Case presentation
In this case report we present a 64-year-old man with a history of IgG kappa paraproteinemia
for 14 years with no signs of multiple myeloma or plasmacytoma who presented to the
renal clinic with new onset hypokalemia and increase in serum creatinine. His past
medical history was remarkable for a diagnosis of necrobiotic xanthogranuloma for
30 years treated with multiple modalities including chlorambucil, thalidomide, cryotherapy,
intravenous immunoglobulin, and electron beam therapy. He also had a history of squamous
cell carcinoma, melanoma, bilateral carotid artery disease, coronary artery disease,
and hypertension. He had no fevers, cough, dyspnea, abdominal pain, nausea, or vomiting
but did complain of a worsening headache over the last week. He also reported increased
urinary frequency and thirst but denied any dysuria or hematuria. His medications
included aspirin, clopidogrel, amlodipine, carvedilol, hydralazine, and atorvastatin.
He started no new medications and reported no sick contacts. His blood pressure was
152/82 mmHg. On physical examination, the patient appeared comfortable with a clear
oropharynx, cardiac exam with regular rate and rhythm and no murmurs, rubs, or gallops,
clear lung sounds, soft and non-tender abdomen, no lower extremity edema, and numerous
erythematous plaques on his trunk and extremities. His initial labs at presentation
are summarized in Table 1. Of note, his creatinine was 1.0 mg/dL 10 months prior.
Urine sediment examination showed occasional epithelial cells and white blood cells
as well as hyaline casts. A renal ultrasound showed a right kidney of 11.9 cm with
mild fullness of collecting system and a left kidney of 10.4 cm with no signs of hydronephrosis.
A bone marrow biopsy 1.5 years prior to presentation showed findings consistent with
a plasma cell dyscrasia but did not meet criteria for myeloma. Plasma cells were 5%
without lymphoid infiltrates. Flow cytometry showed abnormal plasma cells that were
kappa restricted. Cytogenetics were normal.
Table 1
Initial laboratory values
Variable
Reference Range
Lab value
Blood
Sodium (mmol/L)
137-146
139
Potassium (mmol/L)
3.5-5.3
3.2
Chloride (mmol/L)
98-107
96
Carbon dioxide (mmol/L)
23-32
27
Urea nitrogen (mg/dL)
5-25
21
Creatinine (mg/dL)
0.6-1.4
1.69
Glucose (mg/dL)
70-100
120
Calcium (mg/dL)
8.6-10.3
8.9
Albumin (g/dL)
4.0-5.0
3.1
Phosphorous (mg/dL)
2.7-4.5
3.2
Magnesium (mg/dL)
1.3-2.7
1.7
Uric Acid (mg/dL)
2.6-6.0
5.6
Aspartate aminotransferase (U/L)
6-40
30
Alanine aminotransferase (U/L)
10-49
18
Alkaline phosphatase (U/L)
35-130
76
Total Bilirubin (mg/dL)
0-1.0
0.4
Hemoglobin (g/dL)
12.0-17.0
11.6
Hematocrit (%)
35.0-50.0
35.2
White-cell count (per mm3)
4,500-11,000
8,900
Platelet count (per mm3)
150,000-400,000
265,000
Kappa light chains (mg/dL)
3.3-19.4
48.7
Lambda light chains (mg/dL)
5.7-26.3
1.53
Free Kappa/lambda ratio
0.26-1.65
31.9
M-spike, SPEP (g/dL)
None
1.19 IgG Kappa
Urine
Urinalysis
Blood
Negative
Negative
Glucose
Negative
Negative
Protein
Negative
++
Specific gravity
1.000-1.035
1.011
pH
5.0-8.0
7.0
Sediment
Red blood cell (/hpf)
0-3
2
White blood cell (/hpf)
0-4
1
Casts
Negative
Negative
Crystals
Negative
Negative
Chemistry
Spot urine protein/creatinine (g/g)
< 0.15
2.94
Spot urine microalbumin/creatinine (g/g)
0-0.03
1.68
Urine potassium/Cr (mEq/g)
0-14
49.7
Urine M spike (mg/24hr)
None
244 IgG Kappa
Urine total protein (g/24hrs)
< 0.08
2.2
Differential diagnosis
A middle age patient presented with new-onset renal dysfunction, worsening albuminuria,
and increased urinary frequency and thirst. His evaluation was notable for a urinalysis
with no blood but urine total protein/creatinine of 2.94 g/g and urine albumin/creatinine
of 1.68 g/g. The new onset of proteinuria along with renal dysfunction helped guide
the differential diagnosis for acute kidney injury. Proteinuria generally is categorized
as tubular or glomerular in origin. Given the history of paraproteinemia, the new
increase in proteinuria could result from an increase in the paraprotein burden. Given
the modest level of free light chains and that more than half of the total protein
found in the urine was albumin, the proteinuria was not due to increased urinary free
light chains but rather glomerular in origin. The paraprotein can cause glomerular
injury leading to albuminuria. Proteinuria can also be associated with proximal tubule
dysfunction, which is considered low molecular weight proteinuria and there is a larger
difference between urinary total protein and albumin excretion. Although tubular injury
can lead to albuminuria, it is not typically to the degree noted in this case. The
patient had a significant cancer history, although no new treatment during the time
course of the renal dysfunction and no signs of recurrence of skin cancer. Of note,
he did have new onset hypokalemia with urine chemistry suggestive of potassium wasting
and a known underlying IgG kappa paraproteinemia.
Hypokalemia
Hypokalemia is uncommonly associated with acute kidney injury. To determine the etiology
of hypokalemia, it is important to first identify if there is a decrease in potassium
intake, an increase in potassium output, or a transcellular shift of potassium. The
elevated spot urinary potassium/creatinine ratio in this patient prior to potassium
supplementation suggested increase urinary potassium excretion as the etiology of
hypokalemia. Urinary potassium wasting can result from a number of different causes
including: 1) genetic defects in tubular sodium reabsorption increasing distal sodium
delivery, a key regulator of potassium excretion, 2) hypomagnesemia, which decreases
tonic inhibition of secretory potassium channels, 3) varied forms of hyperaldosteronism
leading to upregulation of sodium and potassium conductances in the connecting tubule
and collecting duct, or 4) increase in urinary anions (e.g. bicarbonate) that are
excreted with countercations such as potassium to maintain electroneutrality. Hypokalemia
with acute kidney injury is a unique feature of leptospirosis, however, there was
no recent travel or other clinical signs to suggest infection. Given the history of
paraproteinemia and high urinary pH, proximal tubule dysfunction with proximal renal
tubular acidosis (pRTA) was suspected since it may lead to bicarbonate urinary wasting
and associated hypokalemia. Proximal tubulopathy from paraproteinemia is often associated
with global proximal tubule dysfunction (Fanconi syndrome). However, this patient
had normal serum levels of phosphorus and uric acid with no evidence of glucosuria
indicating that some functions of the proximal tubule remain preserved.
Monoclonal gammopathy with renal disease
Monoclonal paraproteins can have an array of different effects on the kidney. Until
early 2000’s, monoclonal gammopathy (MG) was categorized into monoclonal gammopathy
of unknown significance (MGUS), smoldering multiple myeloma (SMM), and multiple myeloma
(MM) based on: 1) monoclonal protein quantification on protein electrophoresis, 2)
monoclonal plasma cell percentage on bone marrow biopsy, and 3) evidence of end organ
damage such as renal failure. While this system offered some useful insight on risk
stratification and prognosis, a significant proportion of MGUS population developed
progressive renal disease. This observation added a new category to the previous classification:
monoclonal gammopathy of renal significance (MGRS)1. A study conducted between January
2000 and August 2016 found 44 of 2,935 MGUS patients during that time were diagnosed
with MGRS suggesting up to 1.5% of MGUS patients have renal complications attributed
to their monoclonal gammopathy2. MGRS is further categorized based on the presence
and type of organized deposits (Figure 1). If organized deposits are detected, the
histopathology can be diagnosed based on the shapes and sizes on the deposits. Fibrillary
deposits are usually 7-12 nm; immunotactoids are 17-52 nm hollow centered microtubules;
and crystalline can present with various sizes and shapes usually in rhomboid or needle
form.
Figure 1
An outline of renal pathologies associated with monoclonal gammopathy of renal significance.
There is an increased association of monoclonal gammopathy with disease entities denoted
to have no monoclonal immunoglobulin deposits making the relation with monoclonal
disease unclear. The disease entities with monoclonal immunoglobulin deposits generate
organized or non-organized deposits. The organized deposits can then be differentiated
based on the diameter of the individual filaments.
Histopathology
Light microscopy (LM)
A kidney biopsy was completed for further evaluation. Figure 2a shows Periodic Acid
Schiff (PAS) stained kidney section with three glomeruli with varied degrees of chronic
changes: one glomerulus is globally sclerosed, another glomerulus shows features of
collapsing glomerulopathy, and the third glomerulus has mild mesangial expansion.
There are some interspersed normal appearing tubules, some hypertrophic with obvious
PAS-positive protein reabsorption granules in the cytoplasm along with basal nuclei
(yellow arrow), while adjacent tubules reveal PAS-negative lacy cytoplasm (blue arrow)
(Figure 2c). Figure 2b shows a higher magnification of a glomerulus with collapsing
features, including extensive protein reabsorption granules in multiple epithelial
cells and a collapsed tuft.
Figure 2
Light microscopy of kidney biopsy a) Paraffin section stained with Periodic Acid Schiff
(PAS) showing three glomeruli and tubules with varying degrees of chronic changes;
b) Higher magnification of a glomerulus with PAS-positive protein reabsorption granules
in epithelial cells and segmental tuft collapse (arrows); c) Higher magnification
of proximal tubules with PAS-positive proteinaceous granules (yellow arrow), and adjacent
tubules with PAS-negative lacy cytoplasm (blue arrow). Scale bar: 50µm
Immunofluorescence (IF)
Figure 3a and b shows an IF stain on paraffin sections pretreated with protease for
antigen retrieval. Of note, the kappa restriction on IF can often be missed due to
masking of epitopes in the ultrastructure of light chain crystals and thus paraffin
sections treated with protease can help increase detection of kappa light chains by
up to three-fold in patients with light chain proximal tubulopathies3. There was significant
kappa light chain restricted staining of the proximal tubules and a mild increase
in staining intensity in a single glomerulus for kappa compared to lambda light chains.
Figure 3
Immunofluorescence on protease-treated paraffin sections revealing kappa restricted
(4+) light chain deposition in the glomerulus and tubules. Scale bar: 50µm.
Electron microscopy (EM)
Further evaluation with transmission electron microscopy (TEM) was completed. Figure
4a shows a podocyte with mild foot effacement but numerous needle-like crystal inclusions
in lysosomes (yellow arrow) and protein reabsorption granules (blue arrow). These
crystals are seen at higher magnification in 4c and show a regular, geometric substructure.
The proximal tubules on TEM (Figure 4b) show significant disorganization with crystal
deposition, increase in lysosomes, and complete occlusion of the lumen. Upon closer
inspection, the crystals demonstrate a substructure (Figure 4d) similar to the one
seen in the glomeruli.
Figure 4
Electron microscopy demonstrating podocyte and proximal tubule crystalline deposits.
a) Podocyte with foot process effacement and elongated crystal-like inclusions within
lysosomes (yellow arrow) and protein reabsorption granules (blue arrow). b) Proximal
tubule with numerous, distorted lysosomes and significant swelling with luminal occlusion.
Higher magnification of crystals with periodic substructure found in podocytes (c)
and proximal tubules (d). Scale bar: 1µm
Final diagnosis
The final diagnosis of the patient was crystalline light chain proximal tubulopathy
and podocytopathy with collapsing features secondary to monoclonal gammopathy.
Discussion
Light chain proximal tubulopathy (LCPT)
LCPT is a histopathological diagnosis associated with monoclonal gammopathy that is
characterized by the accumulation of light chain in the proximal tubule. The renal
biopsy, in this case, showed classic features of LCPT - 1) diffuse and severe acute
tubular injury with cellular hypertrophy and luminal occlusion, 2) detection of light
chain (exclusively kappa restricted) in proximal tubule by immunofluorescence, and
3) intracytoplasmic crystals on electron microscopy. In the largest cohort of LCPT
patients published in 20164, the diagnosis was most frequently made in males with
a median age of 60. Patients with LCPT often present with Fanconi Syndrome. In this
case, the patient did not present with Fanconi syndrome suggesting there were enough
spared proximal tubules to maintain function. There was significant albuminuria in
this patient, also often not seen in LCPT patients, and shown to be glomerular in
origin with evidence of collapsing glomerulopathy. Upon examination of the electron
microscopy, intracytoplasmic crystals could be identified inside the podocytes. These
inclusions demonstrate the ability of podocytes to endocytose proteins and light chains,
a process that is conducted similarly to the proximal tubule via cubulin5. Though
rare, a previous case report has also shown collapsing glomerulopathy associated with
LCPT with similar intracytoplasmic crystals within the podocytes, summarizing the
few reported cases of this association6. Patients with LCPT are most frequently diagnosed
with MGRS followed by MM, smoldering myeloma, non-Hodgkin lymphoma, and chronic lymphocytic
leukemia. During a median follow-up period of 39 months, patients treated with stem
cell transplantation and chemotherapy showed lower mortality and renal failure when
compared to an observation group suggesting the value of aggressive intervention.
However, authors also pointed out that patients who did not receive stem cell transplantation
nor chemotherapy were older and had higher initial serum creatinine.
Pathophysiology of light chain intracellular aggregation
Intracellular immunoglobulin light chain aggregation is shown to be associated with
biochemical properties of individual light chain clones. A review of patients with
light chain proximal tubulopathy showed that the characteristics of the pathogenic
urinary light chain is quite homogenous despite the phenotypic heterogeneity in patients
and their clinical course. Of the 9 patients with urinary light chains analyzed, 8
had V kappa I variability subgroup with similar characteristic residues at key positions7.
A key feature of the V kappa I variability subgroup was its resistance to proteolysis.
A separate study evaluated the protease resistance of a specific 12 kDa fragment of
the light chain in patients with cast nephropathy or LCPT by cathepsin B. In this
study, there was complete or partial degradation of the light chains from 12 cast
nephropathy patients and 4 control patients while 4 patients with LCPT had no degradation
of 12 kDa fragment by cathepsin B8. This data suggests that proteolysis-resistant
light chains are associated with LCPT and due to impaired degradation overwhelm the
proximal tubule lysozymes ultimately leading to light chain aggregation and tubular
dysfunction.
Follow-Up
The patient was referred to the hematology/oncology clinic where a bone marrow core
biopsy showed a normocellular bone marrow with less than 5% plasma cells suggestive
of plasma cell dyscrasia without overt multiple myeloma. He was treated with cyclophosphamide,
bortezomib, and dexamethasone. He briefly had stabilization of kidney function with
decrease in paraprotein but developed recurrent disease 1.5 years later. A repeat
bone marrow biopsy at that time showed 15% plasma cells with kappa light chain dominance
consistent with overt myeloma. He was then started on treatment with daratumumab and
bortezomib. A repeat bone marrow biopsy showed marked hypocellularity and less than
5% plasma cells, however, his kappa light chain production continued to be high. He
ultimately had progressive chronic kidney disease and was started on hemodialysis
three years after presentation.