Nephrology Case Challenge: Man on Keto Diet Has Severe Diarrhea and Neurogenic Bladder

C. Elena Cervantes, MD


February 06, 2023

AL amyloidosis is more common in men than in women, with a mean age at diagnosis of 63 years. The incidence ranges between 8.9 and 12.5 per million person-years on the basis of different population-based studies in the United States and Europe.[4,5,6] The prevalence has increased owing to improved survival and ranges between 40 and 58 affected individuals per million person-years.[1,6] Two risk factors for AL amyloidosis have been identified: monoclonal gammopathy and single nucleotide polymorphisms.[1]

A monoclonal gammopathy is a clonal plasma cell proliferation that produces excessive Ig light chain. Of note, a monoclonal protein and abnormal free light chain ratios have been consistently detected at least 4 years before the diagnosis of AL amyloidosis.[7] Patients with MGUS are nine times more likely to develop AL amyloidosis than are those without MGUS. In addition, multiple myeloma has been shown to coexist with AL amyloidosis in 10%-38% of cases, and 1% of patients with preexisting myeloma will develop AL amyloidosis.[8,9]

Single nucleotide polymorphisms (SNPs) are variations in the DNA that inform the genetic contributors to disease, response to medications, and other factors in specific populations. In patients with AL amyloidosis, SNPs have been identified in at least 10 loci, suggesting a genetic susceptibility. The strongest reported associations are in SNPs near the genes CCND1 and SMARCD3.[10]

The cytotoxicity mechanisms are complex and differ between soluble protein and insoluble amyloid fibrils. These mechanisms will not be covered in this discussion.

The clinical manifestations of systemic AL amyloidosis resemble more common conditions in older patients, such as fatigue and weight loss; therefore, evidence of organ damage leads to the diagnosis.[3] The heart and/or the kidneys are involved in more than 95% of patients with AL amyloidosis, and more than 90% have increased levels of the amino-terminal fragment of type B natriuretic peptide (NT-proBNP) in serum or albuminuria.[11] Because of the high sensitivity of these biomarkers, experts suggest that they be included in the regular follow-up panel for patients with a monoclonal protein and abnormal free light chain ratios, as they may represent the first sign of organ involvement.[12]

At diagnosis, approximately 70% of patients with amyloidosis have kidney involvement, and 4%-5% require dialysis. The amyloid protein deposits primarily in the glomeruli, manifesting as a nephrotic syndrome (proteinuria > 3 g/24 h, edema, and hypoalbuminemia) with or without kidney dysfunction.[3,13] Fewer than 10% of patients present with an isolated decline in eGFR, in which the vasculature and tubulointerstitial space are predominantly affected.

Cardiac involvement manifests as heart failure with preserved ejection fraction and determines the prognosis for survival. Therefore, if the index of suspicion is high, echocardiography or cardiac MRI should be performed. Imaging results that suggest cardiac involvement warrant a biopsy.

Although direct biopsy of the affected organ leads to the diagnosis, less invasive tests such as subcutaneous fat aspiration, bone marrow biopsy, or lip biopsy can be diagnostic in 50%-85% of cases.[14,15] However, identifying the precursor protein is crucial to guide therapy. On tissue biopsy, AL amyloidosis is characterized by Congo red positivity, with green birefringence under polarized light. Mass spectrometry is considered the gold standard method to identify the parent protein, with a sensitivity of 88% and a specificity of 96%, which are higher than with immunochemical techniques.[16,17]

Local vs systemic involvement should be identified when an amyloid deposit is detected. Localized disease can be observed in the bladder, larynx, stomach, colon, skin, eyelids, lungs, and urinary tract. It has a good prognosis and does not require systemic chemotherapy.

AL amyloidosis can be staged through different systems. The Mayo Clinic proposed the first one in 2004, and it was revised to include the difference between involved and uninvolved circulating free light chains (dFLC).[18] Currently, the staging system includes NT-proBNP (≥ 1800 pg/mL), cardiac troponin T ([cTnT] ≥ 0.025 ng/mL), and dFLC levels (≥ 180 mg/L). The presence of zero, one, two, or three markers above the cutoffs determines which patients are in stages I, II, III, or IV, respectively.[18]

Other organ-specific staging approaches include the cardiac staging system, determined by NT-proBNP and troponin levels, and the renal staging one, which evaluates the level of proteinuria and eGFR. The diagnosis of stage I kidney disease is made on the basis of both proteinuria < 5 g/24 h and an eGFR > 50 mL/min/1.73 m2. Stage II relies on either proteinuria > 5 g/24 h or an eGFR < 50 mL/min/1.73 m2, and stage III includes both of these markers.[19]

Treatment aims to rapidly reduce the amyloid precursor and enhance the reabsorption of amyloid deposits to improve cardiac function and prolong survival. However, there is no standard of care for treatment. Depending on the patient's risk profile, the amyloid precursor can be targeted with autologous stem cell transplantation (SCT), chemotherapy, immunotherapy targeting the B-cell clone, or a combination method. Clinical trials are underway to develop immunotherapies that promote the reabsorption of amyloid deposits.[1]


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