Table of Contents
Case Scenario
Chloe is a 24-year old female who had been previously diagnosed with SLE. She is currently in remission with good SLE control, but recently she has been suffering from persistent headaches, mild bilateral lower limb swelling and some facial puffiness. She had also noticed that she passed several bouts of reddish urine in the last few days.
On examination, she was pale with peri-orbital edema and dry, cracked lips. Her skin was splotchy and dry, and she had a bounding low-volume pulse. Her blood pressure reading measured a massive 200/130 mmHg and she had stony dullness in the left lower lung zone. She had pitting edema of both lower limbs and bilaterally swollen metatarsophalangeal joints.
To understand what’s really going on here, we will have to get to know about “Lupus Nephritis,” the topic of today’s discussion.
What is Lupus nephritis?
To answer this question, we must first familiarize ourselves with the term Systemic Lupus Erythematosus (SLE). This name has made its way into almost every medical textbook and discussion both for its wide-spread prevalence as well as for its systemic consequences. It is best described as a multi-systemic, inflammatory autoimmune disorder (where the body’s immune system attacks its own cells) and it presents with a spectrum of problems. The most common and possibly the least worrying problems include arthralgia and rashes, whereas the most serious problems are renal and cerebral disease.
How common is it?
At least a third of SLE patients develop renal disease – known as lupus nephritis. A quarter of these patients will sadly progress to End-stage renal disease (ESKD) within ten years.
How would these patients present?
Now that we have a basic idea of SLE and its serious renal complications, what would we expect if a patient with SLE develops lupus nephritis? For that, let’s take a look at the classes of lupus nephritis that may occur. Beware that these classes are divided not based on their presentation, but on the features seen on renal biopsy. There are six classes of lupus nephritis identified by the International Society of nephrology, which will be discussed in more detail under renal biopsy (of investigations).
Class I – Patients are asymptomatic at this stage, but they may be symptomatic for features of SLE.
Class II – Mild renal disease which presents mostly with features of nephritic syndrome like:
- Hematuria – microscopic at this stage
- Proteinuria – microscopic again
- Usually there is no hypertension at this stage.
- Oedema (periorbital, leg or sacral)
Class III – These patients have clinically detectable hematuria and proteinuria and will also show features of active SLE.
Class IV – Clinically, they will progress to nephrotic syndrome (which means that your patient will be losing more than 3.5 g of protein per day in their urine). Look out for other features of nephrotic syndrome. For example, they would have:
- Edema – mostly around the face and eyes (periorbital) and pitting edema over their feet (dependent edema)
- Hypovolemia – as most of the fluid in their circulation is dragged into the interstitial compartment without enough albumin to hold it inside. So, look for dry lips and mucous membranes, a bounding, low-volume pulse, and cold peripheries.
- Hypercoagulability – which just means that they have a high chance of getting sudden thrombi in their circulation.
- Hyperlipidemia – their levels of low-density lipoproteins, a.k.a – the bad cholesterols, are elevated.
Besides features of classic nephrotic syndrome, they may have hypertension (usually not seen in nephrotic syndrome) and features associated with it, such as:
- Headache
- Dizziness
- Visual disturbances
- Signs of cardiac decompensation.
Also, look out for increased rates of bacterial infection, which indicate that their immune system is deteriorating.
As you may already have guessed, this class is the most severe but also the most common form of lupus nephritis.
Class V – this is a combination of Class III and IV, but surprisingly has a good prognosis.
Class VI – This is where the patient has come to a very advanced stage of the disease. They will most definitely progress to CKD (Chronic Kidney disease). The features they present with are variable depending on how bad their kidneys are damaged. Overall, a diagnosis will have to be made based on their albumin/creatinine ratio and their glomerular filtration rate which is beyond the scope of this discussion.
Your Differentials
It is usually challenging to diagnose lupus nephritis or its stages without doing a renal biopsy. But some of the differentials that may cross your mind include:
- Granulomatosis with polyangiitis (earlier known as Wegener’s granulomatosis)
- Polyarteritis nodosa
- Diffuse proliferative glomerulonephritis
- Chronic glomerulonephritis
- Membranous glomerulonephritis
- Rapidly progressive glomerulonephritis – RPGN can also occur with lupus nephritis and has a poor prognosis.
On examination:
Always keep in mind that you will find features of generalized active SLE along with features of nephritic syndrome or nephrotic syndrome, depending on which class of disease your patient has.
General examination:
- Fever, depression, fatigue, and weight loss (beware that these features don’t appear in all patients)
- Skin – photosensitivity, a characteristic “butterfly rash,” vasculitis, purpura and urticaria, and Raynaud’s phenomenon (transient spasm of blood vessels in the fingers causing a characteristic transition from white to blue to red).
- Pallor – due to anemia of chronic disease
- Edema – periorbital, sacral, and dependent edema.
- Arthritis of small joints, pain in the hip joints – avascular necrosis of hip joints
- Hypertension – if the patient has glomerulonephritis
Eyes:
Retinal vasculitis can cause infarcts which may present as episcleritis, conjunctivitis (look for red, watery eyes with a gritty sensation), or optic neuritis, but blindness is uncommon.
Nervous system:
Depending on the complications of SLE, they may have cerebral lupus and thus present with:
- Fits
- Hemiplegia
- Ataxia
- Polyneuropathy
- Cranial nerve lesions
- Psychosis
- Demyelinating syndromes
Cardiac manifestations:
- Pericarditis – pericardial rub, pleuritic chest pain which may radiate to the left shoulder which is exacerbated by lying down and relieved on sitting up.
- Endocarditis – usually, this form of endocarditis (called Libman-Sacks endocarditis) is a non-bacterial endocarditis which is asymptomatic, but sometimes it can present with valvular dysfunction heard as murmurs.
- Aortic valve lesions – characteristically aortic stenosis will be heard as mid systolic murmur associated with angina, dyspnoea, and syncope; while aortic regurgitation is an early diastolic murmur radiating from the aortic area to the left sternal edge.
- Some may have cardiac decompensation and features of ischemic heart disease (these patients may have an increased tendency to form clots in their blood because of a subtype of SLE called the antiphospholipid syndrome).
Abdominal manifestations:
- Mouth ulcers – commonly a presenting feature of SLE
- About 20% of patients will present with abdominal pain
- Ascites – another manifestation of edema from hypoproteinemia
Lungs:
- Pleural effusion
- Pleurisy
- Restrictive lung disease (rarely)
Renal manifestations:
- Hematuria
- Frothy urine – in nephrotic range proteinuria
What investigations will you order and why?
It is very important to assess the renal function of these patients because it will greatly affect prognosis and widen the treatment available for them. So, a panel of tests can be used to asses renal function, including:
- Urine full report – this is the basic test we do in the ward setup. It will help to confirm and quantify both the hematuria and the proteinuria, while giving a general idea of the class of lupus nephritis our patient has. It can also identify microscopic hematuria, cellular casts, and proteinuria and may help rule out a few of our differentials.
- Blood urea nitrogen (BUN)
- Serum creatinine assessment
Although these are used to assess renal function, it must be kept in mind that neither of these are specific as they will change according to the patient’s muscle bulk, activity, and diet. Importantly, serum creatinine will only begin to rise once about 50% of renal function deteriorates, so it is a late marker of renal disease.
- A spot urine test for creatinine and protein concentration (normal creatinine excretion is 1000 mg/24 h/1.75 m2; normal protein excretion is 150-200 mg/24 h/1.75 m2; normal urinary protein-to-creatinine ratio is < 0.2)
- A 24-hour urine test for creatinine clearance and protein excretion
- Serum albumin (usually 3.4-5.4 g/dl) and urine albumin/creatinine ratio (in men, it is usually around 17 mg/g of creatinine, but in women, it can be as high as 25 mg/g of creatinine) may be earlier indicators of lupus nephritis.
Other investigations should focus on identifying SLE:
- Full blood count – lookout for normochromic normocytic anemia – due to anemia of chronic disease or autoimmune hemolytic anemia. It may also show leucopenia, lymphopenia, or thrombocytopenia
- ESR will be raised, while CRP will usually be normal unless the patient has a coexisting infection, lupus arthritis, or lupus pleuritis.
- Serum complement – C3 and C4
- Autoantibodies – these are one of the most important investigations in making a diagnosis of SLE. ANA, anti-Rho, anti-La, anti-Sm, and importantly, anti-dsDNA should be tested. Some patients may also have antiphospholipid antibodies.
During an acute flare, there will be reduced C3 and C4, and high levels of anti-dsDNA with a high ESR. These settle with treatment, but anti-dsDNA may remain elevated.
Renal biopsy:
Usually, we can arrive at a fairly accurate diagnosis of lupus nephritis once we complete a thorough clinical history, examination, and support it with relevant investigations. But, doing a renal biopsy is essential to confirm our diagnosis, and most importantly, to differentiate between the disease classes. As we will realize later, the class of lupus nephritis will determine how we treat this patient. Some of these treatment methods can be very toxic and have a lot of adverse effects. It will also give us an idea of the prognosis of this disease.
A trained doctor will perform the renal biopsy under ultrasound or CT guidance. During the procedure, the patient may need light sedation and a local anesthetic to keep them comfortable.
As a resident, we need to know how to prepare our patients for renal biopsy:
- They must be kept fasting for at least eight hours before the biopsy. This includes both food and drink.
- They should have a routine Full blood count and urine full report obtained to make sure they have no pre-existing infections
- If they are on any medications which could affect blood coagulation (including anticoagulants and antiplatelet drugs), they have to be stopped due to the risk of hemorrhage from the procedure.
- NSAIDs, aminoglycosides, and other nephrotoxic drugs also must be stopped as they may increase the chance of the patient having an acute kidney injury after the procedure.
- A proper allergic history must be obtained as they could be allergic to the local anesthetic, sedative, or plasters used.
The renal biopsy results will be used to separate classes of lupus nephritis:
- Class I: Minimal mesangial lupus nephritis (LN) – with immune deposits but normal on light microscopy.
- Class II: Mesangial proliferative LN – Mesangial hypercellularity and matrix expansion
- Class III: Focal LN – involving <50% of glomeruli, with subdivisions for acute or chronic lesions. Subepithelial deposits are seen.
- Class IV: Diffuse LN – involving >50% of glomeruli, classified by the presence of segmental and chronic lesions. Subendothelial deposits are seen.
- Class V: Membranous LN – affects 10-20% of patients and is a combination of classes III and IV.
- Class VI: Advanced sclerosing LN – more than or equal to 90% of globally sclerosed glomeruli without residual activity. It represents the most advanced stages of the above classes and also includes healing.
Diagnosis
Although a renal biopsy may prove to be confirmatory, sampling errors can occur. So, a renal biopsy must always be correlated with the clinical features and lab work. With all considerations, a diagnosis of Lupus nephritis along with staging can be made.
How will you manage this patient?
The aim of treatment is to normalize renal function or at least stop or slow the progression of renal disease. We will have to treat the patient according to the stage of the disease. Other than for lupus nephritis, we must also treat for the extra-renal manifestations of SLE, which we will not approach in this discussion.
Class I – This stage is asymptomatic and does not usually require treatment. If there is any symptomatic treatment that can be given, it can be offered to the patient.
Class II – Even though this class runs a benign course, we usually prescribe hydroxychloroquine because evidence suggests that it improves the outcome of lupus nephritis and reduces the likelihood of lupus flares. We can also prescribe corticosteroids along with this or alone as it will suppress inflammation.
Class III, IV, V – The principle of treatment in all these classes is to use immunosuppressive therapy, but the outcomes will depend on the clinical characteristics, histologically-seen renal damage, the initial response to treatment, ethnicity, and also on the future flares the patient may get.
As induction therapy, mycophenolate mofetil (MMF), or high-dose cyclophosphamide can be prescribed. But low-dose cyclophosphamide is usually a better choice for white populations as it has fewer adverse effects and a lower chance of developing toxicity. Furthermore, cyclophosphamide may be inferior to MMF in black and Hispanic populations too.
Most patients respond well to induction therapy. For maintenance, we can administer MMF, azathioprine, or ciclosporin to reduce the risk of relapse. Of these, MMF is considered the most superior.
Newer therapies that are still not confirmed to be therapeutic include rituximab (monoclonal chimeric antibody against CD20) and calcineurin inhibitors like Tacrolimus. They have shown some short-term benefits in patients with severe lupus nephritis and in certain ethnic groups. Leflunomide, a pyrimidine synthesis inhibitor, may also prove beneficial in certain ethnic groups.
As symptomatic treatment, hypertension and proteinuria must always be treated. Usually, it is beneficial to begin medication that can address both these features, such as ACE inhibitors or ARBs, as they have reno-protective effects in patients with albuminuria.
Hyperlipidemia may require treatment with statins. Patients may have to be prescribed Calcium supplements to prevent secondary osteoporosis and sometimes a bisphosphonate may be prescribed if their renal function allows it.
Diet too should be modified to reduce lipids. If the patient’s kidneys don’t work well, , proteins can also be restricted. It is also important to express to the patient the importance of a salt-restricted diet in controlling hypertension. They should stay well hydrated and take adequate vitamins and minerals in their diet to promote immunity.
Follow-up
Patients with lupus nephritis should have regular follow-up to monitor the progression of the disease. This involves repeating renal function tests and blood work regularly because some of the treatment prescribed can also have nephrotoxic effects. Likewise, these patients will have to be monitored for developing concurrent infections because they are on immunosuppressive therapy. Other side effects include electrolyte imbalances (including hyperkalemia – requiring ECG monitoring) and elevation of liver enzymes.
Patients who are being treated for lupus nephritis cannot become pregnant as the medication may be teratogenic for the fetus. They should use a suitable contraceptive, and if they still want a pregnancy, specialist consultation is required. Drugs like cyclophosphamide are known to cause infertility and amenorrhea, so patients should be informed of these effects beforehand.
Usually, there is a good response to treatment, but if medication is not taken consistently, lupus nephritis can progress from one class to another during an inter-biopsy interval. The best prognosis has been seen with classes I, II, and V. Patients in class VI may need dialysis, or even renal transplants as they may not respond to treatment. However, they can still be treated for extra-renal manifestations of SLE to improve their quality of life.
References
Kumar & Clark’s Clinical Medicine – Edition 10 [Cited March 23, 2021]
Hutchison’s Clinical Methods – Edition 24 [Cited March 23, 2021]
Oxford Handbook of Acute Medicine [Cited March 23, 2021]
Churchill’s pocketbook of Differential Diagnosis [Cited March 23, 2021]
LEOEVEY A, NAGY S, PETRANYI J. [Contributions to the differential diagnosis of “lupus nephritis”]. Bull Off Chambre Synd Med Seine. 1961 Aug 18;56:1390-3. German. PMID: 13760901.
https://emedicine.medscape.com/article/330369-overview