Lupus Nephritis

I. What every physician needs to know.

Lupus nephritis is a common complication of Systemic Lupus Erythematosus (SLE). Upwards of 50-60% of all lupus patients will develop renal involvement and if not recognized and treated promptly it can lead to end stage renal disease requiring dialysis. It is important to keep in mind that patients with lupus nephritis may present asymptomatically and therefore physicians must keep renal issues in the forefront when evaluating a lupus patient.

Lupus nephritis occurs due to immune complex deposition in any or all renal compartments, including the glomeruli, tubules, and interstitium. IgG is the most prevalent antibody found but IgM, and IgA can be seen as well. These auto-antibodies cause activation of both the classic and alternative complement pathways and so C1, C3 and properdin may be found on biopsy.

Lupus nephritis is often an insidious manifestation of SLE. While the hallmark of disease is proteinuria, patients will often not report symptoms such as nocturia, foaming of the urine and lower extremity edema until they are in renal failure or nephrotic. Therefore, regular screening of the serum creatinine and urine for protein is imperative.

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Concerns for lupus nephritis are raised when there is greater than 0.5g of protein in a 24hour urine collection or greater than 3+ protein on a urine dipstick. Often times there will be also be concomitant hematuria or pyuria (>5RBC or WBC/ high power field) on urinalysis (UA) in the absence of infection as well as red and white cell casts. Clinicians must remember that the UA and urine protein collections are the key to diagnosis and the results must be interpreted quickly.

Renal biopsy is essential to determine the class of lupus nephritis. Lupus nephritis was initially categorized by the World Health Organization’s classification criteria, however this system was revised into the International Society of Nephrology and Renal Pathology Society (ISN/RPS) classification criteria which consists of the following classes:

Class I: Minimal mesangial lupus nephritis

Class II: Mesangial proliferative lupus nephritis

Class III: Focal lupus nephritis

Class IV: Diffuse lupus nephritis

Class V: Membranous lupus nephritis

Class VI: Advanced sclerotic lupus nephritis

Class III and IV are further stratified into active versus chronic disease activity and Class IV is further categorized into segmental versus global glomerular lesions. Knowing the class of lupus nephritis is important, since certain classes have prognostic implications. For example, classes III and IV tend to have a worse prognosis and a higher rate of progressing to renal failure than classes II and V. Also patients with more evidence of chronicity may respond less to treatment.

II. Diagnostic Confirmation: Are you sure your patient has Lupus Nephritis?

The only way to be certain of the diagnosis of lupus nephritis is by performing a renal biopsy. Clinical suspicion should be raised in SLE patients with evidence of proteinuria and/or active urinary sediment with decreased serum complement levels (C3 and C4) and high levels of anti-double stranded DNA antibodies.

A. History Part I: Pattern Recognition:

In the outpatient setting lupus nephritis patients can be asymptomatic, however when admitted for the disease patients usually present with signs and symptoms of renal failure. Patients may present with elevated serum creatinine, hypertension, and proteinuria. UA may show evidence of pyuria, red cell casts, or white cell casts. In addition, patients may also have evidence of nephrotic syndrome with lower extremity and peri-orbital edema as well as decreased serum albumin. See SLE section for diagnostic criteria for lupus.

B. History Part 2: Prevalence:

Lupus nephritis is most common in the first 2 years of onset of SLE, and its frequency decreases after 5 years with the disease. 50% to 60% of adults and 30% to 80% of children with lupus develop lupus nephritis. Racial and ethnic minority populations have a greater prevalence and worse disease-prognosis where they more often progress to end stage renal disease.

C. History Part 3: Competing diagnoses that can mimic Lupus Nephritis.

Other diagnoses on the differential include (and the ways to distinguish them from lupus nephritis are):

Cryoglobulinemia. To distinguish from lupus nephritis, send serum cryoglobulins, a hepatitis panel, and a SPEP. As in SLE nephritis, complement levels are often low, as cryoglobulins fix complement; however, cryoglobulinemia can present with other signs such as palpable purpura and neuropathy.

ANCA-associated vasculitis. To distinguish from SLE nephritis, send anti-myeloperoxidase and anti-proteinase-3 antibodies. Serum complements are often normal. This disease is pauci-immune on biopsy, can present with pulmonary renal syndrome with pulmonary infiltrates, hemorrhage and hemoptysis as well as renal failure.

Post-streptococcal glomerulonephritis. Patients may have a history of a viral syndrome in the recent past. ASO titers will be elevated and C3 level will be low, but C4 level will not be low.

Goodpasture’s disease. To distinguish from SLE nephritis, send anti-GBM antibody. Serum complements are normal. This can also present like ANCA vasculitis with pulmonary-renal syndrome, however other signs of ANCA-associated vasculitis will be absent.

Thin basement membrane disease: Also called benign familial hematuria. There will be diffuse thinning of the basement membrane on electron microscopy secondary to abnormal type IV collagen. Can present with hematuria from micro to macroscopic. Patients rarely have proteinuria. Progression to renal insufficiency is usually a gradual process and prognosis is quite good.

Hereditary nephritis (Alport Syndrome): Genetic disease from abnormalities in type IV collagen resulting in glomerular disease, hearing loss, and eye abnormalities. (Often presents with persistent microscopic and occasionally gross hematuria in childhood and can progress to renal failure by the 3rd decade of life.)

IgA nephropathy: Often presents with frank hematuria post URI, where in lupus nephritis patients usually have microscopic hematuria. IgA deposition on biopsy along with C3 is diagnostic.

Henoch-Schönlein Purpura: Most common form of vasculitis in children usually after preceding URI, however 10% of cases seen in adults. (Tetrad of palpable purpura, abdominal pain, renal disease and arthritis/arthralgias. Disease is an immune-complex mediated vasculitis secondary to IgA and C3 deposition in affected tissues. Diagnosis is usually clinical but biopsy shows IgA on immunofluorescence.)

Minimal change disease: Major cause of nephrotic syndrome in children and adults. Presents with sudden onset of nephrotic syndrome usually after a URI or systemic infection. On biopsy glomerulus appears normal, and there are no immune-complexes on immunofluorescence. On electron microscopy see effacement of the podocytes.

Focal segmental glomerulosclerosis: Frequent in all age groups. Possibly a variant of minimal change disease (MCD). Often presents with nephrotic syndrome. See focal areas of mesangial sclerosis and in pauci-immune on biopsy. On electron microscopy see effacement of the podocytes like in MCD.

Pre-eclampsia: Possible complication of lupus nephritis during pregnancy. (See new onset of hypertension and proteinuria after 20th week of pregnancy, where urinary sediment is usually normal. Biopsy shows endothelial cell edema and capillary damage. There is no effacement of the podocytes on biopsy.)

D. Physical Examination Findings.

Again, there are no real stigmata of lupus nephritis on physical exam. Patients may have physical exam findings consistent with lupus – rash, alopecia, oral/nasal ulcers and signs of synovitis. If nephrotic from lupus nephritis, patients may have nondependent edema such as periorbital edema and upper extremity edema as well as anasarca.

E. What diagnostic tests should be performed?

Lupus nephritis is suspected in a patient with signs and symptoms of lupus as well as evidence of renal disease such as:

increased proteinuria of 3+ on a urine dipstick or

> 0.5 g/24 h protein collection,

> 5 RBC or WBC/hpf in the absence of infection,

red or white cell casts,

increasing serum creatinine.

If lupus nephritis is suspected based upon these initial tests, subsequent tests can include:

Urine culture to rule out infection in the setting of hematuria or pyuria.

Spot urine protein: creatinine ratio to quantify and confirm proteinuria.

Serum complement levels. If both C3 and C4 are low, this is suspicious of SLE disease activity and several mimickers above can be ruled out.

Anti double-stranded DNA levels – if low the test is not helpful, but if elevated it is useful to confirm increased SLE disease activity

The gold standard for diagnosis of lupus nephritis is a biopsy with lupus nephritis as classified by the International Society of Nephrology/Renal Pathology Society classification system. Renal biopsy is necessary to qualify the type of lupus nephritis which helps guide treatment and prognosis overall. Indications include:

Nephritic urine sediment (glomerular hematuria and cellular casts)

Glomerular hematuria with proteinuria (>0.5 to 1.0 gm/day)

Glomerular hematuria with proteinuria of <0.03 gm/day and low C3 and/or positive anti-ds DNA

Proteinuria >1.0 to 2.0 gm/day (especially if C3 is low and/or positive anti-ds DNA)

The main indications for repeat renal biopsy include worsening proteinuria, acute renal failure, and treatment failure or relapse.

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

There is no need to get computed tomography (CT) imaging or magnetic resonance imaging (MRI) to evaluate the renal parenchyma.

III. Default Management.

First, the clinician should recognize that the “dirty” UA in the SLE patient and the absence of a positive urine culture is inconsistent with infection and should raise suspicion for a lupus nephritis flare. Serologic studies need to be drawn as above, and the patient needs to be started on high dose steroids. A nephrology consult should be called for a potential renal biopsy and either consult with rheumatology or nephrology regarding further immunosuppression of the patient. Renal biopsy should not delay onset of treatment, as it can be done while the patient is being treated.

A. Immediate management.

If in renal failure from lupus nephritis, patients should immediately be pulsed with steroids at one gram of methylprednisolone per day for the first 3 days. The dose can be given all at once, or in divided doses if patient cannot tolerate one gram at a time due to side effects such as agitation, delirium, and hyperglycemia. Patients may present with acute indications for emergent dialysis, which should be initiated as necessary (see section on acute renal failure). If not in renal failure, it is possible to treat the lupus nephritis patient with 1 mg/kg of body weight of oral prednisone.

B. Physical Examination Tips to Guide Management.

If the patient is nephrotic, the clinician should look for signs of decreasing edema. Careful attention must be paid to blood pressure, glucose control, and fluid status in the setting of renal failure. If other findings of a lupus flare are present, those should be followed as well (see section on SLE).

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

The following labs should be monitored in a lupus nephritis flare:

C3 and C4 levels should rise in response to treatment.

Anti-ds DNA levels should fall in response to treatment.

Serum creatinine levels should fall in response to treatment and glomerular filtration rate should rise.

Spot urine protein to creatinine ratios should be checked and trended – it should decrease in response to treatment.

D. Long-term management.

After patients are pulsed with methylprednisolone for 3 days, prednisone can be started at 1 mg/kg/day that will be gradually tapered as an outpatient by either a nephrologist or rheumatologist. Further acute management of renal disease with cyclophosphamide or mycophenolate mofetil (MMF) should be considered in consultation with either nephrology or rheumatology.

Tight blood pressure control should be a high priority during the patient’s hospital stay. An ACE inhibitor or an ARB can be initiated once the patient is out of acute renal failure. In addition, patients with nephrotic range proteinuria should receive aggressive lipid management with a statin. Proteinuria is also a risk factor for a DVT or renal vein thrombosis and patients with any signs or symptoms of either condition should be anticoagulated and treated as appropriate.

E. Common Side-Effects of Management.

1. Immediately pulse dose steroids with methylprednisolone 1 gm IV daily x 3 days.

a. Monitor for delirium, agitation, hyperglycemia, hypertension, increased fluid retention.

2. After 3 days, start 1 mg/kg/day of prednisone.

a. Monitor for same symptoms as above.

3. If severe enough renal disease start cyclophosphamide as an inpatient.

a. Monitor for hemorrhagic cystitis with daily UA.

b. Patients will need aggressive intravenous fluids administration and MESNA to bind and flush out the metabolite, acrolein.

If mycophenolate started as an inpatient monitor for GI toxicity, especially diarrhea.

4. Patients receiving steroids should also receive a proton pump inhibitor.

5. Sequelae of long term steroid use such as osteoporosis should be managed with calcium, vitamin D, and bisphosphonates (if woman is not of child-bearing years).

6. Insomnia from high dose steroids can be treated with benzodiazepines.

7. As outpatient need to monitor CBC in the setting of cyclophosphamide and mycophenolate for leukopenias, anemia, and thrombocytopenia.

IV. Management with Co-Morbidities.

A. Renal Insufficiency.

Renally dose mycophenolate mofetil and cyclophosphamide based on the GFR.

a. Cyclophosphamide: If GFR< 10 decrease dose by 25% if on HD decrease by 50%

b. Mycophenolate: GFR<25 maximum dose 1g BID

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure.

There may be increased fluid retention due to need for steroids. Additionally, doses of diuretics need to be adjusted to desired level of urine output secondary to renal failure and albumin levels if patient has nephrotic range proteinuria. If patients require cyclophosphamide and cannot receive large amounts of intravenous normal saline, they may need continuous bladder irrigation to prevent hemorrhagic cystitis.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

Patients will have increased hyperglycemia while on steroids and insulin will need to be adjusted accordingly. In addition, depending on the level of renal failure, insulin might not be cleared as effectively and patients might need less insulin. Glucose should be checked via finger stick prior to meals and prior to bed in order to adjust insulin accordingly.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

Patients can develop significant infections while on high doses of steroids as well as with cyclophosphamide and MMF such as Pneumocystis jiroveci pneumonia (PCP), progressive multifocal leukoencephalopathy (PML), BK virus as well as other opportunistic infections. Prophylaxis with sulfamethoxazole and trimethoprim (Bactrim) is often used with concurrent cyclophosphamide.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

If experiencing significant diarrhea secondary to mycophenolate can change to mycophenolic acid. Patients on MMF can develop GI bleed and perforation, colitis, and pancreatitis.

J. Hematologic or Coagulation Issues.

No change in standard management. Patients may be hypercoagulable from their comorbidities and with nephrotic range proteinuria and would need warfarin long term. Can develop leukopenia, anemia and thrombocytopenia from both cyclophosphamide and MMF.

K. Dementia or Psychiatric Illness/Treatment.

High dose steroids can superimpose a delirium or psychosis on top of underlying dementia and other psychiatric illnesses. Patients should be monitored and medications adjusted accordingly.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

If patient is on high dose steroids, monitor blood pressure, glucose, and look for signs of agitation. If on cyclophosphamide monitor for hematuria. Otherwise, follow as you would any other admission for new onset renal disease.

B. Anticipated Length of Stay.

There is so much variability in this disease that it is difficult to predict a goal length of stay. It would require a minimum of 3 days for pulsing with IV steroids.

C. When is the Patient Ready for Discharge?

When renal function is improving, complement levels are rising, anti-ds DNA levels are decreasing, and patients are able to take PO steroids, they can be discharged with close outpatient follow-up.

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom?

Patients will require outpatient follow-up in 7-10 days with general internal medicine, rheumatology, and nephrology especially.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

Renal biopsy if not performed in the hospital.

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

C3 and C4 levels, anti-ds DNA levels, serum creatinine, Spot urine protein/creatinine ratio, urinalysis, CBC, serum albumin.

E. Placement Considerations.

If patients require hemodialysis as outpatients, hepatitis B and TB testing should be ordered as soon as dialysis is initiated to facilitate dialysis center placement as an outpatient.

F. Prognosis and Patient Counseling.

The degree of renal failure and the biopsy results help predict the prognosis overall. This should be done in consultation with renal follow-up as an outpatient once the “flare” has subsided or stabilized.

VI. Patient Safety and Quality Measures.

Appropriate Prophylaxis and Other Measures to Prevent Readmission.

If patients received cyclophosphamide, SMX/TTP is given for PCP prophylaxis. A proton pump inhibitor, calcium, and vitamin D and possibly a bisphosphonate should be given while the patient is taking steroids. Patients with renal failure should be told to avoid NSAID use. All patients should have their CBC monitored, and receive influenza and strep pneumonia vaccinations.

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