15 Questions with Dr. Michael Madaio on "Kidney Issues and Lupus"
Dr. Michael P. Madaio is Charbonnier Professor and Chairman of the Department of Medicine at the Medical College of Georgia. In addition to his Chair responsibilities, Dr. Madaio practices nephrology, and has an active laboratory focused on immunology mechanisms of renal disease. He and his colleagues have formed a multidisciplinary group focused on improving the health of lupus patients. Dr. Madaio has served on a variety of advisory boards, editorial boards and committees, including the Lupus Foundation of America, the American Society of Nephrology, and the National Kidney Foundation. He has coauthored numerous original publications related to lupus and lupus nephritis, and he is a co-editor of the Rheumatology and the Kidney textbook.
Here he is, in his own words.
"As a speaker for the Lupus Foundation of America, I get many questions pertaining to lupus involvement of the kidneys. This is a potential serious complication that requires prompt recognition, classification and treatment. Therapy is directed at controlling inflammation and preventing disease flares, while minimizing therapy’s side effects and limiting the consequences of chronic kidney disease. Representative questions and answers are discussed below."
How do I know if I have lupus nephritis?
Between thirty and fifty percent of lupus patients will develop inflammation in the kidneys, termed nephritis, at some time during the course of their illness. Often the diagnosis of systemic lupus erythematosus (SLE) is made before nephritis appears; however, occasionally nephritis is the first manifestation of SLE.
The symptoms of nephritis are often non-specific including increased fatigue and lethargy. Other signs of lupus may or may not be present (e.g. skin rash, joint swelling). In some patients, generalized swelling (i.e. edema) may be present as a sign of nephritis.
On examination, your physician will be alerted by the presence of high blood pressure (i.e. hypertension) or an increase requirement for high blood pressure medications. Typical findings of a lupus flare involving other areas of the body may or may not be present.
Laboratory results are key to the initial diagnosis, and they are useful in monitoring disease activity (e.g. for the presence flares of nephritis). The blood level of creatinine (i.e. creatinine level), examination of the urine (i.e. routine and 24 hour urine collection for measurement of protein leak from the kidneys, termed proteinuria), are the initial tests performed. The blood creatinine level is used as a marker for the kidney’s filtration rate (termed the glomerular filtration rate and abbreviated as GFR). The normal range for serum creatinine is 0.5 to 1.1 mg/dl, with some minor variation, depending on the laboratory. With severe lupus nephritis and reduction in GFR, the serum creatinine increases. The normal GFR, adjusted for body surface area, is similar in men and women, and is in the range of 100-130 ml/min/1.73M2. (see http://www.kidney.org/kidneydisease/ckd/knowGFR.cfm) Since men typically have more muscle mass, their serum creatinine will be higher than women, for the same GFR.
A key point is that the serum creatinine may remain within the normal range during a lupus nephritis flare, despite a significant reduction in the GFR or kidney function. For example, take a 50 kg, 25year old Caucasian woman with a lupus nephritis flare, whose creatinine increases from 0.6 (normal for her weight and age) to 1.1 mg/dl. This represents a 50% decrease in kidney function (GFR) from 122 ml/min to 61 ml/minute. Both serum creatinine values (i.e. 0.6 and 1.1) are reported in the normal laboratory range, however in this situation, there is a profound reduction in function. Concluding that both values are normal would be erroneous. Prompt recognition is particularly important in the early stages of lupus nephritis, since delay in recognition and treatment may lead to irreversible scarring and permanent loss of function.
Additionally, when the kidney is injured during lupus nephritis its blood filtration properties are also altered. Normally the tiny filters (termed glomeruli) allow passage of salts and water into the urine, but they limit passage of larger substances, such as proteins and cells. With lupus nephritis, these tiny filters are damaged, so that they leak. As a result, blood products and proteins are filtered, they appear in the urine, and they can easily be detected in a freshly voided sample. The presence of red blood cells and white blood cells can easily be visualized, and their presence is indicative of active nephritis. (Hematuria refers to the presence of red blood cells in the urine whereas pyuria refers to the presence of white blood cells in the urine.) Furthermore, with damage to the filters, proteins from the blood also leak into the urine (termed proteinuria), and this is another sign or indicator of nephritis. Proteinuria can be screened for by routine testing of a urine sample. However to determine the severity of the leak, a timed urine collection is often required, where, patients are instructed to collected urine over 24 hour period. For convenience sometimes a ‘spot’ urine protein: creatinine ratio will be performed on a routine urine sample to estimate the amount of protein leak. This provides a rough assessment of the degree of proteinuria, is more convenient and useful when following patients over time.
Major changes in urinary parameters usually indicate changes in disease activity. For example, the appearance of hematuria and proteinuria not previously detected may be indicative of active lupus nephritis, whereas disappearance of hematuria and proteinuria often represents resolution of disease. Investigators are searching for better serum and urinary 'biomarkers' as a more sensitive means to predict flares of lupus nephritis at its earliest stage, so that therapy can be initiated before significant (and potentially irreversible) damage occurs. Ideally they will be used to accurately predict the severity of lupus nephritis and the need for therapy without having to obtain a kidney biopsy.
When and why is it necessary to perform a kidney biopsy?
Biopsy of the kidney determines the type of lupus nephritis, the severity of inflammation and the degree of fibrosis (scarring). Inflammation is potentially reversible with therapy, whereas scarring is not. The information is used to guide therapy. Not everyone with lupus needs a kidney biopsy. For example if there is no evidence of nephritis (i.e. normal: serum creatinine, urinalysis, urine protein excretion), a renal biopsy is not necessary. With abnormal findings, however a biopsy is performed to determine the type and severity of disease. The International Society of Nephrology/American Society of Nephrology divides the pathologic classification of lupus nephritis into major subtypes. Types I and II represent mild disease, where specific treatment is not required. By contrast, Types III and IV represent severe inflammatory disease with likely progression to end stage kidney disease if untreated. Type V in a non-inflammatory type disease (requiring treatment) and Type VI represents chronic, irreversible, scarring approaching near end stage disease.
Although the pathologic findings must be interpreted in the context of the clinical findings in an individual patient, in general, immunosuppressive therapy (see below) is indicated for Types III, IV and V nephritis, since the probability of progression to renal failure, if untreated, is high. Careful observation is the typical plan for type II, whereas Type VI disease will not respond to therapy. Early detection of lupus nephritis is key, since early treatment can limit progression of disease to renal failure (see below).
Since 'flares' (defined as periods of increased disease activity) characterize the course of individuals with lupus, repeat kidney biopsy is often necessary to determine whether alterations of kidney function (e.g. increased serum creatinine, increased proteinuria) represent flares of lupus nephritis or ‘another cause of altered kidney function. This may be especially important for lupus patients with a history of nephritis, where their lupus seems to be in remission, but their renal function (e.g. GFR) is deteriorating. The question that arises is whether the decreased function is due to active nephritis or other factors. If it is due to active lupus nephritis, treatment is indicated, whereas if other factors are involved, the treatment is directed at correcting the other factors, when possible.
The results of a renal ultrasound and a renal biopsy are very helpful in guiding therapy in this situation. Typically the ultrasound is performed first, since it is non invasive. The appearance of small, shrunken kidneys is indicative of scarring and irreversible disease, and therapy is typically not effective in this situation. If the kidneys are of normal size, a kidney biopsy may be performed to distinguish the degree of active disease vs. scarring, to guide treatment.
Let’s briefly consider some common 'other factors' unrelated to lupus that may be involved in this situation. With progressive loss of kidney function, there are secondary responses in the body that occur that cause further decline in kidney function, independent of lupus activity. For example, high blood pressure is common, and poorly controlled blood pressure may contribute to renal failure to progressive disease. Additionally with loss of the kidney’s filtering units, there is an adaptive response by the remaining units, in that they filter more blood per unit. This response turns out to be maladaptive as the increased work of remaining units lead to further scarring and loss of function (independent of lupus activity). Persistent proteinuria, due to incomplete healing, in the absence of ongoing lupus activity, may also contribute to progressive loss of function. The good news is that there are medications that can reduce blood pressure and proteinuria, thereby slowing loss of kidney function (see below).
When considering the best course of treatment, the probability that the disease will respond to treatment must be considered in the context of the potential side effects of additional immunosuppressive therapy. For example, if there is substantial inflammation but not much scarring, the disease is potentially reversible and further immunosuppressive may be considered. If on the other hand, there is substantial scarring without much inflammation, immunosuppressive therapy may not be administered. Instead slowing progression by other means may be pursued. Preemptive renal transplantation, if lupus is inactive may also be considered.
What are the treatment options for active lupus nephritis?
The pathologic categories that require immunosuppressive and anti-inflammatory therapy are classes III, IV and V. Class III and IV, termed 'focal proliferative' and 'diffuse proliferative' lupus nephritis, respectively, have a similar prognosis and response to therapy, whereas Class IV has a better prognosis and will be considered separately. It is emphasized that the type and severity of disease can vary with time, so that a patient with mild or no disease may develop more severe disease later over time (or vice versa). Thus, flares may prompt the need for repeat kidney biopsy to define the type of nephritis.
In any situation, prompt diagnosis and treatment are essential. High dose steroids and immunosuppressive agents are the cornerstone of therapy. For active disease flares, prednisone (approximately 1 mg/kg, oral) is administered. If there is very severe disease on the biopsy, pulse steroids (e.g. intravenous solumedrol, 0.5 to 1 gram boluses; 3 doses), followed by the oral dosing, are sometimes administered. In addition to steroids, either cyclophosphamide (CTX) or mycophenolate mofitil (MMF or CellCept®), are administered. The CTX may be given as an oral, daily dose (starting at 2 mg/kg/day) or as monthly intravenous boluses (typically 0.5 to 1 gram tittered to depression of the white blood cell count). Another regiment includes 'induction therapy' with CTX for 6 months followed by a maintenance course of either MMF or Azathioprine (AZA or Immuran) for one to two years. CTX is considered conventional therapy, with the best outcomes; however it has a higher side effect profile than either MMF or AZA. The induction/maintenance option is promising with reduced side effects, but longer-term studies with more patients are needed to determine relative efficacy.
Major side effects of therapy include infection, which may be life threatening. With CTX, lupron may be administered to inhibit ovulation in the short term, thereby preserving fertility in the long run. Over the past ten years, steroids (e.g. prednisone, solumedrol) have been used more judiciously, with more rapid tapering, so that after one to three months or so (depending on response), lower doses are used. This approach has reduced side effects.
New drugs are being evaluated both to treat flares and to reduce the frequency of flares. These include immunosuppressive agents that have been approved for other diseases (e.g. rheumatoid arthritis, renal transplantation) and novel agents developed for lupus. Information regarding these studies can be found on the LFA, NIH and related websites.
How will I know if I am in remission? How will I know if I flare?
With therapy, disease typically remits over weeks to months. If treated early, return to baseline function is common. However sometimes, either proteinuria may persist or the serum creatinine may not return to baseline. In this situation, repeat renal biopsy is sometimes used to determine whether there is ongoing active disease or significant scarring. In the first situation, additional immunosuppressive therapy will be considered; in the latter situation, it will not. Overall, this approach limits potential side effects from therapy.
Is there anything that can be done if I have reduced kidney function without active lupus nephritis requiring specific treatment?
Yes. First of all, maintenance immunosuppression is very helpful in preventing lupus nephritis flares, thereby limiting deterioration of kidney function. Other general measures are also important in limiting progression of kidney disease and include: strict blood pressure maintenance (120/80 goal), control of hyperlipidemia, smoking cessation, and control of blood electrolytes (e.g. calcium, phosphate, bicarbonate). Use of ACE inhibitors and ARBs to control blood pressure are particularly helpful in patients with persistent proteinuria, to limit progression.
Cardiovascular and bone health are essential, as cardiovascular disease and bone disease are accelerated in women with lupus. The reasons are complex and relate to the disease itself, the consequences of disease (e.g. hypertension, vascular inflammation, nephritis) and side effects of the treatments (e.g. steroids). Meticulous attention to control of these organ systems is essential to maintain overall health, and this is ideally carried out by a team of rheumatologists, nephrologists cardiologists and primary care providers.
What are my options if my kidneys fail?
Transplantation and dialysis. With rapidly progressive disease, dialysis is the initial option, with transplantation considered, after lupus is controlled. However many patients progress more slowly, and pre-emptive transplantation should be considered (i.e. before dialysis is absolutely required, when the filtration rate is 10 to 20% of normal). In this situation, lupus must otherwise be inactive. Living donors (i.e. related or unrelated) should be the first option given superior outcomes, but cadaver transplantation is a reasonable option. Transplantation prolongs life and improves quality of life. Lupus flares are less common after transplantation, in part due to the immunosuppression administered, although they may occasionally occur.
Is there a relation to having lupus and having chronic kidney infections and stones? If so, is there a way to prevent them? -- Greenfield, WI
Lupus patients are not usually at increased risk for kidney stones. However, kidney stones are common in the general population and lupus patients may get them. They may cause severe pain, especially when they block outflow of urine. Infection may also complicate the situation. Either infection or kidney stones may contribute to worsening kidney function (independent from lupus), and they should be treated promptly. To prevent damage from the kidney stones, treatment should be directed both at getting rid of existing stones and preventing new stone formation. Infection when present should be promptly treated. Treatment strategies include medical and surgical management to remove stones and prevent recurrent stone formation.
I am constantly having flank pain. I have multiple kidney stones in each kidney. My rheumatologist recently told me that the outer part of both my kidneys has become very thin. Is this due to the Lupus and inflammation with my kidneys? -- Alamogordo, NM
Thinning of the outer part of the kidney (or cortex) is an indicator of scarring and irreversible disease. Lupus nephritis may cause this condition.
My daughter was diagnosed with lupus nephritis last year. We don't think of it as a death sentence, but it still worries me as her mother. She has stage 2 lupus nephritis. What exactly does that mean and is there any certain thing that we can do to help ensure the good health of her kidneys? She was taking cholesterol and blood pressure meds, but she's pregnant now and can't they didn't want her to take them. -- Alexis, NC
Please do not think of it as a death sentence. The goal of therapy is to achieve a normal life style. Lupus nephritis is classified into six stages. Stages 1 and 2 are mild forms, usually asymptomatic and do not require specific immunosuppressive therapy. However, patients should be followed closely (e.g. every 3-6 months) for signs of more severe nephritis. Generalized swelling, dark urine, increased medication requirement to control blood pressure are warning signs that should prompt a physician appointment. Repeat kidney biopsy is not necessary, if the blood and urine tests remain normal, however it may be required if they worsen. Blood pressure and cholesterol control, along with smoking cessation are critical to health.
Blood pressure should be controlled during pregnancy, but some medications should be avoided, because of side effects to the fetus (e.g. ACE inhibitors). Azathiaprine and prednisone are acceptable. Cytoxan and Cellcept should not be used. If possible, all medications should be reviewed with your rheumatologist, nephrologist and obstetrician prior to getting pregnant.
What are the complications associated with lupus nephritis and pregnancy and what are the chances of carrying and delivering a healthy baby? -- Pine Bush, NY
Spontaneous abortions (miscarriages) are more common. Patients should generally be in remission (without active nephritis) and on the lowest dose of prednisone possible. Imuran (azathioprine) is relatively safe, and therefore it should be substituted for either cytoxan or CellCept months before considering pregnancy, to improve the chances of carrying and delivering a healthy baby. Other medication adjustments may be necessary, as indicated in the response to a previous question.
Is it safe to take azathioprine and prednisolone for many years and get pregnant? -- Athens, Greece
Patients may still get pregnant after taking azathioprine and prednisone for many years. Woman should be in remission prior to getting pregnant. Ideally they should be tapered off all medication, but sometimes this is not possible. As indicated previously, CellCept and Cytoxan should be avoided in pregnant patients and individuals thinking about getting pregnant, because of fetal toxicity.
Can you discuss the protective effect that Lisinopril has on the kidneys? -- Boston, MA
Linsinopril is a class of drugs called angiotensin converting enzyme inhibitors (ACE-I). They have a number of beneficial and protective effects including: lowering of systemic blood pressure, more effectively lowering of blood pressure with the kidney itself, and reducing proteinuria. These drugs reduce the progression of chronic kidney disease (i.e. how quickly function deteriorates) more than other anti-hypertensive agents, and they are frequently used in patients with kidney disease, especially those with proteinuria. Angiotensin receptor blockers (ARB) have similar beneficial effects, as importantly, to limit the rate of deterioration of kidney function, it is essential that blood pressure be controlled to normal levels (120/80), whatever agents are used.
What are the dangers of taking Tylenol or Motrin (ibuprofen) if you are diagnosed with lupus nephritis? -- Wilmington, DE
In higher than recommend doses Tylenol may be toxic to the kidneys and the liver. The toxicity is exacerbated by alcohol consumption. Nevertheless, in the usual dose, it is relatively safe and it may relieve pain. Motrin, is a non-steroidal anti-inflammatory drug (NSAID). It may cause a reduction in the kidney’s filtration rate in individuals with preexisting kidney disease.
Some NSAIDs have rarely caused an inflammatory nephritis, termed acute interstitial nephritis.
Should patent with SLE nephritis drink more water or less? -- Cupertino, CA
You should avoid extremes of water restriction and water excess. Based on the results of you blood electrolytes, your physician will tell you if you are drinking too much or too little water.
I was diagnosed with lupus nephritis in 1989. In 2001 tests revealed protein in my urine and a kidney biopsy confirmed kidney involvement. I was placed on CellCept for 2 years. The lupus and nephritis went into remission and I was taken off the CellCept. Unfortunately, the nephritis resurfaced in Jan. 2010 and I am now on CellCept again. Is it necessary to have another kidney biopsy now or ever? -- Detroit, MI
Kidney biopsy is useful to diagnosis lupus nephritis and to determine the degree of inflammation and fibrosis. In some situations, in lupus patients, it is useful to distinguish whether deteriorating kidney function is due to lupus or another cause (e.g. medication). In others it is useful to help distinguish whether the deterioration is due to active lupus nephritis or progressive renal disease, without active inflammation (e.g. due to high blood pressure). In the former situation, immunesuppressive treatment of active disease may be administered, by contrast, in the latter situation, reducing the immunosuppressive therapy, while more aggressively treating of high blood pressure may be the best option.
Once a patient has had lesions from lupus throughout kidneys, how likely are your kidneys to be the first place that another flare may center? My treatment at the time involved, Imuran and steroids over a 2 year span of time. -- Sinton, TX
Recurrent episodes of nephritis are common. This is the reason treatment regimens involve 'induction therapy' to treat the 'flare' of lupus nephritis and 'maintenance therapy' to prevent recurrence of flares. High dose steroids and an immunosuppressive agent are typically used to induce remission. With improvement, the steroids are tapered off (or to very low levels), and the immunosuppressive therapy is continued. Some regimens involve switching the induction and maintenance drug, to maximize their benefits and minimize their side effects. A common regimen involves induction with cyclophosphamide (e.g. for 6 months) and maintenance with either Immuran or myclophenamate mofitil (MMF) for one to two years.
In some individuals, the type of kidney involvement may change, and repeat kidney biopsy is necessary to help define the type of lupus nephritis and the most appropriate treatment.