Lupus nephritis and kidney transplantation: A narrative review of patient and graft outcomes

Table 1 International Society of Nephrology/Renal Pathology Society Classification of Lupus Nephritis (2018 revision) and its clinical implications

Class	Key histological features	2018 revision updates	Clinical implications
Class I	Minimal mesangial LN; immune complex deposition confined to mesangium	Emphasis on subtle mesangial deposits	Usually asymptomatic; normal urinalysis; excellent prognosis
Class II	Mesangial proliferative LN; mesangial hypercellularity and matrix expansion	Clarified distinction between mesangial hypercellularity vs deposits only	Mild disease; hematuria/proteinuria; generally favorable outcomes
Class III	Focal LN; < 50% of glomeruli affected with segmental/global endocapillary or extracapillary proliferation	Activity/chronicity indices introduced; segmental vs global lesions highlighted	Variable course; risk of progression; requires immunosuppression
Class IV	Diffuse LN; ≥ 50% of glomeruli affected; extensive endocapillary/extracapillary proliferation	Activity/chronicity scoring; segmental vs global lesions emphasized	Most severe and common form; high risk of renal failure; aggressive therapy needed
Class V	Membranous LN; diffuse thickening of glomerular capillary walls due to subepithelial deposits	Recognition of mixed class V + III/IV lesions	Presents with nephrotic syndrome; risk of progression if mixed lesions present
Class VI	Advanced sclerosing LN; ≥ 90% of glomeruli globally sclerosed	Highlighted as irreversible stage	Poor prognosis; progression to ESKD; supportive care or renal replacement therapy

LN: Lupus nephritis; ESKD: End-stage kidney disease.

Table 2 Markers of disease activity in lupus nephritis

Marker	Type	Significance for disease activity	Clinical implications
Anti-dsDNA antibodies	Serological	Correlate with disease activity and renal involvement	Rising titers often precede LN flares; useful for monitoring
Serum creatinine	Clinical	Reflects renal function and progression	Elevated levels indicate impaired kidney function and possible ESKD
Complement C3 and C4	Serological	Low levels indicate complement consumption due to active immune complex disease	Hypocomplementemia is a marker of active LN and flare risk
Anti-C1q antibodies	Serological	Associated with immune complex deposition and LN activity	Predictive of renal involvement and poor prognosis
Anti-chromatin antibodies	Serological	Linked to active nephritis and systemic disease	May serve as adjunct marker for LN activity
Anti-Sm antibodies	Serological	Specific for SLE, associated with severe disease	Presence indicates higher risk of multi-organ involvement
Anti-ribosomal P autoantibodies	Serological	Associated with neuropsychiatric lupus and systemic activity	May complicate LN with extra-renal manifestations
Serum IFN-I	Serological	Reflects immune dysregulation and ongoing inflammation	Elevated levels linked to refractory disease and poor outcomes
MCP-1	Urinary	Marker of renal inflammation and monocyte recruitment	Elevated levels predict LN activity and progression
BAFF	Urinary	Promotes B-cell survival and autoantibody production	High levels associated with LN activity and relapse risk
MMP-7	Urinary	Reflects tissue remodeling and renal injury	Elevated levels linked to chronic damage and poor prognosis
IgG, IgA, IgM deposits	Histological (biopsy)	Indicate immune complex-mediated glomerular injury	Presence confirms LN diagnosis and activity
C1q, C3 deposits	Histological (biopsy)	Evidence of complement activation in renal tissue	Associated with active LN and severity of disease
Tissue ANA	Histological (biopsy)	Nuclear antigen deposition in kidney tissue	Supports diagnosis of LN and immune-mediated injury
Extraglomerular immune deposits	Histological (biopsy)	Indicate widespread immune complex deposition	Associated with severe LN and poor prognosis
Endothelial tubular reticulum inclusion bodies	Histological (biopsy)	Reflect interferon activity and immune activation	Linked to active LN and systemic disease burden

Anti-dsDNA: Anti-double-stranded deoxyribonucleic acid; LN: Lupus nephritis; ESKD: End-stage kidney disease; anti-C1q: Anti-complement component 1q; anti-Sm: Anti-Smith; SLE: Systemic lupus erythematosus; IFN-I: Type I interferon; MCP-1: Monocyte chemoattractant protein-1; BAFF: B-cell activating factor; MMP-7: Matrix metalloproteinase-7; Ig: Immunoglobulin; C3: Complement component 3; C1q: Complement component 1q; ANA: Antinuclear antibody.

Table 3 Determinants and key indicators for transplant matching in lupus nephritis and its clinical implications

Indicator	Type	Significance	Implications in LN
HLA matching	Genetic/immunological	Cornerstone of transplant success; closer matching reduces rejection and improves graft survival	Mismatches, especially at HLA-DR and HLA-C loci, increase rejection risk; careful prioritization of typing is critical
PRA and DSA	Immunological	Elevated PRA and DSAs indicate heightened sensitization from transfusions, pregnancies, or disease activity	High titers are strongly associated with graft rejection, including hyperacute rejection; pre-transplant interventions (plasma exchange, IVIG, rituximab, proteasome inhibitors) can reduce risk
Disease quiescence and serological activity	Clinical/serological	Active disease increases recurrence and systemic complications	Anti-dsDNA, complement (C3, C4), and anti-C1q must be monitored to confirm remission before transplantation
CDC-XM	Laboratory test	Detects HLA and non-HLA antibodies but is prone to false positives in autoimmune patients	May misinterpret sensitization due to non-specific binding, prozone effect, incomplete typing, or non-HLA antibodies
FCXM	Laboratory test	More sensitive than CDC; detects pre-formed antibodies against donor lymphocytes	Preferred method; pronase digestion enhances the accuracy of B-cell cross-matching
High-Resolution HLA typing (sequencing-based)	Genetic/Laboratory	Provides precise identification of donor-specific HLA antibodies	Improves matching accuracy; limited feasibility in deceased donor transplantation due to time constraints
Non-HLA Antibodies (MICA, AT1R, poikilodulin, myocardin, microtubulin, collagen)	Immunological	Account for approximately 38% of graft losses vs 18% from HLA mismatches	Contribute to fibrosis, immune modulation, and graft failure; must be considered in risk stratification
Crossmatch testing (general)	Laboratory test	Negative crossmatch essential to prevent hyperacute rejection	Provides safeguard against unforeseen immunological incompatibilities in autoimmune background
Comorbid conditions and systemic involvement	Clinical	LN often coexists with cardiovascular disease, neuropsychiatric lupus, or vasculitis	Extra-renal involvement must be controlled before transplantation to avoid poor outcomes
Donor characteristics	Clinical	Donor age, health, and source (living vs deceased) influence graft survival	Living donor transplantation is preferred; it allows better timing, reduces dialysis exposure, and improves prognosis
Immunological risk stratification	Clinical/immunological	Helps tailor immunosuppressive regimens post-transplant	LN recipients require vigilant balancing to prevent rejection and recurrence while minimizing infection/malignancy risks

LN: Lupus nephritis; HLA: Human Leukocyte Antigen; PRA: Panel reactive antibody; DSAs: Donor-specific antibodies; IVIG: Intravenous immunoglobulin; Anti-dsDNA: Anti-double-stranded deoxyribonucleic acid; anti-C1q: Anti-complement component 1q; C3: Complement component 3; C4: Complement component 4; CDC-XM: Complement-dependent cytotoxicity crossmatch; FCXM: Flow cytometry crossmatch; CDC: Complement-dependent cytotoxicity; MICA: Major histocompatibility complex class I chain-related molecule A; AT1R: Angiotensin II type 1 receptor.