Kembara Xtra - Medicine - Lupus Nephritis

​Kembara Xtra - Medicine - Lupus Nephritis 
Renal disease in systemic lupus erythematosus (SLE) patients
 The American College of Rheumatology (ACR) criteria include persistent proteinuria >500 mg/day or 3 on a dipstick and/or the presence of cellular casts; alternatively, spot urine protein-to-creatinine ratio (UPCR) >0.5 and "active urinary sediment" (>5 RBC/HPF, >5 WBC/HPF in the absence of infection, or cellular casts—RBC or WBC casts) are acceptable.Clinical signs and symptoms predominantly brought on by glomerular disease mediated by immune complexes. Vascular and tubulointerstitial involvement frequently coexist. Clinical symptoms, abnormalities in the urine, autoantibodies, and a kidney biopsy are used to make the diagnosis.
Treatment and prognosis are influenced by the histologic class, according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS).
Early diagnosis enhances kidney results.

Epidemiology 

SLE is most common in people between the ages of 15 and 45. Between 25 and 30 years old is the average age of diagnosis.
 Female is more prevalent than male (10:1)
Lupus nephritis (LN), which is more severe in youth and men and less severe in older adults, affects both sexes equally once SLE starts and is more prevalent in African American and Asian populations.
Incidence
● SLE: 1 to 22/100,000
Up to 60% of SLE patients eventually develop LN, while 25-50% of SLE patients first present with nephritis.
Pediatric Considerations LN is more prevalent and severe in children: 60–80% of kids develop it at the beginning of SLE or shortly after.
Prevalence
SLE: 7 to 159/100,000

Pathophysiology and Etiology 
Glomeruli, tubules, the interstitium, and the vasculature are all damaged by immune complex-mediated inflammation.
Reduced glomerular filtration rate (GFR) is brought on by varying degrees of mesangial growth, crescent formation, and fibrinoid necrosis in the glomeruli.
Sclerosis and glomerular loss are consequences of persistent inflammation that persists.
Reduced renal function results from tubulointerstitial damage (edema, inflammatory cell infiltrate acutely; chronic tubular atrophy) with or without tubular basement membrane immune complex deposition.
Immune complex deposition and non-inflammatory necrosis in arterioles are two examples of vascular lesions.
SLE is a complex illness with multigenic inheritance, although its specific cause is yet unknown.
Dysregulated apoptosis is influenced by defective T-cell autoregulation and polyclonal B-cell hyperactivity.
Nuclear antigen self-tolerance is inhibited by poor clearance of apoptotic cells.
Autoantibodies against DNA, C1q, actin, and other nuclear components form.
Activation of complement, inflammatory response, and tissue damage are brought on by the deposition of circulating immune complexes or autoantibodies that bind to regional nuclear antigens.
 There is significant variation in the severity of LN due to interactions between genetic, hormonal, and environmental variables.
Genetics: Clustering in families, polygenic inheritance, and identical twins with a 25% concordance rate
 The interaction of genes with overall SLE risk and genes specific to the kidney and epigenetic alterations
RISK ELEMENTS
Younger age, African American or Hispanic ethnicity, higher number of ACR SLE criteria, longer duration of the disease, hypertension, lower socioeconomic position, ancestry of SLE, anti-dsDNA antibodies, and low albumin to globulin ratio

Accompanying Conditions 

Other organ systems are frequently affected by SLE.


Examine the patient's history for SLE symptoms or indications. Frequent symptoms of active nephritis include fever, peripheral edema, nausea, vomiting, headaches, and vertigo.

Clinical examination: signs of synovitis, fever, hypertension, pleural/pericardial rub (serositis), skin rash, edema, arthritis, alopecia, oral ulcers, and skin rash.
DISTINCTIVE DIAGNOSIS
Primary glomerular disease Secondary renal involvement in various systemic diseases such polyarteritis nodosa, antiglomerular basement membrane disease, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Henoch-Schönlein purpura (HSP), and viral infections

Laboratory Results 

The gold standard for identifying and categorizing LN is renal biopsy.
Nephritis is indicated by active urine sediment.
Low C3, C4, and CH50 complement levels, along with autoantibodies, support LN.
Initial examinations (lab, imaging)
Regular serologic indicators of SLE include antinuclear antibody (ANA), anti-dsDNA, anti-Ro, anti-La, anti-RNP, anti-Sm, antiphospholipid (aPL) antibody, C3, C4, CH50, CBC with differential, and C-reactive protein (CRP).
Follow-Up Tests & Special Considerations for Renal Ultrasound
Check for hematuria and proteinuria in the urine every three months, and check for C3, C4, anti-dsDNA, serum albumin, and creatinine in the blood.
 Manage patients in accordance with National Kidney Foundation recommendations for treating chronic kidney disease (CKD): https://kdigo.org/guidelines/ckd-evaluation-andmanagement/.
The biomarker panel of lipocalin-like prostaglandin synthase (LPGDS), ceruloplasmin, and 1-acid glycoprotein (AGP) corresponds with disease activity in children.
pregnant women's issues
Renal function declines throughout pregnancy. At-baseline renal impairment, active illness, hypertension, and proteinuria are risk factors.
High serum creatinine levels, significant proteinuria, hypertension, and anticardiolipin antibodies are risk factors for miscarriage.
Mycophenolate mofetil (MMF) and renin-angiotensin system blockage are not recommended during pregnancy; however, azathioprine is safe to use and falls within FDA pregnancy category D.
Interpretation of Tests
Regarding immunofluorescence microscopy for renal biopsy:
Immune complex deposits with the "full house" of C1q, IgG, IgA, IgM, and IgM are strongly indicative of LN.
● The histologic classification of the Revised ISN/RPS 2003 directs therapy choices: https://jasn.asnjournals.org/content/jnephrol/15/2/241.full.pdf? with-ds=yes. 2008 categorization revisions are awaiting approval.
LN is divided into six classes: purely mesangial (class I-minimal mesangial LN and class II-mesangial proliferative LN), focal proliferative LN with 50% or more glomeruli (class III), diffuse proliferative LN with 50% or more glomeruli (class IV), membranous LN (class V), and advanced sclerosis LN (class VI); subdivisions for activity (A) and chronicity (
Class III and IV focal and diffuse proliferative LN are frequent and most likely to proceed to ESRD.


Management 
Keep an eye on your bone density; improve your calcium and vitamin D consumption, BMI, and frequent exercise.
Eat a low-sodium diet and stay out of the sun or ultraviolet radiation.
MEDICATION
Note: None of the other drugs listed below have been FDA-approved for LN in addition to methylprednisolone, prednisone, and belimumab.
Initial Line
Class I+II LN: no special treatment. Maintain UPCR; blockage of the renin-angiotensin system (ACEI or ARB) to control blood pressure and proteinuria (e.g., lisinopril 5–40 mg/day PO, losartan 25–100 mg/day PO)
 Class III or IV [V] proliferative LN
Principles guiding care:
- Patients with baseline nephrotic range proteinuria may need a further 6 to 12 months. - Avoid delays; proteinuria reduction of at least 25% by 3 months, 50% by 6 months, and UPCR target 0.5 to 0.7 by 12 months are the minimum goals.
Steroids plus an immunosuppressive drug for induction (high-dose steroids may be adequate for mild class III):
- Glucocorticoids: oral prednisone (0.3 to 0.5 mg/kg/day) for up to 4 weeks, reduced to 7.5 mg/day by 3 to 6 months, followed by methylprednisolone pulses (total dose 500 to 2,500 mg). AND
- Cyclophosphamide: 6 treatments of low dose IV cyclophosphamide (0.5 g every 2 weeks). OR - MMF: 2 to 3 g/day for 6 months is the suggested dose. MMF has less adverse effects while still being as effective as cyclophosphamide in inducing remission.
- For patients with nephrotic range proteinuria, MMF (target dose 1 to 2 g/day) combined with calcineurin inhibitor (CNI) is an alternative.
– For individuals at high risk for kidney failure, high-dose IV cyclophosphamide (0.50 to 0.75 g/m2) given monthly for six doses is an alternative.
– Tacrolimus, MMF, and glucocorticoids were found to be superior than cyclophosphamide and glucocorticoids in the Asian population.


Maintenance treatments include: - Glucocorticoids: low-dose oral prednisone (2.5 to 5.0 mg/day) AND - MMF 1 to 2 g/day, especially if used as an initial treatment; OR azathioprine: (2) 2 mg/kg/day PO[A]
- The ideal period is unknown, but gradual withdrawal (starting with glucocorticoids) after at least 3 to 5 years of treatment results in a full clinical response.
Pure class V LN: favorable outlook, no standard of care
- Oral prednisone (20 mg/day reduced to 5 mg/day after 3 months) in combination with MMF (2 to 3 g/day) and an IV methylprednisolone pulse (500 to 2,500 mg)
- CNI (particularly tacrolimus) and IV cyclophosphamide, either as a monotherapy or in combination with MMF, are options for patients with nephrotic range proteinuria.
Belimumab has been proven to improve outcomes when used in conjunction with routine initial and subsequent therapy as 10 mg/kg IV every two weeks for three doses, followed by maintenance dosage every four weeks for a total of 100 weeks.
All LN, regardless of class, unless contraindicated; maximum daily dose not to exceed 5 mg/kg/day; modify for GFR with routine ophthalmologic follow-up
Next Line
Refractory LN: Treatment that fails to work after three to four months. Recommend multitarget treatment. Alternately, switch cyclophosphamide for MMF, rituximab for CNI or belimumab for IVIG, stem cell transplantation for IVIG, and plasma exchange for plasma.


Nephrology referral consultations for both initial management and relapses

Further Therapies 

RAS blocking is advantageous due to its impact on proteinuria and hypertension; review of vaccinations; and treatment of hypertension and other modifiable cardiovascular risk factors.
Low-dose aspirin for an aPL profile with high risk

Surgical Procedures: Recurrent LN ranges between 0% and 30%; graft loss owing to recurrence is uncommon. Renal transplant for ESRD when appropriate. Patient and graft survival rates similar to non-SLE patients.


Admission 

Criteria for admission and initial stabilization
Severe extrarenal manifestation, uncontrolled hypertension, acute kidney injury, nephrology input for care, and renal biopsy



Patient Monitoring: UPCR, urine microscopy, serum albumin, creatinine, antibody titers, C3, C4, and blood pressure at least every three months for the first two to three years, then every six to twelve months if there is no sign of disease activity. Hydration in accordance with an immunosuppressive regimen, CBC, and LFT

Salt-reduced diet. eGFR less than 60 mL

Patient education, adherence to medication, and self-monitoring for recurrence are all important.


10-year survival rates of 88% and 94% were seen in SLE patients with and without renal disease, respectively.
Relapse rates are at 35%. Within 10 years, 10-20% of individuals advance to ESRD.
5-year renal survival of class IV LN increased from 30% to >80% in the last two decades.
The best prognostic factor is proteinuria remission.
Other factors include starting treatment within three months of the diagnosis, normal creatinine, Caucasian race, and modest baseline proteinuria.
Crescententic diffuse proliferative LN, increased activity/chronicity index, APOL 1 risk alleles, African American race, lower socioeconomic level, poor response to treatment, high creatinine at baseline, uncontrolled hypertension, and relapse are all associated with a bad prognosis.

Complications Vascular thromboses with aPL antibodies Risks of immunosuppressive therapy: infections, malignancies, GI upset, primary amenorrhea with cyclophosphamide, teratogenic effect of MMF About 10–20% of patients develop ESRD necessitating dialysis/kidney transplantation.