Clinical mismatches leading to the misdiagnosis of multiple myeloma as diabetic nephropathy: A case report

Abstract

BACKGROUND

Diabetic nephropathy (DN), characterized by the presence of protein in the urine, is a primary contributor to chronic kidney disease. Nonetheless, the clinical considerations often overlook non-diabetic renal disease (NDRD). Multiple myeloma (MM) is a blood cancer, which can present as renal impairment like DN, leading to delays in diagnosis and prognosis.

CASE SUMMARY

A 60-year-old lady with 12 years of type 2 diabetes (T2D) developed severe anemia with progressive renal insufficiency. Contrary to the occurrence of DN, her clinical profile revealed a suboptimal blood glucose control but three major mismatches. These mismatches were disproportionately severe anaemia not in keeping with the degree of renal impairment; a large gap between high total urinary protein and low albuminuria; and absence of hypertension or edema despite advanced renal failure. A serum protein electrophoresis and bone marrow biopsy were found to confirm the presence of λ-type MM (stage III, group B). Following systemic chemotherapy (bortezomib/dexamethasone), her renal function and anemia improved significantly.

CONCLUSION

When patients with T2D present with atypical renal features, clinicians should consider the possibility of NDRD. Identifying clinical mismatches is essential for the early diagnosis of MM in patients with diabetes.

Key Words: Type 2 diabetes; Multiple myeloma; Diabetic nephropathy; Anemia; Non-diabetic renal disease; Clinical Mismatch; Case report

Core Tip: This case report highlights the diagnostic pitfalls of diabetic nephropathy and identifies three key clinical mismatches—anemia-renal mismatch, protein-albumin gap, and volume-hypertension mismatch—as critical red flags for suspecting multiple myeloma in patients with diabetes. In this patient with a 12-year history of type 2 diabetes, the presence of severe anemia disproportionate to renal impairment, massive total proteinuria with a low urinary albumin-to-creatinine ratio, and the absence of hypertension or edema served as vital clues for identifying non-diabetic renal disease.

INTRODUCTION

Diabetic nephropathy (DN) is the leading cause of chronic kidney disease (CKD) globally[1] and the most common cause of renal impairment in patients with long-standing type 2 diabetes (T2D)[2]. However, the coexistence of non-diabetic renal disease (NDRD) is frequently overlooked, with multiple myeloma (MM) being a critical but often misdiagnosed etiology. Misdiagnosing MM-induced cast nephropathy as DN leads to delayed chemotherapy and irreversible renal failure[3,4]. Although both conditions present with proteinuria and decreased glomerular filtration rates, their underlying pathophysiologies differ significantly. In clinical practice, reliance on routine screening could miss indicators of hematologic malignancy.

This report describes a 60-year-old woman with T2D initially misdiagnosed with DN. Through this case analysis, we highlight three important clinical mismatches that provide key diagnostic clues: Anemia-renal, protein-albumin, and volume-hypertension mismatches. Acknowledging these dissociations is crucial for ensuring early treatment and better prognosis of patients with diabetes and unusual renal presentations.

CASE PRESENTATION

Chief complaints

A 60-year-old Chinese woman with a 12-year history of T2D presented in July 2025 with a 2-month history of progressive fatigue and severe anemia.

History of present illness

The patient was admitted to the Department of Endocrinology of the Second Hospital of Hebei Medical University because of general fatigue. Prior to hospitalization, she had been treated with 1500 mg/day of metformin. Her fasting blood glucose level was approximately 7 mmol/L, and her postprandial 2-hour blood glucose level fluctuated between 12 mmol/L and 15 mmol/L. Two months before hospitalization, she developed general fatigue and anemia, and her hemoglobin (Hb) level was 66 g/L. One month before admission, she visited a hematology clinic because of the aggravation of fatigue. Her serum total iron binding capacity and serum iron were within normal ranges, her serum folic acid and vitamin B₁₂ levels were slightly elevated, and the Coombs test was negative. Her serum creatinine (Cr) level was increased (220 μmol/L; normal range 41-81 μmol/L), and her estimated glomerular filtration rate (eGFR) was 22 mL/minute/1.73 m². Bone marrow cytology revealed 5% mature plasma cells, reduced proliferation of nuclear cells in the bone marrow, and a high frequency of plasma cells. No naïve cells were observed on the peripheral blood slides. These results were suggestive of bone marrow hyperplasia alongside iron deficiency and decreased megakaryocytes. Bone marrow pathology indicated that bone marrow cell counts were generally normal, albeit with an increased erythroid ratio. The patient had received long-term oral hematinic supplementation to treat anemia. Thus, she was admitted to the Department of Endocrinology in our hospital for further treatment of DN (Table 1).

Table 1 Timeline of clinical events and interventions in 2025.

Date (2025)	Clinical events and interventions
May	Onset of progressive fatigue and symptoms of anemia
June	Visited hematology clinic; Hb: 66 g/L, Cr: 220 μmol/L. Initial bone marrow cytology showed 5% plasma cells
July 13	Admitted to the Department of Endocrinology for suspected DN
Mid of July	Discovery of the three clinical mismatches (anemia-renal, protein-albumin gap, and lack of hypertension/edema)
Late of July	Performed follow-up bone marrow biopsy and serum free light chain testing
August 10	Confirmed diagnosis of λ-type multiple myeloma (stage III, group B)
August 30	Transferred to hematology; initiated bortezomib and dexamethasone chemotherapy
September 18	Follow-up: Hb rose to 84 g/L, Cr decreased to 147.8 μmol/L. Discharged after remission

Hb: Hemoglobin; Cr: Serum creatinine; DN: Diabetic nephropathy.

History of past illness

The patient had a 12-year history of T2D and osteoporosis. There was no history of hypertension, chronic liver disease, or preexisting renal disorders.

Personal and family history

The family history was noncontributory regarding renal or hematologic diseases.

Physical examination

The examination results were as follows: Temperature, 36.7 °C; pulse, 78 beats/minute; respiratory rate, 19 breaths/minute; and blood pressure, 110/60 mmHg. She appeared chronically ill, her skin was pale, and her palpebral conjunctivae were anemic. Superficial lymph nodes were impalpable, and no tenderness was detected throughout the body. No abnormality was detected in her lungs, heart, or abdomen. No edema was observed in her lower extremities.

Laboratory examinations

Routine blood examination revealed moderate anemia (Hb, 81 g/L; red blood cell count, 2.57 × 10⁹/L), decreased leukocytes (white blood cell count, 2.9 × 10⁹/L, with 61.52% neutrophils, 28.72% lymphocytes, 8.88% monocytes, 0.70% eosinophils, and 0.18% basophils), and a reduced platelet count (70 × 10⁹/L). Liver function, blood electrolytes, and blood lipids were all within normal ranges. Her glycated Hb level was 6.6%, indicating stable long-term glycemic control. Although the routine urine examination was initially negative for glucose and protein, a striking discordance was observed between the 24-hour urinary protein level (1.07 g/24 hours) and the urinary albumin-to-creatinine ratio (UACR; 52 mg/g), indicating a significant protein-albumin gap. Despite normal levels of serum iron, folic acid, and vitamin B₁₂ and an elevated ferritin level (1153.5 ng/mL), the patient’s anemia and renal function deteriorated progressively, with her Cr level rising to 291 μmol/L and eGFR declining to 15.27 mL/minute/1.73 m² (Figure 1). Diseases of the digestive tract were excluded by a detailed medical history, occult blood stool analysis, and abdominal computed tomography (CT). Furthermore, anasarca, hypertension, and hyperlipidemia were excluded. Her manifestations were not entirely consistent with DN. The patient had severe anemia with pancytopenia, and malignant hematopathy was considered. Thus, bone marrow aspiration and biopsy were performed. Bone marrow cytology indicated that nuclear cell proliferation was active. Granulocytes were dominated by middle- and late-stage cells, and the erythron was mainly composed of middle- and late-stage erythroid cells. Plasma cells were more common, including 16% mature plasma cells and 2% immature plasma cells. Platelet piles were visible, which suggested plasmacytosis in the bone marrow. The results of the bone marrow biopsy supported a diagnosis of plasma cell myeloma (Figure 2). Specifically, hematoxylin and eosin staining revealed active proliferation of nuclear cells with a significant increase in plasma cell clusters (Figure 2A and B). Immunohistochemical analysis further characterized these cells, showing strong positivity for plasma cell markers CD38 (Figure 2C) and CD138 (Figure 2D). Most notably, the plasma cells exhibited monoclonal expression of the lambda (λ) light chain (Figure 2E), while staining for the κ light chain was largely negative (Figure 2F). Flow cytometry of bone marrow revealed 4% abnormal plasma cells. Serum and urinary free light chain λ (FLC-λ) levels were significantly increased at 3025 mg/L (normal range 5.71-26.3 mg/L) and 1980 mg/L (normal range 0.81-10.1 mg/L), respectively, whereas the serum and urinary κ/λ ratios were markedly decreased at 0.004 (normal range 0.26-1.65) and 0.0219 (normal range 0.461-4.0), respectively. The abnormal immunoglobulin test results were indicative of λ-type MM proteinemia. The urine Bence-Jones protein test was positive.

Figure 1 Changes of hemoglobin and serum creatinine. A: The changes of hemoglobin (Hb) were showed in during hospitalization, Hb rose to 84 g/L; B: Serum creatinine decreased gradually to 147.8 μmol/L after chemotherapy. The patient was admitted to the hospital on July 13, 2025. A chemotherapy began to be carried out on August 30, 2025. Hb: Hemoglobin; CREA: Creatinine; eGFR: Estimated glomerular filtration rate.

Figure 2 Bone marrow obtained before the initiation of chemotherapy regimens. A: Haematoxylin and eosin (H&E) staining (× 40); B: H&E staining (× 100); C-F: Immunohistochemical staining for CD38 (× 100; C), CD138 (× 100; D), lambda (× 100; E), and kappa (× 100; F).

Imaging examinations

Urinary ultrasound revealed a normal kidney size and structure without stones. Bone density testing confirmed osteoporosis. Fundus photography highlighted retinal hemorrhages and exudates [indicative of diabetic retinopathy (DR)], which initially supported the DN diagnosis but did not explain the rapid renal decline (Figure 3).

Figure 3 Color fundus photography of the patient. A: Left eye; B: Right eye. Both images demonstrate characteristic features of proliferative diabetic retinopathy, including retinal hemorrhages, exudates, and neovascularization.

FINAL DIAGNOSIS

Thus, a diagnosis of λ-type MM (stage III, group B) was rendered.

TREATMENT

Initially, the patient was managed under the presumptive diagnosis of stage 4 CKD secondary to DN. Metformin was discontinued, and a comprehensive treatment plan was initiated, including glycemic control with insulin aspart and insulin glargine, improvement of renal microcirculation, and subcutaneous injection of erythropoietin (EPO). However, given the lack of clinical response and subsequent confirmation of λ-type MM, the treatment strategy was promptly adjusted. The patient was transferred to the Division of Hematology, where she received a systemic chemotherapy regimen consisting of bortezomib combined with dexamethasone. During this period, injection steroid was given in the presence of an active infection after maintaining the intensive insulin to maintain stable glycemic control and continued supportive measures to renal complications. Further inspection for potential gastrointestinal adverse effects.

OUTCOME AND FOLLOW-UP

The treatment proved effective. The serum levels of FLC-λ and Cr decreased from 3025 mg/L to 1235 mg/L and 147.8 μmol/L (eGFR, 32.87 mL/minute/1.73 m²) respectively, whereas the Hb level increased to 84 g/L. The confirmation of recovery led to the discharge of the patient (Table 1).

DISCUSSION

Diagnostic challenges in overlapping DN and MM

Clinical differentiation between DN and MM remains exceedingly difficult because their presentations of proteinuria and progressive renal insufficiency markedly overlap. Whereas glucose is the primary cause of CKD in patients with diabetes, some studies indicate that NDRD can occur in 30% or more of patients with T2D[5]. MM is particularly dangerous as it can manifest as cast nephropathy, leading to a clinical course similar to that of DN.

Recent studies highlight that the classical natural history of DN is where the development of microalbuminuria and macroalbuminuria is associated with a declining glomerular filtration rate. This infers the clinicians’ default position is DN[6]. Nevertheless, this diagnostic inertia can prevent the identification of unusual characteristics. As DN is primarily a glomerular illness with significant albumin leakage, the kidney damage due to MM mainly inflicts the tubulointerstitium via deposition of the monoclonal light chain[7].

Studies have shown that particular findings, including no hypertensive volume overload and severe, out-of-proportion anemia features, are essential to differentiate MM from DN[8]. In addition, depending exclusively on the UACR could be misleading, as this ratio does not detect the presence of the non-albumin proteins Bence-Jones proteins characteristic of MM. As observed in the latest updates on hematological malignancies, an early screening offered by serum free light chain (sFLC) is important to avert irreversible renal damage. Moreover, targeted therapy such as bortezomib can lead to better outcomes, if given early[9].

Initial differential diagnosis and clinical reasoning

When this patient was first assessed, we considered several causes for simultaneous progressive renal failure and severe anemia. Differentiating between common and systemic diseases were part of the diagnostic procedures.

DN: Considering the patient’s 12 years history of T2D and DR, the top presumptive diagnosis was DN. The rapid progression of her renal decline necessitated this reconsideration and not the slow progressive nature of classic DN, which is what the above case reflects. Additionally, hypertension and edema, which are signs of volume overload in advanced DN, were absent in this case.

CKD-related anemia: Anemia due to EPO deficiency is common in renal impairment, however it is usually commensurate to the stage of kidney disease. This situation saw the patient’s Hb nadir of 62 g/L to be much lower than expected (90-100 g/L) for her eGFR. This mismatch between anemia and renal problems raised the suspicion of primary involvement of bone marrow.

Nutritional or hemolytic anemia: Initial screening for iron deficiency (serum ferritin), folic acid deficiency (serum methylmalonic acid), and vitamin B₁₂ deficiency indicates negative or elevated. A negative Coombs test and no evidence of gastrointestinal bleeding (as confirmed by vital occult blood and abdominal CT tests) rules out haemolytic anaemia and chronic blood loss.

Glomerulonephritis: Though other causes of NDRD can also lead to proteinuria, the observed protein- albumin gap (24-hour urinary protein of 1.07 g/24 hours vs UACR of 52 mg/g) was telling. In the case of typical glomerulonephritis, albumin leaks into the glomeruli. This striking difference suggests overflow proteinuria of nonalbumin proteins such as Bence-Jones proteins. The eventual bone marrow biopsy and sFLC assays due to these clinical mismatches confirmed λ-type MM characterization.

In this instance, three clinical incompatibilities culminated in the correct diagnosis, which is summarized and compared with the classic DN (Table 2).

Table 2 Comparative analysis of typical diabetic nephropathy vs. manifestations in this patient.

Feature	Typical DN	Manifestations in this patient	Clinical significance
Anemia severity	Proportional to CKD stage (Hb approximately 90-100 g/L at eGFR 15-20 mL/minute/1.73 m2)	Severe anemia (Hb nadir 62 g/L)	Disproportionate anemia suggests bone marrow involvement
Proteinuria composition	Primarily albumin (high UACR)	Non-albumin protein (low UACR 52 mg/gvs high 24 hours-TP 1.07 g)	Indicates “overflow” light chains rather than glomerular leak
Blood pressure	Usually hypertensive due to volume overload	Normotensive (110/60 mmHg)	Points toward tubulointerstitial damage over glomerular damage
Edema	Common (systemic/peripheral)	Absent	Inconsistent with volume overload typical of advanced DN
Renal decline	Chronic and gradual progression	Rapidly progressive renal insufficiency	Red flag for NDRD

CKD: Chronic kidney disease; Hb: Hemoglobin; UACR: Urinary albumin-to-creatinine ratio; DN: Diabetic nephropathy; eGFR: Estimated glomerular filtration rate; TP: Total protein; NDRD: Non-diabetic renal disease.

Anemia-renal mismatch: Disproportionate severity

The proper diagnosis of renal impairment depends heavily on certain laboratory markers which may differ in various physiological states and patient groups. Understanding these relationships is important in identifying early functional decline; recent studies of renal markers have highlighted this. The severe anemia in this patient clearly dissociated from the renal parameters expected in typical DN[10].

Anemia associated with EPO deficiency occurs in typical DN and is correlated with CKD stage[11]. Usually, in a typical DN, Hb levels of 90-100 g/L (depending on EPO status) are seen when eGFR declines to 15-20 mL/minute[12]. Yet, the Hb level of the patient dropped down to a nadir of 62 g/L, which was grossly low compared to serum Cr of 291 μmol/L; eGFR- 15.27 mL/minute/1.73 m². The presence of such severe anaemia which is inconsistent with the degree of kidney malfunction should always raise suspicion for primary bone marrow disorders.

Protein-albumin gap: Overflow vs glomerular leak

The added diagnostic complexity is a differential between metabolic kidney damage and antibody-related disorders. A recent study of autoantibodies and systemic disease indicates the need for screening and investigation of other immune-mediated disorders. The finding of monoclonal light chains gave a clue to think beyond diabetes in this case[13].

DN is defined as albumin leaking through the glomerulus. In this instance, the large total proteinuria of 1.07 g/24 hours and low UACR of 52 mg/g points to significant protein-albumin mismatch in the nephron level. This marked difference suggests the preponderance of nonalbumin constituents in urinary protein. Monoclonal immunoglobulin light chains, also known as Bence-Jones proteins, are a classic type of non-albuminuria seen in clinical practice. They are an important diagnostic clue for renal impairment due to MM[14,15]. The term MM-related overflow proteinuria refers to the excretion of abnormal serum proteins, which is distinct from the damage to the glomerular basement membrane seen in typical DN.

Volume-hypertension mismatch: Absence of classic signs

Advanced DN with a large rise in creatinine usually presents with volume overload and hypertension[16]. The patient was normotensive and had no edema, both helpful clinical clues to say that tubulointerstitial injury (cast nephropathy) is involved, not a glomerular injury[17].

A systematic evaluation of multiple laboratory parameters is essential for high-fidelity diagnosis, especially in complicated cases involving coexisting chronic diseases. Evidence suggesting that comprehensive laboratory screening can refine diagnostic accuracy for systemic conditions supports our proposed algorithm for patients with diabetes and atypical features. This multifaceted approach ensures that non-diabetic etiologies are not overlooked[18].

Practical screening and diagnostic recommendations

To prevent the misdiagnosis of NDRD in patients with T2D, we propose a systematic screening approach based on the clinical mismatch principle.

Indications for extended screening

Clinicians should move beyond routine albuminuria (UACR) and initiate a plasma cell dyscrasia workup if any of the following atypical features are present: Rapid decline in renal function (unexplained or sudden drop in eGFR inconsistent with the natural history of DN); protein-albumin gap [high total 24-hour urinary protein (> 1.0 g) but a relatively low or normal UACR]; and isolated severe anemia (significantly lower than expected Hb levels based on the degree of CKD).

Diagnostic algorithm for suspected MM in T2D

Step 1: Perform 24-hour urinary protein electrophoresis and sFLC assays.

Step 2: Calculate the free light chain κ/λ ratio. A significantly abnormal ratio is highly suggestive of monoclonal gammopathy.

Step 3: Conduct bone marrow aspiration and biopsy if step 1 or 2 is positive, even if the initial clinical suspicion for MM was low.

Early intervention

Establishing an early diagnosis permits the timely initiation of targeted therapies such as bortezomib, which can effectively reverse cast nephropathy and prevent permanent dialysis.

CONCLUSION

This case highlights that MM can closely mimic DN in patients with long-standing diabetes. Both anemia-renal (severe anemia with moderate renal dysfunction) and protein-albumin mismatch (massive proteinuria with low UACR) are high yield clinically. Clinicians should retain a high index of suspicion, in addition to screening for plasma cell dyscrasia, in patients with diabetes and atypical renal presentations. This delay would hamper the diagnosis and adversely affect the outcome. The case shows that renal failure in a patient with long-standing diabetes should not be reflexively attributed to DN. Our clinical experience suggests that ‘clinical dissonance’ is the most powerful source of reconsidering a diagnosis. Severe anemia that is out of proportion to the CKD stage and a marked protein-albumin gap are important flags for MM. It is important to understand that only using routine markers such as UACR can cause diagnostic inertia and fail to detect monoclonal proteins. Clinicians must maintain a high degree of suspicion. When the clinical picture is atypical, they must use sFLC assays and 24-hour urine electrophoresis proactively. In the end, the diagnosis of a non-diabetic kidney disease early will change the prognosis of the patient from irreversible renal failure to a manageable remission by suitably targeted hematologic therapy.

ACKNOWLEDGEMENTS

We would like to express our sincere gratitude to Chao Pang and Zeng-Fang Hao for their expert advice and invaluable guidance during the preparation of this manuscript.