SCCM Resource Library-Scleroderma Renal Crisis

Video Transcription

Hello, I'm Eleanor Valenzi. I'm an assistant professor in the pulmonary division at the University of Pittsburgh with a focus on interstitial lung disease.  Today, I'm going to be thinking about my other hat as an ICU provider and how a group of our patients with scleroderma often come to our attention in the intensive care unit.  So systemic sclerosis, as most of you are familiar, is a multi-system autoimmune disorder that results in fibrosis of the skin,  lungs, and other visceral organs including the kidneys, heart, and gut most commonly. It unfortunately has the highest mortality amongst  rheumatic diseases still and about 50-70 percent of patients are going to go on to die of causes related to their scleroderma. So it still has a significant unmet clinical need  and importance for ongoing research in these patients. You can see here a couple of the classic manifestations and how these patients come to our attention in the ICU.  So on the left, you can see that sclerodactyly or significant skin thickening of the hands and fingers here as well as ulcerations related to severe Raynaud's phenomenon.  These patients may develop severe ulcers that require use of IV vasodilators in the ICU at times. In the middle, you have a patient here who has a pretty small oral aperture  due to skin thickening and around her mouth, which is a common location for it to occur. So this is the dreaded difficult airway for a small oral opening patient.  Then on the right, you can see an example of a chest CT from one of my patients who has interstitial lung disease related to her scleroderma, who has an NSIP-like pattern here,  and these patients may end up with respiratory failure requiring times in the ICU or lung transplant even. Renal crisis actually used to be the leading cause of  death in scleroderma until the advent of treatment for that. So you can see here from a classic study by Steen et al in 2007, looking at the causes of disease in scleroderma,  the purple represents scleroderma renal crisis, and then up until the early 90s, this was the leading cause of death in scleroderma. As we develop better treatments for this,  you can see pulmonary hypertension in the blue and interstitial lung disease in the yellow here became the leading causes of death. On more recent data,  ILD is actually now the main cause of death in scleroderma as we've developed better treatments for pulmonary arterial hypertension in these patients.  Renal disease overall is pretty prevalent in scleroderma. So about 50 percent of patients with scleroderma are going to have clinical evidence of some amount of renal involvement.  If you go just by elevated serum creatinines, evidence of any proteinuria or hypertension, but it's typically not progressive in most patients.  As you can imagine, there can be a lot of other causes for these findings, such as hypertension of other causes, CKD that may be related to heart failure, medications, etc.  But a few patients will go on to develop renal crisis. So the three main hallmarks of this and how we come to recognize it is that  somebody has abrupt onset of moderate to severe hypertension, they have acute kidney injury, and then their urinalysis and urine sediment is pretty bland.  So it tends to be normal with only mild proteinuria with few castor cells. The pathology of this is not completely understood unfortunately,  but it is thought to be associated with increased vascular permeability, renin secretion, activation of the coagulation cascade.  As overall, systemic sclerosis is a disease with a lot of vascular findings, in addition to those sclerotic fibrotic findings often set off by the TGF-beta cascade.  Important other manifestations to help recognize scleroderma renal crisis, and that may need additional treatments and attention involved with it,  are most commonly microangiopathic hemolytic anemia with thrombocytopenia. So this happens in up to 50 percent of cases concurrently with their renal crisis,  and it's a spectrum in some cases of having more prominent kidney injury to having more prominent hematologic findings. There have been some efforts to potentially separate this  into a separate disease classification, but right now these are all along the same spectrum. Again, we see this in about 50 percent of cases.  Depending on the degree of hypertension, people develop other complications similar to malignant hypertension. So they can get severe hypertensive retinopathy,  hypertensive encephalopathy that can result in seizures or status epilepticus, acute heart failure, as well as acute manifestations of pericarditis are common.  Overall, renal crisis still occurs in about 5 to 20 percent of patients with the diffuse cutaneous form of scleroderma,  meaning it's involving more than 5 to 10 percent of their body surface area. It's pretty rare in our limited cutaneous patients,  so those who may just have the more classic sclerodactyly findings, for example. Renal crisis is an early manifestation of disease.  So it's almost exclusively happens in the first 4 to 5 years of someone's disease, and then median duration is about 7 and a half months  from a patient's first non-Raynaud's manifestation of disease. So many patients with scleroderma have had Raynaud's for 10, 20 years before they go on to develop scleroderma.  So this meaning their first findings of skin thickening or lung disease, for example. Another important thing to realize is that about 10 percent of  cases of renal crisis are going to be normotensive. So they're not going to have that moderate to severe hypertension. They will generally still have, however,  an increase in their blood pressure compared to their baseline. So the thin otherwise healthy young person who had a blood pressure normally of 90s over 50s,  120 over 80 could still be renal crisis for them. These normotensive cases have been associated with worse outcomes in multiple studies,  and this is probably because these patients have later recognition of their disease and subsequently later initiation of treatment of their renal crisis.  The important risk factors in patients with scleroderma to watch out for, and this should raise your suspicion of renal crisis,  people who have rapidly progressive or diffuse skin disease. So these are those early patients who, whether or not they've been started on treatment yet or  continuing to have new areas of skin thickening involvement, worsening, thickening in the areas they do have involvement, tightening of that oral aperture,  they're the highest risk for getting renal crisis. Like I said, this is early stage disease and the earlier in their disease, they are the higher risk they are for this.  So year one is higher risk than year five, for example. Patients who have tendon friction rubs or large joint contractures,  which are some of the musculoskeletal findings of scleroderma we don't classically think about but can happen in patients with  the more inflammatory phenotype are higher risk for developing this as well. In terms of the autoantibodies,  so there's multiple autoantibodies that have been associated with scleroderma. Patients who have a positive autoantibody to RNA polymerase III are at the highest risk for this.  So you take large case series of renal crisis patients, about 50-60 percent of those patients will have RNA polymerase III antibodies versus  only about 10-20 percent of all comers with scleroderma will have that. Patients with anti-centromere antibodies are actually at  the least risk for this from an autoantibody perspective, and that tends to correlate more often with the limited cutaneous findings as well. So those fit together.  Cyclosporine use has been associated with increased risk of this. I will say this is a pretty rarely used treatment in scleroderma in the United States now.  So we don't encounter this as much, but there is some increased risk. One important one to keep in mind as ICU providers is glucocorticoid use.  So this is a common question I get when one of my patients is amid the ICU of how to manage their glucocorticoids if they're potentially needed for another treatment, for example.  So we know that moderate to high-dose corticosteroids, so the equivalent of 15 milligrams of prednisone or higher, or equivalent drug to that,  within the prior six months significantly increases the risk of someone developing renal crisis. So in a case series of 110 patients, this came out to an odds ratio of as high as  4.37 for going on to develop renal crisis. This has subsequently been confirmed in other retrospective studies, as well as a prospective study that identifies 70 percent of  patients had received corticosteroids recently or at the time of their development of renal crisis. So if we are using steroids in scleroderma patients,  we really try to use the lowest dose possible for the least period of times, and it's extremely rare that you'll see a patient with  scleroderma receiving more than 15 milligrams of prednisone for any reason. We do not treat these patients with high doses of corticosteroids as outpatients,  like you might see in many other autoimmune diseases, for example. The proposed mechanism of this association with steroids is that  increases expression of renal endothelin receptors, as well as sodium and volume retention.  If we do a renal biopsy in our patients at the time of renal crisis, what you'll see is a thrombotic microangiopathy with prominent small vessel involvement.  You know, this is along the spectrum of other thrombotic microangiopathies, so things like TPP, HUS, spleen and hypertension,  the antibospholipid antibody syndrome that we heard about.  And it's going to have that small vessel involvement along with myxoid intimal changes, the classic onion skin lesions of the arterioles,  one of which you can see here from a renal crisis biopsy. You're going to have different degrees of thrombi, as well as fibrointimal sclerosis.  And we know that if you do biopsy these patients, the degree of involvement, including the number of thrombi identified, does correlate with their renal outcome.  So those patients with worse renal disease, more thrombi on their biopsies, do have higher likelihood of needing dialysis, as well as death.  Kidney biopsy, importantly, does not definitively diagnose renal crisis. So this is mostly used nowadays to rule out other causes, as opposed to confirm the diagnosis of this.  While there's not a current accepted guidelines, per se, for diagnosis, there has been an effort to move towards getting a new consensus diagnosis for this.  So this is from our recent classification criteria by the Scleroderma Renal Crisis Working Group that did a consensus methodology.  And this is as close as we have to current diagnostic guidelines. So this includes having a blood pressure greater than or equal to 140 or 90,  or an increase in your systolic pressure greater than 30, or an increase in your diastolic pressure greater than 20, in order to include those normotensive renal crisis patients.  So in addition to the blood pressure changes, you have to have at least one manifestation of kidney injury, microangiopathic hemolytic anemia, and thrombocytopenia,  retinopathy, encephalopathy, acute heart failure, or acute pericarditis. In this case, acute kidney injury was defined by current guidelines  showing an increase in your serum creatinine of 0.3 milligrams per deciliter,  or 1.5 times the baseline assumed to be within the most recent week, or a decrease in your urine output to 0.5 mils per kg over the last six hours.  So how do we treat this once we've identified it or are highly suspicious for this? So first of all, it's important to treat this.  We saw it used to be the leading cause of mortality. And previously untreated, scleroderma renal crisis would progress  to end-stage renal disease or kidney disease over about one to two months. In most patients, it was death within a year.  Now with treatment, we focus on rapid blood pressure control, and we know that that stabilizes or improves kidney function in about 70% of patients.  ACE inhibitors are the mainstay of treatment for this, and this is really what caused that complete change in the mortality curve for scleroderma patients.  ACE inhibitors have been shown to be associated with greater antihypertensive effect in these patients, improved preservation of their kidney function,  and improved survival in scleroderma renal crisis. And this is based on retrospective as well as prospective studies.  You know, I will say there are no randomized controlled trials of ACE inhibitors in scleroderma renal crisis, and there aren't going to be  based on the clearly demonstrated superior effect of these medications. So this is one of those non-double-blind, randomized RCT drugs that we're just going to have to accept  and are using widely for treatment of these patients with good effect.  With the advent of ACE inhibitors for this, the one-year survival of renal crisis actually improved from about 15% to 76%.  So again, really strong demonstrated effect with the level of evidence that we have.  There's pretty limited evidence currently on the use of ARBs or renal inhibitors for these patients.  You could suppose by the mechanism of action of these that we should have a similar effect, but clinical trials have not been done to show that.  And there is anecdotal evidence and case reports of patients who were switched from an ACE inhibitor to an ARB later on and had recurrence of their renal crisis.  So that has also led to some concern about using those as alternative treatment.  So, you know, what is the real-life guidance of dosing? How do we do this in real effect? So the goal is to return people to their baseline blood pressure within 72 hours.  Captopril is the preferred agent pretty much worldwide for rapid onset and its short duration of action, allowing us to really frequently titrate it in these patients.  So typically we start Captopril at about 12.5 milligrams, dosing it every eight hours. And we escalate that very quickly in 12.5 to 25 milligram increments  every four to eight hours. The maximum Captopril dose is very high, about 450 milligrams for 24 hours. And we will push these patients up to 150 milligrams  every eight hours if necessary, in order to bring their blood pressure down.  If the patient's got CNS involvement as well, so if they're having hypertensive encephalopathy, you know, they may, they probably need more rapid blood pressure  decreased than you're going to get in the first 24 hours from just escalating the Captopril. And so we will start these patients on nitroprusside infusions concurrently.  And then we'll wean that down as the Captopril dosing is increased every four to eight hours.  There's no strong guidelines or evidence on what the best second line agent is. If you're not able to get full effect with Captopril,  the expert opinion consensus tends to be to use calcium channel blockers, such as amlodipine as the preferred second agent for this currently.  And eventually, as patients have resolution of their renal crisis and improvement, we'll go on to transition them to lower doses of long-acting ACE inhibitor indefinitely.  So they don't have to stay on the Captopril. You know, we change them to something that has 20, Q24 hour dosing eventually. And then they stay on that indefinitely at the, you know,  dose that they can titrate. Even if they are normotensive, we will try to keep them on a low dose.  Concurrently with this, we also follow the patient's lab work. And usually while you're going to see the creatinine rise initially, while you're up trading the ACE inhibitor,  that should not stop you from up-tritrate unit or continuing it. And their hemoglobin and their platelets, their haptoglobin, their LDH counts,  those findings of their hemolytic anemia and thrombocytopenia are all going to improve pretty quickly with this in most patients, even if the creatinine is still initially rising.  There are some reports of using plasma exchange for patients who have a more refractory microangiopathic hemolytic anemia,  although it's not an upfront initial treatment in these patients the way it is for some other hemolytic disorders.  Low dose liprosin infusions have also rarely been used for some patients.  And still about 20 to 50% of scleroderma renal crisis patients may require dialysis at some point.  Of those who do require dialysis, about 50% will go on to have renal recovery if treatment with ACE inhibitors is continued.  And so even if the patient's on dialysis, certainly while in the ICU, and even if they're on dialysis upon discharge from the hospital,  we continue ACE inhibitors in these patients if the dose is tolerated,  and many will go on to have later renal recovery. Because of this chance of late renal recovery, we do delay transplant to at least 12 to 18 months in these patients.  We know that if they get transplanted, unfortunately the graft survival is not as high as the general renal transplant population,  even though the recurrence rate is only about 2 to 5%. So it's probably due to other factors from the underlying disease.  So we look at survival stratified by renal outcome.  You know, we can see more recent one-year survival may be as high as about 82% for these patients, while 10-year survival is still pretty low,  usually due to other complications of the disease.  Interestingly, patients with higher blood pressure at presentation actually were associated with better outcomes,  perhaps due to earlier treatment in those patients and less permanent damage that occurs in the kidneys.  And we also saw that ACE inhibitor treatment prior to scleroderma renal crisis, so patients who were already on the drug for hypertension, for example,  that was actually associated with a worse outcome. So while there's no RCTs that have been done for ACE inhibitors for prevention of scleroderma renal crisis,  this and other case series have led people not to use them  as the first line antihypertensive if the patients are recurring them. We will, if the patient's already on them and develops scleroderma, we will leave them on their ACE inhibitors  as long as they don't have several of those high-risk features. But if they have several high-risk features,  like rapidly progressing skin disease and RNA polymerase III, for example, we may change them to a different antihypertensive as an outpatient.  So in summary, scleroderma renal crisis is a life-threatening complication of systemic sclerosis manifested by severe hypertension, its complications,  AKI, and a bland urine sediment. About 50% of these patients will also have microenteropathic kenolytic anemia with significant thrombocytopenia.  And early recognition is important as ACE inhibitors are the primary treatment and must be started early with rapid dose escalation to restore baseline blood pressure  and stabilize and improve kidney function in these patients.  Thank you for your attention.

Video Summary

In this video, Dr. Eleanor Valenzi discusses scleroderma renal crisis, which is a life-threatening complication of systemic sclerosis. Systemic sclerosis is an autoimmune disorder that results in fibrosis of various organs, including the skin, lungs, and kidneys. Scleroderma renal crisis is characterized by abrupt onset of severe hypertension, acute kidney injury, and a bland urine sediment. Treatment of scleroderma renal crisis involves rapid blood pressure control, primarily with angiotensin-converting enzyme (ACE) inhibitors. ACE inhibitors have been shown to improve kidney function and survival in these patients. Other manifestations of scleroderma renal crisis may include microangiopathic hemolytic anemia and thrombocytopenia. Early recognition of scleroderma renal crisis is important for initiating treatment promptly. While renal crisis used to be the leading cause of death in scleroderma, the development of ACE inhibitor treatment has significantly improved outcomes.

Asset Subtitle

Renal, Immunology, 2022

Asset Caption

Primary immunologic disorders are infrequent but devastating causes of morbidity and mortality in the ICU. The rapidity with which these conditions can progress requires equally swift recognition and intervention. These rare conditions can go unrecognized, leading to increased harm to patients. This session's expert panel will discuss key features of three uncommon but important immunologic disorders for the critical care clinician, with a goal of ensuring quick initiation of needed therapy.

Meta Tag

Content Type Presentation

Knowledge Area Renal

Knowledge Area Immunology

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Renal

Tag Immunology

Year 2022

Keywords

scleroderma renal crisis

systemic sclerosis

autoimmune disorder

hypertension

angiotensin-converting enzyme inhibitors

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