RPS Case of the Month
The heart of the matter
Amélie Dendooven, MD, PhD1
Idan Jeger, MD and Koen De Boeck, MD2
1. University Hospital of Ghent and University of Antwerp, Belgium2. ZNA, Antwerp, Belgium
A 52-year-old male without any medical history presents to his GP with fatigue and shortness of breath. His blood pressure is normal, but a blood analysis reveals renal insufficiency (eGFR 55ml/min). Urine analysis reveals slight proteinuria (800 mg/g Cr) without hematuria. The patient is referred to the nephrologist. An elevated serum free light chain in the blood of 420ml/l (lambda) is detected; additionally, the urine is positive for lambda free light chains. A bone marrow biopsy shows 15% plasma cells, with lambda restriction. No osteolytic lesions can be detected with subsequent imaging. A kidney biopsy is performed.
Figure 1: PAS staining shows generally preserved renal tissue. The glomeruli show a normocellular, intact appearance. The tubules are dilated with cytoplasmic thinning (arrow) indicative of tubular injury; there are no inclusions nor casts.
Figure 2: IF for lambda (top) shows positive resorption droplets in proximal tubular epithelium. IF for kappa was completely negative(bottom).
Figure 3: EM shows abundant mottled lysosomes in the cytoplasm of proximal tubular epithelial cells.
Figure 4: On the Congo red stain, a few vascular amyloid deposits can be detected.
Figure 5: A subsequent cardiac biopsy (performed after the results of the kidney biopsy and after cardiac ultrasound revealed significant ventricular wall thickening) shows extensive amyloid deposits around myocardial cells (upper panel: HE, lower panel: Congo red). Staining for lambda (not shown here) was positive.
Light chain proximal tubulopathy (lambda) and light chain amyloidosis in the context of a smouldering myeloma.
Light chain proximal tubulopathy comes in two forms:
- Light chain proximal tubulopathy with crystals, usually related to a kappa clone. This is the easiest form to diagnose as the cytoplasm of proximal tubular epithelial cells is often very pink and granular and shows clear (most often kappa) light chain restriction on immune studies. Often however, antigen retrieval is needed to demonstrate this since IF on frozen sections can be negative. Electron microscopy in this disorder reveals conspicuous electron dense crystals of various sizes and shapes (rhomboid or needle-like forms are often detected). Clinically, this form is associated with a (partial) Fanconi syndrome.
- Light chain proximal tubulopathy without crystal deposition. The majority of these show lambda deposition, as in this case. IF on frozen sections reveals light chain restriction of protein-absorption droplets in proximal tubular epithelial cells, otherwise light microscopy shows little abnormalities apart from tubular epithelial damage. Electron microscopy shows mottled, irregular lysosomal structures in the cytoplasm of proximal tubular cells. Fanconi syndrome is often not present, as in this patient.
Both forms of light chain proximal tubulopathy are extremely rare, around 0.5 to 3% of monoclonal Ig-associated kidney diseases. Ninety percent of patients have a detectable underlying plasma cell disorder - often a myeloma - that was not apparent before the renal presentation. As such, this is a rare but critically important diagnosis and can pinpoint patients amenable to clone-directed treatment.
In this case, mentioning the minute Congo red positive deposits in the kidney biopsy led the clinicians to suspect cardiac amyloidosis as the cause of the patient’s exertional dyspnea. Cardiac biopsy confirmed this hypothesis and led to treatment with a daratumumab-based regimen. First follow-up visits showed amelioration of cardiac and renal symptoms as well as a complete hematologic remission.Light chain proximal tubulopathy without crystal deposition- although claimed by some authors to be more common than light chain proximal tubulopathy with crystal deposition- is not an easy diagnosis. It is sometimes disputed since histologic signs can be mild and subjective and since light chain reabsorption can be expected with a urinary free light chain excess. EM is helpful to ascertain the diagnosis. Most important, clinicopathologic discussion is a prerequisite to link histologic findings to end-organ damage.
1. Larsen CP, Bell JM, Harris AA, Messias NC, Wang YH, Walker PD. The morphologic spectrum and clinical significance of light chain proximal tubulopathy with and without crystal formation. Mod Pathol. 2011 Nov;24(11):1462-9. doi: 10.1038/modpathol.2011.104. Epub 2011 Jun 24. PMID: 21701535.
2. Sethi S, Rajkumar SV, D'Agati VD. The Complexity and Heterogeneity of Monoclonal Immunoglobulin-Associated Renal Diseases. J Am Soc Nephrol. 2018 Jul;29(7):1810-1823. doi: 10.1681/ASN.2017121319. Epub 2018 Apr 27. PMID: 29703839; PMCID: PMC6050917.
3. Kapur U, Barton K, Fresco R, Leehey DJ, Picken MM. Expanding the pathologic spectrum of immunoglobulin light chain proximal tubulopathy. Arch Pathol Lab Med. 2007 Sep;131(9):1368-72. doi: 10.5858/2007-131-1368-ETPSOI. Erratum in: Arch Pathol Lab Med. 2008 Jan;132(1):13. Leehy, David J [corrected to Leehey, David J]. PMID: 17824791.
4. Messiaen T, Deret S, Mougenot B, Bridoux F, Dequiedt P, Dion JJ, Makdassi R, Meeus F, Pourrat J, Touchard G, Vanhille P, Zaoui P, Aucouturier P, Ronco PM. Adult Fanconi syndrome secondary to light chain gammopathy. Clinicopathologic heterogeneity and unusual features in 11 patients. Medicine (Baltimore). 2000 May;79(3):135-54. doi: 10.1097/00005792-200005000-00002. PMID: 10844934.5. Feurstein S, Zoller J, Schwab C, Schreiner S, Mundt H, Breitkreutz I, Schneider B, Beimler J, Zeier M, Waldherr R, Gröschel S, Müller-Tidow C, Schönland SO, Hegenbart U. Concurrent light chain amyloidosis and proximal tubulopathy: Insights into different aggregation behavior-A case report. EJHaem. 2022 Sep 8;3(4):1377-1380. doi: 10.1002/jha2.555. PMID: 36467828; PMCID: PMC9713218.