Glomerular deposition disease
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2], Aida Javanbakht, M.D.
Synonyms and keywords: light chain deposition disease
Overview
Localized deposition of fibrils and proteins in glumerole is called glomerular deposition disease.
Light chain deposition disease (LCDD) is one of the glomerular deposition disease. It's a rare blood cell disease which is characterized by deposition of fragments of infection-fighting immunoglobulins, called light chains, in the body. These light chain deposits damage organs and cause disease. The kidneys are almost always affected and this often leads to Chronic renal failure. About half of people with light chain deposition disease also have multiple myeloma. Unlike in AL Amyloidosis, in which light chains are laid down in characteristic amyloid deposits, in LCDD, light chains are deposited in non-amyloid granules. Light chains in LCDD are kappa light chains in granular shape[1].
Classification
Glomerular deposition diseases are classified in 5 types of diseases:
- LCDD
- Amyloidosis
- Fabry's disease
- Fibrillary immuno-tactoid glumerulopathy: The diagnosis is based on pathology finding. Infiltration of fibrills make glomerular structures in the kidney. Fibrills are larger than amyloid fibrils. Patients usually asymtomatic but, sometimes have proteinuria and hematuria. Prognosis is poor and ESRD will happen in half of the patients [2].
- Collagenofibrotic glomerulopathy: A rare disease and the diagnosis is based on pathology finding. Type III collagen fibers deposit in the subendothelial and mesangium in the kidney. Negetive with Congo red and thioflavin stains. There is no specific threatment for it[3] .
Pathophysiology
Pathogenesis:
Deposits of abnormal or extra production of proteins, lipids and fibrills in the glomeruls cause glomerular deposition diseases.
-In LCDD:
light chains are small polypeptides produced by B lymphocytes.They are sub units of antibodies. Kappa and Lambda are two types of light chains. Excess production of Kappa chain and accumulation in the renal glumerulus cause LCDD. The exact mechanism of increase production of light chains and reason that renal attracts them is unknown. These chains can deposit in all parts of renal glumeruls and tubuls.
Accumulation of monoclonal light chains and matrix proteins → ↑ quantity and activity of transforming growth factor-beta (TGF-beta). TGF-beta → inhibit mesangial cell proliferation and ↑ matrix protein production
- ↑ matrix proteins accumulation → compress the glomerular capillaryies → renal failure [4].
Besides glumerulus,light chains may accumulate in renal tubular→ tubular casts→ interstitial inflammation→ renal failure [5].
- In Amyloidosis:
Amyloids (misfolding and aggregation of normally soluble proteins) deposit in the nephrones and cause renal failure.
- In Fabry's disease:
A deficiency of the enzyme alpha galactosidase A causes deposition of glycolipid in the nephrones and cause renal failure.
- In Fibrillary immuno-tactoid glumerulopathy:
Fibrills (larger than amyloids) deposit in subendothelial and mesangium of the nephrones and cause function impairment.
- In Collagenofibrotic glomerulopathy:
Type III collagen fibers deposit in the subendothelial and mesangium in the kidney.
Microscopic Pathology
On light microscopy:
-In LCDD:
- No glomerular and vascular abnormality
- Some tubular dilation with flattened epithelium→ suggest acute tubular injury
- Negative Congo Red stain
- In Amyloidosis:
- Typical green birefringence under polarized light after Congo red staining (appears in red under normal light)
- In Fabry's disease:
- Hypertrophic podocytes of glomerul, foamy appearing vacuoles and mesangial widening. Vacuolated cells will be seen in PAS stain [6].
- In Fibrillary immuno-tactoid glumerulopathy:
- Capillary wall thickening, matrix expansion,interstitial infiltration and necrosis in renal tubules and negative Congo red stain [7].
- In Collagenofibrotic glomerulopathy:
- Diffuse increase in the mesangial matrix, capillary walls widening, and collagen fibers in the glomerular basement membrane[8].
On electron microscopy :
-In LCDD:
- Ground-pepper–like deposits in the mesangial and the endothelial of the glomerular basement membrane. Also, in renal tubules if there is tubular involvement.
- In Amyloidosis:
- Endothelium, glomerular basement membrane, and podocytes thickening [9].
- In Fabry's disease:
- Deposition of glicolipids in lysosomes of podocytes and glomerular parietal epithelial cells.
- In Fibrillary immuno-tactoid glumerulopathy:
- Predominant fibrils in the subepithelial of glomerular capillary.
- In Collagenofibrotic glomerulopathy:
- Deposition of irregular collagenous fibers in the mesangium and subendothelial space of the renal glumerol [10].
Genetics
- Fabry's disease is X-linked recessive.
- Hereditory types of amyloidosis is autosomal dominant.
- There exact genetic association for LCDD, Fibrillary immuno-tactoid glumerulopathy, and Collagenofibrotic glomerulopathy are unknown.
Causes
The specific etiology that cause extra or abnormal production of fibrills and chains in the glomerular depositional diseases is unknown.
Differentiating from Other Diseases
Epidemiology and Demographics
The incidence of glomerular deposition disease depends on the type of the disease. Collagenofibrotic glomerulopathy and Fibrillary immuno-tactoid glumerulopathy are rare. LCDD is unknown. Most of the patients are men with the mean age of 58 years [1]. The incidence of amyloidosis is 1.2 per 100,000 individuals per year [11]. The incidence of Fabry's disease is 1 in 50,000 males [12].
Renal involvement is the most common cause of mortality and morbidity in these patients. Survival varies between months to 10 years in patients with LCDD [13].
Risk Factors
There are no established risk factors for glomerular deposition disease.
Screening
There is insufficient evidence to recommend routine screening for glomerular deposition disease.
Natural History, Complications, and Prognosis
Prognostic factors of glomerular deposition diseases at presentation [1]:
- Age
- underlying hematologic disease
- Light chain deposition in other organs
- Renal function
- other medical diseases like diabetic nephropathy
The median time to progression to chronic renal failure in LCDD is 2.7 years. After 5 years, about 37% of patients with LCDD are alive and do not have end stage renal disease.
Diagnosis
Diagnostic Study of Choice
- Complete blood test
- Urine and serum electrophoresis
- Serum and urine immunoglobulin free light chain assays [14]
- Biopsy is the gold standard test
History and Symptoms
All organs can be effected by Glomerular deposition diseases especially in LCDD. Most of the time kidney is involved [15]. Usually patients are asymptomatic in early stages. Symptoms are nonspecific like fatigue and weight loss. Rapidly progressive glomerulonephritis or acute tubulointerstitial nephritis cause renal failure in these patients. Other than the kidneys, liver and heart are the most commonly involved organs. Deposition of light chains in the liver may lead to hepatomegaly, portal hypertension and liver failure. The heart is affected in up to 80% of patients with LCDD, and may cause arrhythmias restrictive cardiomyopathy, cardiomegaly, and congestive heart failure [16].
Physical Examination
- Depends on involvement of the organ you may find organomegaly like hepatomegaly
- Polyneuropathy
Laboratory Findings
- Proteinuria (30-50% of cases have nephrotic syndrome)[17]
- Hematuria (usually microscopic)
- Abnormal liver enzyme ( in case of liver involvement)
Electrocardiogram
Arrhythmia like atrial fibrillation ( in case of heart involvement).
X-ray
There are no pathognomonic and specific x-ray findings associated with LCDD.
Echocardiography or Ultrasound
- Echocardiography:
In case of heart involvement: ↓ EF, diffuse hypokinesia, left ventricular concentric hypertrophy, ↓ diastolic compliance [18]
- Ultrasound:
No findings associated with renal Glomerular deposition diseases.
CT scan
- In severe cases the size of the organ will ↑.
- No pathognomonic and specific finding associated with Glomerular deposition diseases.
MRI
- In severe cases the size of the organ will ↑.
- No pathognomonic and specific finding associated with Glomerular deposition diseases.
Other Imaging Findings
There are no other imaging findings associated with Glomerular deposition diseases.
Other Diagnostic Studies
There are no other diagnostic studies associated with Glomerular deposition diseases.
Treatment
Medical therapy:
70% of cases without therapy will have ESRD. There is no standard treatment for Glomerular deposition diseases. Medical therapy options for LCDD are:
- Symptomatic treatment for renal dysfunction like ACE inhibitors
- Chemotherapy with Bortezomib
- High-dose melphalan in conjunction with autologous stem cell transplantation
- If patient has LCDD and Multiple Myeloma (MM), should receive treatment per MM guideline
Surgery
In case of ESRD→ Kidney transplant
Primary Prevention
There are no established measures for the primary prevention of Glomerular deposition diseases.
Secondary Prevention
There are no established measures for the secondary prevention of Glomerular deposition diseases.
References
- ↑ 1.0 1.1 1.2 Pozzi C, D'Amico M, Fogazzi GB, Curioni S, Ferrario F, Pasquali S, Quattrocchio G, Rollino C, Segagni S, Locatelli F (December 2003). "Light chain deposition disease with renal involvement: clinical characteristics and prognostic factors". Am. J. Kidney Dis. 42 (6): 1154–63. PMID 14655186.
- ↑ Alpers CE, Kowalewska J (January 2008). "Fibrillary glomerulonephritis and immunotactoid glomerulopathy". J. Am. Soc. Nephrol. 19 (1): 34–7. doi:10.1681/ASN.2007070757. PMID 18045849.
- ↑ Nimmagadda S, Mukku K, Devaraju SR, Uppin MS (2017). "Unusual cause of glomerular deposition disease: Collagenofibrotic glomerulopathy". Indian J Nephrol. 27 (1): 62–65. doi:10.4103/0971-4065.179300. PMC 5255993. PMID 28182050.
- ↑ Zhu L, Herrera GA, Murphy-Ullrich JE, Huang ZQ, Sanders PW (August 1995). "Pathogenesis of glomerulosclerosis in light chain deposition disease. Role for transforming growth factor-beta". Am. J. Pathol. 147 (2): 375–85. PMC 1869812. PMID 7639331.
- ↑ Herrera GA (June 2000). "Renal manifestations of plasma cell dyscrasias: an appraisal from the patients' bedside to the research laboratory". Ann Diagn Pathol. 4 (3): 174–200. PMID 10919389.
- ↑ Alroy J, Sabnis S, Kopp JB (June 2002). "Renal pathology in Fabry disease". J. Am. Soc. Nephrol. 13 Suppl 2: S134–8. PMID 12068025.
- ↑ Rosenstock JL, Markowitz GS, Valeri AM, Sacchi G, Appel GB, D'Agati VD (April 2003). "Fibrillary and immunotactoid glomerulonephritis: Distinct entities with different clinical and pathologic features". Kidney Int. 63 (4): 1450–61. doi:10.1046/j.1523-1755.2003.00853.x. PMID 12631361.
- ↑ Gubler MC, Dommergues JP, Foulard M, Bensman A, Leroy JP, Broyer M, Habib R (August 1993). "Collagen type III glomerulopathy: a new type of hereditary nephropathy". Pediatr. Nephrol. 7 (4): 354–60. PMID 8398640.
- ↑ SPIRO D (1959). "The structural basis of proteinuria in man; electron microscopic studies of renal biopsy specimens from patients with lipid nephrosis, amyloidosis, and subacute and chronic glomerulonephritis". Am. J. Pathol. 35 (1): 47–73. PMC 1934814. PMID 13617410.
- ↑ Aoki T, Hayashi K, Morinaga T, Tomida H, Hishida M, Yamamoto S, Kajiwara N, Tamai H (May 2015). "Two brothers with collagenofibrotic glomerulopathy". CEN Case Rep. 4 (1): 85–89. doi:10.1007/s13730-014-0145-y. PMC 5413714. PMID 28509277.
- ↑ Khan MF, Falk RH (November 2001). "Amyloidosis". Postgrad Med J. 77 (913): 686–93. PMC 1742163. PMID 11677276.
- ↑ Spada M, Pagliardini S, Yasuda M, Tukel T, Thiagarajan G, Sakuraba H, Ponzone A, Desnick RJ (July 2006). "High incidence of later-onset fabry disease revealed by newborn screening". Am. J. Hum. Genet. 79 (1): 31–40. doi:10.1086/504601. PMC 1474133. PMID 16773563.
- ↑ Lin J, Markowitz GS, Valeri AM, Kambham N, Sherman WH, Appel GB, D'Agati VD (July 2001). "Renal monoclonal immunoglobulin deposition disease: the disease spectrum". J. Am. Soc. Nephrol. 12 (7): 1482–92. PMID 11423577.
- ↑ Yadav P, Leung N, Sanders PW, Cockwell P (April 2015). "The use of immunoglobulin light chain assays in the diagnosis of paraprotein-related kidney disease". Kidney Int. 87 (4): 692–7. doi:10.1038/ki.2014.333. PMC 4863638. PMID 25296094.
- ↑ Ronco PM, Alyanakian MA, Mougenot B, Aucouturier P (July 2001). "Light chain deposition disease: a model of glomerulosclerosis defined at the molecular level". J. Am. Soc. Nephrol. 12 (7): 1558–65. PMID 11423587.
- ↑ Koopman P, Van Dorpe J, Maes B, Dujardin K (December 2009). "Light chain deposition disease as a rare cause of restrictive cardiomyopathy". Acta Cardiol. 64 (6): 821–4. doi:10.2143/AC.64.6.2044752. PMID 20128164.
- ↑ Buxbaum JN, Chuba JV, Hellman GC, Solomon A, Gallo GR (March 1990). "Monoclonal immunoglobulin deposition disease: light chain and light and heavy chain deposition diseases and their relation to light chain amyloidosis. Clinical features, immunopathology, and molecular analysis". Ann. Intern. Med. 112 (6): 455–64. PMID 2106817.
- ↑ Mohan M, Gokden M, Gokden N, Schinke C (March 2016). "A Case of Cardiac Light Chain Deposition Disease in a Patient with Solitary Plasmacytoma". Am J Case Rep. 17: 173–6. PMC 4801155. PMID 26988342.