An 82-year-old man presented to the emergency department for evaluation of worsening dry cough, lower-extremity edema, and fatigue. His symptoms began about 2 weeks earlier, which prompted him to come to the emergency department. At that time, a presumptive diagnosis of congestive heart failure exacerbation was made, and he was admitted for intravenous diuresis with furosemide. He was discharged to his home after his lower-extremity edema partially improved. However, he worsened clinically and returned to the hospital 1 week after discharge.
His past medical history was significant for the following:
Rheumatoid arthritis, diagnosed about 5 years earlier and treated with methotrexate since diagnosis
Stage 2 chronic kidney disease, diagnosed about 2 years earlier, with no documented proteinuria or hematuria and no structural kidney abnormalities found on computed tomography of the abdomen and pelvis around the time of diagnosis
Diffuse large B-cell lymphoma, diagnosed about 3.5 years earlier and treated with 6 cycles of chemotherapy (rituximab, cyclophosphamide, hydroxydaunorubicin [or doxorubicin], vincristine, and prednisone); posttreatment positron emission tomography showed complete remission with no recurrence noted on follow-up imaging
Heart failure with preserved ejection fraction
Hypertension.
The patient had no known family history of solid or hematologic malignancy. His home medications included methotrexate, amlodipine, carvedilol, allopurinol, aspirin, and simvastatin.
INITIAL EVALUATION
The patient’s blood pressure was 151/60 mm Hg, heart rate was 69 beats per minute, and he had a new oxygen requirement of 2 L/min to maintain 95% saturation. On physical examination, he was not in acute distress. Cardiovascular examination revealed normal heart sounds without jugular venous distension or murmurs. Respiratory examination was remarkable for bilateral coarse breath sounds. Skin examination revealed 2+ pitting edema on the bilateral lower extremities with no rash or ulcers. Neither lymphadenopathy or hepatosplenomegaly was appreciated.
Blood test results
Remarkable results from complete blood cell count and other blood tests included the following:
Hemoglobin 10.6 g/dL (reference range 13.5–17.5)
Mean corpuscular volume 97.3 fL (80–100)
White blood cell count 5.55 × 109/L (4.0–11.0)
Neutrophils 3.12 × 109/L (1.5–8.0)
Lymphocytes 0.5 × 109/L (1.0–3.0)
Monocytes 1.61 × 109/L (0.2–1.0)
Immature granulocytes 0.22 × 109/L (< 0.1)
Platelet count 147 × 109/L (150–450)
Serum creatinine 1.8 mg/dL (0.74–1.35; this represented a rise from his baseline of 1.0–1.2)
Albumin 3.8 g/dL (3.5–5.0)
B-type natriuretic peptide 3,476 pg/mL (< 92).
Urinalysis
A urine dipstick test showed 3+ blood (none), 1+ protein (none), and 2+ leukocyte esterase (none). A fresh urine sediment test revealed more than 20 red blood cells per high-power field, more than 20 white blood cells per high-power field, and abundant hyaline casts (> 10/low-power field). Although no red cell casts, white cell casts, or dysmorphic erythrocytes were identified, delayed transport to the laboratory may have contributed to degradation of any cellular casts (an important consideration when interpreting results).
Imaging studies
Chest radiograph was concerning for pulmonary edema. Kidney and bladder ultrasonography was negative for hydronephrosis or structural abnormalities. Echocardiography showed preserved ejection fraction (56%), normal right ventricular size and function, left ventricular hypertrophy, and grade 1 diastolic dysfunction.
INITIAL MANAGEMENT
Due to concerns for recurrent exacerbation of heart failure with preserved ejection fraction, intravenous furosemide was started. Despite adequate diuresis, his serum creatinine increased to 2.7 mg/dL. Given the patient’s persistent kidney dysfunction, a nephrology team was consulted to investigate the etiology of acute kidney injury on chronic kidney disease (stage 2).
DIFFERENTIAL DIAGNOSIS
1. Which is the most likely etiology of this patient’s acute kidney injury?
Cardiorenal syndrome
Prerenal azotemia due to overdiuresis
Acute interstitial nephritis
Intrinsic kidney pathologies
Cardiorenal syndrome involves a complex and bidirectional relationship between the heart and the kidneys, in which dysfunction in 1 organ causes or worsens dysfunction in the other.1 Cardiac insufficiency causes elevated central venous pressure, leading to venous congestion in the kidneys, ultimately resulting in decreased glomerular filtration rate.1,2 This activates the renin-angiotensin-aldosterone system and sympathetic nervous system, leading to sodium and water retention, further impairing kidney function.3 Eventually, this phenomenon creates a cycle in which both heart and kidney failure are exacerbated.
Although the patient had new edema and significantly elevated brain natriuretic peptide levels, the absence of jugular venous distension, lack of gallop, and failure of creatinine to improve despite adequate diuresis argued against heart failure exacerbation as the primary cause. His respiratory symptoms improved partially with diuresis, suggesting a multifactorial process. The presence of proteinuria and hematuria shifted suspicion toward an intrinsic glomerular process. While immune complex–mediated glomerulonephritis often produces red blood cell casts, only abundant hyaline casts were identified; the absence of red blood cell casts may have reflected sampling limitations and degeneration of cellular casts during transport.
In prerenal azotemia due to overdiuresis, a decrease in kidney perfusion leads to an increase in nitrogenous waste products in the blood, particularly creatinine and urea. Overdiuresis occurs when aggressive diuretic therapy reduces effective circulating volume, causing decreased kidney perfusion and a subsequent rise in serum creatinine without intrinsic kidney damage.4 Urinalysis reveals concentrated urine with elevated specific gravity and occasionally shows hyaline casts. Notably, creatinine levels usually improve after discontinuation of the diuretics. Although our patient’s urinalysis revealed hyaline casts, the presence of hematuria and proteinuria suggested an intrinsic kidney disease.
Acute interstitial nephritis involves an immunologic reaction in which the offending drug or its metabolites act as antigens that trigger the recruitment of inflammatory cells. This inflammatory infiltrate, comprising lymphocytes, eosinophils, and occasionally plasma cells, results in interstitial edema and tubular damage. It is often triggered by medications such as penicillins, cephalosporins, and nonsteroidal anti-inflammatory drugs. The classic clinical presentation includes fever, rash, and eosinophilia, but most patients do not present with all 3.5 A presumptive diagnosis is usually based on recent exposure to a culprit drug, sterile pyuria with a negative urine culture, and the presence of white blood cell casts, with biopsy providing confirmation. Even though our patient was taking methotrexate, which can cause acute interstitial nephritis at high doses used in chemotherapy,6,7 he had no supportive urinary findings, and the combination of hematuria and proteinuria favored a glomerular process over an interstitial one.
Intrinsic kidney pathologies include the following:
Acute tubular necrosis, the most common cause of acute kidney injury in hospitalized patients, is typically characterized by muddy brown granular casts on urine microscopy and occurs due to ischemia or nephrotoxins
Glomerular diseases, in contrast, present with features of either nephrotic syndrome (marked proteinuria and edema) or nephritic syndrome (hematuria, hypertension, red cell casts, and impaired kidney function)
Infiltrative diseases, such as amyloidosis or lymphomatous invasion of the kidney, can lead to progressive proteinuria and chronic kidney dysfunction, often with bland urinary sediment and minimal hematuria.8
In our patient, rapidly worsening kidney function with 3+ hematuria, 1+ proteinuria, more than 20 red blood cells per high-power field, and the absence of muddy brown casts favored an active glomerular inflammatory process instead of acute tubular necrosis or a slowly progressive deposition disorder.
Furthermore, as noted, our patient had an approximately 2-year history of stage 2 chronic kidney disease with a stable creatinine level between 1.0 and 1.2 mg/dL and glomerular filtration rate between 60 and 80 mL/min/1.73 m3. Mild fluctuation in creatinine is common in chronic kidney disease, especially during illness or diuresis, which occasionally leads to diagnostic inertia. However, a high index of suspicion for an acute kidney pathology is necessary when creatinine continues to worsen, particularly in the presence of new urinary findings. This patient’s rapidly deteriorating kidney function, as well as new-onset hematuria and proteinuria, prompted an aggressive workup to find the cause of the acute kidney injury.
CASE CONTINUED: ADDITIONAL URINE AND SERUM TESTING
A 24-hour urine protein measurement revealed proteinuria of 0.68 g/day (< 0.15 g/day), and the urine protein-to-creatinine ratio was elevated at 0.45 mg/mg (< 0.15 mg/mg).
Serum complement levels were also measured to check for potential immune-mediated glomerular disease. The C4 level was markedly low at less than 2 mg/dL (15–45), while C3 was normal at 109 mg/dL (88–201). Serum cryoglobulins were positive. Rheumatoid factor was markedly elevated at more than 650 U/mL from a baseline level of 313 U/mL measured 3 years earlier.
Due to the patient’s history of hematologic malignancy, serum protein electrophoresis was performed to evaluate for monoclonal gammopathy, which revealed a monoclonal spike of 0.1 g/dL (0) in the gamma region. Immunofixation electrophoresis confirmed the presence of a monoclonal immunoglobulin (Ig) M lambda light chain. Quantitative immunoglobulin analysis showed an IgG level of 219 mg/dL (600– 1,600), IgM 552 mg/dL (40–230), and IgA 4 mg/dL (70–400).
HOW CAN THESE TEST RESULTS BE INTERPRETED?
Notably, this patient had a chronically elevated baseline rheumatoid factor because of his rheumatoid arthritis. However, the recent significantly increased rheumatoid factor level in the absence of signs or symptoms of rheumatoid arthritis flare, and in the setting of monoclonal IgM spike, low C4, and cryoglobulins, suggested that the rheumatoid factor activity was mediated by the monoclonal IgM itself, as seen in type II cryoglobulinemia. In this condition, monoclonal IgM often serves as a rheumatoid factor directed against polyclonal IgG, forming immune complexes that drive complement consumption and vascular injury.9 These findings, along with hematuria and proteinuria, further raised suspicion for an underlying glomerular process.
CASE CONTINUED: KIDNEY BIOPSY
A decision was made to pursue a kidney biopsy. The immunofluorescence pattern on kidney biopsy revealed granular mesangial and segmental capillary loop deposits staining for IgM (2+ to 3+), kappa (trace), and lambda (1+ to 2+). Further staining on formalin-fixed paraffin-embedded tissue after pronase digestion revealed mesangial and segmental capillary loop staining for IgG (3+ to 4+), IgM (2+ to 3+), IgA (equivocal), C3 (1+), kappa (trace to 1+), and lambda (3+ to 4+) and cryoglobulin plugs staining for IgG, IgM, kappa, and lambda. On electron microscopy, subendothelial electron-dense deposits were present.
2. Combining the biopsy findings with the other clinical and laboratory data, what is the most likely diagnosis?
Infection-related glomerulonephritis
IgA nephropathy
Cryoglobulinemic glomerulonephritis
Anti–glomerular basement membrane disease
Infection-related glomerulonephritis typically presents with low complement levels (C3 more commonly than C4) and is associated with a history of recent infection, particularly a streptococcal infection. The kidney biopsy usually shows subepithelial humps on electron microscopy.10 None of these features were present in our patient.
IgA nephropathy is characterized by mesangial deposition of IgA, and often presents with episodic hematuria after an upper respiratory infection. Its presentation can vary, including gross hematuria, microscopic hematuria with or without proteinuria, nephrotic syndrome, or rapidly progressive glomerulonephritis. IgA nephropathy does not typically present with low C4 levels or monoclonal protein on immunofixation electrophoresis.11
Cryoglobulinemic glomerulonephritis typically presents with low C4 levels, monoclonal protein on immunofixation electrophoresis, and proliferative glomerulonephritis with pseudothrombi on kidney biopsy. While a monoclonal protein can support the diagnosis, cryoglobulinemic glomerulonephritis may occur without it.12 These findings align with our patient’s presentation, especially in the context of a monoclonal gammopathy. Specifically, kidney biopsy demonstrated proliferative glomerulonephritis with numerous intracapillary pseudothrombi, consistent with cryoglobulinemic glomerulonephritis. The immunofluorescence staining pattern indicated a mixed type rather than type I cryoglobulinemia. The patient’s serum cryoglobulins, consisting of a mixture of monoclonal IgM with rheumatoid factor activity and polyclonal IgG, also suggested type II or mixed cryoglobulinemia.
Anti–glomerular basement membrane disease is characterized by rapidly progressive glomerulonephritis. It can also present with pulmonary manifestations such as alveolar hemorrhage. The pathognomonic finding on a kidney biopsy is immunofluorescence showing linear IgG staining along the glomerular basement membrane, and light microscopy usually shows crescentic glomerulonephritis, which is not consistent with our patient’s kidney biopsy findings.13 It does not typically present with low complement levels or monoclonal protein on immunofixation electrophoresis.
CASE CONTINUED: BONE MARROW BIOPSY AND DIAGNOSIS
In addition to findings that suggested mixed type cryoglobulinemic glomerulonephritis, the serum monoclonal IgM lambda spike was concerning for a B-cell lymphoproliferative disorder. Therefore, a bone marrow biopsy was performed, which showed a small abnormal population of CD19+ B cells, along with a subset of monoclonal plasma cells expressing lambda light chains, consistent with Waldenström macroglobulinemia.
Overall, the presence of monoclonal IgM lambda and cryoglobulins, along with bone marrow findings and proliferative glomerulonephritis with pseudothrombi observed on kidney biopsy, supported the diagnosis of Waldenström macroglobulinemia–associated cryoglobulinemic glomerulonephritis.
CRYOGLOBULINEMIC GLOMERULONEPHRITIS
Cryoglobulinemic glomerulonephritis is a form of kidney inflammation characterized by the deposition of cryoglobulins (ie, abnormal proteins usually consisting of immunoglobulins and complement components) within the small blood vessels of the glomeruli. Cryoglobulins precipitate from serum or plasma at temperatures below 37°C (98.6°F), causing obstruction and triggering immune-mediated injury of the kidney tissue. Patients often present with proteinuria, hematuria, and varying degrees of kidney impairment.14
There are 3 types of cryoglobulinemia: I, II, and III (Table 1).15 Types II and III are commonly referred to as mixed cryoglobulinemia. Chronic hepatitis C virus infection is often associated with mixed cryoglobulinemia. Other potential causes include infections (hepatitis B or human immunodeficiency virus), autoimmune diseases (Sjögren disease, lupus, rheumatoid arthritis), or lymphoproliferative disorders. In our patient, serologic testing for hepatitis C virus, hepatitis B virus, human immunodeficiency virus, and autoimmune disease was negative. The Meltzer triad, which consists of palpable purpura, arthralgia, and weakness, can be occur in patients with mixed cryoglobulinemia,16 but our patient did not have any of these signs or symptoms.
Types of cryoglobulinemia with associated disorders and clinical manifestations
Waldenström macroglobulinemia–associated cryoglobulinemic glomerulonephritis
A monoclonal IgM lambda spike, markedly elevated serum IgM, and bone marrow involvement by a lymphoplasmacytic process supported Waldenström macroglobulinemia as the underlying driver of the cryoglobulinemia in this patient, rather than rheumatoid arthritis. It is also important to note that our patient’s presentation met criteria for monoclonal gammopathy of renal significance, while cryoglobulinemic glomerulonephritis is a specific type of monoclonal gammopathy of renal significance.17 The cryoglobulinemia was attributed to the monoclonal immunoglobulins produced by the clonal plasma cells in the bone marrow, which were directly responsible for the kidney injury, even without other classic systemic features of cryoglobulinemia.
The characteristic biopsy pattern of cryoglobulinemic glomerulonephritis involves the presence of endocapillary proliferation and intracapillary infiltration of monocytes, along with either glomerular pseudothrombi or deposition of cryoglobulin substructures noted under electron microscopy. Direct immunofluorescence reveals positive staining of monoclonal IgM with specificity for lambda or kappa light chains in the walls of glomerular capillaries or mesangium or glomerular pseudothrombi.9,18–22
3. What is the next best step in this patient’s treatment?
High-dose steroids and treatment of underlying malignancy
Low-dose corticosteroids and nonsteroidal anti-inflammatory drugs
Anti-CD38 therapy
Plasma exchange alone
High-dose steroids and treatment of the underlying malignancy are the recommended management strategies for Waldenström macroglobulinemia–associated cryoglobulinemic glomerulonephritis. Pulsed doses of steroids (1,000 mg daily for 3 days), followed by a steroid taper, prevent immune-complex formation. The preferred first-line treatment for symptomatic Waldenström macroglobulinemia includes a combination of either bendamustine (an alkylating agent) and rituximab (a monoclonal anti-CD20 antibody) or ibrutinib (a tyrosine kinase inhibitor) with or without rituximab. Rituximab is avoided as a first therapy because it can cause IgM flare, resulting in hyperviscosity. It is typically incorporated into the treatment regimen after a first response is achieved.9,17,23
Low-dose corticosteroids and nonsteroidal anti-inflammatory drugs are insufficient for managing severe cryoglobulinemic vasculitis with kidney involvement. Although corticosteroids can help control inflammation, they are typically used in higher doses and in combination with other therapies to treat the underlying condition.24
Anti-CD38 therapy, daratumumab, is reserved for treating the underlying malignancy in refractory cases.25 Additionally, an immunosuppressive agent is first warranted to reduce kidney inflammation.
Plasma exchange is typically necessary in patients with life-threatening vasculitis, marked hyperviscosity, or refractory kidney failure not improving with immunosuppressive therapy. Our patient did not present with hyperviscosity or catastrophic vasculitic complications (pulmonary hemorrhage or extensive skin necrosis) requiring immediate plasmapheresis to remove circulating cryoglobulins.26
In our patient, a multidisciplinary approach was used to address both the kidney and hematologic aspects of his disease. The patient was started on high-dose methylprednisolone and a bendamustine-based chemotherapy regimen. Additionally, rituximab was planned to be added cautiously in subsequent cycles to minimize the risk of an IgM flare.
WALDENSTRÖM MACROGLOBULINEMIA
Waldenström macroglobulinemia is a subtype of lymphoplasmacytic lymphoma, a rare B-cell lymphoproliferative disorder accounting for 1% to 2% of hematologic malignancies.27 It is characterized by infiltration of the bone marrow with lymphoplasmacytic cells and elevated levels of monoclonal IgM in the serum.28,29 The incidence of Waldenström macroglobulinemia is higher in White individuals and males (55%–70%), with a median age at diagnosis between 63 and 68 years.28
Risk factors for Waldenström macroglobulinemia include preexisting IgM monoclonal gammopathy of undetermined significance, autoimmune disorders (eg, rheumatoid arthritis, Sjögren disease, and Crohn disease), and infections (including hepatitis and human immunodeficiency virus).30,31 More specifically, rheumatoid arthritis is a well-known risk factor for B-cell lymphomas, particularly diffuse large B-cell lymphoma, likely due to chronic immune stimulation and dysregulated immune surveillance. In addition, long-term methotrexate therapy has been linked to methotrexate-associated lymphoproliferative disorders, though these are most often Epstein-Barr virus–positive and may regress after withdrawal of the drug.32,33
In our patient, the occurrence of Waldenström macroglobulinemia years after treatment for diffuse large B-cell lymphoma represented a second primary B-cell malignancy rather than transformation, as reverse progression from diffuse large B-cell lymphoma to Waldenström macroglobulinemia is exceptionally rare. In contrast, Waldenström macroglobulinemia transforms into diffuse large B-cell lymphoma in up to 10% of cases.34 Survivors of aggressive lymphomas such as diffuse large B-cell lymphoma remain at elevated risk for secondary hematologic malignancies, including multiple myeloma and Waldenström macroglobulinemia.35 This patient’s combination of underlying autoimmune disease, prolonged immunomodulatory therapy, and prior lymphoma likely contributed to his cumulative risk of developing Waldenström macroglobulinemia.
Symptoms related to Waldenström macroglobulinemia result from elevated serum IgM levels and clonal plasma cell infiltration of the bone marrow and extra-medullary sites. Bone marrow infiltration leads to cytopenias, especially anemia, resulting in excessive fatigue. Elevated serum IgM levels can also cause hyperviscosity and cryoglobulinemia.28,34 Kidney involvement is rare in Waldenström macroglobulinemia (< 8%), with cryoglobulinemic glomerulonephritis as one of the most common kidney manifestations.30,36
CONCLUSION
This is an interesting case of Waldenström macroglobulinemia with rapidly progressive kidney failure due to cryoglobulinemic glomerulonephritis as the presenting manifestation. The association between Waldenström macroglobulinemia and cryoglobulinemic glomerulonephritis is well-documented; however, de novo presentation of Waldenström macroglobulinemia with cryoglobulinemic glomerulonephritis is less common. This case highlights the significance of a systematic diagnostic approach and underscores that seemingly common presentations, such as glomerulonephritis, can have uncommon and serious underlying causes.
TAKE-HOME POINTS
Unexplained kidney dysfunction, particularly with proteinuria and hematuria, warrants a thorough investigation, including consideration of hematologic malignancies.
A kidney biopsy enables the precise identification of the underlying pathology, guiding treatment decisions.
Cryoglobulinemic glomerulonephritis can be the presenting manifestation of Waldenström macroglobulinemia.
DISCLOSURES
Dr. Anwer has disclosed consulting, teaching and speaking, and acting as a research principal and co-principal investigator for Bristol-Meyers Squibb Co., and consulting for Caribou Bio. The other authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.
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- Article
- INITIAL EVALUATION
- INITIAL MANAGEMENT
- DIFFERENTIAL DIAGNOSIS
- CASE CONTINUED: ADDITIONAL URINE AND SERUM TESTING
- HOW CAN THESE TEST RESULTS BE INTERPRETED?
- CASE CONTINUED: KIDNEY BIOPSY
- CASE CONTINUED: BONE MARROW BIOPSY AND DIAGNOSIS
- CRYOGLOBULINEMIC GLOMERULONEPHRITIS
- WALDENSTRÖM MACROGLOBULINEMIA
- CONCLUSION
- TAKE-HOME POINTS
- DISCLOSURES
- REFERENCES
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