Common variable immunodeficiency (CVID) comprises a heterogeneous group of disorders characterized by impaired antibody provision. It is the most frequent symptomatic primary antibody disorder, with a prevalence of approximately 1 : 25,000 to 1 : 50,000 [
Kidney involvement in CVID has been described only sporadically in isolated case reports. Renal granuloma [
Although the most common renal diseases present with a significant reduction in glomerular filtration rate (GFR), in its acute (generally reversible) or chronic (almost always irreversible) forms, several factors can also affect renal tubular function. Renal tubular acidosis (RTA), nephrogenic diabetes insipidus, and electrolyte abnormalities are clinical entities that can go unnoticed in clinical practice, especially in their milder forms. Although overlooked by the attending physician, such disturbances can have short- and long-term complications [
While GFR is usually calculated in daily medical practice from serum creatinine, tubular function, although altered in interstitial nephropathies such as renal granuloma, is not routinely evaluated. Because CVID has been associated with renal interstitial alterations in several cases [
This is a cross-sectional study of 12 patients with CVID diagnosis, undergoing clinical follow-up at Hospital Universitário Walter Cantídio of Universidade Federal do Ceará. The study was carried out from January to July 2014. The diagnosis of CVID was based on the ESID/Pan-American Group for Immunodeficiency [ onset of immunodeficiency at age older than 2 years; absent isohemagglutinins, poor response to vaccines, or both; exclusion of defined causes of hypogammaglobulinemia.
The patients were undergoing treatment with intravenous immunoglobulin infusion every 4 weeks. The CVID group was compared to a control group that consisted of 12 age- and sex-matched healthy volunteers.
The study protocol was reviewed and approved by the Ethics Committee of Hospital Universitário Walter Cantídio, Federal University of Ceará, in Fortaleza, Brazil. Patients were included in the study only after signing the informed consent form.
At the medical consultation, signs and symptoms were evaluated, and the following aspects were recorded: age, gender, previous chronic diseases (heart failure, arterial hypertension, diabetes mellitus, cancer, or autoimmune diseases), recurrent urinary tract infection (≥2 episodes in six months or ≥3 in one year), time of diagnosis, use of other concomitant drugs, previous infectious complications, and their sequelae. The following laboratory parameters were evaluated: plasma and urine creatinine (
GFR was estimated using the CKD-EPI formula [
Urinary concentrating capacity was evaluated by the ratio between urinary and plasma osmolality (
CVID patients were compared with the control group. Fisher’s exact test and chi-square test were used to analyze categorical frequencies in the patients’ group. Differences between two independent continuous variables were evaluated using Student’s
The study included 12 unrelated adult CVID patients (7 men and 5 women; age range, 17 to 57 years; median age, 28 years), followed up at Hospital Universitário Walter Cantídio, Fortaleza, Ceará, Brazil. At the symptom onset, the median age was 16.5 years (range, 2 to 37 years). The symptoms perceived at disease onset were repeated respiratory tract infections (66.7%), persistent diarrhea (25%), and recurrent sinusitis and otitis media (8.3%). The median age at CVID diagnosis was 20 years (age range, 10 to 56 years) with a median delay of 3 years (ranging from 0 to 37 years). Four patients had splenomegaly. No patient had a diagnosis of autoimmune disease or recurrent urinary tract infection. The median time of disease duration at the time of the study was 10 years (range 1 to 38 years). All patients were undergoing regular immunoglobulin infusions. Complete demographic and clinical data of CVID patients are shown in Table
Common variable immunodeficiency patient’s characteristics.
Patient | Age (y), sex | Time of disease (y) | Splenomegaly | Bronchiectasis | Persistent diarrhea | Urine pH |
GFR (mL/min/1.73 m2) | Albumin excretion rate (mg/g) | MCP-1 (pg/mg-Cr) | |
---|---|---|---|---|---|---|---|---|---|---|
1 | 26, m | 19 | Yes | Yes | No | 5.65 | 3.2 | 212 | 1.1 | 11.3 |
2 | 31, f | 10 | No | Yes | No | 5.39 | 4.1 | 114 | 4.2 | 42.2 |
3 | 19, f | 6 | No | Yes | No | 5.32 | 2.5 | 91 | 3.2 | 16.1 |
4 | 22, m | 20 | No | Yes | No | 5.71 | 3.4 | 98 | 3.5 | 12.8 |
5 | 31, m | 19 | No | Yes | No | 5.49 | 2.4 | 96 | 2.6 | 18.3 |
6 | 57, f | 28 | No | No | Yes | 5.37 | 2.6 | 93 | 3.5 | 4.7 |
7 | 28, m | 1 | No | Yes | No | 6.21 | 1.1 | 138 | 4.2 | 89.5 |
8 | 39, f | 3 | Yes | No | No | 5.43 | 2.3 | 98 | 5.1 | 45.8 |
9 | 17, m | 8 | No | Yes | Yes | 5.75 | 1.4 | 144 | 4.5 | 31.5 |
10 | 57, m | 38 | Yes | Yes | Yes | 5.4 | 2.3 | 129 | 4.4 | 91.7 |
11 | 18, f | 3 | Yes | No | Yes | 5.46 | 2.1 | 149 | 16 | 178.9 |
12 | 44, m | 10 | No | No | Yes | 6.3 | 2.4 | 90 | 0.8 | 32.9 |
All CVID patients had normal GFR (>90 mL/min/1.73 m2). The median GFR was 106 mL/min/1.73 m2 (range 90–212). As a measure of glomerular barrier integrity, urinary albumin excretion rate was measured, and all patients had values within the normal range. Urinary MCP-1 levels (a marker of inflammatory state—see in Discussion) were also measured, and there was a trend towards no difference when CVID patients were compared with controls (47.9 ± 14.5 versus 42.1 ± 7.1 pg/mg creatinine,
Urinary MCP-1 levels in CVID patients and control subjects.
The comparison between the CVID patients and the control group showed no differences in age, gender, and systolic and diastolic blood pressure (Table
Demographic and clinical data of CVID patients and subjects controls.
CVID patients | Control | ||
---|---|---|---|
Age (years) | 32.4 ± 4.1 | 31.6 ± 1.8 | 0.8 |
GFR (mL/min/1.73 m2) | 121.0 ± 10.4 | 112.2 ± 2.8 | 0.8 |
Albumin/creatinine excretion rate (mg/g) | 4.4 ± 1.1 | 3.1 ± 1.1 | 0.04 |
0.9 ± 0.5 | 0.5 ± 0.1 | 0.5 | |
7 ± 3.3 | 5.6 ± 0.8 | 0.2 | |
7.9 ± 0.4 | 7.4 ± 0.1 | 0.1 | |
1.5 ± 7.7 | 9.0 ± 0.1 | 0.4 | |
2.5 ± 0.2 | 3.4 ± 0.1 | <0.001 | |
Urinary MCP-1 (pg/mg-Cr) | 48 ± 14.5 | 42.1 ± 7.1 | 0.7 |
FE: fractional excretion.
Urine/plasma osmolality (
Urine pH before and after acidification test in CVID patients and controls. Urine pH under 5.3 after test is considered normal.
Tubular handling of other electrolytes (sodium, potassium, calcium, and chlorine) was also evaluated, but all patients had serum values within normal ranges, and no significant difference in excretion fraction of such electrolytes could be detected in comparison with that of control subjects (see Table
This is the first study that evaluated glomerular and renal tubular function in CVID patients. The main finding of our study is finding that CVID showed a trend towards an association with specific functional renal tubular dysfunctions (e.g., impaired urinary concentration and acidification capacities). In fact, almost all evaluated patients presented both disturbances.
To the best of our knowledge, the only study evaluating renal disorders in CVID, in addition to case reports, is one evaluating glomerular filtration rate only, using serum creatinine-based formulas [
In our cohort, no CVID patients had glomerular filtration rate alterations or glomerular filtration barrier damage/inflammation markers. Although we studied a relatively low number of patients, we can suggest that CVID patients are at low risk of developing severe renal impairment in association with glomerular function.
However, when tubular function was assessed, we surprisingly observed a trend towards urinary acidification and concentration capacity impairment. None of the patients were able to show urinary pH reduction < 5.3 after oral acid load. To ascertain that the urinary acidification test was performed adequately, all control subjects showed adequate urinary pH reduction. Because all CVID patients had normal levels of serum bicarbonate at baseline (>24 mEq/L), we can affirm that these patients had incomplete distal renal tubular acidosis. In incomplete distal RTA, net acid excretion is maintained at a rate equal to acid generation. This is achieved by an increase in ammonium excretion that offsets the reduction in titratable acid excretion caused by the high urine pH [
The second impaired tubular function observed in CVID patients was the urinary concentration capacity. CVID patients showed lower maximum urinary concentrations after a 12 h water and food fasting when compared to control subjects. Although we did not measure serum antidiuretic hormone (ADH) levels, CVID patients’ failure to achieve high urinary osmolality in comparison with controls after a 12 h water and food fasting strongly suggests there is an incomplete tubular response to ADH. Although these patients showed normal osmolality values at baseline and had no polyuria complaints, this incapacity to achieve maximum urinary concentration can predispose these patients to hypovolemia and dehydration under stress conditions.
It is a challenge to suggest any mechanisms for these tubular alterations in CVID patients, and, at present, we can only suggest possible pathways. We had previously demonstrated similar alterations in leprosy patients [
The main limitation of the present study is our inability to progress regarding the pathophysiology of renal tubular disorders disclosed in CVID patients. Studies focusing on direct antibodies against renal tubular components through immunohistochemistry and additional morphological studies from renal biopsies will contribute to our understanding of renal involvement in CVID. Also, we studied a reduced number of patients, and, therefore, it is not possible to obtain definitive results.
In conclusion, we performed the most complete renal evaluation in CVID patients to date. We found no alterations in glomerular function or inflammation. However, we observed a trend towards an elevated prevalence of tubular dysfunction in CVID, mainly related to urinary acidification and concentration capacity alteration.
The funding sources had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
The authors declare that they have no conflicts of interest.
Alexandre Braga Libório and Alice Maria Costa Martins are recipients of a grant from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Alexandre Braga Libório is a recipient of a grant from the Fundação Cearense de Apoio ao Desenvolvimento Científico e Tecnológico (FUNCAP).