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Abstract
Full-house pattern on immunofluorescence (IF) on kidney biopsy in a patient without systemic lupus erythematosus is termed as nonlupus full-house nephropathy (FHN). In this study, we retrospectively compiled patients with nonlupus FHN and compared them with lupus FHN for clinicopathological presentation. We included patients with full-house IF patterns in renal biopsies collected from March 2007 to August 2018, clinical and histopathological data at the time of presentation were studied retrospectively. Treatment received and outcome at the end of follow-up was studied. Patients with nonlupus FHN who did not show any systemic disease (idiopathic group) were compared with a group of lupus nephritis patients. Of 178 patients, 34 had nonlupus FHN with 21 having idiopathic nonlupus FHN and 13 patients having secondary nonlupus FHN (membranous nephropathy, IgA nephropathy, postinfection glomerulonephritis). Males were more often in idiopathic nonlupus FHN patients than lupus FHN patients (P = 0.005). Kidney biopsies more often showed a mesangial (P = 0.0006) and less proliferative pattern of injury (P = 0.0002) and less intense C1q staining (P = 0.0001) in idiopathic nonlupus than lupus FHN. Clinically, idiopathic nonlupus FHN presented with more proteinuria (P = 0.0059) and less complement consumption (P = 0.001) than lupus FHN patients. Compared to lupus FHN, nonlupus has mainly nephrotic syndrome as clinical presentation. There was no difference in the clinical outcome between lupus FHN and idiopathic nonlupus FHN. Nonlupus FHN is not a very common condition and has less female involvement than in lupus FHN. Idiopathic nonlupus FHN has certain histopathological features with less C1q staining by IF, less frequent proliferative lesions and higher mesangial or membranous lesions by light microscopy compared to lupus FHN. Regarding outcomes, there is no significant difference between lupus FHN and idiopathic nonlupus FHN.
Introduction 
Patients with lupus nephritis (LN) typically have full-house deposits of immunoglobins on immunofluorescence (IF) staining in renal biopsy. The full-house pattern on IF is characterized by concomitant deposition of immunoglobulins - IgG, IgA, and IgM - and two complement system components - C3 and C1q - in renal tissue.[1] Light microscopy features can have various patterns. The main cause of this full-house pattern is LN. Nephritis with a full-house pattern in IF on renal biopsy along with extrarenal signs and symptoms of systemic lupus erythematosus (SLE) is consistent with LN. Diagnostic challenge results when patients present with various histopathologic lesions in combination with a full-house pattern by IF without the presence of auto-antibodies and other signs or symptoms of SLE. In this setting, the biopsy findings have been termed nonlupus “full-house nephropathy” (FHN).[2]
Wen and Chen first described nonlupus FHN in 24 patients and found that two patients developed SLE on follow-up for 24 months. Membranous glomerulopathy was the most common cause of nonlupus FHN in this study.[2] In a study by Sam et al, 23 patients with FHN were evaluated 12 patients were found to be SLE and 10 patients had membranous nephropathy.[3] In a recent study by Rijnink et al, 32 patients had nonlupus FHN with 20 patients having idiopathic nonlupus FHN and 12 patients having secondary nonlupus FHN. Patients with nonlupus FHN had poor renal survival and thus required careful consideration.[4]
Since there is a scarce literature on nonlupus FHN and it remains unclear how to classify and treat nonlupus FHN patients in whom the origin of FHN is idiopathic. In this study, we identified patients with nonlupus FHN describing the clinical presentation and histopathology of these patients and were compared them with those of lupus FHN patients according to four or more American College of Rheumatology[5] or Systemic Lupus International Collaborating Clinics (SLICC) criteria.[6]
Methods The renal biopsy archives from March 2007 to August 2018 in the Department of Nephrology, Gauhati Medical College (GMC), Guwahati, Assam, India, were searched and reviewed. In this study all patients with native renal biopsies showing full-house IF, which was defined as concurrent positive staining for IgA, IgG, IgM, C3, and C1q with ≥1+ intensity on a 0–3+ scale were included. Only those biopsies showing granular fluorescent staining along the capillary walls, in the mesangium or both were included. The study included adults as well as children. Clinical and histopathological data at the time of presentation were studied retrospectively. Renal biopsies were reviewed by expert nephropathologist.
The renal biopsy specimens were examined under light microscopy, direct IF techniques. Renal biopsy specimens were fixed in 4.5% buffered formaldehyde for light microscopy. Stains employed in examination included periodic acid–Schiff, hematoxylin and eosin, Masson’s trichrome, and silver methenamine. For IF microscopy, sections were frozen in liquid nitrogen and cryostat sections and were stained using fluorescein isothiocyanate–labeled antisera to human IgA, IgG, IgM, C3, and C1q.
The detailed clinical data of patients were retrospectively analyzed. Baseline clinical examination included serum anti-double stranded deoxyribose nucleic acid (anti-dsDNA) antibodies, antinuclear antibodies (ANA), hemoglobin, white blood cell count, red blood cell count, platelet count, serum albumin, serum creatinine (SCr), complement 3 (C3), and complement 4 (C4), urine routine microscopy, and 24-h urine protein done. Estimated glomerular filtration rate was determined by the CKD-EPI equation.[7] ANA was checked by the IF in Hep-2 cells, dsDNA was determined by enzyme-linked immunosorbent assay. The diagnosis of SLE was based on the criteria established by the SLICC.[6] Idiopathic forms of FHN as well as those associated with diseases other than lupus, were included and studied.
Induction as well as maintenance immunosuppression was recorded for all patients. Patients with follow up of minimum six months were included. The end of follow-up was defined as the last visit to the nephrology clinic or before referral to renal replacement therapy. End-stage renal disease (ESRD) was defined as need of dialysis for more than three months or renal transplantation. Renal outcomes studied included complete response (CR), partial response (PR), doubling of Cr, ESRD, and death. CR was defined as return of SCr to the previous baseline, plus a decline in the proteinuria to less than 500 mg/day, PR was defined as stabilization (±25%), or improvement of SCr, but not to normal, plus a >50% decrease in proteinuria or if nephrotic range proteinuria >50% decrease plus proteinuria <3 g/day.
Statistical Analysis Quantitative data were expressed as mean ± standard deviation, and median (interquartile range). Differences of numerical data with normal distribution were tested by Student’s t-test. Categorical data were interpreted in the form of constituent ratio and percentage and com-pared by the Chi-square test. Statistical significance was considered as P <0.05.
Results Of the 178 patients included in this study from March 2007 to August 2018, 144 had FHN with lupus and 34 patients had nonlupus FHN. Average number of glomeruli in lupus FHN was 17.1 ± 2.82 and in nonlupus FHN was 15.2 ± 3.3. Among nonlupus FHN, 21 patients had idiopathic nonlupus FHN and 13 patients had nonlupus FHN due to secondary causes like membranous nephropathy, IgA nephropathy, postinfectious glomerulonephritis (PIGN).
Clinicopathological features of study population
[Table 1] describes the clinicopathological features of our study population. Out of 178 patients in our study population, 27 patients were males and 151 patients were females with a male-to-female ratio of 1:5.6. Mean age of the patients in our study population was 23.12 ± 4.7 years. Hematuria, asymptomatic proteinuria (40.4%) was the most common clinical presentation of our study population followed by nephrotic syndrome in 36.5%. Acute GN (AGN) was present in 14% of patients and rapidly proliferative GN (RPGN) in 9% of patients. Hemoglobin in our study population was 10.50 ± 1.5 g/dL with a mean Cr of 2.15 ± 1.2. 24-h urine proteinuria in our study population was 2.34 ± 1.2 g/day and serum albumin was 2.62 ± 1.1 g/dL. Systolic and diastolic blood pressure of the study population was 137.4 ± 16.6 mm Hg and 82.4 ± 10 mm Hg, respectively. Low C3 complement was seen in 126 (70.7%) patients and low C4 was seen in 78 (43.8%) patients. On IF microscopy, IgG was the predominant immunoglobulin deposited, followed by IgM and C3 complement.
Clinical features of idiopathic nonlupus FHN patients compared to lupus FHN patients
In our study population, 34 patients had nonlupus FHN. Out of 34 nonlupus FHN, 21 patients had idiopathic FHN while as 13 patients had secondary causes. Among secondary causes of FHN, PIGN was the most common cause (four patients), followed by IgA nephropathy in three patients and membranous nephropathy in two patients. Out of 21 patients with idiopathic FHN, 11 patients presented with nephritic syndrome, four patients with AGN, and three patients each with RPGN and subnephrotic proteinuria plus/or hematuria. [Table 2] shows the clinical characteristics of idiopathic nonlupus FHN compared to lupus FHN. Compared to lupus FHN, idiopathic nonlupus patients had higher male to female ratio (P = 0.005). Idiopathic nonlupus FHN patients had higher age at the time of presentation compared to lupus FHN (P = 0.0036).
Table 2: Clinical characteristics of patients with lupus full-house nephropathy compared with idiopathic nonlupus full-house nephropathy at the time of renal biopsy.More patients presented with nephrotic syndrome in idiopathic nonlupus FHN compared to lupus FHN (52% vs. 35%), although it was not statistically significant. Idiopathic nonlupus FHN had significantly higher proteinuria (P = 0.0059) and systolic blood pressure (P = 0.0328) compared to lupus FHN. Compared to lupus FHN, idiopathic nonlupus FHN had significantly lower consumption of both C3 (P = 0.0001) and C4 (P = 0.0099). ANA and anti-dsDNA were significantly higher in idiopathic nonlupus compared to lupus FHN (P = 0.0001).
Histopathologic features of idiopathic nonlupus FHN compared to lupus FHN
The kidney biopsies of the patients with idiopathic nonlupus FHN were categorized as no lesions (9.5%), mesangioproliferative lesions (14.3%), focal proliferative lesions (23.6%), diffuse proliferative GN (19%), membrano-proliferative lesions (9.5%), membranous lesions (19%) and crescentric lesions (4.8%). [Table 3] shows the histopathological findings of idiopathic nonlupus FHN as compared to lupus FHN. Biopsy findings were classified into different LN classes according to the International Society of Nephrology and the Renal Pathology Society classification.[8] The distributions of LN classes were significantly different between lupus FHN and idiopathic nonlupus FHN (P = 0.004323). Class IV lesions were significantly more prevalent in lupus FHN while as class III was more prevalent in nonlupus FHN. Proliferative lesions were significantly more prevalent in lupus FHN (P = 0.0002) while as mesangial/no lesions were significantly more prevalent in nonlupus FHN (P = 0.0006). Chronic lesions in biopsies (glomerulosclerosis, interstitial fibrosis, and tubular atrophy) were similar between lupus and idiopathic nonlupus FHN. On IF staining, C1q staining was significantly higher in lupus FHN compared to idiopathic nonlupus FHN while as staining of other immunoglobins and complement were similar between these two groups.
Table 3: Histopathologic findings in patients with lupus full-house nephropathy compared with nonlupus full-house nephropathy.Treatment of idiopathic nonlupus FHN patients
[Table 4] depicts the treatment received in our study. Eighteen patients out of 21 patients of idiopathic nonlupus FHN received immunosuppressive treatment while as three patients (14.3%) did not receive any immunosuppressive treatment. Seven patients (33.3%) received cyclophosphamide and steroid combination as initial treatment while as 6 patients (28.6%) received steroids alone as initial treatment. Mycophenolate mofetil (MMF) and calcineurin inhibitors in combination with steroid were given in three and two patients, respectively. No maintenance immunosuppression was given in 11 patients (52%). Azathioprine and MMF with steroid were used for maintenance treatment in six and four patients, respectively.
On comparing the treatment of lupus FHN and idiopathic nonlupus FHN, there was a significant difference in the number of patients receiving steroids alone between two groups (P = 0.0001). There was no significant difference in the receiving cyclophosphamide plus steroid between the two groups (50.7% vs. 33.3%, P = 0.1645). However, a significant number of idiopathic nonlupus FHN received no maintenance therapy (6.3% vs. 52.4%, P = 0.0001).
Comparison of outcomes of idiopathic nonlupus FHN with lupus FHN patients
[Table 5] shows the outcome of patients of idiopathic nonlupus FHN. CR was seen in seven patients (33.3%) and PR in nine patients (42.8%). ESRD developed in two patients (9.5%). One patient died over time while as doubling of Cr was seen in three patients (14.3%). Comparing the outcomes of idiopathic nonlupus FHN with lupus FHN were not significantly different.
Regarding renal survival, ESRD was seen in more patients of LN (20.1%) compared to 9.5% of idiopathic nonlupus FHN patients (P = 0.3716).
Discussion In this study, we tried to elucidate the clinical and histological pattern of nonlupus FHN. Of 178 patients with FHN, 34 (19%) patients had nonlupus FHN with 21 patients having idiopathic nonlupus FHN. This proportion of nonlupus FHN among FHN is variable in the literature. In the study by Rijnink et al, 21.5% of patients with FHN had nonlupus FHN.[4] In another study by Dias et al, 5.5% of patients with FHN had nonlupus FHN while in the study by Wen and Chen, nonlupus FHN constituted 25% of FHN.[2],[9] To restrict the group of patients with idiopathic nonlupus FHN, we considered a number of secondary causes of nonlupus FHN patients: membraneous nephropathy, IgA nephropathy, and PIGN. We defined idiopathic nonlupus FHN by the absence of sufficient SLE criteria and exclusion of other diagnoses.
We compared idiopathic nonlupus FHN group with LN group. About gender distribution in nonlupus FHN, we showed a higher frequency of male to female ratio compared to the LN group. Similar findings were seen by Rijnink et al and Dias et al[4],[9] while publications by Ruggiero et al in children and Wen and Chen in adults showed an equal gender distribution.[2],[10] Age of presentation of our patients with idiopathic nonlupus FHN was significantly higher than patients with LN, as was seen in the studies by Rijnink et al and Wen and Chen.[2],[4]
The clinical presentation did not differ significantly between lupus and nonlupus FHN. Nephrotic syndrome was the most common presentation (52%) in nonlupus FHN while as aymptomatic proteinuria and hematuria were the most common presentation in lupus FHN (44%).Similar findings were seen by Rijnink et al and Dias et al.[4],[9] Proteinuria was significantly more in nonlupus FHN than in nonlupus FHN, while as serum albumin was significantly low in nonlupus FHN than in lupus FHN. This finding was similar to the findings by Wen and Chen, Rijnink et al and Dias et al.[2],[4],[9] Systolic blood pressure was significantly higher in patients with lupus FHN compared to idiopathic nonlupus FHN. However, there was no difference in the diastolic blood pressure between lupus and idiopathic nonlupus FHN, which was similar to the studies by Rijnink et al and Dias et al.[2],[9] Complement consumption was significantly more with lupus FHN than idiopathic nonlupus FHN. This finding was also seen by Rijnink et al.[4]
In a study by Wen and Chen membranoproliferative and membranous lesions were more often seen in idiopathic nonlupus.[2] In a study by Rijnink et al, higher proportion of class IV lesions were seen in lupus FHN than in idiopathic nonlupus FHN.[4] Thus, there is still lack of clarity regarding predominant histology in the idiopathic nonlupus. Histopathological findings in our study showed significant difference between lupus and idiopathic nonlupus FHN. In our study, lupus FHN had predominantly class IV lesions while as class III was predominantly seen in idiopathic nonlupus FHN. Chronic lesions in biopsies (glomerulosclerosis, interstitial fibrosis, and tubular atrophy) were similar between lupus and idiopathic nonlupus FHN as were seen by Rijnink et al.[4] On IF staining, C1q staining was significantly higher in lupus FHN compared to idiopathic nonlupus FHN while as staining of other immunoglobins and complement were similar between these two groups. This finding was also seen in Rijnink et al.[4]
The pathogenesis and cause of idiopathic nonlupus of FHN have not been explained yet. The pathogenetic mechanism may be similar to the LN, as there is a similarity in pathology. In LN, immune complexed in the glomerulus can originate from preformed circulatory immune complexes as well as in situ formation. The microscopic pattern of injury in LN depends on the quantity, size, and type of the immune complexes.[11] Full-house glomerular deposits in LN are seen due to polyclonal activation of B cells in this situation, leading to increased immune response.[4] Full-house glomerular deposits in idiopathic nonlupus FHN can be due to defective immune complex clearance following abnormal immune complex overload or handling.[12] Unidentified antigens either endogenous or exogenous, may be leading to immune complexes in idiopathic nonlupus FHN. Furthermore, genetic defect in the clearance of immune complexes, such as FcƔ, as is seen in SLE can be implicated in idiopathic nonlupus FHN.[13]
We compared the outcome of idiopathic nonlupus FHN (included CR, PR, ESRD, death and doubling of Cr with lupus FHN. There was no significant difference in the outcomes of idiopathic nonlupus FHN and lupus FHN. This result was in contrast to the study by Rijnink et al, in which they have seen a higher rate of ESRD with idiopathic nonlupus FHN. However, in their study more than half of the patients didn’t receive any immunosuppressive drugs.[4] This is in contrast to our study, with 18 out of 21 idiopathic nonlupus FHN patients receiving immunosuppressive treatment. In the study done by Ruggiero et al, the use of immunosuppressive drugs in pediatric nonlupus FHN patients resulted in favorable outcomes, thus suggesting the role of immunosuppression in these patients.[10] In another study by Dias et al, no difference in development was seen in the development of ESRD between idiopathic nonlupus FHN and lupus FHN. In this study also majority (82.2%) of idiopathic nonlupus FHN patients received immunosuppressive drugs.[9] Thus, the difference between our study and Rijnink et al’s study could be due to the use of immunosuppression in our study, raising the possibility that these patients (idiopathic nonlupus) may benefit from immunosuppression.
Conclusion Nonlupus FHN is not a very common condition and affects females less compared to LN which has more female predominance. Compared to lupus FHN, nonlupus has mainly nephrotic syndrome as clinical presentation. Nonlupus can be due to secondary to systemic disease or idiopathic. Idiopathic nonlupus FHN has certain histopathological features with less C1q staining by IF, less frequent proliferative lesions, and higher mesangial lesions by LM compared to lupus FHN. Regarding outcomes, there is no significant difference between lupus FHN and idiopathic nonlupus FHN.
Acknowledgments
The authors would like to thank all the supporting staff at the Department of Nephrology, Gauhati Medical College and Hospital for their help in conducting this study.
Conflict of interest: None declared.
References 
Correspondence Address:
Manzoor Ahmad Parry
Department of Nephrology, Sher-i-Kashmir Institute of Medical Sciences, Soura, Srinagar, Jammu and Kashmir
India
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/1319-2442.367824
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