Paraproteinemia, also termed monoclonal gammopathy, refers to the abnormal presence of excessive monoclonal proteins—known as paraproteins—in the bloodstream. These proteins, which are monoclonal immunoglobulins, are typically produced by a single clone of mature B lymphocytes, most often plasma cells, and can contribute to significant kidney injury.

With advancements in diagnostic tools and the growing use of serum and renal paraprotein testing, the detection of monoclonal immunoglobulins (MIg) has increased considerably. Paraproteinemia-related kidney disorders are predominantly observed in the elderly. In such individuals, these abnormalities may coexist with infections, immune- mediated diseases, malignancies, or primary renal conditions.

While renal complications of paraproteinemia are commonly linked to immunoproliferative disorders such as multiple myeloma (MM), B-cell non-Hodgkin lymphoma (NHL), lymphoplasmacytic lymphoma (LPL), plasmacytoma, or AL amyloidosis, they may also arise from non-malignant monoclonal gammopathies. To describe such isolated renal involvement, the term “monoclonal gammopathy of renal significance” (MGRS) has been introduced. MGRS refers to kidney injury caused by monoclonal immunoglobulin without meeting hematologic criteria for malignancy. It has been noted that approximately 72% of MGRS cases progress to renal impairment, while around 18% may eventually evolve into multiple myeloma.

The renal manifestations associated with MGRS are diverse and include well-known conditions like AL amyloidosis and monoclonal immunoglobulin deposition disease (MIDD), as well as recently recognized disorders such as proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) and C3 glomerulopathy associated with monoclonal gammopathy. In most instances, definitive identification of paraprotein- related renal damage requires a kidney biopsy. This is essential to distinguish paraprotein-induced pathology from unrelated kidney diseases. Paraproteins can also be encountered in more aggressive disorders such as multiple myeloma or secretory B-cell lymphomas.

A renal biopsy is often necessary to determine the nature and extent of the lesion, particularly in cases of suspected paraproteinemia. Accurate diagnosis is achieved through a combination of light microscopy, immunofluorescence (IF), and electron microscopy when required.

Study Period: The research was conducted over a span of 2 years, allowing for a comprehensive analysis of the data collected. This extended duration provided ample time to observe any trends or changes in the study parameters over time. Procedures: During the study, renal biopsies were meticulously examined using both light microscopy and immunofluorescence techniques.

Biochemical investigations were also a crucial part of the study, including the analysis of serum creatinine levels, 24- hour urinary protein excretion, serum protein electrophoresis, and free light chain ratio. These tests provided valuable insights into the physiological and biochemical changes occurring in the patients' bodies, helping to guide the diagnosis and treatment strategies.

All the relevant clinical details including age, sex and clinical presentation was acquired from the requisition form, clinical file and by interactions with the patient and the concerned. All the necessary laboratory parameters including complete blood count, Serum creatinine, Blood urea nitrogen (BUN), 24 hour urinary protein and routine microscopy of urine was performed as part of routine investigations.

All the renal biopsy specimens was submitted for appropriate fixation in Michel’s medium , Glutaraldehyde or 10 percent buffered formalin followed by processing as per the standard protocols of gross and microscopic examination.

All biopsies samples was processed further for immunofluorescence and also for light microscopy .

Histopathological Processing: Renal biopsy specimens were fixed in 10% neutral buffered formalin, dehydrated through ascending grades of alcohol, and embedded in paraffin using standard protocols. Sections of 3 μm thickness were obtained and stained with hematoxylin and eosin (H&E), periodic acid–Schiff (PAS), Masson’s trichrome and congo red (for amyloidosis) stains to evaluate glomerular, tubular, interstitial, and vascular morphology.

Immunofluorescence Technique:

For immunofluorescence (IF) studies, a portion of the fresh biopsy was placed in Michel’s transport medium and subsequently washed in buffer upon receipt. The tissue was then frozen in a cryostat, and 3–5 μm thick sections were prepared. These sections were rinsed with buffer and incubated for one hour with fluorescein-labeled polyclonal antibodies against human IgG, IgA, IgM, complement components (C3, C4, C1q), fibrinogen, and light chains (kappa and lambda). Following incubation, slides were washed and mounted with aqueous medium for fluorescence microscopy

This study analyzed 30 cases of renal disease linked to paraproteinemias using immunofluorescence for diagnosis. Patients were mainly middle-aged to elderly adults, with more males. Common symptoms were proteinuria, hematuria, and kidney injury. Many patients had hypertension and diabetes. Mean age was 54.1 years. Gender distribution was 76.7% males and 23.3% females as shown in table (I). Immunofluorescence was key for diagnosis, showing positivity for kappa light chains and minimal lambda chains.

Table-I: Demographic parameters and values

Final Diagnoses as shown in table (III):
- LCDD: 13 cases (43.3%)
- AL Amyloidosis: 7 cases (23.3%)
- Monoclonal TIN: 6 cases (20%)
- MCN: 4 cases (13.3%)

Light Chain Analysis as shown in table (IV) :
- Kappa restriction: 21 cases (70%)
- Lambda restriction: 9 cases (30%)

Serum Parameters:
- Mean serum creatinine:
- TIN: 3.4 mg/dL
 - LCDD: 3.13 mg/dL
- MCN: 2.96 mg/dL
- AL Amyloidosis: 2.9 mg/dL

The mean laboratory values observed among the patients were as follows: serum creatinine was 3.1 mg/dL, 24-hour urine protein was 5.06 g/day, haemoglobin level averaged 11.04 g/dL, and total serum protein was 7.12 g/dL as shown in table (II).

Table-II. : Biochemical Parameters and mean range

Proteinuria: All cases showed proteinuria, with the highest mean in TIN (5.59 g/day)
Immunoflouresence Findings :
- Strong kappa positivity in LCDD and TIN
- Lambda positivity confined mostly to AL amyloidosis
- C3 and C1q were occasionally positive
- IgG, IgA, and IgM were consistently negative, supporting light chain–predominant deposition

Table III. : Final Diagnoses Summary

TABLE IV: Light Chain Analysis

FIGURE 1 : (A)40x (H & E stain) Tubulointerstitial Nephritis with Mesangial Expansion.(B)40x (MT stain) Tubulointerstitial Nephritis with Mesangial Expansion(C)40x (PAS stain) Tubulointerstitial Nephritis with Mesangial Expansion(D)Kappa +++ positivity  In Tubulointerstitial Nephritis

FIGURE 2: (A) 40x (H & E stain) Nodular glomerulosclerosis in Light Chain Deposition Disease(B) 40x (PAS stain) Nodular glomerulosclerosis in Light Chain Deposition Disease(C) 40x (MT stain) Nodular glomerulosclerosis in Light Chain Deposition Disease(D)Kappa +++ positivity Mesangial And Glomerular Basement Membrane Deposits In Light Chain Deposition Disease

FIGURE 3: (A) 40x (H & E Stain) Eosinophilic Amorphous Deposits In Renal Amyloidosis(B) 40x (H & E Stain) Eosinophilic Amorphous Deposits In Renal Amyloidosis(C) 40x (Congo Red Stain) Amorphous Deposits In Renal Amyloidosis(D) Lambda ++ positivity Deposits in mesangium , interstitium and vessel in Renal Amyloidosis

FIGURE 4: (A) 40x (H & E Stain) Tubular Casts In Myeloma Cast Nephropathy (B) Kappa +++ positivity in intraluminal Casts (tubular lumen) In Myeloma Cast Nephropathy

FIGURE 5  & 6 : M BAND in serum electrophoresis.

This study demonstrates that renal diseases associated with paraproteinemias are diverse in presentation and pathology. LCDD was the most common entity (43.3%), followed by AL amyloidosis, monoclonal TIN, and MCN. These findings align with previously reported series such as Nasr et al. (2012)^.5

Kappa light chain restriction (70%) predominated in LCDD and TIN, while lambda was more often associated with AL amyloidosis. IF showed strong monoclonal light chain deposition in glomeruli and tubules, with minimal immunoglobulin heavy chain involvement.

All patients exhibited significant proteinuria and renal impairment. AL amyloidosis cases showed nephrotic-range proteinuria, whereas TIN and MCN patients had higher creatinine levels, reflecting tubular damage.

Serum Biochemical Findings and Their Diagnostic Implications

The mean serum creatinine level was 3.1 mg/dL, indicating moderate to severe renal dysfunction across the cohort.

24-hour urine protein excretion averaged 5.06 g, reflecting significant proteinuria, with many cases likely within the nephrotic range.

Mean hemoglobin was mildly reduced (11.04 g/dL), consistent with anemia of chronic disease or renal anemia. The mean serum creatinine levels varied among the diagnostic groups, with the highest being in tubulointerstitial nephritis (3.4 mg/dL), followed by LCDD (3.13 mg/dL), myeloma cast nephropathy (2.96 mg/dL), and AL amyloidosis (2.9 mg/dL). Nasr et al. emphasized that interstitial involvement, particularly fibrosis and inflammation, strongly predicts renal impairment, which is consistent with our findings .

underscores the substantial renal impairment common in paraproteinemia-related nephropathies. This value is comparable to those reported in studies of patients with light chain cast nephropathy or light chain deposition disease, where renal dysfunction is a hallmark of presentation.⁶

Proteinuria was a near-universal finding, ranging from subnephrotic to nephrotic levels, and is considered a hallmark of monoclonal gammopathy-associated kidney diseases. In particular, diseases such as light chain deposition disease (LCDD) and AL amyloidosis typically present with massive proteinuria, often due to glomerular deposition of light chains disrupting the glomerular filtration barrier .

The 24-hour urine protein excretion values in this cohort frequently exceeded 3.5 g/day, signifying nephrotic-range proteinuria in a subset of patients. This aligns with previous reports highlighting that nephrotic syndrome is a common presentation in diseases such as MIDD and amyloidosis .

Notably, hemoglobin levels were reduced in many patients, likely reflecting chronic kidney disease-associated anemia, as well as bone marrow involvement in cases with underlying plasma cell dyscrasia or lymphoproliferative disorders. This finding has both diagnostic and prognostic value, especially in settings where multiple myeloma or systemic amyloidosis is suspected .

Overall, these serum biochemical abnormalities support the presence of paraprotein-mediated renal injury and emphasize the importance of integrating serologic, histopathologic, and immunofluorescence data for accurate diagnosis and management.

Histopathologically, nodular glomerulosclerosis, mesangial expansion, and amyloid fibrils were common inLCDD and amyloidosis. MCN showed cast formation and TIN had interstitial inflammation with light chain deposition.

Serum protein electrophoresis in this study showed monoclonal kappa spikes predominantly in LCDD and monoclonal lambda spikes in AL amyloidosis. These patterns are consistent with previous research and support the hypothesis that the type of light chain correlates strongly with the underlying renal lesion . Detecting monoclonal spikes on electrophoresis or immunofixation further confirms the systemic nature of these disorders.^1,3

The combination of IF, SPEP, sFLC ratio, and light microscopy provided a robust diagnostic framework. Routine negativity for IgG, IgA, IgM supports the cost- effective omission of these markers in known or suspected light chain diseases.^1,3

Our study underscores the importance of early renal biopsy and clone-directed therapy in MGRS to prevent progression to ESRD. IF, including paraffin IF where needed, remains a cornerstone in diagnosis.³

This study provides an overview of paraproteinemia- associated renal diseases. Histopathological subtypes, serum electrophoresis findings, and urine protein levels were analyzed. Nodular glomerulosclerosis and renal amyloidosis were common lesions. LCDD/MIDD showed nodular sclerosis, mesangial expansion, and kappa/lambda restriction. MCN cases demonstrated tubular injury. AL Amyloidosis cases correlated with Congo red–positive deposits. TIN with monoclonal deposits exhibited inflammation and fibrosis. Renal biopsy and immunofluorescence play a critical role in diagnosis. Light chain distribution aligned with histological patterns.

Our findings demonstrate that IF staining for IgG, IgA, and IgM was consistently negative across most cases, supporting the established pattern in which monoclonal light chains (kappa or lambda) are the predominant deposits, while heavy chains are typically absent or minimally involved (Bridoux et al., 2015; Nasr et al., 2012). A notable exception is in proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID), where IgG positivity may be observed.

Routine use of heavy chain stains (IgG, IgA, IgM) may not be necessary in all cases, especially when light chain– related disease is already suspected. Using these stains only when needed ,based on clinical findings and biopsy patterns, can make the diagnostic process more cost- effective, particularly in settings with limited resources, without compromising accuracy.

IF and histopathology guide therapeutic strategies. Early detection of IF changes enables timely intervention. The histopathological and final diagnoses observed in this study closely mirror the established international experience, validating the patterns of renal injury induced by monoclonal gammopathies. These correlations highlight the critical role of combining detailed histologic examination with immunofluorescence and serologic studies to achieve accurate diagnosis and guide therapy. Importantly, the study underscores the need for vigilant evaluation of all renal compartments, as monoclonal gammopathy–associated lesions may be subtle and easily overlooked without specialized techniques.

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