**2. Scleroderma renal crisis**

### **2.1 Epidemiology**

SRC occurs usually in early dcSSc (11%), as compared to patients with lcSSc (4%) [2, 3]. SRC is more common in rapidly progressing disease, SRC was previously reported up to 25% of SSc, but over time, it was found that incidence of renal crisis appeared to have decreased since improvement of early diagnostics [1].

Historically, study of Steen and Medsger [4] presented change of mortality causes during 1972–2002 years. This study showed that SRC as the cause decreased from 42 to 6% of SSc-related deaths, while the proportion of other causes of death increased: pulmonary fibrosis rose from 6 to 33% and pulmonary arterial hypertension from 22 to 28%. Large data were obtained prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort. The EUSTAR database was inaugurated in June 2004 and represents a multinational, prospective, and open SSc cohort [5]. According to EUSTAR data, SSc-related deaths include pulmonary fibrosis 19%, pulmonary arterial hypertension 14%, arrhythmia 6%, heart failure 7%, and SRC 4%. Non–SSc-related deaths in total 4% include infection 13%, malignancy 13%, and cardiovascular 12%. Renal causes accounted for the death of 10 patients (4%), all due to renal crisis. Renal crisis was fatal in 16% of all patients experiencing renal crisis [5].

### **2.2 Pathogenesis of scleroderma renal crisis**

Pathogenesis is characterized by series of insults (**Figure 1**):


**43**

**Figure 2.**

*Renal Involvement in Systemic Sclerosis DOI: http://dx.doi.org/10.5772/intechopen.87187*

thrombi (unlike the pathology seen in hemolytic-uremic syndrome and throm-

Histopathological findings of SRC are more frequently manifested by severe involvement of small arteries and arterioles. Early vascular changes are characterized by intimal accumulation of myxoid material in the interlobular and arcuate arteries, which results in severe luminal narrowing (**Figure 2**). Sometimes microthrombi are developed in the affected vessels and fragmented red blood cells can be

*Early vascular changes are characterized by intimal accumulation of pale myxoid material in the small artery,* 

*which results in severe luminal narrowing (Methenamine-silver stain).*

botic thrombocytopenic purpura) [7].

*The mechanisms in the pathogenesis of SRC. Adapted from Steen et al. [8].*

**2.3 Renal histopathology**

**Figure 1.**

**Figure 1.**

*New Insights into Systemic Sclerosis*

**2. Scleroderma renal crisis**

**2.2 Pathogenesis of scleroderma renal crisis**

narrowing [6].

Pathogenesis is characterized by series of insults (**Figure 1**):

phocytes and monocytes) in the renal vasculature [6].

**2.1 Epidemiology**

Scleroderma renal crisis (SRC) is a dramatic and classical scleroderma manifestation, historically known as dominant cause of scleroderma-related death. Currently, the leading causes of death in scleroderma are pulmonary fibrosis and pulmonary arterial hypertension [1]. Regardless, one-year SRC outcomes remain poor, with over 30% mortality and 25% of patients remaining dialysis-dependent. To make the summary complete, possible drug-related adverse events including

from toxic renal involvement to renal acute renal failure must be mentioned.

SRC occurs usually in early dcSSc (11%), as compared to patients with lcSSc (4%) [2, 3]. SRC is more common in rapidly progressing disease, SRC was previously reported up to 25% of SSc, but over time, it was found that incidence of renal crisis appeared to have decreased since improvement of early diagnostics [1].

Historically, study of Steen and Medsger [4] presented change of mortality causes during 1972–2002 years. This study showed that SRC as the cause decreased from 42 to 6% of SSc-related deaths, while the proportion of other causes of death increased: pulmonary fibrosis rose from 6 to 33% and pulmonary arterial hypertension from 22 to 28%. Large data were obtained prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort. The EUSTAR database was inaugurated in June 2004 and represents a multinational, prospective, and open SSc cohort [5]. According to EUSTAR data, SSc-related deaths include pulmonary fibrosis 19%, pulmonary arterial hypertension 14%, arrhythmia 6%, heart failure 7%, and SRC 4%. Non–SSc-related deaths in total 4% include infection 13%, malignancy 13%, and cardiovascular 12%. Renal causes accounted for the death of 10 patients (4%), all due to renal crisis. Renal crisis was fatal in 16% of all patients experiencing renal crisis [5].

• *Changes in intima and endothelium*: Initially, there is injury to the endothelial cells with intimal thickening and proliferation in the arcuate and interlobular arteries [6].

• *Absence of inflammation*: There is a notable absence of inflammatory cells (lym-

• *Vascular injury*: Platelet factors are released causing increased vascular permeability, fibrin deposition, and collagen formation, which lead to further luminal

• *Renal ischemia*: Narrowed renal arterioles decrease renal cortical blood flow [6].

• *Activation of renin*: Renal ischemia and episodic renal vasospasm "renal Raynaud phenomenon" contribute to decrease of blood flow. Decreased renal blood flow causes hyperplasia of the juxtaglomerular apparatus and release of renin [6].

• *Secondary small vessel changes*: endothelial injury is associated with thrombus formation. Intravascular thrombi and mucoid intimal edema may be seen in renal histology. Small vessel thrombi are more abundant than glomerular

**42**

*The mechanisms in the pathogenesis of SRC. Adapted from Steen et al. [8].*

thrombi (unlike the pathology seen in hemolytic-uremic syndrome and thrombotic thrombocytopenic purpura) [7].

### **2.3 Renal histopathology**

Histopathological findings of SRC are more frequently manifested by severe involvement of small arteries and arterioles. Early vascular changes are characterized by intimal accumulation of myxoid material in the interlobular and arcuate arteries, which results in severe luminal narrowing (**Figure 2**). Sometimes microthrombi are developed in the affected vessels and fragmented red blood cells can be

### **Figure 2.**

*Early vascular changes are characterized by intimal accumulation of pale myxoid material in the small artery, which results in severe luminal narrowing (Methenamine-silver stain).*

### **Figure 3.**

*Two types of glomerular injury associated with scleroderma renal crisis. Ischemic collapse of glomerulus with wrinkling of glomerular basement membrane corresponds to arterial stenosis.*

### **Figure 4.**

*Two types of glomerular injury associated with scleroderma renal crisis. Thrombotic microangiopathy with occlusion of outgoing arteriole is characterized by the congestion and hemorrhagic necrosis of the tuft (Methenamine-silver stain).*

### **Figure 5.**

*Prominent intimal concentric lamination within an interlobular artery (arterial onion skin lesion) with irreversible reduction of the arterial lumen (Methenamine-silver stain).*

**45**

*Renal Involvement in Systemic Sclerosis DOI: http://dx.doi.org/10.5772/intechopen.87187*

fibrosis in the course of time.

Pathology IKEM, Prague.

injury) and segmental or global sclerotic lesions.

**2.4 Definition, diagnosis, and classification**

with absence of kidney impairment.

seen in vessel wall. Microthrombi in arterioles can also progress to the glomeruli. When the arterioles incoming to glomeruli are predominantly affected, the morphological features in glomeruli are characterized by ischemia with wrinkling of glomerular basement membrane and ischemic collapses of glomeruli (**Figure 3**). When microthrombi are developed mainly in outgoing arterioles, the corresponding pathology is severe congestion and hemorrhagic necrosis of the tufts (**Figure 4**). Later arterial injury is characterized by change of edematous mucoid intima to the concentric lamination and so called onion skin lesion (**Figure 5**) with significant luminal reduction. In glomeruli, the lesion is represented by double contouring of glomerular basement membrane (as a result of prolonged or repeated endothelial

Because blood supply in the kidney is represented by end vessels without collaterals, each area of kidney tissue after arterial luminal narrowing must suffer from severe ischemia or even tissue necrosis. In histopathology, pronounced ischemia leads to tubular injury in the intersticium and tubular atrophy with interstitial

Since none of these findings are specific for SRC, the pathological diagnosis

Histopathology: with courtesy of Eva Honsová, MD., PhD. Department of

SRC is defined as new onset of accelerated arterial hypertension and rapidly progressive oliguric renal failure during the course of SSc. There are differences between the criteria used to *define SRC* [1]. Occasionally, more modest elevations in blood pressure and renal dysfunction and at times normotensive presentations were found [9, 10]. The diagnosis is complicated in the case of malignant hypertension

SRC was defined in a minority of studies and criteria were heterogeneous [10]. It is a problem to establish criteria for SRC, because the clinical spectrum of SRC is broad, ranging from accelerated hypertension to normotensive patients 7% [10]. Arterial hypertension is a typical symptom in SRC accompanied by classical complications such as hypertensive encephalopathy, retinopathy, congestive heart failure, hemolysis, etc. Diagnosis of SRC in patients without pre-existing SSc diagnosis and in normotensive SRC patients is difficult, mainly in the absence of renal biopsy [10, 11]. Only one study up to now has partially validated criteria for SRC (**Table 1**) [8]. It was proposed by experts in 2003. It included items for systolic and diastolic blood pressure, serum creatinine, proteinuria, hematuria, microangiopathic hemolytic anemia, and renal histopathology. These are known as the Ancona criteria for SRC [8]. Recently, the Scleroderma Clinical Trials Consortium (SCTC) and Scleroderma Renal Crisis Working Group generate a core set of items to develop classification criteria for SRC using Delphi methodology. The final core set of items to develop classification criteria for SRC contains domains: blood pressure arise, kidney impairment, hematological changes, thrombotic microangiopathy, and organ dysfunction. A consensus definition of SRC is urgently needed to standardize data collection on SRC [9]. Novel concepts of SRC classification included the stratification of SRC:

• *definite SRC*: defined as at least two of: new onset hypertension, microangio-

• *subacute forms of SRC*: such as hypertension, renal insufficiency, and renal sediment changes in the absence of microangiopathic hemolytic anemia [9, 10]

pathic hemolytic anemia (MAHA), and rising creatinine

must be supported by appropriate clinical and serological data [9].

### *Renal Involvement in Systemic Sclerosis DOI: http://dx.doi.org/10.5772/intechopen.87187*

*New Insights into Systemic Sclerosis*

*Two types of glomerular injury associated with scleroderma renal crisis. Ischemic collapse of glomerulus with* 

*Two types of glomerular injury associated with scleroderma renal crisis. Thrombotic microangiopathy with occlusion of outgoing arteriole is characterized by the congestion and hemorrhagic necrosis of the tuft* 

*Prominent intimal concentric lamination within an interlobular artery (arterial onion skin lesion) with* 

*irreversible reduction of the arterial lumen (Methenamine-silver stain).*

*wrinkling of glomerular basement membrane corresponds to arterial stenosis.*

**Figure 3.**

**Figure 4.**

*(Methenamine-silver stain).*

**44**

**Figure 5.**

seen in vessel wall. Microthrombi in arterioles can also progress to the glomeruli. When the arterioles incoming to glomeruli are predominantly affected, the morphological features in glomeruli are characterized by ischemia with wrinkling of glomerular basement membrane and ischemic collapses of glomeruli (**Figure 3**). When microthrombi are developed mainly in outgoing arterioles, the corresponding pathology is severe congestion and hemorrhagic necrosis of the tufts (**Figure 4**).

Later arterial injury is characterized by change of edematous mucoid intima to the concentric lamination and so called onion skin lesion (**Figure 5**) with significant luminal reduction. In glomeruli, the lesion is represented by double contouring of glomerular basement membrane (as a result of prolonged or repeated endothelial injury) and segmental or global sclerotic lesions.

Because blood supply in the kidney is represented by end vessels without collaterals, each area of kidney tissue after arterial luminal narrowing must suffer from severe ischemia or even tissue necrosis. In histopathology, pronounced ischemia leads to tubular injury in the intersticium and tubular atrophy with interstitial fibrosis in the course of time.

Since none of these findings are specific for SRC, the pathological diagnosis must be supported by appropriate clinical and serological data [9].

Histopathology: with courtesy of Eva Honsová, MD., PhD. Department of Pathology IKEM, Prague.

### **2.4 Definition, diagnosis, and classification**

SRC is defined as new onset of accelerated arterial hypertension and rapidly progressive oliguric renal failure during the course of SSc. There are differences between the criteria used to *define SRC* [1]. Occasionally, more modest elevations in blood pressure and renal dysfunction and at times normotensive presentations were found [9, 10]. The diagnosis is complicated in the case of malignant hypertension with absence of kidney impairment.

SRC was defined in a minority of studies and criteria were heterogeneous [10]. It is a problem to establish criteria for SRC, because the clinical spectrum of SRC is broad, ranging from accelerated hypertension to normotensive patients 7% [10]. Arterial hypertension is a typical symptom in SRC accompanied by classical complications such as hypertensive encephalopathy, retinopathy, congestive heart failure, hemolysis, etc. Diagnosis of SRC in patients without pre-existing SSc diagnosis and in normotensive SRC patients is difficult, mainly in the absence of renal biopsy [10, 11].

Only one study up to now has partially validated criteria for SRC (**Table 1**) [8]. It was proposed by experts in 2003. It included items for systolic and diastolic blood pressure, serum creatinine, proteinuria, hematuria, microangiopathic hemolytic anemia, and renal histopathology. These are known as the Ancona criteria for SRC [8].

Recently, the Scleroderma Clinical Trials Consortium (SCTC) and Scleroderma Renal Crisis Working Group generate a core set of items to develop classification criteria for SRC using Delphi methodology. The final core set of items to develop classification criteria for SRC contains domains: blood pressure arise, kidney impairment, hematological changes, thrombotic microangiopathy, and organ dysfunction. A consensus definition of SRC is urgently needed to standardize data collection on SRC [9].

Novel concepts of SRC classification included the stratification of SRC:


### **SRC is defined as following, requiring both:**

A new onset of blood pressure >150/85 mm Hg obtained at least twice over a consecutive 24-hour period. This blood pressure is chosen because it is defined by the New York Heart Association as significant hypertension.

Decrease in the renal function as defined by a decrement of at least 10% in the estimated GFR (eGFR) or GFR of <90 (mL/min/1.73 m2 . When possible, a repeat serum creatinine and recalculation of the GFR should be obtained to corroborate the initial results.

**In order to corroborate further the occurrence of acute renal crisis, it would be desirable to have any of the following, if available:**


Notes


*SRC, scleroderma renal crisis; GFR, glomerular filtration rate.*

### **Table 1.**

*Clinical criteria for definition of scleroderma renal crisis [1].*

New concept also includes the addition of ACE inhibitor responsiveness as a characteristic of hypertension (in *probable SRC*) and the addition of more specific time frames for measurement of blood pressure (taken twice, 2 hours apart, within 3 days of first event-associated observation) [10].

In addition to heterogeneity and rarity, the absence of a gold standard and classification criteria are important challenges for research on SRC. The development of new criteria is important to improve the definition of normotensive SRC. In this case, performing kidney biopsy and examination of biomarkers (including anti-RNA III polymerase) are important and promising.

### **2.5 Role of kidney biopsy in diagnosis of scleroderma renal crisis**

Kidney biopsy is not mandatory for diagnosis of SRC. In patients at risk of SRC with its typical clinical presentation, kidney biopsy is usually not performed. However, it should be considered in all patients with atypical presentation and findings, especially in normotensive patients, patients with ANCA positivity, severe proteinuria, and nephrotic syndrome.

In most patients, we cannot perform kidney biopsy immediately as severe hypertension and frequently present thrombocytopenia significantly increase the risk of bleeding. Biopsy is usually performed within a few days after blood pressure correction and is done with reasonably low risk in patients with blood pressure below 160/90 mmHg and thrombocyte count above 100 × 109 /l.

**47**

*Renal Involvement in Systemic Sclerosis DOI: http://dx.doi.org/10.5772/intechopen.87187*

**2.6 Predictive and risk factors**

predictor of SRC (HR: 2.33) [14].

the occurrence of SRC [11, 15, 18–22].

development of SRC [17].

opportunity in SSc.

females [15].

SRC [5].

fundamentally [12].

Identification of SRC predictive factors (before the development of SRC) is essential (**Table 2**). The vast majority of SRC cases (75–80%) occur in patients with diffuse skin involvement, i.e., skin scleroderma proximal to knee and elbow (dcSSc patients), and rapid progression of skin thickening has been shown to be associated with the development of SRC [12]. Arthritis, palpable tendon friction rubs, swollen fingers, and distal parts of hands are routine syndrome in patients with early dcSSc [13]. Tendon friction rubs were confirmed to be an independent

SRC starts early, most often less than 4 years after the first SSc symptom, although SRC patients have minimal or even no skin changes at the time of the diagnosis of SRC. Males are proportionately more frequently affected than

On the other hand, patients previously called as CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and Telangiectasia) rarely develop SRC. These patients are subgroup of lcSSc

When talking about risk factors of death, a history of renal crisis (HR 2.89), presence of proteinuria (HR 3.09), elevated acute phase reactants (HR 1.79), elevated creatine kinase (HR 1.73), and muscle weakness (HR 1.55) were associated with decreased survival [5, 16]. On the other hand, since the introduction of ACE inhibitors, renal crisis appears to have become an increasingly less frequent terminal event [4]. In EUSTAR cohort, except one individual, all patients dying from renal crisis were on an ACE inhibitor at the time of death. Prednisone equivalents above 15 mg daily have been implicated in exacerbating

Several retrospective studies suggest that glucocorticoids are associated with a higher risk of SRC. Blood pressure and renal function should be carefully monitored in patients with SSc treated with glucocorticoids [17]. Evidence regarding the impact of steroid use on the development of SRC comes mainly from retrospective studies, most of which showed significant association between steroid exposure and

A retrospective analysis including 140 patients with SRC showed that high doses of steroids (prednisone ≥30 mg/day) were used frequently in patients with SSc with normotensive SRC (64%) as compared with those with hypertensive SRC (16%) suggesting an association between the use of high-dose steroids and the risk of normotensive SRC, which is associated with worse prognosis [11]. Glucocorticoids are routinely used for the management of interstitial lung disease, puffy fingers, and skin involvement. These indications are not recommended (because of insufficient evidence of efficacy); however, the experts recognize their use in everyday practice in the management of inflammatory manifestations such as musculoskeletal involvement (arthritis, tendonitis, myositis—in overlap with idiopathic inflammatory myopaties), pericarditis, pleuritis (in overlap with SLE), nonspecific symptoms such as skin itching/burning, fatigue, and appetite (with empiric basis) [17, 23]. Considering the potential risk of SRC associated with steroid use, the experts recommend that patients with SSc treated with steroids should be carefully monitored with respect to the

It can be summarized that glucocorticoids have a very narrow or no therapeutic

### **2.6 Predictive and risk factors**

*New Insights into Systemic Sclerosis*

GFR of <90 (mL/min/1.73 m2

**the following, if available:**

• flash pulmonary edema • oliguria or anuria

Notes

**Table 1.**

hypertension.

**SRC is defined as following, requiring both:**

be obtained to corroborate the initial results.

• new onset of urinary red blood cells (excluding other causes)

and arterioles, fibrinoid necrosis, and glomerular shrinkage

• microangiopathic hemolytic anemia on blood smear • retinopathy typical of acute hypertensive crisis

observed in glucocorticoid scleroderma users.

*SRC, scleroderma renal crisis; GFR, glomerular filtration rate.*

*Clinical criteria for definition of scleroderma renal crisis [1].*

New concept also includes the addition of ACE inhibitor responsiveness as a characteristic of hypertension (in *probable SRC*) and the addition of more specific time frames for measurement of blood pressure (taken twice, 2 hours apart, within

A new onset of blood pressure >150/85 mm Hg obtained at least twice over a consecutive 24-hour period. This blood pressure is chosen because it is defined by the New York Heart Association as significant

Decrease in the renal function as defined by a decrement of at least 10% in the estimated GFR (eGFR) or

**In order to corroborate further the occurrence of acute renal crisis, it would be desirable to have any of** 

• renal biopsy with typical features including onion skin proliferation within the walls of internal arteries

• Cases of typical SRC histological appearance have been associated with scleroderma in the absence of hypertension; these cases of normotensive SRC are reported to have a particularly poor outcome, and their precise relationship to the more typical hypertensive SRC is not known. Normotensive SRC was

• Up to one fifth of cases of SRC with hypertension have been identified as the presenting feature of systemic sclerosis, and so, in these cases, pre-existing diagnosis of systemic sclerosis will not be present.

. When possible, a repeat serum creatinine and recalculation of the GFR should

In addition to heterogeneity and rarity, the absence of a gold standard and classification criteria are important challenges for research on SRC. The development of new criteria is important to improve the definition of normotensive SRC. In this case, performing kidney biopsy and examination of biomarkers (including anti-

Kidney biopsy is not mandatory for diagnosis of SRC. In patients at risk of SRC with its typical clinical presentation, kidney biopsy is usually not performed. However, it should be considered in all patients with atypical presentation and findings, especially in normotensive patients, patients with ANCA positivity, severe

In most patients, we cannot perform kidney biopsy immediately as severe hypertension and frequently present thrombocytopenia significantly increase the risk of bleeding. Biopsy is usually performed within a few days after blood pressure correction and is done with reasonably low risk in patients with blood pressure

/l.

3 days of first event-associated observation) [10].

RNA III polymerase) are important and promising.

proteinuria, and nephrotic syndrome.

**2.5 Role of kidney biopsy in diagnosis of scleroderma renal crisis**

below 160/90 mmHg and thrombocyte count above 100 × 109

**46**

Identification of SRC predictive factors (before the development of SRC) is essential (**Table 2**). The vast majority of SRC cases (75–80%) occur in patients with diffuse skin involvement, i.e., skin scleroderma proximal to knee and elbow (dcSSc patients), and rapid progression of skin thickening has been shown to be associated with the development of SRC [12]. Arthritis, palpable tendon friction rubs, swollen fingers, and distal parts of hands are routine syndrome in patients with early dcSSc [13]. Tendon friction rubs were confirmed to be an independent predictor of SRC (HR: 2.33) [14].

SRC starts early, most often less than 4 years after the first SSc symptom, although SRC patients have minimal or even no skin changes at the time of the diagnosis of SRC. Males are proportionately more frequently affected than females [15].

On the other hand, patients previously called as CREST (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly and Telangiectasia) rarely develop SRC. These patients are subgroup of lcSSc fundamentally [12].

When talking about risk factors of death, a history of renal crisis (HR 2.89), presence of proteinuria (HR 3.09), elevated acute phase reactants (HR 1.79), elevated creatine kinase (HR 1.73), and muscle weakness (HR 1.55) were associated with decreased survival [5, 16]. On the other hand, since the introduction of ACE inhibitors, renal crisis appears to have become an increasingly less frequent terminal event [4]. In EUSTAR cohort, except one individual, all patients dying from renal crisis were on an ACE inhibitor at the time of death. Prednisone equivalents above 15 mg daily have been implicated in exacerbating SRC [5].

Several retrospective studies suggest that glucocorticoids are associated with a higher risk of SRC. Blood pressure and renal function should be carefully monitored in patients with SSc treated with glucocorticoids [17]. Evidence regarding the impact of steroid use on the development of SRC comes mainly from retrospective studies, most of which showed significant association between steroid exposure and the occurrence of SRC [11, 15, 18–22].

A retrospective analysis including 140 patients with SRC showed that high doses of steroids (prednisone ≥30 mg/day) were used frequently in patients with SSc with normotensive SRC (64%) as compared with those with hypertensive SRC (16%) suggesting an association between the use of high-dose steroids and the risk of normotensive SRC, which is associated with worse prognosis [11].

Glucocorticoids are routinely used for the management of interstitial lung disease, puffy fingers, and skin involvement. These indications are not recommended (because of insufficient evidence of efficacy); however, the experts recognize their use in everyday practice in the management of inflammatory manifestations such as musculoskeletal involvement (arthritis, tendonitis, myositis—in overlap with idiopathic inflammatory myopaties), pericarditis, pleuritis (in overlap with SLE), nonspecific symptoms such as skin itching/burning, fatigue, and appetite (with empiric basis) [17, 23]. Considering the potential risk of SRC associated with steroid use, the experts recommend that patients with SSc treated with steroids should be carefully monitored with respect to the development of SRC [17].

It can be summarized that glucocorticoids have a very narrow or no therapeutic opportunity in SSc.


Anti-RNA polymerase I/II/III presence ELISA anti-RNA polymerase III ≥157 IU Anti-centromere absence Anti-nRNP presence ANA speckled immunofluorescence lipocalin-2 high levels [24] sCD147 high levels [25] angiogenin high levels endothelin-1 high levels HLA-DRB1\*0407 HLA-DRB1\*1304

### **Risk factors developed during SSc**

Skin changes acceleration Hemoglobin, thrombocyte decrease Cardiac involvement—new *Pericarditis Congestive heart failure*

### **Drugs**

Cocaine [26] Glucocorticoid treatment Cyclosporine A Absence of calcium channel blocker

### **Factors without evidence of SRC risk**

Previous blood pressure arise Abnormal dip-stick and light proteinuria Chronic elevation of serum creatinine Presence of antibodies: anti-topoisomerase, anti-centromere

*SRC, scleroderma renal crisis; SSc, systemic sclerosis; FVC, forced lung vital capacity; DLCO, diffusing capacity for carbon monoxide; RNA, ribonucleic acid; ELISA, enzyme-linked immunosorbent assay; nRNP, nucleic ribonucleic protein; ANA, antinuclear antibodies; HLA, human leucocyte antigen.*

### **Table 2.**

*Clinical and laboratory predictors of scleroderma renal crisis and worse outcome. Adapted from Bose et al. [6].*

**49**

*Renal Involvement in Systemic Sclerosis DOI: http://dx.doi.org/10.5772/intechopen.87187*

may be also an early finding [1].

*2.7.3 Kidney injury, conditio sine qua non*

or worsening) on cardiac echocardiography [1].

*2.7.1 Early symptoms*

*2.7.2 Blood pressure*

guidelines [27].

overlaps [28].

*2.7.5 Target organ dysfunction*

*2.7.4 Cardiopulmonary system*

**2.7 Clinical manifestation of scleroderma renal crisis**

Sometimes SRC symptoms are nonspecific, for example, fatigue or not feeling well. Typically, patients complain of severe headache, blurred vision, or other encephalopathic symptoms with the onset of accelerated hypertension. Seizures

Most patients have striking increase of blood pressure at the onset of SRC. Above 90% patients have blood pressure levels >150/90 mm Hg, 30% have diastolic pressure >120 mm Hg, and <10% of SSc have a normal blood pressure. In addition to thinking about absolute values, clinically important risk factors arise of 30 mmHg

Acute kidney injury is defined as any of the following: increase in serum creatinine by >26.5 μmol/L (> 0.3 mg/dl) within 48 hours; increase in serum creatinine to >1.5 times baseline, which is known or presumed to have occurred within the prior 7 days, and urine volume <0.5 ml/kg/h for 6 hours. This is the definition of acute kidney injury from the Kidney Disease Improving Global Outcomes (KDIGO)

Patients with SRC often present with congestive heart failure presented as dyspnea, paroxysmal nocturnal dyspnea or pulmonary edema, serious ventricular arrhythmias, cardiac arrest, or large pericardial effusion [11]. Interestingly, this is primarily owing to the stress of hypertension on the heart, effects of hyperreninemia, and fluid overload secondary to oliguric renal failure. Some patients have primary scleroderma myocardial involvement contributing to these consecutive insults [1]. Acute pericarditis is diagnosed if the patient has at least 2 of the 4 following criteria: (1) pericarditis chest pain; (2) pericardial rub; (3) new widespread ST-elevation or PR depression on electrocardiogram; (4) pericardial effusion (new

Pulmonary hemorrhage is a rare life-threatening status, which has occurred in several of SRC patients [10]. Etiopathogenesis is associated with pulmonary edema and hemorrhagic diathesis. In differential diagnosis, diffuse alveolar hemorrhagia and acute renal failure were rarely observed in cases of ANCA systemic vasculitis and SSc

Typically, hypertensive retinopathy (hemorrhages, hard and soft (cotton wool) exudates, and/or disc edema, not attributable to other causes), confirmed by an ophthalmologist, is observed. Hypertensive encephalopathy is characterized by headache, altered mental status, seizures, visual disturbances, and/or other focal or diffuse neurologic signs not attributable to other causes. Acute congestive heart

systolic and 20 mmHg diastolic blood pressure (repeatedly measured) [1].

### **2.7 Clinical manifestation of scleroderma renal crisis**

### *2.7.1 Early symptoms*

*New Insights into Systemic Sclerosis*

Race—black Gender—male sex **SSc characteristics** Short course of SSc

*Heart failure Pericarditis*

*FVC <75% expected value DLCO low/decrease* Muscle involvement *Muscle weakness Higher creatine kinase level Myalgias or myopathy* Arthritis/Arthralgias **Genetics and biomarkers** Anti-RNA polymerase III presence Anti-RNA polymerase I/II/III presence ELISA anti-RNA polymerase III ≥157 IU

Anti-centromere absence Anti-nRNP presence

ANA speckled immunofluorescence lipocalin-2 high levels [24] sCD147 high levels [25] angiogenin high levels endothelin-1 high levels HLA-DRB1\*0407 HLA-DRB1\*1304

**Risk factors developed during SSc**

Skin changes acceleration Hemoglobin, thrombocyte decrease Cardiac involvement—new

*Congestive heart failure*

Glucocorticoid treatment Cyclosporine A

Previous blood pressure arise

Absence of calcium channel blocker **Factors without evidence of SRC risk**

Abnormal dip-stick and light proteinuria Chronic elevation of serum creatinine

Presence of antibodies: anti-topoisomerase, anti-centromere

*protein; ANA, antinuclear antibodies; HLA, human leucocyte antigen.*

*SRC, scleroderma renal crisis; SSc, systemic sclerosis; FVC, forced lung vital capacity; DLCO, diffusing capacity for carbon monoxide; RNA, ribonucleic acid; ELISA, enzyme-linked immunosorbent assay; nRNP, nucleic ribonucleic* 

*Clinical and laboratory predictors of scleroderma renal crisis and worse outcome. Adapted from Bose et al. [6].*

*Pericarditis*

**Drugs** Cocaine [26]

**SRC patient-specific characteristics**

Diffuse cutaneous systemic scleroderma Modified Rodnan skin score (>14 or 20) Musculoskeletal contractures Tendon friction rubs Pitting scars on finger tips Cardiopulmonary manifestation

**48**

**Table 2.**

Sometimes SRC symptoms are nonspecific, for example, fatigue or not feeling well. Typically, patients complain of severe headache, blurred vision, or other encephalopathic symptoms with the onset of accelerated hypertension. Seizures may be also an early finding [1].

### *2.7.2 Blood pressure*

Most patients have striking increase of blood pressure at the onset of SRC. Above 90% patients have blood pressure levels >150/90 mm Hg, 30% have diastolic pressure >120 mm Hg, and <10% of SSc have a normal blood pressure. In addition to thinking about absolute values, clinically important risk factors arise of 30 mmHg systolic and 20 mmHg diastolic blood pressure (repeatedly measured) [1].

### *2.7.3 Kidney injury, conditio sine qua non*

Acute kidney injury is defined as any of the following: increase in serum creatinine by >26.5 μmol/L (> 0.3 mg/dl) within 48 hours; increase in serum creatinine to >1.5 times baseline, which is known or presumed to have occurred within the prior 7 days, and urine volume <0.5 ml/kg/h for 6 hours. This is the definition of acute kidney injury from the Kidney Disease Improving Global Outcomes (KDIGO) guidelines [27].

### *2.7.4 Cardiopulmonary system*

Patients with SRC often present with congestive heart failure presented as dyspnea, paroxysmal nocturnal dyspnea or pulmonary edema, serious ventricular arrhythmias, cardiac arrest, or large pericardial effusion [11]. Interestingly, this is primarily owing to the stress of hypertension on the heart, effects of hyperreninemia, and fluid overload secondary to oliguric renal failure. Some patients have primary scleroderma myocardial involvement contributing to these consecutive insults [1].

Acute pericarditis is diagnosed if the patient has at least 2 of the 4 following criteria: (1) pericarditis chest pain; (2) pericardial rub; (3) new widespread ST-elevation or PR depression on electrocardiogram; (4) pericardial effusion (new or worsening) on cardiac echocardiography [1].

Pulmonary hemorrhage is a rare life-threatening status, which has occurred in several of SRC patients [10]. Etiopathogenesis is associated with pulmonary edema and hemorrhagic diathesis. In differential diagnosis, diffuse alveolar hemorrhagia and acute renal failure were rarely observed in cases of ANCA systemic vasculitis and SSc overlaps [28].

### *2.7.5 Target organ dysfunction*

Typically, hypertensive retinopathy (hemorrhages, hard and soft (cotton wool) exudates, and/or disc edema, not attributable to other causes), confirmed by an ophthalmologist, is observed. Hypertensive encephalopathy is characterized by headache, altered mental status, seizures, visual disturbances, and/or other focal or diffuse neurologic signs not attributable to other causes. Acute congestive heart

failure is characterized by typical symptoms (e.g., breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (e.g., elevated jugular venous pressure, pulmonary crackles, and peripheral edema) [1, 6].

### **2.8 Laboratory findings**

### *2.8.1 Autoantibodies*

Antinuclear antibodies (ANA) are hallmark of connective tissue diseases. In case of Raynaud phenomenon, puffy fingers, nailfold capillaroscopy finding with typical microvascular changes, and ANA can alert to the very early diagnosis of SSc and may determine etiology of malignant hypertension. ANA are seen in 95% of SSc.

The presence of scleroderma-specific antibodies may confirm SSc diagnosis, anti-topoisomerase I predicts diffuse SSc, but only 10% of SRC has anti-topoisomerase I positivity [6, 29] (**Figure 6**).

Anti-RNA polymerase III is a scleroderma-specific antibody and is seen only in diffuse scleroderma. About 24–33% of these patients develop SRC [30–32]. It was showed that anti-RNA polymerase is strongly associated with SRC, OR 6.4 [33]. This statement is valid with the exception of geographical variability. For example, the difference in prevalence of autoantibodies among SRC patients between the Italian and other population might originate from the lower prevalence of anti-RNA polymerase III among Italians [34]. Anti-RNA polymerase III is associated with worse prognosis of SRC including Dialysis, persistence on dialysis, and survival [1].

### **Figure 6.**

*Diagram showing subsets of systemic sclerosis associated with kidney involvement stratified by antibodies. Colored areas represent approximated proportion in patients. Adapted from Kuwana M and Medsger A [35]. SSc, systemic sclerosis; SRC, dSSc, diffuse cutaneous systemic sclerosis; lSSc, limited cutaneous systemic sclerosis; scleroderma renal crisis; anti-RNA polymerase III, anti-ribonucleic acid polymerase III antibodies; ANCA, anti-neutrophil cytoplasmic antibodies; anti-ds DNA, antibodies against double-stranded (ds) DNA.*

**51**

of SRC [1, 40].

*Renal Involvement in Systemic Sclerosis DOI: http://dx.doi.org/10.5772/intechopen.87187*

different interpretation of SRC [1, 6, 36].

• lupus nephritis, and

*2.10.1 Prevention*

**2.9 Differential diagnosis of scleroderma renal crisis**

The most common differential diagnoses are

*2.8.2 Microangiopathic hemolytic anemia and thrombocytopenia*

SRC is a disease characterized by thrombotic microangiopathy with typical blood laboratory findings—new or worsening anemia, presence of schistocytes or other red blood cell fragments in peripheral blood smear, and thrombocytopenia <100.000, confirmed by manual smear. Typical features are laboratory evidence of hemolysis, including elevated lactate dehydrogenase, reticulocytosis, and/or low/ absent haptoglobin and negative direct anti-globulin test. In differential diagnosis, other types of thrombotic microangiopathies need to be excluded (see **Table 3**). In some cases, thrombotic thrombocytopenic purpura has been reported in scleroderma patients, but it is unclear whether it was an isolated coexisting disease or a

• anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis,

Thrombotic thrombocytopenic purpura (TTP) /hemolytic-uremic syndrome (HUS)/disseminated intravascular coagulation (DIC)/heparin-induced thrombocytopenia (HIT)/ pre-eclampsia or HELLP syndrome refers to an acronym used to describe the clinical condition that leads to hemolysis, elevated liver enzymes, and

Other differential diagnoses reported included membranous and membranoproliferative nephropathies, other vasculitis (including polyarteritis nodosa, mixed cryoglobulinemia, and Goodpasture syndrome), drug-induced nephropathies (due to D-penicillamine or cyclosporin A), oxalate nephropathy, renal artery stenosis,

Despite significant decrease in incidence of SRC, no reliable preventive measures

Patients at risk should have their blood pressure controlled well. However, ACE inhibitors that are recommended for SRC treatment have not been shown to have protective effect before SRC onset and do not improve outcome of SRC [18, 19]. On the other hand, there are some reports of negative impact of ACE inhibitors on worse outcome of SRC, if ACE inhibitors were used in prevention

were identified. To decrease the risk of SRC development, we have to identify patients at high risk. Risk factors are discussed above (see chapter "Predictive and Risk Factors"), and we should take special caution in patients with dSS in the early stages of the disease (less than 5 years from diagnosis) with rapid progression of skin thickening, palpable tendon friction rubs, and anti-RNAP III antibodies [39]. Clinically, most important modifiable factor seems to be glucocorticoid treatment. Doses as high as 15 mg of prednisone are associated with increased incidence of

• diseases associated with thrombotic microangiopathy (**Table 4**).

low platelets/catastrophic antiphospholipid syndrome (CAPS), etc. [37].

and pre-renal causes (e.g., sepsis and dehydration) [10].

**2.10 Management of scleroderma renal crisis**

SRC in several studies (see below).

*New Insights into Systemic Sclerosis*

**2.8 Laboratory findings**

erase I positivity [6, 29] (**Figure 6**).

*2.8.1 Autoantibodies*

in 95% of SSc.

survival [1].

failure is characterized by typical symptoms (e.g., breathlessness, ankle swelling, and fatigue) that may be accompanied by signs (e.g., elevated jugular venous pres-

Antinuclear antibodies (ANA) are hallmark of connective tissue diseases. In case of Raynaud phenomenon, puffy fingers, nailfold capillaroscopy finding with typical microvascular changes, and ANA can alert to the very early diagnosis of SSc and may determine etiology of malignant hypertension. ANA are seen

The presence of scleroderma-specific antibodies may confirm SSc diagnosis, anti-topoisomerase I predicts diffuse SSc, but only 10% of SRC has anti-topoisom-

*Diagram showing subsets of systemic sclerosis associated with kidney involvement stratified by antibodies. Colored areas represent approximated proportion in patients. Adapted from Kuwana M and Medsger A [35]. SSc, systemic sclerosis; SRC, dSSc, diffuse cutaneous systemic sclerosis; lSSc, limited cutaneous systemic sclerosis; scleroderma renal crisis; anti-RNA polymerase III, anti-ribonucleic acid polymerase III antibodies; ANCA, anti-neutrophil cytoplasmic antibodies; anti-ds DNA, antibodies against double-stranded (ds) DNA.*

Anti-RNA polymerase III is a scleroderma-specific antibody and is seen only in diffuse scleroderma. About 24–33% of these patients develop SRC [30–32]. It was showed that anti-RNA polymerase is strongly associated with SRC, OR 6.4 [33]. This statement is valid with the exception of geographical variability. For example, the difference in prevalence of autoantibodies among SRC patients between the Italian and other population might originate from the lower prevalence of anti-RNA polymerase III among Italians [34]. Anti-RNA polymerase III is associated with worse prognosis of SRC including Dialysis, persistence on dialysis, and

sure, pulmonary crackles, and peripheral edema) [1, 6].

**50**

**Figure 6.**

### *2.8.2 Microangiopathic hemolytic anemia and thrombocytopenia*

SRC is a disease characterized by thrombotic microangiopathy with typical blood laboratory findings—new or worsening anemia, presence of schistocytes or other red blood cell fragments in peripheral blood smear, and thrombocytopenia <100.000, confirmed by manual smear. Typical features are laboratory evidence of hemolysis, including elevated lactate dehydrogenase, reticulocytosis, and/or low/ absent haptoglobin and negative direct anti-globulin test. In differential diagnosis, other types of thrombotic microangiopathies need to be excluded (see **Table 3**). In some cases, thrombotic thrombocytopenic purpura has been reported in scleroderma patients, but it is unclear whether it was an isolated coexisting disease or a different interpretation of SRC [1, 6, 36].

### **2.9 Differential diagnosis of scleroderma renal crisis**

The most common differential diagnoses are


Thrombotic thrombocytopenic purpura (TTP) /hemolytic-uremic syndrome (HUS)/disseminated intravascular coagulation (DIC)/heparin-induced thrombocytopenia (HIT)/ pre-eclampsia or HELLP syndrome refers to an acronym used to describe the clinical condition that leads to hemolysis, elevated liver enzymes, and low platelets/catastrophic antiphospholipid syndrome (CAPS), etc. [37].

Other differential diagnoses reported included membranous and membranoproliferative nephropathies, other vasculitis (including polyarteritis nodosa, mixed cryoglobulinemia, and Goodpasture syndrome), drug-induced nephropathies (due to D-penicillamine or cyclosporin A), oxalate nephropathy, renal artery stenosis, and pre-renal causes (e.g., sepsis and dehydration) [10].

### **2.10 Management of scleroderma renal crisis**

### *2.10.1 Prevention*

Despite significant decrease in incidence of SRC, no reliable preventive measures were identified. To decrease the risk of SRC development, we have to identify patients at high risk. Risk factors are discussed above (see chapter "Predictive and Risk Factors"), and we should take special caution in patients with dSS in the early stages of the disease (less than 5 years from diagnosis) with rapid progression of skin thickening, palpable tendon friction rubs, and anti-RNAP III antibodies [39]. Clinically, most important modifiable factor seems to be glucocorticoid treatment. Doses as high as 15 mg of prednisone are associated with increased incidence of SRC in several studies (see below).

Patients at risk should have their blood pressure controlled well. However, ACE inhibitors that are recommended for SRC treatment have not been shown to have protective effect before SRC onset and do not improve outcome of SRC [18, 19]. On the other hand, there are some reports of negative impact of ACE inhibitors on worse outcome of SRC, if ACE inhibitors were used in prevention of SRC [1, 40].

