Renal Manifestations of Common Variable Immunodeficiency : Kidney360

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Original Investigations: Glomerular and Tubulointerstitial Diseases

Renal Manifestations of Common Variable Immunodeficiency

Caza, Tiffany N.; Hassen, Samar I.; Larsen, Christopher P.

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Kidney360 1(6):p 491-500, June 2020. | DOI: 10.34067/KID.0000432020
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Common variable immunodeficiency (CVID) is one of the most common primary immunodeficiencies, yet it is overall rare, affecting one in 25,000–50,000 whites and one in 100,000 individuals worldwide (1) and has near equivalent prevalence in men and women. CVID consists of a heterogenous group of primary immunodeficiency disorders characterized by a marked reduction in antibody production (IgG, IgM, and IgA), poor humoral responses to protein or polysaccharide vaccines, and an exclusion of other causes of hypogammaglobulinemia. A genetic cause for CVID can be identified in a minority of patients, with only 2%–10% of patients showing monogenic forms (2). CVID is most often diagnosed between ages 20 and 40 years, usually with a long delay from onset of symptoms to clinical recognition (average 6–8 years), as the symptoms are not specific, and infections are common in children.

Patients with CVID have a variety of disease manifestations, including recurrent bacterial infections, autoimmunity, chronic lung disease, gastrointestinal disease, lymphoid hyperplasia, granulomatous disease, and an increased risk of malignancy (3). Treatment of CVID is aimed at life-long Ig replacement, which reduces risk of bacterial infections, but does not affect autoimmune and inflammatory manifestations of the disease (3).

Renal failure is a rare complication of CVID, affecting approximately 2% of patients. In a cohort of 240 patients with CVID, five were found to have CKD (4). Ig replacement therapy in hypertonic solutions has been shown to be nephrotoxic and can result in reversible acute tubular injury. The presence of proteinuria or an active urinary sediment is not typical for intravenous Ig (IVIg)–induced renal injury, and is an indication for renal biopsy in patients with CVID. To date, there are no case series of renal biopsies from patients with CVID, making it difficult to determine whether individual case reports of renal disease in CVID represent sporadic events or are related to the underlying pathophysiology. Here, we present the first case series and review of the literature of the nephropathology in patients with CVID.

Materials and Methods

Case Selection

Approval for this study was obtained by the Solutions Institutional Review Board, and the ethical principles highlighted by the Declaration of Helsinki were followed. A retrospective analysis of 10 years of renal biopsy specimens using our database of patients with a clinical history of CVID was performed (n=22 patients, comprising 27 renal biopsy specimens) from January 1, 2010 to December 31, 2019. During this time period, there were 27 renal biopsies from patients with CVID out of a total of 110,918 cases (0.02%). Patients with primary immunodeficiency of unknown cause, as well as patients with a clinical or family history with x-linked (Bruton) agammaglobulinemia, severe combined immunodeficiency, Wiskott–Aldrich syndrome, DiGeorge syndrome, IgA deficiency, chronic granulomatous disease, and hyper-IgE syndrome were also studied, but only a small overall number of patients were available for analysis (n=18 cases in total).

Clinical notes at the time of biopsy and at follow-up were also reviewed. Data abstracted from the medical records included history of infections, comorbid health conditions, medications (including IVIg therapy), serum creatinine, and proteinuria. Patients without proteinuria on urinalysis did not have quantitative proteinuria or serum albumin values available. Follow-up serum creatinine and quantitative proteinuria values were also obtained. A history of infections, serum creatinine, and proteinuria values were available for the majority of patients. Serum creatinine values at the time of biopsy were available from 18 patients, 14 of which had follow-up creatinine values. Proteinuria data was available for 18 patients, ten of which had quantitative proteinuria. Seven of the ten patients with quantitative proteinuria values had follow-up quantitative proteinuria data. Quantitative proteinuria included both spot urine protein-to-creatinine ratio values and 24-hour urine collections.

A literature review was performed of all reported cases of native renal biopsies in patients with CVID that were indexed on PubMed, Scopus, or Google Scholar (n=24 manuscripts and two conference abstracts).

Renal Biopsy

All cases were processed for light, immunofluorescence, and electron microscopy. Formalin-fixed tissue was prepared for light and electron microscopy. For light microscopy, biopsies were fixed in formalin, dehydrated using alcohols, and embedded in paraffin wax after microwave processing. Paraffin sections were cut at 3 µm thickness, and stained with hematoxylin and eosin, periodic acid–Schiff, Masson trichrome, Jones methenamine silver, and Congo Red. For preparation of electron microscopy, 1 mm cubes of formalin-fixed tissue were removed, dehydrated with alcohols, and embedded in an epon–araldite resin. An ultramicrotome was used to cut 1-µm thick sections, stained with toluidine blue, and examined by light microscopy. Thin sections were examined by electron microscopy.

Samples for immunofluorescence microscopy were received in Michel transport medium, washed with Michel wash buffer, and frozen with optimal cutting medium at −20°C. Sections were cut at 4 µm thickness, rinsed, and stained with fluorescein-tagged rabbit anti-human polyclonal antibodies. Evaluation for IgG, IgA, IgM, C3, C1q, fibrinogen, and κ and λ light chain were performed for all cases. Dako antibodies were added for 30 minutes, rinsed, and cover-slipped in mounting medium. The staining intensity was semiquantitative on a 0–3+ scale. For membranous glomerulopathy (MG) cases, if sufficient frozen tissue was available, sections were stained with mouse anti-human antibodies to IgG1, IgG2, IgG3, and IgG4.

Immunohistochemical and Immunofluorescence Staining

For MG cases, immunohistochemistry for phospholipase A2 receptor (catalog number HPA012657, PLA2R, PLA2R rabbit polyclonal antibody; Sigma), and immunofluorescence for thrombospondin type 1 containing 7A (catalog number AMAB91234, THSD7A, THSD7A mouse monoclonal antibody; Atlas antibodies), exostosin-1 (catalog number PA5–60699, EXT1, EXT1 rabbit polyclonal antibody; Invitrogen), and neural EGF-like 1 (catalog number PA5–27958, NELL1, NELL1 rabbit polyclonal antibody; Invitrogen) were performed. PLA2R staining was performed on frozen tissue by immunohistochemistry. THSD7A, EXT1, and NELL1 staining was performed on formalin-fixed, paraffin-embedded tissue sections after pro-K digestion. THSD7A antibodies were crosslinked with Alexa Fluor 488 goat anti-mouse IgG for detection by immunofluorescence. EXT1 or NELL1 antibodies were crosslinked with Rhodamine Red-X-AffiniPure goat anti-rabbit IgG antibodies at 1:100 for 30 minutes (catalog number 111–295–144; Jackson Immunoresearch). Granular capillary loop staining was considered a positive result, with an absence of staining indicating a negative result. IgG subclasses were performed on cases of MG. IgG antibodies were all direct FITC conjugates (IgG1, Jackson Immunoresearch catalog number 115–095–205; IgG2, Jackson Immunoresearch catalog number 115–095–207; IgG3, Sigma catalog number F4641; and IgG4, Sigma catalog number F9889).

Immunophenotyping of interstitial lymphoid infiltrates in cases of tubulointerstitial nephritis (TIN) was done by CD3 (catalog number 103R-98; Cell Marque), CD4 (catalog number 104R-18; Cell Marque), CD8 (catalog number 108R-18; Cell Marque), CD20 (catalog number 120M-88; Cell Marque), and CD68 (catalog number 168M-98; Cell Marque) immunohistochemistry on formalin-fixed, paraffin-embedded tissue of patients with TIN. The relative percentage of T cells (CD3+) to B cells (CD20+), and the CD4/CD8 ratio for T cell–rich infiltrates was assessed, as were estimates by evaluating multiple ×400 microscopic fields.

For statistical analyses, t tests were used to evaluate differences between groups.


Clinical Manifestations

All 22 patients in our cohort had a clinical diagnosis of CVID. Two patients had a genetic diagnosis, with one patient having LPS-responsive beige-like anchor gene deficiency and the other patient having an anomaly in chromosome pairs 3 and 18. In the majority of patients in our cohort, CVID was diagnosed by hypogammaglobulinemia for IgG, IgM, and IgA, identified in a work-up initiated because of recurrent or unusual infections. These included sinusitis, otitis media, pharyngitis, pneumonia, colitis (Clostridium difficile, cytomegalovirus), and skin infections. Eighteen of 22 patients received long-term IVIg therapy every 3–4 weeks. One patient underwent splenectomy, one patient underwent rituximab therapy, and one patient was deceased at follow-up.

The mean age of patients with CVID at the time of renal biopsy was 37.7 years (range, 2–69 years; SD±20.6 years). The mean serum creatinine was 1.97±1.76 mg/dl, which was higher on average for patients with TIN (mean, 2.75 mg/dl) than MG (mean, 1.62 mg/dl), although it was not statistically significant (P=0.54, unpaired t test). Mean proteinuria was 3.25 g±4.82 g/24 h.

Patients with CVID presented with a variety of immunodeficiency-related manifestations and comorbid conditions, including developmental, hematologic, cardiovascular, pulmonary, gastrointestinal, endocrine, oncologic, and rheumatologic disorders (Supplemental Table 1).

Patients with CVID with MG were more likely to have IgE-mediated comorbidities, including allergies, asthma, and eosinophilic esophagitis, than patients with acute or chronic TIN. As IgE is formed from cross-switching from IgG1 in germinal centers (5,6), there may be a link between IgG1-dominant MG and IgE-mediated disease manifestations.

Recurrent infections were frequent within the CVID cohort, but there was no stratification between type of infection and renal manifestations. Patients with MG and CVID had a history of chronic otitis media, upper respiratory infections (including pharyngitis [in two patients] and sinusitis), lower respiratory infections (including pneumonia in five patients and bronchiectasis in two patients), colitis (cytomegalovirus and C. difficile), and skin infections (in two patients). Patients with CVID with TIN similarly had a history of pharyngitis, pneumonia, and enteritis.

AKI and proteinuria were the leading indications for renal biopsy in CVID. Proteinuria was present at the time of biopsy for 18 of 27 biopsies (67%). AKI was present at the time of biopsy for ten patients (36%), and two patients had anuria (9%). Four patients underwent repeat biopsy, and the findings for three patients were similar, with only slight differences in activity and chronicity compared with the initial biopsy. In one case, a patient with a proliferative immune-complex GN developed MG in addition to proliferative immune-complex GN at follow-up.

Immune-Complex GN in Patients with CVID

Thirteen of 22 (59%) patients had immune-complex GN with capillary loop immune deposits. Nine patients had subepithelial deposits and met the criteria for MG, one patient had subendothelial deposits and was diagnosed with membranoproliferative GN with IgG3κ deposits, one patient had C3 glomerulopathy, and the remaining two patients had a proliferative immune-complex GN. In the patient with membranoproliferative GN with IgG3κ deposits, serum immunofixation and free light-chain assays were performed to exclude a paraprotein-related process, although presence of a clone below the limits of detection cannot be excluded. Immunofixation was negative for a paraprotein and a serum free light-chain assay showed a normal κ/λ ratio. One of the biopsy specimens containing mesangioproliferative GN had coexistence of a severe thrombotic microangiopathy with impending cortical necrosis in addition to an immune-complex GN. This biopsy specimen had ischemic, hypoperfused glomeruli, severe tubular injury with focal acute tubular necrosis, and severe microangiopathic changes within glomeruli and vessels.

Of the MG cases, eight of 13 cases contained mesangial deposits in addition to subepithelial and intramembranous deposits, whereas the remaining five had no mesangial or paramesangial deposits (Table 1). All cases were PLA2R, THSD7A, EXT1, and NELL1 negative (Supplemental Figure 1). IgG subclass staining shows strong IgG1 positivity along glomerular capillary loops in all four tested cases. IgG2, IgG3, and IgG4 were negative (Figure 1). IgG deposits were present within all cases and there was variable expression of IgA (seven of 13, 54%), IgM (six of 13, 46%), C3 (nine of 13, 69%), and C1q (four of 13, 23%). Global glomerulosclerosis ranged from 2% to 37%. Interstitial fibrosis was mild in 11 of 13 patients, moderate in one of 13 patients, and severe in one of 13 patients. There was moderate arteriosclerosis in three of 13 cases (23%), with no cases showing severe vascular disease. Four cases showed an associated proliferative component, with mesangial hypercellularity, endocapillary hypercellularity, and/or fibrinoid necrosis or crescent formation (Figure 2).

Table 1. - Immune-complex GN in patients with CVID
Parameter Frequency of Finding, N=13
Male 6/13
Female 7/13
Proteinuria 13/13
Capillary loop immune deposits 13/13
 Subepithelial 13/13
 Subendothelial 2/13
Membranous glomerulopathy 9/13
 With no mesangial deposits 1/9
 With mesangial deposits 8/9
Proliferative GN with monoclonal IgG3κ deposits 1/13
C3-dominant membranous-like glomerulopathy 1/13
IgG 12/13
IgA 7/13
IgM 7/13
C3 12/13
C1q 4/13
Membranous glomerulopathy in patients with CVID. Clinical and renal biopsy characteristics from eight patients with CVID with capillary loop immune deposits are shown. The frequency of immunofluorescence positivity is identified. CVID, common variable immunodeficiency.

Figure 1.:
MG in patients with CVID is IgG1 subclass restricted. A PAS stain showing a glomerulus with mild mesangial expansion and prominent capillary loops (A). A JMS stain showing thickened glomerular capillary loops with formation of holes (B). IgG subclasses showing IgG1 granular capillary loop deposits (C), which were negative for IgG2 (D), IgG3 (E), and IgG4 (F) immune deposits. CVID, common variable immunodeficiency; JMS, Jones methenamine silver; MG, membranous glomerulopathy; PAS, periodic acid–Schiff.
Figure 2.:
Proliferative changes are identified within glomeruli in patients with CVID with MG. (A) PAS stain showing a membranoproliferative pattern of glomerular injury, magnification ×400. (B) PAS stain showing mesangial and endocapillary hypercellularity, magnification ×400. (C) Cellular crescent formation on JMS stain, magnification ×400. (D) Focus of fibrinoid necrosis in a glomerulus with endocapillary hypercellularity, hematoxylin and eosin stain, magnification ×400; arrow indicates area of fibrinoid necrosis. (E) Segmental sclerosis, PAS stain, magnification ×400; arrow indicates region of segmental sclerosis. (F) Subepithelial and mesangial electron-dense deposits seen by electron microscopy.

Electron microscopy was evaluated from the patients with CVID with MG to evaluate the stage of the electron-dense deposits. All cases showed at least stage 2 electron-dense deposits (range, stages 2–4), with reaction of the underlying glomerular basement membrane (Figure 2F).

At follow-up, patients with CVID with MG had a mean serum creatinine of 1.06±0.59 mg/dl. Proteinuria persisted in six patients. One patient died of complications arising from a concurrent acute thrombotic microangiopathy.

TIN in Patients with CVID

The second most common diagnosis in our CVID cohort was acute or chronic TIN, affecting six of 22 (27%) patients with CVID (Table 2). The lymphocytic infiltrates all contained >90% CD3+ T cells, and showed a normal CD4/CD8 ratio in four of six cases, whereas two cases had a reduced ratio (Figure 3). The normal ratio of CD4/CD8 T cells circulating within is approximately 1.5–2.5, and a ratio <1 is considered abnormal. Infiltrates within the interstitium should reflect that seen within the peripheral blood; however, this could not be confirmed, as only one patient had peripheral blood flow cytometry performed (one of the CD8+ T cell–dominant cases with a low CD4/CD8 ratio).

Table 2. - Acute tubulointerstitial nephritis in patients with CVID
Parameter Frequency of Finding, N=6
Male 2/6
Female 4/6
Clinical presentation
 AKI 4/6
 Proteinuria 2/6
Interstitial inflammatory infiltrates
 Patchy 1/6
 Severe, diffuse 5/6
CD3+ >> CD20+ 6/6
CD4+ > CD8+ 4/6
CD8+ > CD4+ 2/6
Tubulitis 6/6
Interstitial fibrosis
 Mild 2/6
 Severe 4/6
Arteriolosclerosis 3/6
 None/mild 2/6
 Moderate/severe 3/6
 Unable to assess 1/6
Glomerular immune complexes 3/6 have IgG, κ, λ in mesangium
Acute tubulointerstitial nephritis in patients with CVID. Clinical and renal biopsy characteristics from six patients with CVID with acute tubulointerstitial nephritis are shown. Immunohistochemical staining to characterize lymphoid infiltrates included CD3, CD20, CD4, and CD8, and all cases displayed T cell dominance with >90% CD3+ T cells. CVID, common variable immunodeficiency; CD, cluster of differentiation.

Figure 3.:
Some cases of tubulointerstitial nephritis in CVID are CD8 + T cell–predominant. A haematoxylin and eosin (H&E) stained section shows replacement of renal parenchyma with a diffuse lymphocytic infiltrate (A). Scattered CD68+ histiocytes are seen within the infiltrate (B). Immunohistochemistry shows that the infiltrate is comprised of predominantly CD3+ T cells (C), with rare CD20+ B cells (D). The infiltrate shows few CD4+ T cells (E) and is CD8+ T cell dominant (F), with a reduced CD4/CD8 ratio.

Mesangial immune complexes for IgG, κ, and λ were concurrently present in three of six patients with CVID with TIN (50%). Global glomerulosclerosis ranged from 0% to 87%. Interstitial fibrosis was moderate to severe in three of six cases (50%). In previously reported cases of TIN owing to CVID, all showed T cell–rich infiltrates, and four of seven (57%) were CD8+ T cell dominant (17–1819202112). There was mild arteriosclerosis in one case and there were no cases that showed moderate or severe vascular changes. At follow-up, four of six patients had persistent CKD stage 3 or above (83%). One patient who had a CD8+ T cell–rich TIN underwent bone marrow biopsy and was found to have CD8+ natural killer–like T cell lymphoma. The other case of CD8+ T cell–rich TIN was found to be a benign, reactive infiltrate.

Other Renal Biopsy Findings in Patients with CVID

Other renal biopsy diagnoses included acute tubular injury (n=1), amyloid light-chain amyloidosis (n=1), diabetic glomerulosclerosis (n=1), thin glomerular basement membranes (n=1), pauci-immune sclerosing GN (n=1), and arterionephrosclerosis (n=1). Three of these cases showed mesangial immune complexes of IgM and/or C3. Congo Red staining was positive for the case of amyloid light-chain amyloidosis, with apple-green birefringence on polarization, but was negative for all of the remaining cases. A summary of the clinical and histopathologic features of all CVID cases in our cohort is provided in Supplemental Table 2.

Renal Biopsies of Primary Immunodeficiency in Patients without CVID

To compare CVID renal biopsy findings with those of other primary immunodeficiencies, we performed a database search of cases of Bruton agammaglobulinemia (n=2), Wiskott–Aldrich syndrome (n=1), severe combined immunodeficiency (n=2), DiGeorge syndrome (n=2), IgA deficiency (n=4), chronic granulomatous disease (n=1), hyper-IgE syndrome (n=1), and primary immunodeficiency not otherwise specified (n=5). The mean age of the patients was 29.7 years (range, <1 month to 86 years). Despite finding a low number of overall cases (n=18), nine patients with non-CVID primary immunodeficiency had a proliferative GN (mesangial and/or endocapillary proliferative, with or without the presence of crescents) and two had an MG. A single patient had acute TIN. Therefore, similar kidney biopsy manifestations may be seen in patients with other primary immunodeficiencies other than CVID. This data is provided in Table 3.

Table 3. - Histopathologic features of non-CVID primary immunodeficiencies
Patient Immunodeficiency Diagnosis % GGS IF/TA AS AH Immunofluorescence
1 X-linked agammaglobulinemia Proliferative immune-complex GN 36 20–30 Mild None Trace IgA, 1+ IgG, 2+ C3, mesangial + capillary loop
2 X-linked agammaglobulinemia Proliferative immune-complex GN 12 None None None Trace IgA, 3+ IgG, trace C3, 1–2+ C1q, mesangial + capillary loop
3 Wiskott–Aldrich Proliferative GN plus membranous glomerulopathy 50 20–30 None Mild 3+ IgA, 3+ IgG, trace IgM, 2–3+ C3, trace C1q, mesangial + capillary loop
4 Severe combined immunodeficiency ATI 71 >50 None Moderate None
5 Severe combined immunodeficiency Congenital nephrotic syndrome, Finnish type 4 10–20 None None None
6 DiGeorge syndrome Diffuse proliferative immune-complex GN 11 30 None None 3+ IgM, 1+ C3, 1–2+ C1q, mesangial + capillary loop
7 DiGeorge syndrome Crescentic GN 17 <10 None None Pauci-immune w/positive ANCA serology
8 Chronic granulomatous disease Crescentic GN 43 20 Severe Moderate Pauci-immune w/positive ANCA serology
9 Job syndrome/hyper-IgE Advanced sclerosing glomerulopathy 74 80 Severe Severe IgA 2+, IgG 3+, IgM 3+, κ 2+, λ 2+, mesangial and capillary loop
10 Primary immunodeficiency, not otherwise specified Membranous glomerulopathy 0 None None None IgG 2+, κ 2+, λ 2+ capillary loop deposits
11 Primary immunodeficiency, not otherwise specified FSGS 0 None None None C3 2+ mesangial
12 Primary immunodeficiency, not otherwise specified Acute tubular injury 0 10 No arteries for evaluation None Negative within glomeruli
13 Primary immunodeficiency, not otherwise specified Moderate global glomerulosclerosis, IF/TA, and arteriosclerosis 29 40 Moderate None None
14 Primary immunodeficiency, not otherwise specified Mesangial immune-complex deposition, increased GGS 39 10 Moderate Mild IgM 3+, C3 1+, κ 2+, λ 3+ mesangial
15 IgA deficiency Acute interstitial nephritis, mesangial immune-complex deposition 0 5–10 None None IgG 2+, IgM 2+, C3 1–2+, κ 2+, λ 2+ mesangial
16 IgA deficiency Mild global glomerulosclerosis, IF/TA, and arteriosclerosis 5 20–30 Mild to moderate Mild None
17 IgA deficiency Minimal change disease 0 None None None None
18 IgA deficiency Mesangiopathic glomerulopathy with IgG deposits 44 20 Severe Moderate IgG 2+, κ 1+, λ 1+ mesangial
The diagnoses; glomerular, tubulointerstitial, and vascular scarring; and immunofluorescence staining are shown. + refers to positive staining and is graded on a 1+ to 3+ scale. 1+ indicates mild staining, 2+ indicates moderate, and 3+ indicates severe. CVID, common variable immunodeficiency; GGS, global glomerulosclerosis; IF/TA, interstitial fibrosis/tubular atrophy; AS, arteriosclerosis; AH, arteriolar hyalinosis; ATI, acute tubular injury.


The most common findings on renal biopsy in patients with CVID were MG and acute or chronic TIN. MG in patients with CVID often had mesangial immune deposits and were PLA2R, THSD7A, EXT1, and NELL1 negative with IgG1 restriction (13). Identification of MG in patients with CVID is important as nephrotic-range proteinuria results in increased renal losses of Ig, worsening their immunocompromised state and increasing susceptibility to infections. In these patients, it is difficult to achieve IgG levels >500 mg/dl despite high doses of IgG replacement (14). Persistently low Ig levels increases risk of recurrent infections and their complications. A total of 26 CVID biopsies were reported, including 24 manuscripts and two abstracts. Of these cases, eight patients had an immune-complex GN (9–10111213141522), including six patients with MG, and two with a membranoproliferative GN.

Eight patients had an acute interstitial nephritis (7–1819202112), one of which was granulomatous and one of which occurred concurrently with MG. Eight cases showed amyloid A amyloidosis (23–24252627282930). Other reported cases include minimal change disease (n=1) (31), antiglomerular basement membrane nephritis (n=1) (32), and acute tubular necrosis (33) (n=1, see Table 4). Although our findings of an increased incidence of MG and acute interstitial nephritis parallel that reported in the literature, we did not have any cases in our series of amyloid A amyloidosis. This may represent improved control of chronic infections in this patient cohort.

Table 4. - Previously reported cases of CVID-associated kidney disease in the literature
Case No. Age Sex Diagnosis Creatinine Proteinuria Pathology Treatment Outcomes Reference
1 13 M Membranous 0.39 7.7 g IgG, IgM, C3, C4, C1q deposits Methylprednisolone, cyclosporine, IVIg Reduced proteinuria (15)
2 15 M Membranous and AIN NA NA IgG capillary loop deposits Antimicrobial agents Died at age 15 yr; pneumonia (16)
3 17 F MPGN 1.1 3 g IgM, C3, C1q deposits Methylprednisolone, IVIg, rituximab No proteinuria at 4 mo (17)
4 33 F Membranous 222 μmol/L 2.7 g IgG, IgM, C3 deposits Methylprednisolone Died at age 38 yr; pneumonia (22)
5 36 F Membranous 0.6 8 g IgG, C3 deposits Corticosteroids, rituximab Reduced proteinuria (18)
6 55 M Membranous 0.92 0.9 IgG capillary loop deposits IVIg Reduced proteinuria (19)
7 59 M Membranous NA 25 g IgG capillary loop deposits Methylprednisolone Died at age 61 yr (20)
8 22 M MPGN NA 0.9 g IgA, IgM, IgG, C3, C1q deposits Corticosteroids Improved renal function (21)
9 8 F AIN 10.1 NA Mononuclear infiltrate, 50% IF Peritoneal dialysis Listed for renal transplantation (7)
10 21 F AIN 164 μmol/L NA CD8+ T cell infiltrate IVIg Stable renal function (8)
11 24 F AIN NA NA CD8+ T cell infiltrate; severe IF Prednisone, MMF, cyclosporine Dialysis, listed for transplant (9)
12 28 F AIN 2.7 0.4 g CD3+ T cell infiltrate, CD4>8 Corticosteroids Recovery, then recurrence (10)
13 31 F AIN NA NA CD8+ T cell infiltrate Corticosteroids Improved renal function (11)
14 44 M AIN WNL NA CD8+ T cell infiltrate Corticosteroids, azathioprine Improved renal function (12)
15 47 M GIN 2.1 NA Non-necrotizing granulomas Corticosteroids Improved renal function (34)
16 24 F Amyloid A amyloidosis 1.1 4.5 Amyloid A deposition IVIg NA (23)
17 24 F Amyloid A amyloidosis NA NRP Amyloid A deposition (thyroid) IVIg NA (24)
18 28 M Amyloid A amyloidosis NA 9 Amyloid A deposition Ciprofloxacin, metronidazole No improvement (25)
19 29 F Amyloid A amyloidosis NA 9 Amyloid A deposition Antibiotics, IVIg, losartan, cilazapril Persistent NRP (26)
20 29 M Amyloid A amyloidosis 1.8 11.8 Amyloid A deposition Losartan, ramipril, IVIg Reduced proteinuria (27)
21 40 M Amyloid A amyloidosis NA 3.4 Amyloid A deposition Angiotensin receptor blocker NA (28)
22 48 M Amyloid A amyloidosis NA “Massive” Amyloid A deposition Antibiotics, IVIg No infections in 2 yr (29)
23 49 F Amyloid A amyloidosis 233 μmol/L 5.5 Amyloid A deposition IVIg Stable renal function (30)
24 32 M ATN (suspected) 1.33 NA Biopsy not performed Cessation of IVIg Improved renal function (33)
25 15 F Anti-GBM nephritis 486.2 μmol/L 29.4 Necrotizing crescents, linear IgG staining Corticosteroids, rituximab, cyclophosphamide Died, age 15 CMV encephalomyelitis (32)
26 12 M Minimal change 0.5 8.2 Mesangial hypercellularity, diffuse FPE Corticosteroids No recurrence at 2 yr (31)
CVID, common variable immunodeficiency; M, male; IVIg, intravenous Ig; AIN, acute interstitial nephritis; NA, not applicable; F, female; MPGN, membranoproliferative GN; IF, immunofluorescence; MMF, mycophenolate mofetil; WNL, within normal limits; GIN, granulomatous interstitial nephritis; NRP, nephrotic-range proteinuria; ATN, acute tubular injury; GBM, glomerular basement membrane; CMV, cytomegalovirus; FPE, foot process effacement.

Patients with CVID with acute or chronic TIN had CD3+ T cell–predominant inflammatory infiltrates and increased tubulointerstitial fibrosis. Patients with chronic TIN had a higher creatinine level and worsened kidney function than patients with an immune-complex GN. In a study of bone marrow biopsy specimens from patients with CVID, diffuse and nodular CD3+ T cell infiltrates were common within the marrow, which correlates with an increase in CD4, CD45RO, and soluble IL-2R expression on T cells. This correlates with increased memory T cells, as well as a block in B cell development from the pre–B-1 to the pre–B-II phase (35).

Autoimmunity is common in patients with CVID because of several possible mechanisms. There are B cell receptor-editing defects, which lead to a loss of checkpoint control. These defects can lead to persistence of autoreactive B cell clones that escape apoptosis. In addition to B cell defects, there is defective T cell function, with impaired CD4+ T cell activation and a depletion of regulatory T cells. Chronic and recurrent infections could also induce autoimmune responses by bystander lymphocyte activation, superantigen activation, and via epitope spreading. As CVID is a heterogeneous disease resulting from a loss of checkpoint inhibition, its histopathology mimics nephrotoxicities arising from checkpoint inhibitors. Interestingly, in a 10-year, single-center case series of renal pathology of checkpoint inhibitor therapies, the findings included acute TIN, MG, C3 glomerulopathy, and amyloid A amyloidosis (36)—the same findings seen in patients with CVID.

In summary, CVID is a primary immunodeficiency disorder characterized by hypogammaglobulinemia, recurrent infections, and systemic autoimmune/inflammatory manifestations. A majority of patients with CVID do not display renal manifestations, but those who do show a disproportionate increase in MG and T cell–rich acute TIN. These were the leading causes of nephropathology in patients with CVID who underwent biopsy in our cohort and within the literature. CVID should be considered as a potential cause of PLA2R-, THSD7A-, EXT1-, and NELL1-negative MG or acute interstitial nephritis, especially when seen in a young patient without a known cause, who has a history of repeated infections.


All authors have nothing to disclose.



Supplemental Material

This article contains supplemental material online at

Supplemental Figure 1. Membranous glomerulopathy in CVID patients is PLA2R (A), THSD7A (B), EXT (C), and NELL1 (D) negative for granular capillary loop staining.

Supplemental Table 1. Co-morbid conditions in CVID patients with kidney disease.

Supplemental Table 2. Histopathology and follow-up data from patients with common variable immunodeficiency


This work was previously reported in abstract form (Caza and Larsen: Renal Manifestations of Common Variable Immunodeficiency. Lab Invest 99: 1–36, 2019).

Author Contributions

T. Caza conceptualized the study, was responsible for data curation, formal analysis, investigation, and methodology, wrote the original draft, and reviewed and edited the manuscript. S. Hassen was responsible for data curation and investigation, and reviewed and edited the manuscript. C. Larsen conceptualized the study, was responsible for formal analysis, funding acquisition, investigation, project administration, supervision, validation, and visualization, and reviewed and edited the manuscript.


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Glomerular and Tubulointerstitial Diseases; Glomerular disease; Immunodeficiency; Membranous nephropathy; Renal biopsy; Tubulointerstitial nephritis

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