Monoclonal immunoglobulin deposition disease

Introduction

Monoclonal immunoglobulin deposition disease (MIDD) is characterized by the deposition of monoclonal light and/or heavy chains within glomerular, tubular, and vessel wall basement membranes. Three subtypes of MIDD have been described and they are subdivided according to the composition of monoclonal protein deposited. The most common form of MIDD is light chain deposition disease (LCDD), where either kappa or lambda light chains are deposited in tubular, glomerular, and vessel wall basement membranes. Much less common than LCDD are heavy chain deposition disease (HCDD) and light and heavy chain deposition disease (LHCDD), which show basement membrane accumulation of a monoclonal immunoglobulin heavy chain, either with a corresponding monoclonal light chain (LHCDD) or without an accompanying light chain (HCDD). ^, In contrast to the fibrils seen in amyloidosis, the deposits of MIDD lack substructure. In the past, the term monoclonal immunoglobulin deposition disease has been used as a generic term to encompass a wide variety of paraprotein-related diseases including light chain amyloid and cast nephropathy. In this chapter, we restrict ourselves to the currently accepted narrower usage of the term as defined earlier, or what has been historically called Randall-type monoclonal immunoglobulin deposition disease . For much of the chapter we combine our discussion of patients with LCDD, LHCDD, and HCDD, referring to them as patients with MIDD. Notable differences between subtypes of MIDD are pointed out where appropriate and summarized in Table 9.1 .

Epidemiology of monoclonal immunoglobulin deposition disease

MIDD is a relatively rare disease. The incidence of pure MIDD (MIDD in the absence of light chain cast nephropathy or amyloidosis) in native kidney biopsies has been reported to range from 0.32% in a study from Columbia University Medical Center in New York up to 0.7% of renal biopsies processed at the Mayo Clinic. Overall, MIDD appears to be approximately half as common as amyloidosis. In an autopsy series of patients with multiple myeloma (MM), LCDD was found in 5% of patients, whereas amyloid was detected in 11%. Similarly, out of the 1078 biopsies studied at Columbia University between 2000 and 2014 with paraprotein deposition in the kidney, pure MIDD was identified in 209 (19%), compared with amyloidosis in 451 (41%), and light chain proximal tubulopathy in only 54 (5%).

The association of MIDD with underlying hematologic conditions has varied across different studies as our understanding of plasma cell dyscrasias has evolved and new definitions of MM have emerged. In a recent report by Kourelis et al., 57% of patients with MIDD had either smoldering MM or MM. The literature indicates that MM is present in roughly half of patients with LCDD and LHCDD, but the percentage has been reported as high as 58% to 65% for those with LCDD. ^{, ,} In contrast, HCDD has a much lower reported incidence of MM compared with LCDD and LHCDD, with reports ranging from 19% to 33%. ^{, ,} After the introduction of the term monoclonal gammopathy of renal significance ( MGRS ), virtually all patients with MIDD have been shown to have a plasma cell dyscrasia. ^{, ,}

Patient characteristics of those diagnosed with MIDD are notable for mean age, typically in the late 50s, although ages have ranged from patients in their 20s to patients over 90 years. ^{, , ,} In the series by Nasr et al., approximately one-third of patients with MIDD were under 50 years of age. In patients with LCDD, there appears to be a male predominance, with approximately twice as many men as women. This is in contrast to HCDD, where men and women appear to be equally affected. ^{, , ,} Race is not reported in all studies; however, in those large case series where it was, patients were white in more than 80% of the cases. ^{, ,} Of interest, the only study with a significant number of black patients (22%) was from a single institution in New York, and four of five of those patients had either HCDD or LHCDD. The only large case series from Asia, reported to date by Li et al., examined 48 patients, all of whom were Chinese, and age and gender data were similar to the trends described previously. It is difficult to draw meaningful conclusions regarding any differences in racial involvement, given that most of the reports have come from geographic areas where there is not a wide range of racial diversity and the majority of patients studied were white.

Clinical manifestations of monoclonal immunoglobulin deposition disease

Whereas MIDD can present as a multisystem disease, renal manifestations typically predominate. More than 83% of the patients reported with MIDD and kidney disease had renal insufficiency based on serum creatinine greater than 1.2 mg/dL or chronic kidney disease (CKD) stage 2/3. Many patients experience a rapid decline in renal function. ^{, , ,} Proteinuria is present in almost all patients with MIDD, and about 40% to 50% of patients will have nephrotic range proteinuria. ^{, ,} The prevalence of nephrotic range proteinuria and nephrotic syndrome seems to be higher in those with HCDD. In contrast to amyloidosis, hypertension is widely present at the time of diagnosis in patients with MIDD, with two large series reporting hypertension in approximately 80% of patients. ^, However, reports of hypertension in LCDD ^, may be closer to 50%, whereas patients with HCDD have a higher incidence with nearly 100% of them being affected. ^{, , ,} Incidence of microscopic hematuria is reported to range from 60% to 90% of the cases of MIDD and also appears to be somewhat more common in patients with HCDD. ^{, ,} Hypocomplementemia was absent in all 12 patients with LCDD reported by Lin et al., but was present in three of six of their HCDD patients. Bridoux et al. reported low C3 in five of their 15 patients with HCDD; four of these patients had γ1-HCDD and the other had γ3-HCDD, correlating with the known complement fixing abilities of immunoglobulin (Ig)G subtypes 1 and 3. Of note, a recent report from China did show C3 hypocomplementemia in up to one-third of patients with LCDD.

Whereas renal manifestations in MIDD typically predominate, extrarenal involvement in multiple organ systems is well described. From the first descriptions of LCDD by Randal et al. in the 1970s, it was demonstrated that visceral deposition in multiple organs was a feature of the disease. LCDD has been described to involve the heart, liver, lungs, pancreas, thyroid, skin, lymph nodes and spleen, muscles, and the gastrointestinal and neurologic systems. As reported by Ganeval et al., when extrarenal manifestations were specifically evaluated for, they were found in all MIDD patients. Light chain deposits were found in the blood vessels walls of most organs. Heart and liver involvement are the most commonly described extrarenal sites of MIDD involvement. Heart disease is reported in up to 80% of cases with LCDD; however, whether the etiology of the cardiac disease can be attributed to MIDD is unknown, because most patients do not undergo heart biopsy or have evidence of an infiltrative process in the heart. A significant portion of the cardiac disease in MIDD patients may relate to confounding factors, specifically age and renal impairment. ^{, ,} In the past, cardiac involvement may have been historically underdiagnosed because of lack of usage of immunohistologic and electron microscopic methods in endomyocardial biopsies. Lack of uniformity in nomenclature also hampers our ability to estimate cardiac involvement because in the cardiac literature, some studies refer only to cardiac nonamyloidotic immunoglobulin deposition disease (CIDD), light-chain cardiomyopathy, or simply describe cases as cardiomyopathies with light chain deposition disease. Toor et al. reported the experience of one MM referral center where less than 2% of the patients referred for evaluation of MM underwent cardiac biopsy. Of those, 20% (six patients) had CIDD. In total, eight cases were analyzed but four of eight patients also had proven concomitant amyloidosis in other organs. Interestingly, none of the patients had any symptoms related to heart failure. The median age for these patients at presentation and diagnosis was somewhat earlier (median age of 49.5 years, range 40–64 years). In general, in patients with cardiac manifestations, the most common clinical features include congestive heart failure, usually with a restrictive pattern, arrhythmias, and conduction anomalies. In two series in which echocardiography was reported, 10/13 patients had left ventricular hypertrophy. ^,

In one of the earliest case series, liver deposits were found in almost all of the patients who underwent hepatic tissue analysis. Hepatomegaly and moderate abnormalities in liver function tests are often observed; however, more rarely, cases of portal hypertension, hepatic insufficiency, and death from fulminant liver failure have also been described. Histologic features of liver involvement include abnormal chromophilic material along sinusoids, in vascular walls, and in basement membranes of biliary ductules under light microscopy. Portal areas were enlarged by fibrosis and usually contained abnormal material. The distribution of lesions varied from patient to patient. ^, The burden of deposits in liver biopsies has been described as moderate to severe, but mild lesions with nearly normal sinusoids are also seen. ^,

Pulmonary symptoms and involvement of the respiratory system are less common. Respiratory symptoms can be heterogeneous, involving multiple sites including the large airways. Pulmonary involvement can be very indolent and patients may remain asymptomatic for several years, although severe cases requiring lung transplant have been reported. Histologically, pulmonary involvement can be characterized by either diffuse involvement or a more nodular distribution. Newer images with high resolution computed tomography scans show that almost all patients with pulmonary involvement have thin-walled cysts, usually with pulmonary nodules.

Neurologic involvement in MIDD is common, with up to 20% to 30% of patients having peripheral neuropathy caused by deposits along the nerve fibers. ^{, ,} Central nervous system involvement is rare likely because of limited crossing of paraproteins through the blood-brain barrier. However, “aggregomas”—a term coined by Rostagano et al., and described as localized tumoral masses of Congo-red-negative monoclonal nonfibrillar Ig light chain, have also been reported. ^, Isolated “aggregomas” without evidence of any plasma cell dyscrasia and presenting with large, intracerebral lesions exerting significant mass effect have been recently reported. ^,