgA nephropathy.

How to cite this article:
Chandra A, Kaul A, Aggarwal V. Immunoglobulin A nephropathy in a patient with IgG kappa light-chain myeloma. Saudi J Kidney Dis Transpl 2017;28:937-41

How to cite this URL:
Chandra A, Kaul A, Aggarwal V. Immunoglobulin A nephropathy in a patient with IgG kappa light-chain myeloma. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2022 May 24];28:937-41. Available from: https://www.sjkdt.org/text.asp?2017/28/4/937/211350



   Introduction Top


Plasma cell dyscrasias are frequently encountered malignancies with the production of monoclonal immunoglobulin (Ig), causing a variable set of pathologic changes in the kidney. A number of advances have been made in explaining the molecular mechanisms of paraprotein-mediated kidney injury and the Multiple types of glomerular involvement have been described in plasma cell dyscrasias such as membranoproliferative glomerulonephritis (GN), diffuse proliferative, crescentic, or cryoglobulinemic variety.[1] IgA myeloma can rarely result in Henoch-Schonlein purpura and IgA nephropathy.[2] IgA nephropathy and IgA lambda myeloma with mesangial proliferative GN have been reported.[3] An interaction between mesangial cells and IgA immune complexes could be a possible mechanism for glomerular injury in IgA nephropathy.[4]

Activation of the transcription factor, nuclear factor kB (NF-kB), has been shown to be involved in the development of human GN.[5] Inhibitors of NF-kB may provide potential agents for treatment of immune complex GN.

In this paper, we report a patient with IgA nephropathy and IgG kappa myeloma who responded dramatically to chemotherapy targeted toward myeloma.


   Case Report Top


A 55-year-old man presented with facial puffiness and edema in both lower limbs for the last four months before admission along with low backache and generalized weakness. On initial physical examination, the patient presented no signs of uremia. His blood pressure was 130/80 mm Hg, heart rate was 76/min, and respiratory rate was 16/min. His abdomen was distended, with moderate ascites. The initial laboratory blood tests showed: hemoglobin 9.2 g/dL; platelets 92,000/mm3; white blood cells 5,600/mm3; prothrombin activity 100%; iron, 90 mg/dL; ferritin 243 ng/mL; transferrin saturation 39%; creatinine 1.3 mg/dL; random blood glucose 92 mg/dL; uric acid 9.2 mg/dL; albumin 3.2 g/dL; protein 8.2 g/dL; sodium 139 mmol/L; potassium 4.7 mmol/L; s. calcium 11.2 mg/dL; phosphorus 3.10 mmol/L; lactic dehydrogenase 335 U/L; alkaline phosphatase 50 U/L; IgG 330 mg/dL; IgM 46 mg/dL; IgA 330 mg/dL (reference value: 68–423 mg/dL); and 24-h proteinuria 3.8 g/24 h. Urinalysis revealed proteinuria 3+, 2-3 leukocytes/mm3 and 7–8 erythrocytes/ mm3, with erythrocyte dysmorphism; urine culture was negative. The urine Bence Jones protein test was negative. The following serological tests were nonreactive: anti-human immunodeficiency virus, anti-hepatitis C virus, hepatitis B surface antigen, anti-nuclear antibody, anti-DNA, anti-glomerular basement membrane antibodies, and antineutrophil cytoplasmic antibodies. Serum complement levels were normal. Ultrasonography showed that the right and left kidney measured 12.2 cm × 6.6 cm × 3.3 cm and 12.6 cm × 5.7 cm × 4.2 cm, respectively, with an increase in echogenicity in the renal parenchyma. The patient had anemia, hypercalcemia, hypoalbuminemia, hyperuricemia, high lactate dehydrogenase (LDH) levels, altered albumin-protein ratio, with mildly enlarged kidneys. Considering the possibility of multiple myeloma, serum electrophoresis was performed which showed M band in the gamma region which on immunofixation was IgG kappa type. Bone marrow biopsy showed 13%–15% plasma cells. The abdominal fat pad was negative for amyloid. However, in view of active urinary sediment and nephrotic range proteinuria, an ultrasound-guided renal biopsy was performed. Light microscopy showed 14 glomeruli of which, one was globally sclerosed, and the remaining showed focally and segmentally accentuated increase in mesangial cellularity and matrix. The interstitium showed mild mixed inflammatory cell infiltrate [Figure 1]. Malignant cells or fractured casts were absent. Immunofluorescence (IF) revealed diffuse mesangial granular staining in the glomeruli for anti-IgA (3+) and C3 (2-3+), staining for lambda light chains was positive and staining for k-light chains was negative. No evidence of amyloid deposits was observed using Congo red staining. On electron microscopy, the glomeruli showed patent capillaries and maintained foot processes. There were paramesangial, mesangial, and occasional subendothelial deposits along with increase in mesangial matrix cellularity. Thus, mesangio proliferative GN due to IgA nephropathy was diagnosed. The patient was then administered chemotherapy comprising of injection bortezomib and dexamethasone. Bortezomib was given at a dose of 1.3 mg/m2. Six cycles consisting of four doses of bortezomib, on days 1, 4, 8, and 11, with an interval of 21 days were administered. A 40 mg daily dose of dexamethasone was administered on four consecutive days at the start of each bortezomib dosing. The patient showed dramatic response to chemotherapy with reduction of proteinuria after the fifth cycle. After the sixth cycle of chemotherapy, repeat serum electrophoresis showed no M band.
Figure 1: Section from the renal biopsy showing glomeruli displaying patent capillary loops and increase in mesangial matrix and cellularity (Periodic acid-Schiff ×400).

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   Discussion Top


In our case, a definitive diagnosis of IgA GN was made only after the renal biopsy report with IF was available. In light of the low serum IgA concentration in our patient, it is unlikely that the IgA nephropathy was caused by increased production or secretion of IgA by plasma cells. Furthermore, the myeloma was of IgG kappa type and hence, we believe that it was not caused by the myeloma.

Bianchini et al have suggested a causal relationship between IgA nephropathy and IgA myeloma.[6] Verroust and Mery[7] and Zlotnick and Rosenmann[8] have described patients of multiple myeloma with amyloid pathology. Randall et al[9] have described cases showing nodular GN with IF revealing light chain deposition in mesangium and glomerular and tubular basement membranes. Silva et al[10] demonstrated intra- and extra-capillary prolife- rative GN with almost similar IF findings. Renal functions improved in both cases on the treatment of multiple myeloma. Droz et al[11] have reported a case of IgA nephropathy associated with an increase in polyclonal IgA and monoclonal IgA lambda in the serum. There was deposition of only monoclonal IgA lambda in the kidney, thus yielding a diagnosis of IgA nephropathy occurring secondary to monoclonal IgA monoclonal gammopathy.

Our case supports the possibility of occurrence of primary GN in multiple myeloma. The possible different pathogenic mechanisms could be either light chain deposition along glomerular or tubular basement membranes or glomerular immune complex deposition. The identification of specific pathogenesis assumes importance clinically, since glomerular light chain deposition may respond to treatment of myeloma.[3]

Jennette had observed that in addition to the predominance of IgA immunostaining, there was a high frequency of patients (67%), with greater lambda- than kappa-Ig light chain immunostaining.[12] In our patient also, there was predominantly lambda immunoglobulin light chain immunostaining.

There was a similar case report of a patient having the rare combination of IgA nephropathy with lambda-light-chain myeloma reported by Forslund et al.[13] The interesting observation in our case was the dramatic response to bortezomib and dexamethasone treatment, not only with respect to correction of the paraproteins, but also the improvement in IgA nephropathy including the disappearance of IgA deposits in the subsequent renal biopsy.

This observation suggests that inhibitors of NF-kB may be an option to treat IgA nephropathy along with other GN.[14] In addition, we would also like to keep the possibility that the positive course and outcome in our patient may have been due to spontaneous remission of the IgA nephropathy or due to dexame- thasone used in the treatment of myeloma.

NF-kB has been shown to be involved in the pathogenesis of GN. It is through expression of dependent genes such as inducible nitric oxide synthase and cyclooxygenase in the glomerular cells.[15],[16],[17],[18],[19],[20] Its inhibition reduces the glomerular recruitment of mononuclear cells along with mesangial proliferation through reduction of pro-inflammatory cytokines, cell adhesion molecules. Interference of NF-kB activation also reduces apoptosis. Some reports have implicated high albumin concentration as a possible inducer of NF-kB leading to tubular injury.[21],[22] Apart from bortezomib, steroids are also effective in inhibiting NF-kB-inducible gene expression.[16],[23],[24],[25] Other inhibitors of NF-kB are ACE inhibitors, angiotensin II antagonists, and HMG-CoA inhibitors.


   Conclusion Top


Our findings support the idea that drugs modulating NF-kB may add another dimension to therapeutic approach in IgA nephropathy. Besides IgA nephropathy, bortezomib has been reported to potentially benefit idiopathic membranous nephropathy.[25] Currently, a pilot study assessing the effect of one cycle of bortezomib on subjects with severe IgA nephropathy manifested by greater than 1 g of proteinuria/day is underway (NCT01103778 “Pilot study of Velcade® in IgA nephropathy”). The primary objective of this study is to investigate the ability of Velcade® (bortezomib) to induce complete or partial remission in patients with severe IgA nephropathy.

Conflict of interest: None declared.



 
   References Top

1.
Nasr SH, Satoskar A, Markowitz GS, et al. Proliferative glomerulonephritis with monoclonal IgG deposits. J Am Soc Nephrol 2009; 20:2055-64.  Back to cited text no. 1
    
2.
Zickerman AM, Allen AC, Talwar V, et al. IgA myeloma presenting as Henoch-Schönlein purpura with nephritis. Am J Kidney Dis 2000;36:E'  Back to cited text no. 2
    
3.
McLeish KR, Gohara AF, Gillespie C. Mesangial proliferative glomerulonephritis associated with multiple myeloma. Am J Med Sci 1985;290:114-7.  Back to cited text no. 3
    
4.
Gómez-Guerrero C, González E, Hernando P, Ruiz-Ortega M, Egido J. Interaction of mesangial cells with IgA and IgG immune complexes: A possible mechanism of glomerular injury in IgA nephropathy. Contrib Nephrol 1993;104:127-37.  Back to cited text no. 4
    
5.
Ashizawa M, Miyazaki M, Abe K, et al. Detection of nuclear factor-kappaB in IgA nephropathy using Southwestern histochemistry. Am J Kidney Dis 2003;42:76-86.  Back to cited text no. 5
    
6.
Bianchini G, Festuccia F, Laverde G, Cinotti GA. IgA myeloma: A potential outcome of IgA nephropathy. Nephrol Dial Transplant 1999;14:2780-2.  Back to cited text no. 6
    
7.
Verroust P, Mery JP, Morel-Maroger L, Clauvel JP, Richet G. Glomerular lesions in monoclonal gammopathies and mixed cryoglobulinemias IgG-IgM. In: Hamberger J, Maxwell MH, editors. Advances in Nephrology. Vol. 1. Chicago: Year Book Medical Publishers; 1971. p. 161-94.  Back to cited text no. 7
    
8.
Zlotnick A, Rosenmann E. Renal pathologic findings associated with monoclonal gammopathies. Arch Intern Med 1975;135:40-5.  Back to cited text no. 8
    
9.
Randall RE, Williamson WC Jr., Mullinax F, Tung MY, Still WJ. Manifestations of systemic light chain deposition. Am J Med 1976;60:293-9.  Back to cited text no. 9
    
10.
Silva FG, Meryrier A, Morel-Maroger L, Pirani CL. Proliferative glomerulonephropathy in multiple myeloma. J Pathol 1980;130:229-36.  Back to cited text no. 10
    
11.
Droz D, Noel LH, Barbanel C, Leibowitch J. Glomerulonephritis with intercapillary IgA deposits in benign monoclonal gammopathy. Nouv Presse Med 1981;10:3652-3.  Back to cited text no. 11
    
12.
Jennette JC. The immunohistology of IgA nephropathy. Am J Kidney Dis 1988;12:348-52.  Back to cited text no. 12
    
13.
Forslund T, Sikiö A, Anttinen J. IgA nephropathy in a patient with IgG lambda light-chain plasmacytoma: A rare coincidence. Nephrol Dial Transplant 2007;22:2705-8.  Back to cited text no. 13
    
14.
López-Franco O, Suzuki Y, Sanjuán G, et al. Nuclear factor-kappa B inhibitors as potential novel anti-inflammatory agents for the treatment of immune glomerulonephritis. Am J Pathol 2002;161:1497-505.  Back to cited text no. 14
    
15.
Guijarro C, Egido J. Transcription factor-kappa B (NF-kappa B) and renal disease. Kidney Int 2001;59:415-24.  Back to cited text no. 15
    
16.
Sakurai H, Shigemori N, Hisada Y, Ishizuka T, Kawashima K, Sugita T. Suppression of NF-kappa B and AP-1 activation by glucocorticoids in experimental glomerulonephritis in rats: Molecular mechanisms of anti-nephritic action. Biochim Biophys Acta 1997;1362:252-62.  Back to cited text no. 16
    
17.
Gómez-Guerrero C, Duque N, Casado MT, et al. Administration of IgG Fc fragments prevents glomerular injury in experimental immune complex nephritis. J Immunol 2000; 164:2092-101.  Back to cited text no. 17
    
18.
Rovin BH, Dickerson JA, Tan LC, Hebert CA. Activation of nuclear factor-kappa B correlates with MCP-1 expression by human mesangial cells. Kidney Int 1995;48:1263-71.  Back to cited text no. 18
    
19.
Duque N, Gómez-Guerrero C, Egido J. Interaction of IgA with Fc alpha receptors of human mesangial cells activates transcription factor nuclear factor-kappa B and induces expression and synthesis of monocyte chemo- attractant protein-1, IL-8, and IFN-inducible protein 10. J Immunol 1997;159:3474-82.  Back to cited text no. 19
    
20.
Saura M, Zaragoza C, Díaz-Cazorla et al. Involvement of transcriptional mechanisms in the inhibition of NOS2 expression by dexamethasone in rat mesangial cells. Kidney Int 1998;53:38-49.  Back to cited text no. 20
    
21.
Zoja C, Donadelli R, Colleoni S, et al. Protein overload stimulates RANTES production by proximal tubular cells depending on NF-kappa B activation. Kidney Int 1998;53:1608-15.  Back to cited text no. 21
    
22.
Wang Y, Rangan GK, Tay YC, Wang Y, Harris DC. Induction of monocyte chemo-attractant protein-1 by albumin is mediated by nuclear factor kappaB in proximal tubule cells. J Am Soc Nephrol 1999;10:1204-13.  Back to cited text no. 22
    
23.
Lee JI, Burckart GJ. Nuclear factor kappa B: Important transcription factor and therapeutic target. J Clin Pharmacol 1998;38:981-93.  Back to cited text no. 23
    
24.
Seto M, Kim S, Yoshifusa H, et al. Effects of prednisolone on glomerular signal transduction cascades in experimental glomerulonephritis. J Am Soc Nephrol 1998;9:1367-76.  Back to cited text no. 24
    
25.
Hartono C, Chung M, Kuo SF, Seshan SV, Muthukumar T. Bortezomib therapy for nephrotic syndrome due to idiopathic membranous nephropathy. J Nephrol 2014;27:103-6.  Back to cited text no. 25
    

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Correspondence Address:
Abhilash Chandra
Department of Nephrology, Dr. Ram Manohar Lohia Institute of Medical Sciences, Lucknow, Uttar Pradesh
India
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Source of Support: None, Conflict of Interest: None


PMID: 28748903

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    Abstract
   Introduction
   Case Report
   Discussion
   Conclusion
    References
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