Clinicopathologic Features and Prognostic Factors in Biopsy-Confirmed Renal Involvement in Primary Sjőgren Syndrome

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Abstract

Key Points

• Baseline kidney function and chronic structural injury strongly predicted both renal recovery and long-term clinical outcomes.

• Tubulointerstitial nephritis was the predominant lesion in Sjögren syndrome with renal involvement.

• Early detection and management of renal involvement in Sjögren syndrome are critical to preventing irreversible kidney damage.

Background

Renal involvement in primary Sjögren syndrome (SS) is uncommon but clinically consequential. Previous studies have been limited by small samples and incomplete biopsy data. We evaluated a large biopsy-confirmed cohort to characterize clinicopathologic features of SS with renal involvement and identify predictors of renal recovery and long-term outcomes.

Methods

We retrospectively identified adults with SS and kidney biopsy at Mayo Clinic (2012–2025). Clinical, laboratory, and histologic data were extracted. Predictors of complete renal recovery within 6 months, defined as serum creatinine (sCr) returning to within 25% of baseline or <1.4 mg/dl if baseline was unknown, were evaluated using logistic regression. Cox regression assessed long-term risk of a composite end point: newly developed or progressive CKD, ESKD, or all-cause mortality.

Results

Fifty-six patients were included (median age 57 years; 91% female). Extraglandular manifestations occurred in 76% and baseline CKD in 65%. The median sCr at baseline and biopsy was 1.3 and 1.6 mg/dl, respectively. Anti-Sjogren's syndrome antigen A, often linked with Ro ribonucleoprotein was positive in 80%. Low C3 occurred in 14% and low C4 in 25%. Tubulointerstitial nephritis was the predominant lesion (71%). Moderate/severe interstitial fibrosis/tubular atrophy and arteriosclerosis were present in 36% and 41%, respectively. Immunosuppressive therapy was applied in 84%.

Complete recovery occurred in 67%. Over a median 3.9 years (interquartile range, 1.4–7.2), 43% reached the composite end point. Baseline sCr ≥2 mg/dl, 24-hour proteinuria ≥1 g, and presence of segmental glomerulosclerosis were associated with lower odds of recovery (odds ratio=0.16, 0.13 and 0.11, P = 0.02, 0.001 and 0.008, respectively) and higher long-term risk (hazard ratio=4.51, 2.92 and 3.52; P = 0.002, 0.01 and 0.02, respectively). Moderate/severe arteriosclerosis also increased long-term risk (hazard ratio=2.56; P = 0.03).

Conclusions

In biopsy-confirmed SS-related renal involvement, the severity of kidney dysfunction and the extent of chronic glomerular and vascular injury strongly predict renal prognosis. Early detection and targeted management of high-risk features may improve long-term renal outcomes.

Introduction

Primary Sjögren syndrome (SS) is a chronic systemic autoimmune condition marked by lymphoplasmacytic infiltration of exocrine glands, most prominently the salivary and lacrimal glands, resulting in ocular and oral dryness.¹ Beyond these hallmark features, SS exhibits a wide spectrum of extraglandular manifestations that reflect its underlying systemic immune dysregulation. Renal involvement is among the most clinically meaningful of these manifestations^1,2 and carries major implications for long-term morbidity, quality of life, and survival.^1,3,4

The prevalence of kidney disease in SS varies widely across studies, ranging from 1% to 42%.^1,5–8 This broad range may be driven by heterogeneous study designs, geographic and ethnic differences, and variation in the intensity of renal evaluation, particularly the use of biopsy. The most common renal manifestation is chronic tubulointerstitial nephritis (TIN), followed by glomerulonephritis.^2,9–11 Glomerular disease in this setting typically results from deposition of immune complexes, with membranoproliferative patterns constituting the predominant histologic subtype.¹⁰ Multiple retrospective cohorts have suggested several risk factors for renal involvement in SS, including anti-Sjogren's syndrome antigen A, often linked with Ro ribonucleoprotein (Ro/SSA) or anti-Sjogren's syndrome antigen B, often linked with La ribonucleoprotein (La/SSB) antibody levels, hypocomplementemia, elevated immunoglobulin (Ig) levels, and extraglandular disease.^5,9,12,13 Renal involvement, particularly when unrecognized or undertreated, has been linked to accelerated CKD progression, higher rates of hospitalization, and, in some studies, increased mortality.^5,14 Some studies have reported that 10%–20% of patients in SS with renal involvement developed ESKD.^3,15,16 Nonetheless, many previous studies were limited from small sample sizes, lack of biopsy data, or incomplete longitudinal follow-up, restricting the ability to identify robust clinical or pathologic predictors of renal recovery and long-term outcomes.

To address these gaps, we studied a biopsy-confirmed cohort of patients with SS-related renal involvement evaluated at the Mayo Clinic. Our goals were to characterize the clinical, serologic, and histopathologic features at the time of renal biopsy, assess short-term and long-term renal outcomes, and identify clinical and biopsy-based predictors of renal recovery and adverse long-term events. This approach aimed to define prognostic markers that may guide risk stratification, management decisions, and the timing of kidney biopsy in clinical practice.

Methods

Patient Population

We conducted a retrospective study of patients with biopsy-proven SS-related renal involvement across all Mayo Clinic sites between January 2012 and April 2025. Patients younger than 18 years of age and those with a history of kidney transplantation were excluded. The study was approved by the Mayo Clinic Institutional Review Board.

Diagnosis of primary SS was established by treating rheumatologists and documented in the medical record, based on either the 2002 American–European Consensus Group classification criteria and/or the 2016 American College of Rheumatology/European League Against Rheumatism classification criteria. Potentially eligible cases were identified through the Mayo Data Explorer, an institutional database (Supplemental Figure 1). Each case was then reviewed manually in the electronic health record to confirm the diagnosis of SS-related renal involvement through biopsy.

Data Collection

Clinical characteristics, laboratory data, and treatment information were collected. Baseline serum creatinine (sCr) is defined as the most recent outpatient value or the mean of all outpatient measurements obtained within 1 year before biopsy. Kidney biopsy findings were extracted from standardized pathology reports.

Kidney Outcomes

The short-term outcome was renal recovery within 6 months after biopsy, assessed by changes in sCr.¹⁷ Complete recovery is defined as sCr returning to within 25% of baseline or <1.4 mg/dl if baseline was unknown. Partial recovery is defined as ≥50% reduction in sCr from peak value but not meeting criteria for complete recovery. No recovery is defined as failure to meet complete or partial recovery criteria or requirement for ongoing kidney replacement therapy.

Long-term outcome was assessed from 6 months postbiopsy through September 2025 (study end date corresponding to the end of data extraction) by a composite end point: newly developed CKD (in those without CKD at biopsy), CKD progression (in those with preexisting CKD), ESKD, or all-cause mortality. CKD is defined as eGFR <60 ml/min per 1.73 m² for ≥3 months. CKD progression is defined as ≥50% sustained increase in sCr from baseline over 6–12 months. ESKD is defined as eGFR <15 ml/min per 1.73 m², initiation of dialysis, or receipt of a kidney transplant, whichever occurred first. eGFR was calculated using the 2021 CKD-Epidemiology Collaboration equation.¹⁸

Statistical Analysis

Data are presented as median with interquartile range (IQR) and counts with percentages. Changes in sCr over time were analyzed using both a linear mixed-effects model with timepoint as a fixed effect and a subject-specific random intercept to account for within-patient correlation and paired t test. Group comparisons were performed using the Fisher exact test for categorical variables and Wilcoxon/Kruskal-Wallis rank-sum tests for continuous variables. Predictors of complete renal recovery were examined using nominal logistic regression, expressed as odds ratio (OR) with 95% confidence intervals (CI). Long-term risk factors for the composite outcome were assessed with Cox proportional hazards models, expressed as hazard ratio (HR) with 95% CI. Missing data were handled using a complete-case approach. Participants with missing values in any covariate included in a given model were excluded from that analysis. No imputation was performed. Kaplan–Meier method was used to estimate free of composite outcome survival. Patients were followed from the time of biopsy until the occurrence of newly developed CKD, CKD progression, ESKD, death, loss to follow-up, or the study end; the biopsy date was used as time zero for Cox and Kaplan–Meier analyses. Statistical significance was defined as a two-sided P value ≤ 0.05. Analyses were performed with JMP Pro version 18.0 (SAS Institute, Cary, NC).

Results

Baseline Characteristics

A total of 56 patients were included (Supplemental Figure 1). Detailed clinical characteristics are presented in Table 1. The median age at kidney biopsy was 57 years (IQR, 44.3–69), and 91% were female. Sicca symptoms were universal, while parotitis was observed in 6%. Extraglandular manifestations were present in 76%, most commonly involving the musculoskeletal (50%) and dermatologic systems (32%). Fatigue occurred in 45% and weight loss in 9%.

Table 1.

Clinical characteristics of patients with primary Sjogren syndrome renal involvement at presentation

Characteristics	All Cohort (n=56)
Age at kidney biopsy, yra	56.5 (44.3–69)
Sex/Female, n (%)	51 (91.1)
Race, n (%)
Black	1 (1.8)
Hispanic	1 (1.8)
White	54 (96.4)
BMI, kg/m2a	27.0 (23.5–31.5)
Glandular domain at the diagnosis of SS
Dry eyes or mouth, n (%)	53/53 (100)
Parotitis, n (%)	3/53 (5.7)
Extraglandular symptoms, n (%)	41/54 (75.9)
Respiratory system	11 (20.4)
Upper airway disease	5 (9.3)
Interstitial lung disease	6 (11.1)
Musculoskeletal disorders	27 (50.0)
Arthralgia or arthritis	25 (43.6)
Myalgia	1 (1.9)
Fibromyalgia	1 (1.9)
Dermatologic disorders	17 (31.5)
Xerosis	13 (24.1)
Cutaneous vasculitis	2 (3.7)
Raynaud	2 (3.7)
Peripheral neuropathy	8 (14.8)
Hematologic	9 (16.7)
Cryoglobulinemia	4 (7.4)
Autoimmune cytopenia	4 (7.4)
Lymphoma	2 (3.7)
Hypocomplementemia	1 (1.9)
Dysphagia	1 (1.9)
Fatigue, n (%)	24/53 (45.3)
Weight loss, n (%)	5/53 (9.4)
Depression, n (%)	0/53 (0)
Comorbidities, n (%)	30/55 (54.5)
Hypertension	25 (45.5)
Diabetes mellitus	8 (14.5)
Malignancy	6 (10.9)
Cardiovascular disease	4 (7.3)
Baseline sCr, mg/dla	1.3 (0.9, 1.7)
Baseline eGFR, ml/min per 1.73 m2a	45.5 (31.5, 65.8)
Baseline CKD, n (%)	34/52 (65.4)
Reason for kidney biopsy
AKI, n (%)	24 (42.9)
CKD, n (%)	24 (42.9)
Proteinuria, n (%)	10 (17.9)
RTA, n (%)	5 (8.9)
Hematuria, n (%)	4 (7.1)
Timing of kidney biopsy
At diagnosis of SS, n (%)	10/52 (19.2)
After diagnosis of SS, n (%)	42/52 (80.8)
Time from SS diagnosis to biopsy, yrsa	5.5 (1, 13)
Kidney ultrasound findings, n (%)
Normal	37 (66.1)
Kidney stone	7 (12.5)
Medullary sponge kidney	4 (7.1)
Benign cysts	7 (12.5)
Kidney mass	1 (1.8)
Medications, n (%)	35 (62.5)
NSAIDs	8 (14.3)
ACEI/ARBs	14 (25)
Statins	15 (26.8)
PPIs	13 (23.2)

ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; BMI, body mass index; NSAIDs, nonsteroidal anti-inflammatory drugs; PPI, proton-pump inhibitors; RTA, renal tubular acidosis; sCr, serum creatinine; SS, Sjogren syndrome.

^aData are presented as median (interquartile range).

Before biopsy, the median sCr was 1.3 mg/dl (IQR, 0.9–1.7), with a median eGFR of 46 ml/min per 1.73 m² (IQR, 32–66). CKD was already present in 65% of patients. The most common indications for biopsy were AKI (43%), followed by CKD evaluation (43%), proteinuria (18%), and renal tubular acidosis (9%). Notably, 80% underwent biopsy after the diagnosis of SS, with a median interval of 5.5 years (IQR, 1–13).

Laboratory Data at Biopsy

Detailed laboratory parameters are summarized in Table 2. The median sCr at biopsy was 1.6 mg/dl (IQR, 1.3–2.2), with a median eGFR of 36 ml/min per 1.73 m² (IQR, 27–56) and the median 24-hour proteinuria 0.6 g (IQR, 0.2–1.5). Urinalysis demonstrated a median urine pH of 6.2 (IQR, 5.7–6.8), hematuria in 33% of patients, pyuria in 29%, and hypokalemia in 20%.

Table 2.

Laboratory data at kidney biopsy

Parameters	All Cohort (n=56)
Serum creatinine, mg/dla	1.6 (1.3, 2.2)
eGFR, ml/min per 1.73 m2a	36 (27, 56)
24-hour proteinuria, g/24 ha	0.6 (0.2, 1.5)
Urine pHa	6.2 (5.7, 6.8)
Pyuria, n (%)b	16/55 (29.1)
Hematuria, n (%) c
None	37/55 (67.3)
Mild	9/55 (16.4)
Moderate	6/55 (10.9)
Severe	3/55 (5.5)
Urine RTE cell presence, n (%)	2/55 (3.6)
Glycosuria, n (%)	4/55 (7.3)
Urine granular cast, n (%)	4/55 (7.3)
Urine oval fat bodies, n (%)	4/55 (7.3)
Anti-Ro/SSA positivity, n (%)	40/50 (80)
Anti-La/SSB positivity, n (%)	27/50 (54)
RF positivity, n (%)	26/41 (63.4)
IgG, mg/dla	1060 (693, 1510)
C3, mg/dl a	110 (87.3, 125.8)
Low C3 (<60 mg/dl), n (%)	7/52 (13.5)
C4, mg/dl a	20 (13.5, 27)
Low C4 (<15 mg/dl), n (%)	13/53 (24.5)
ESR, mm/ha	49.5 (21.8, 80.3)
CRP, mg/La	7 (3.1, 18.9)
Hemoglobin, g/dla	11.6 (9.8, 13)
Platelets, ×109/La	239 (202, 298)
K + , mmol/L a	4.4 (3.6, 4.7)
Hypokalemia (<3.5 mmol/L), n (%)	11 (19.6)
HCO3−, mmol/La	24 (20, 26)
Anion gap, mmol/La	12 (10, 14)

C3, complement 3; C4, complement 4; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IgG, immunoglobulin G; La/SSB, Sjogren's syndrome antigen B, often linked with La ribonucleoprotein; RF, rheumatoid factor; Ro/SSA, Sjogren's syndrome antigen A, often linked with Ro ribonucleoprotein; RTE, renal tubular epithelial.

^aData are presented as median (interquartile range).

^bDefined as >3 white blood cells/high-power field in men or >10 white blood cells/high-power field in women.

^cMild: 3–10 red blood cells per high-power field, moderate: 11–50 red blood cells/high-power field, severe: ≥51 red blood cells/high-power field.

Serologic findings showed anti-Ro/SSA positivity in 80%, anti-La/SSB positivity in 54%, and rheumatoid factor positivity in 63% of patients. The median serum IgG level was 1060 mg/dl (IQR, 693–1510). The median complement C3 was 110 mg/dl (IQR, 87.3–125.8), with low C3 (<60 mg/dl) in 14%. The median C4 was 20 mg/dl (IQR, 13.5–27), with low C4 (<15 mg/dl) in 25%.

Inflammatory markers were notably elevated: the median erythrocyte sedimentation rate was 49.5 mm/h (IQR, 21.8–80.3) and the median C-reactive protein was 7 mg/L (IQR, 3.1–18.9).

Histologic Features

Kidney biopsy findings are summarized in Table 3. TIN was the predominant lesion, observed in 71% of patients. Glomerular diseases were less frequent, including cryoglobulinemic glomerulonephritis in 11%, membranous nephropathy in 11%, thrombotic microangiopathy in 4%, immune complex–mediated glomerulonephritis in 4%, and membranoproliferative glomerulonephritis in 2%.

Table 3.

Kidney histopathology

Biopsy Findings	All Cohort (n=56)
TIN, n (%)a	40 (71.4)
Cryoglobulinemic GN, n (%)	6 (10.7)
MN, n (%)b	6 (10.7)
TMA, n (%)c	2 (3.6)
ICGN, n (%)d	2 (3.6)
MPGN, n (%) Other histologic findings	1 (1.8)
Global glomerulosclerosis (%)e	17.5 (4.8, 32.3)
Segmental glomerulosclerosis (%)e,f	0 (0, 0) (range 0–42)
Glomerulomegaly, n (%)	1 (1.8)
IFTA, n (%) g
None	13 (23.2)
Mild	23 (41.1)
Moderate	17 (30.4)
Severe	3 (5.4)
Arteriosclerosis, n (%) g
None	15 (26.8)
Mild	18 (32.1)
Moderate	17 (30.4)
Severe	6 (10.7)
Arteriolar hyalinosis, n (%) g
None	42 (75)
Mild	12 (21.4)
Moderate	1 (1.8)
Severe	1 (1.8)
Granuloma, n (%)	1 (1.8)

ICGN, immune complex GN; IFTA, interstitial fibrosis and tubular atrophy; MN, membranous nephropathy; MPGN, membranoproliferative GN; TIN, tubulointerstitial nephritis; TMA, thrombotic microangiopathy.

^aOne with monoclonal gammopathy of renal significance; two with focal segmental glomerulosclerosis (including one with concurrent diabetic nephropathy); three with hypertensive arterionephrosclerosis; and three with acute tubular necrosis (including one with calcium phosphate deposition and one with cryoglobulinemic GN).

^bOne with acute tubular necrosis.

^cOne with focal segmental glomerulosclerosis and hypertensive arterionephrosclerosis.

^dOne with acute tubular necrosis.

^eData are presented as median (interquartile range).

^fWithin the cohort, 86% of individuals (48/56) did not have segmental glomerulosclerosis. Among the 14% of patients (8/56) who had the lesion, the median proportion of affected glomeruli was 12% (interquartile range, 8%–18%).

^gAccording to routine institutional practice, the extent of interstitial fibrosis and tubular atrophy was reported as a percentage and graded as none (<10%), mild (10%–25%), moderate (26%–50%), or severe (>50%). Arteriosclerosis was assessed based on the degree of luminal narrowing, and arteriolar hyalinosis was assessed based on the extent and severity of hyaline thickening of arteriolar walls. Both were reported as none (<10%), mild (10%–25%), moderate (26%–50%), or severe (>50%).

The median global glomerulosclerosis was 17.5% (IQR, 4.8%–32.3%). Eight patients had segmental glomerulosclerosis; the median proportion of affected glomeruli was 12% (IQR, 8%–18%). Interstitial fibrosis and tubular atrophy (IFTA) were present in most patients, graded as mild in 41%, moderate in 30%, and severe in 5%. Arteriosclerosis was more prevalent than arteriolar hyalinosis, with moderate to severe changes observed in 41% and 3.6%, respectively. The vascular findings reported may largely represent nonspecific arteriosclerotic changes rather than vasculopathy directly attributable to SS.

Treatment and Outcomes

Treatment and outcomes are summarized in Table 4. Most patients (84%) received immunosuppressive therapy. Glucocorticoids were the mainstay of treatment, used in 68% of patients—14% received steroids alone, while 54% also received other immunosuppressive agents, such as rituximab. Nonsteroidal immunosuppressive therapy alone was administered to 16% of patients.

Table 4.

Treatment and outcomes

Parameters	All Cohort (n=56)
Without IS therapy, n (%)	9 (16.1)
Steroid uses, n (%)	38 (67.9)
Steroid alone, n (%)	8 (14.3)
Steroid plus other IS agentsa	30 (53.6)
RTX	16 (28.6)
MMF	10 (17.9)
HCQ	5 (8.9)
TAC	1 (1.9)
AZA	4 (7.1)
ABA	1 (1.9)
MTX	1 (1.9)
Initial dose of steroids, mg	45 (40–60)
Maintenance therapy of steroids, n (%)	9 (16.1)
Maintenance dose of steroids, mg	5 (3.75–5)
Duration of steroid therapy, mo	4.5 (2.8–28.5)
Initial intravenous steroid therapy, n (%)	3 (5.4)
Additional IS agents b	9 (16.1)
RTX	3 (5.4)
MMF	7 (12.5)
HCQ	1 (1.9)
Eculizumab	1 (1.9)
Zanubrutinib	1 (1.9)
Daratumumab	1 (1.9)
Lenalidomide	1 (1.9)
RTA treatment, n (%) c	13 (23.2)
Potassium citrate	10 (17.9)
Potassium chloride	2 (3.6)
Sodium bicarbonate	4 (7.1)
Amiloride	1 (1.9)
Spironolactone	1 (1.9)
Short-term outcomes, n (%) d
No recovery	12/54 (22.2)
Partial recovery	6/54 (11.1)
Complete recovery	36/54 (66.7)
Long-term outcomes, n (%) e
Normal kidney functionf	16/54 (29.6)
Stable CKD	19/54 (35.2)
Newly developed CKD	6/54 (11.1)
Progressive CKD	7/54 (13)
ESKD	5/54 (9.3)
Dialysis	5/54 (9.3)
Transplant	3/54 (5.6)
Death	8/54 (14.9)
Long-term composite outcomes, n (%)g	23/54 (42.6)

ABA, abatacept; AZA, azathioprine; HCQ, hydroxychloroquine; IS, immunosuppressive; MMF, mycophenolate mofetil; MTX, methotrexate; RTA, renal tubular acidosis; RTX, rituximab; TAC, tacrolimus.

^aSixteen cases treated with rituximab (two plus plasma exchange, one plus mycophenolate mofetil, one plus mycophenolate mofetil and hydroxychloroquine, one plus mycophenolate mofetil and tacrolimus, one plus azathioprine and abatacept), seven with mycophenolate mofetil, one with methotrexate, three with hydroxychloroquine, one with hydroxychloroquine plus azathioprine, and two with azathioprine.

^bSeven cases treated with mycophenolate mofetil (one plus eculizumab, hydroxychloroquine and plasma exchange, one plus rituximab, Zanubrutinib, daratumumab, and lenalidomide), one with rituximab, and one with rituximab plus plasma exchange.

^cTen cases treated with potassium citrate (two plus sodium bicarbonate), two with potassium chloride (one plus spironolactone and Phos-NaK, the other one plus sodium bicarbonate and amiloride), and one with sodium bicarbonate.

^dShort-term follow-up data were unavailable for two individuals.

^eLong-term follow-up data were unavailable for two individuals.

^fOf the patients who maintained normal kidney function during follow-up, four ultimately died.

^gDefined by newly developed CKD, CKD progression, ESKD, or all-cause mortality.

Short-term renal outcomes within 6 months postbiopsy were available for 54 patients. Complete recovery was achieved in 67%, partial recovery in 11%, and no recovery in 22%. During long-term follow-up (median 3.9 years, IQR, 1.4–7.2), 54 patients had evaluable data. Normal kidney function persisted in 30% (n=16; of them, four died eventually), and stable CKD in 35% (n=19). Twenty-three patients (43%) reached long-term end point: newly developed CKD in 11%, progressive CKD in 13%, ESKD in 9%, and death in 15% of the cohort.

Changes in SCr

Longitudinal changes in sCr during follow-up are presented in Table 5, Supplemental Figure 2, and Supplemental Table 1. Compared with baseline, sCr significantly increased at biopsy (P < 0.001) and 1 month postbiopsy (P = 0.04). Following biopsy and initiation of therapy, sCr progressively declined over time, with significant improvement observed as early as 3 months (P = 0.001) and sustained through 5 years of follow-up.

Table 5.

Linear mixed-effects model for longitudinal serum creatinine change analysis

Timepoint	Effect Estimate (ΔsCr)	95% CI	P Value
Relative to Baseline
At biopsy	+0.36	+0.20 to +0.51	<0.001
After biopsy
1 mo	+0.18	+0.01 to +0.36	0.04
3 mo	+0.09	−0.09 to +0.26	0.33
6 mo	+0.09	−0.09 to +0.26	0.34
1 yr	+0.04	−0.14 to +0.22	0.69
2 yr	+0.03	−0.16 to +0.22	0.74
3 yr	−0.05	−0.25 to +0.16	0.66
4 yr	−0.10	−0.31 to +0.11	0.36
5 yr	−0.02	−0.25 to +0.22	0.89
Relative to at biopsy
After biopsy
1 month	−0.17	−0.35 to −0.00	0.05
3 months	−0.27	−0.44 to −0.11	0.001
6 months	−0.27	−0.44 to −0.10	0.002
1 yr	−0.32	−0.50 to −0.14	0.0004
2 yr	−0.33	−0.51 to −0.14	0.001
3 yr	−0.40	−0.61 to −0.20	0.0001
4 yr	−0.46	−0.67 to −0.25	<0.0001
5 yr	−0.37	−0.61 to −0.14	0.002

CI, confidence interval; sCr, serum creatinine.

Factors Associated with Complete Renal Recovery

Associations between clinicopathologic variables and complete renal recovery are summarized in Table 6 and Supplemental Table 2. In univariable analysis, male sex (OR, 0.10; 95% CI, 0.01 to 0.75; P = 0.02), higher baseline sCr (OR, 0.32; 95% CI, 0.10 to 0.77; P = 0.01), greater 24-hour proteinuria (OR, 0.56; 95% CI, 0.31 to 0.83; P = 0.002), and segmental glomerulosclerosis presence (OR, 0.11; 95% CI, 0.02 to 0.59; P = 0.008) were predictive of lower odds of complete recovery. Patients with baseline sCr ≥2 mg/dl (OR, 0.16; 95% CI, 0.03 to 0.73; P = 0.02) and proteinuria ≥1 g/d (OR, 0.13; 95% CI, 0.03 to 0.44; P = 0.001) demonstrated an even stronger adverse effect. In multivariable analysis, higher baseline sCr (OR, 0.32; 95% CI, 0.09 to 0.81; P = 0.01) and 24-hour proteinuria (OR, 0.68; 95% CI, 0.42 to 0.99; P = 0.04) remained independently associated with poorer recovery, whereas segment glomerulosclerosis demonstrated broadline associations (OR, 0.17; 95% CI, 0.02–1.23; P = 0.08). These findings indicate that both the severity of kidney dysfunction at presentation and the extent of chronic glomerular injury are major determinants of short-term renal recovery.

Table 6.

Factors associated with complete renal recovery

Variables	Univariable Analysis		Multivariable Analysisa
	OR (95% CI)	P Value	OR (95% CI)	P Value
Sex/male	0.10 (0.01 to 0.75)	0.02c
BMI, kg/m2b	1.03 (0.95 to 1.13)	0.46
Age at biopsy, yrb	0.99 (0.96 to 1.03)	0.60
Period between SS diagnosis and kidney biopsy, yrb	0.98 (0.89 to 1.06)	0.55
Extra-glandular manifestations	1.03 (0.24 to 3.96)	0.96
Comorbidities	0.95 (0.30 to 2.98)	0.93
Hypokalemia	0.84 (0.22 to 3.67)	0.81
Baseline sCr, mg/dlb	0.32 (0.10 to 0.77)	0.01c	0.32 (0.09 to 0.81)	0.01c
Baseline sCr ≥2.0 mg/dl	0.16 (0.03 to 0.73)	0.02c
sCr at biopsy, mg/dlb	0.79 (0.46 to 1.35)	0.38
CKD at biopsy	0.29 (0.06 to 1.11)	0.07
Proteinuria at biopsy, g/24 hb	0.56 (0.31 to 0.83)	0.002c	0.68 (0.42 to 0.99)	0.04c
Proteinuria at biopsy ≥1.0 g/24 h	0.13 (0.03 to 0.44)	0.001c
Hemoglobin, g/dlb	1.09 (0.84 to 1.42)	0.53
IgG at biopsyb	1.00 (0.998 to 1.001)	0.36
Low C3 at biopsy	0.71 (0.14 to 4.02)	0.69
Low C4 at biopsy	1.31 (0.35 to 5.57)	0.69
Anti-Ro/SSA positive	1.44 (0.32 to 6.05)	0.62
Anti-La/SSB positive	1.65 (0.50 to 5.71)	0.41
RF positive	0.35 (0.07 to 1.44)	0.15
ESR, mm/hb	0.99 (0.98 to 1.02)	0.77
CRP, mg/Lb	1.02 (0.98 to 1.09)	0.30
ATN	2.13 (0.29 to 43.31)	0.49
TIN	0.87 (0.23 to 2.98)	0.83
Global glomerulosclerosisb	1.02 (0.98 to 1.06)	0.39
Segmental glomerulosclerosis (presence)	0.11 (0.02 to 0.59)	0.008c	0.17 (0.02 to 1.23)	0.08
Moderate/severe IFTA	0.69 (0.21 to 2.31)	0.54
Moderate/severe arteriosclerosis	0.56 (0.18 to 1.79)	0.33
Steroid use	0.87 (0.23 to 2.98)	0.83

ATN, acute tubular necrosis; BMI, body mass index; C3, complement 3; C4, complement 4; CI, confidence interval; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; IFTA, interstitial fibrosis and tubular atrophy; IgG, immunoglobulin G; La/SSB, Sjogren's syndrome antigen B, often linked with La ribonucleoprotein; OR, odds ratio; RF, rheumatoid factor; Ro/SSA, Sjogren's syndrome antigen A, often linked with Ro ribonucleoprotein; sCr, serum creatinine; SS, Sjögren's syndrome; TIN, tubulointerstitial nephritis.

^aCovariates entered into the multivariable model were selected from those associated with the outcome at P < 0.05 in univariable analyses. Given the limited number of events (n=36), a maximum of three covariates was included in the multivariable model, consistent with the conventional rule of approximately one covariate per ten events.

^bPer unit increases in the regressor, indicating that the reported odds ratio corresponds to a one-unit increase in the continuous predictor variable (e.g., 1 mg/dl for serum creatinine).

^cP < 0.05.

The results from two sensitivity analyses excluding patients with unknown baseline sCr or those who also had other renal pathologies occurring concurrently with the dominant lesions known to be associated with SS were essentially unchanged in univariable analysis, with baseline sCr, 24-hour proteinuria, and segmental glomerulosclerosis remaining predictors of poorer recovery (Supplemental Tables 3 and 4).

Factors Associated with Long-Term Composite Outcomes

In SS, renal involvement has been associated with adverse outcomes, including mortality, particularly among patients with CKD and ESKD.^1,3,4 Given the limited number of individual adverse events in our cohort, mortality was initially included as a component of the composite outcome. Unadjusted Cox regression analyses examining predictors of the long-term composite adverse outcome are presented in Table 7 and Supplemental Table 5. Higher baseline sCr was a significant predictor (HR, 2.69; 95% CI, 1.67 to 4.47; P < 0.0001), and patients with baseline sCr ≥2 mg/dl had more than a four-fold increased risk of reaching the composite end point (HR, 4.51; 95% CI, 1.75 to 11.61; P = 0.002). Although proteinuria as a continuous variable did not reach statistical significance (HR, 1.14; 95% CI, 0.93–1.34; P = 0.15), a threshold analysis revealed that patients with proteinuria ≥1 g/24 h had nearly a three-fold increased risk of adverse outcomes (HR, 2.92; 95% CI, 1.26 to 6.76; P = 0.01).

Table 7.

Risk of long-term composite adverse outcomes^a

Variables	HR (95% CI)	P Valueb
Sex/male	1.58 (0.47 to 5.36)	0.46
BMI, kg/m2c	0.99 (0.94 to 1.05)	0.95
Age at biopsy, yrc	1.03 (0.99 to 1.06)	0.09
Period between SS diagnosis and biopsy, yrc	1.06 (1.00 to 1.12)	0.06
Extraglandular manifestations	0.79 (0.28 to 2.24)	0.67
Comorbidities	2.31 (0.90 to 5.91)	0.08
Hypokalemia	1.24 (0.41 to 3.78)	0.69
Baseline sCr, mg/dlc	2.69 (1.67 to 4.47)	<0.0001d
Baseline sCr ≥2 mg/dl	4.51 (1.75 to 11.61)	0.002d
Baseline eGFR, ml/min per 1.73 m2c	0.96 (0.92 to 0.98)	0.0002d
Baseline CKD	2.62 (1.86 to 7.95)	0.04d
sCr at biopsy, mg/dlc	1.63 (1.16 to 2.21)	0.003d
Proteinuria at biopsy, g/24 hc	1.14 (0.93 to 1.34)	0.15
Proteinuria at biopsy ≥1 g/24 h	2.92 (1.26 to 6.76)	0.01d
Hemoglobin, g/dlc	0.84 (0.69 to 1.01)	0.07
IgG at biopsyc	0.99 (0.99 to 1.00)	0.89
Low C3 at biopsy	1.47 (0.48 to 4.50)	0.49
Low C4 at biopsy	0.99 (0.38 to 2.57)	0.98
Anti-Ro/SSA positive	1.55 (0.44 to 5.40)	0.49
Anti-La/SSB positive	0.79 (0.32 to 1.94)	0.60
RF positive	1.89 (0.73 to 4.95)	0.19
ESR, mm/hc	1.00 (0.99 to 1.01)	0.94
CRP, mg/Lc	0.98 (0.94 to 1.01)	0.37
ATN	2.01 (0.46 to 8.81)	0.35
TIN	1.17 (0.45 to 3.03)	0.74
Global glomerulosclerosisc	1.01 (0.98 to 1.03)	0.65
Segmental glomerulosclerosis (presence)	3.52 (1.24 to 9.97)	0.02d
Moderate/severe IFTA	0.99 (0.40 to 2.44)	0.98
Moderate/severe arteriosclerosis	2.56 (1.08 to 6.02)	0.03d
Steroid use	1.25 (0.46 to 3.39)	0.67
Complete renal recovery within 6 mo	0.21 (0.09 to 0.51)	0.001d

ATN, acute tubular necrosis; BMI, body mass index; C3, complement component 3; C4, complement component 4; CI, confidence interval; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HR, hazard ratio; IFTA, interstitial fibrosis and tubular atrophy; IgG, immunoglobulin G; La/SSB, Sjogren's syndrome antigen B, often linked with La ribonucleoprotein; RF, rheumatoid factor; Ro/SSA, Sjogren's syndrome antigen A, often linked with Ro ribonucleoprotein; sCr, serum creatinine; SS, Sjögren syndrome; TIN, tubulointerstitial nephritis.

^aLong-term composite adverse outcomes include newly developed CKD, CKD progression, ESKD, and all-cause-mortality.

^bEffect Wald tests of Cox proportional hazards regression model. Owing to the limited number of events (n=23), a multivariable model for long-term outcomes was not performed.

^cPer unit changes in regressor, indicating that the reported hazard ratio corresponds to a one-unit increase in the continuous predictor variable (e.g., 1 mg/dl for serum creatinine).

^dP < 0.05.

Several histopathologic parameters also showed prognostic relevance, including the presence of segmental glomerulosclerosis (HR, 3.52; 95% CI, 1.24 to 9.97; P = 0.02) and moderate/severe arteriosclerosis (HR, 2.56; 95% CI, 1.08 to 6.02; P = 0.03).

Comorbidities, age at biopsy, and the interval between SS diagnosis and biopsy demonstrated borderline associations (P = 0.08, 0.09, and 0.06, respectively), suggesting potential but nonsignificant trends toward increased long-term risk. Although hemoglobin showed trends toward lower risk of adverse outcomes (P = 0.07), this did not reach statistical significance. Other variables, including use of steroids, their associations with the adverse outcomes were not observed.

In the subcohort excluding patients who also had other renal pathologies occurring concurrently with the dominant lesions known to be associated with SS, baseline sCr and severe arteriosclerosis were also associated with adverse outcomes (Supplemental Table 6). Additional sensitivity analyses excluding mortality alone, and excluding both mortality and patients with unknown baseline sCr, yielded similar results, with baseline sCr, 24-hour proteinuria, and segmental glomerulosclerosis remaining predictors of long-term adverse outcomes (Supplemental Tables 7 and 8). Hemoglobin level and the interval between SS diagnosis and biopsy showed stronger associations in the analysis excluding mortality (Supplemental Table 7).

Kaplan–Meier analysis demonstrated a significantly lower composite outcome–free survival in patients with baseline sCr ≥2 mg/dl compared with those with levels <2 mg/dl, both in the overall cohort and in the subcohort excluding mortality (P = 0.001 and 0.03, respectively), whereas no associations were observed for kidney lesion category (TIN vs glomerulonephritis) or steroid use (Figure 1 and Supplemental Figure 3).

Figure 1.

Kaplan–Meier analysis of long-term composite outcome. Long-term composite adverse outcomes include newly developed CKD, CKD progression, ESKD, and all-cause-mortality. (A) Composite outcome-free survival in the overall cohort. (B) Association between baseline sCr and composite outcome-free survival (P = 0.001). (C) Association between kidney lesion and composite outcome-free survival (P = 0.95). (D) Association between steroid use and composite outcome-free survival (P = 0.66). sCr, serum creatinine; TIN, tubulointerstitial nephritis.

Discussion

This study provides a biopsy-confirmed characterization of SS-related renal involvement and identifies clinicopathologic factors associated with both short-term renal recovery and long-term outcomes. Our findings not only reinforce established knowledge from prior cohorts but also refine prognostic understanding, particularly regarding the effect of chronic glomerular and vascular lesions.

The demographic profile of this cohort, with a median age in the mid-50s and predominantly female patients, is consistent with previous studies.^5,13,19 The high rate of extraglandular manifestations mirrors the systemic disease burden described previously.^4,14 A striking feature of this cohort was the extent of renal impairment at presentation—over 60% had established CKD before biopsy, and the median interval between SS diagnosis and biopsy exceeded 5 years—emphasizing the often slow, insidious, and underrecognized progression of renal involvement in SS. These observations are concordant with earlier reports that renal disease frequently manifests several years after the initial sicca symptoms and may be clinically silent until significant dysfunction has developed.¹⁴

The observed frequencies of renal tubular acidosis and hypokalemia were lower than those reported in several Asian cohorts,²⁰ likely because our study included only SS patients who underwent kidney biopsy and excluded many such cases that typically do not require biopsy. Serologic findings such as hypocomplementemia, elevated erythrocyte sedimentation rate, and C-reactive protein in this cohort highlight a mixed pattern of autoimmunity and systemic inflammation, although these markers were not associated with recovery or long-term outcomes.

Consistent with prior reports,^5,20 TIN was the predominant renal lesion, identified in nearly three quarters of patients. Although glomerular diseases were less common, a diverse range of immune-mediated lesions was observed, including cryoglobulinemic glomerulonephritis, membranous nephropathy, and membranoproliferative glomerulonephritis. The overall frequency of immune complex glomerulonephritis was slightly lower than in prior series,^15,20 which may reflect differences in population characteristics or biopsy referral patterns. Notably, the coexistence of both TIN and glomerular lesions across the cohort emphasizes the broad immunologic footprint of SS and supports the premise that biopsy remains essential for accurate characterization, as clinical findings alone do not reliably differentiate these entities. Chronic histologic injury was notable, with substantial rates of glomerulosclerosis, IFTA, and arteriosclerosis, even when presenting with ostensibly acute renal dysfunction (e.g., AKI). The presence of chronicity underscores the likelihood that renal inflammation in SS often precedes biopsy by years and that subclinical disease progression is common.

In SS-related renal disease, immunosuppressive therapies may be used in selected patients to suppress inflammation and limit progression to fibrosis.² However, their effect on long-term renal outcomes remains uncertain. In this cohort, most patients received immunosuppressive therapy, predominantly glucocorticoids, reflecting standard practice for both TIN and immune complex–mediated glomerular lesions. Short-term outcomes were favorable, with two thirds of patients achieving complete renal recovery. The longitudinal trend in sCr demonstrated early and sustained improvement after biopsy and treatment, with stabilization of renal function through the 5-year follow-up period. These findings parallel reports that appropriately treated SS-related renal disease—particularly TIN—has substantial potential for recovery when chronic injury is limited.^5,7,10 However, the benefit associated with steroid use was not observed in this cohort, which may reflect confounding by indication, variability in dosing protocols, or the predominance of slowly evolving TIN rather than newly developed inflammatory infiltrates. Other immunosuppressive agents, including mycophenolate mofetil and rituximab, were also used in this cohort. Evidence for mycophenolate mofetil in SS-related TIN is mixed: a small case series reported meaningful improvement in kidney function,²¹ whereas other studies did not demonstrate clear clinical benefit.^3,22 By contrast, rituximab in SS has traditionally been used to address refractory sicca symptoms rather than kidney disease.⁷ However, in SS-associated glomerular disease—particularly immune complex and cryoglobulinemic phenotypes—patients often require combination regimens involving corticosteroids, mycophenolate mofetil, and retuximab.^3,7,10 A large multicenter study of noninfectious cryoglobulinemic vasculitis further showed that rituximab combined with corticosteroids was superior to corticosteroid monotherapy or corticosteroid plus an alkylating agent, supporting a potential role for B-cell–directed therapy in select SS-related renal phenotypes.²³ Notably, four patients in our cohort also received plasma exchange. Plasmapheresis is generally reserved for severe or refractory autoimmune manifestations, including life-threatening vasculitis, thrombotic microangiopathy, or pulmonary involvement, and its role in routine SS-related kidney disease remains limited.¹⁰ Overall, these observations underscore the heterogeneity of treatment strategies in SS-related kidney disease and highlight the need for more granular stratification of immunosuppressive regimens—particularly in distinguishing TIN from glomerular disease—to determine whether specific therapeutic combinations meaningfully improve short-term and long-term renal outcomes.

Although short-term renal recovery was generally favorable, adverse long-term outcomes were not uncommon, with 43% reaching the composite end point of newly developed CKD, CKD progression, ESKD, or death. The strong predictive value of baseline kidney function underscores the critical effect of disease severity at first kidney evaluation. Baseline sCr, particularly ≥2 mg/dl, repeatedly emerged as powerful prognostic markers, consistent with prior work showing that delayed recognition of renal involvement in SS contributes to progression.⁴ Proteinuria (≥1 g/d) was also associated with both short-term non-recovery and long-term adverse outcomes, suggesting that proteinuria serves as a surrogate for glomerular involvement, more advanced tubulointerstitial injury, or both. The association between segmental glomerulosclerosis and poorer outcomes further supports the role of chronic glomerular damage as a key structural constraint on renal recovery, suggesting that even focal chronic injury carries substantial prognostic weight. The finding that arteriosclerosis predicted long-term adverse outcomes highlights the importance of renal vascular disease, which may reflect both autoimmune and traditional cardiovascular risk factors. Coexistence of both active and chronic structural injury—particularly segmental sclerosis and arteriosclerosis—also supports the concept that SS-related kidney disease may progress silently for years before clinical detection. By contrast, the presence of TIN itself was not associated with worse long-term outcomes, supporting prior evidence that TIN, when recognized and treated before substantial chronic damage accrues, often follows a favorable trajectory.¹⁰ Interestingly, neither anti-Ro/SSA, anti-La/SSB, low complement levels, extraglandular manifestations, nor steroid therapy demonstrated significant associations with outcomes, reinforcing that renal prognosis in SS is driven more by the severity of kidney involvement itself than by systemic autoimmune activity.

This study provides several actionable insights. Early detection and intervention—ideally before CKD is established—may alter the trajectory of renal decline. These findings argue for a lower threshold to investigate renal abnormalities in SS and highlight a need for standardized treatment algorithms. Therefore, careful monitoring for renal involvement in SS is warranted, and kidney biopsy should be promptly considered when renal dysfunction develops, as it enables differentiation of histologic lesions that differ fundamentally in underlying mechanism, therapeutic implications, and prognosis.

Several limitations should be considered when interpreting these findings. First, as a single-center study conducted at a tertiary referral hospital, the findings may be influenced by referral bias and may not be fully generalizable to patients managed in nontertiary settings. The relatively homogeneous ethnic composition of the study population also limited the applicability of the results to more ethnically diverse populations. Second, this was a retrospective study based on clinically indicated kidney biopsies, which introduces inherent selection bias; patients with milder or transient renal abnormalities were unlikely to undergo biopsy and therefore underrepresented. Although this cohort represents one of the larger biopsy-confirmed series in SS, the absolute sample size and number of events limited statistical power for subgroup and multivariable analyses. In addition, treatment strategies were not standardized and may be affected by physician's preference, disease severity, and temporal practice patterns, making it difficult to isolate the effects of individual therapies on renal recovery. These limitations underscore the need for prospective, multicenter studies with standardized assessments to better define prognostic determinants and optimize management strategies for SS-related renal involvement.

This study adds a contemporary, biopsy-confirmed perspective on SS-related renal involvement and highlights the prognostic relevance of chronic glomerular and vascular injury. Early identification of renal involvement, timely biopsy, and aggressive management of proteinuria and chronic structural injury are necessary to improve long-term outcomes. These findings also highlight the heterogeneous nature of SS-related renal involvement and provide practical markers that clinicians can use to guide prognosis, treatment decisions, and follow-up intensity. Further work is still needed to define optimal therapy and to develop biomarkers that distinguish reversible inflammation from irreversible chronic injury.

Disclosures

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/KN9/B555.

Author Contributions

Conceptualization: Wisit Cheungpasitporn, Jing Miao.

Data curation: Jing Miao, Charat Thongprayoon.

Formal analysis: Jing Miao.

Investigation: Jing Miao.

Methodology: Jing Miao.

Supervision: Jing Miao.

Validation: Alessia Buglioni, Wisit Cheungpasitporn, Fernando C. Fervenza, Jing Miao, Charat Thongprayoon, Ladan Zand.

Writing – original draft: Jing Miao.

Writing – review & editing: Alessia Buglioni, Wisit Cheungpasitporn, Fernando C. Fervenza, Jing Miao, Charat Thongprayoon, Ladan Zand.

Funding

None.

Declarative Statements

This study includes clinical experimentation and received Institutional Review Board or Ethics Committee approval. The need to obtain informed patient consent was waived.

Data Availability Statements

Original data generated for the study will be made available upon reasonable request to the corresponding author. Data Type: Observational Data.

Supplemental Material

This article contains the following supplemental material online at http://links.lww.com/KN9/B556.

Supplemental Table 1. SCr during follow-up

Supplemental Table 2. Clinicopathologic characteristics of patients who developed long-term composite outcomes versus those without.

Supplemental Table 3. Sensitivity analysis: factors associated with complete renal recovery in the subcohort excluding patients with unknown baseline sCr.

Supplemental Table 4. Sensitivity analysis: factors associated with complete renal recovery in the subcohort excluding patients who also had other renal pathologies occurring concurrently with the dominant lesions known to be associated with SS.

Supplemental Table 5. Clinicopathologic characteristics of patients who achieved complete renal recovery versus those without.

Supplemental Table 6. Sensitivity analysis: risk of long-term composite adverse outcomes in the subcohort excluding patients who also had other renal pathologies occurring concurrently with the dominant lesions known to be associated with SS.

Supplemental Table 7. Sensitivity analysis: risk of long-term composite adverse outcomes in the subcohort excluding mortality.

Supplemental Table 8. Sensitivity analysis: risk of long-term composite adverse outcomes in the subcohort excluding mortality and those with unknown baseline sCr.

Supplemental Figure 1. Patient recruitment.

Supplemental Figure 2. Longitudinal changes in sCr during follow-up

Supplemental Figure 3. Sensitivity analysis: Kaplan–Meier analysis of long-term composite outcome excluding mortality.