*Differential diagnosis of thrombotic microangiopathies from the view of scleroderma renal crisis. Adapted from Cervera et al. [37].*

**53**

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

Overlaps with connective tissue disease with

glomerulonephritis (SLE)

Thrombotic microangiopathies

*with a thrombospondin type 1 motif, member 13.*

**Event Differences from SRC** Essential hypertension Without acute renal failure

ANCA-associated glomerulonephritis ANCA positivity, significant Proteinuria,

Renal artery stenosis Absence of systemic symptoms

*Pre-eclampsia Pregnancy Hemolytic uremic syndrome Shigella toxin Thrombocytic thrombocytopenic purpura ADAMTS13 antibody Catastrophic antiphospholipid syndrome Antiphospholipid antibodies*

*Heparin-induced thrombocytopenia Heparin treatment*

*Differential diagnosis of scleroderma renal crisis. Adapted from Bose et al. [6].*

hematuria [38]

antibodies

Anti-dsDNA positivity, other CTD-specific

*2.10.2 Early diagnosis*

**Table 4.**

Therefore, other antihypertensive drugs should be used to treat primary hyperten

sion in these patients. Calcium channel blockers are a preferred option, as these drugs are effective in controlling blood pressure and a positive vasodilatory effect [41].

*Other conditions: membranous nephropathy, drug-induced nephropathies (e.g., cyclosporin A), other vasculitis (e.g., polyarteritis nodosa, mixed cryoglobulinemia, and Goodpasture syndrome), oxalate nephropathy, membranoproliferative nephropathy, pre-renal causes (e.g., sepsis, dehydration, and cardiac or pulmonary vascular involvement), and isolated renal abnormalities. SRC, scleroderma renal crisis; ANCA, antibodies against neutrophils; SLE, systemic lupus erythematosus; CTD, connective tissue diseases; ADAMTS13, a disintegrin and metalloproteinase* 

Early diagnosis and treatment can significantly improve prognosis of the patients. Patients at risk should be instructed to monitor blood pressure at home at least twice a week. They should report sudden increase in blood pressure and blood pressure above 140/90 mmHg. These patients should have their blood pressure quickly normalized and should be evaluated for possible SRC development (evalua

Current treatment of SSc focuses on broad-spectrum immunosuppression or organ-based therapy for separate manifestations such as lung fibrosis, skin and gastrointestinal involvement, pulmonary or systemic hypertension, and kidney impairment [1]. The treatment of SRC is based on three main principles: causal treatment with ACE inhibitors, methods of renal function replacement, and plasma exchange in some patients. For organ complications, supportive treatment is used. SRC without treatment is often lethal. SRC patients should be treated immediately

advisable to admit patients with symptomatic hypertension to intensive care units.

The key to improved outcome is treatment with ACE inhibitors. It should be initiated as soon as possible. Captopril is the preferred option. It has been used in

and aggressively with hospitalization and under careful control (**Figure**

tion of kidney function, presence of MAHA, etc.).

*2.10.3.1 Angiotensin-converting enzyme inhibitors*

*2.10.3 Treatment of scleroderma renal crisis*



**7**) [1]. It is


*Other conditions: membranous nephropathy, drug-induced nephropathies (e.g., cyclosporin A), other vasculitis (e.g., polyarteritis nodosa, mixed cryoglobulinemia, and Goodpasture syndrome), oxalate nephropathy, membranoproliferative nephropathy, pre-renal causes (e.g., sepsis, dehydration, and cardiac or pulmonary vascular involvement), and isolated renal abnormalities. SRC, scleroderma renal crisis; ANCA, antibodies against neutrophils; SLE, systemic lupus erythematosus; CTD, connective tissue diseases; ADAMTS13, a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13.*

### **Table 4.**

*New Insights into Systemic Sclerosis*

**52**

**History and** 

**Scleroderma renal** 

**CAPS**

**TTP-HUS**

**HELLP** 

**Sepsis**

**DIC**

**HIT**

**syndrome**

**crisis**

**condition**

Previous history

Thrombosis Hemolytic anemia

Schistocytes

Fibrinogen Typical antibodies

III

anti-RNA polymerase

aPL

Normal/high

Normal/high

+

+

−/+ −/+

++ ++ Normal/high

ADAMTS13 *TTP, thrombotic thrombocytopenic purpura; HUS, hemolytic uremic syndrome; DIC, disseminated intravascular coagulation; HELLP, hemolysis, elevated liver enzymes and low platelets syndrome; HIT,* 

*heparin-induced thrombocytopenia; APS, antiphospholipid syndrome; CAPS, catastrophic antiphospholipid syndrome; SLE, systemic lupus erythematosus; aPL, antiphospholipid antibodies; ADAMTS13, a* 

*disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; PF-4, platelet factor 4.*

*Differential diagnosis of thrombotic microangiopathies from the view of scleroderma renal crisis. Adapted from Cervera et al. [37].*

**Table 3.**

None

None

None

Normal/high

Normal/low

Normal/low

Normal/high

Anti-PF-4

+

+

−/+ −/+

−/+

−/+

—

—

Small vessels

Systemic sclerosis

APS/SLE/malignancy/

Malignancy/

pregnancy

infection

Infection/

Heparin exposure

malignancy

Small vessels

Large/small

vessels

non

Small vessels

Small vessels

Large/small

vessels

pregnancy

Large/small vessels

*Differential diagnosis of scleroderma renal crisis. Adapted from Bose et al. [6].*

Therefore, other antihypertensive drugs should be used to treat primary hypertension in these patients. Calcium channel blockers are a preferred option, as these drugs are effective in controlling blood pressure and a positive vasodilatory effect [41].

### *2.10.2 Early diagnosis*

Early diagnosis and treatment can significantly improve prognosis of the patients. Patients at risk should be instructed to monitor blood pressure at home at least twice a week. They should report sudden increase in blood pressure and blood pressure above 140/90 mmHg. These patients should have their blood pressure quickly normalized and should be evaluated for possible SRC development (evaluation of kidney function, presence of MAHA, etc.).

### *2.10.3 Treatment of scleroderma renal crisis*

Current treatment of SSc focuses on broad-spectrum immunosuppression or organ-based therapy for separate manifestations such as lung fibrosis, skin and gastrointestinal involvement, pulmonary or systemic hypertension, and kidney impairment [1]. The treatment of SRC is based on three main principles: causal treatment with ACE inhibitors, methods of renal function replacement, and plasma exchange in some patients. For organ complications, supportive treatment is used. SRC without treatment is often lethal. SRC patients should be treated immediately and aggressively with hospitalization and under careful control (**Figure 7**) [1]. It is advisable to admit patients with symptomatic hypertension to intensive care units.

### *2.10.3.1 Angiotensin-converting enzyme inhibitors*

The key to improved outcome is treatment with ACE inhibitors. It should be initiated as soon as possible. Captopril is the preferred option. It has been used in

### **Figure 7.**

*Management of scleroderma renal crisis, adapted from Lynch et al. [50]. ACEi, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; DBP, diastolic blood pressure; HDU, high dependency unit; ITU, intensive therapy unit; MAP, mean arterial pressure; SBP, systolic blood pressure.*

most studies and its short-acting character enables good titration at the start of the treatment. It is usually necessary to use very high doses. Blood pressure should be brought back to normal levels within 2–4 days.

ACE inhibitors have complex effect and decrease blood pressure and plasma renin activity. The dramatic response to therapeutic inhibition of the reninangiotensin system in SRC implicates renin overproduction as a central part of the pathogenesis of SRC [1, 42].

Several cohort studies showed benefit in survival with the use of ACE inhibitors in patients with SRC. The experts recommend immediate use of ACE inhibitors in the treatment of SRC [11, 17–19, 29, 43–48]. Prospective analysis of 108 patients with SRC has suggested that patients on ACE inhibitors (captopril in 47 and enalapril in 8) had a significantly better 1 year survival rate (76%) and 5 years (66%) compared to patients without ACE inhibitors (15% at one and 10% at 5 years, respectively). Treatment with ACE inhibitors was significantly associated with better survival in SRC, after adjustment for age and blood pressure (p < 0.001) [29, 49, 50]. Two recent retrospective studies including 91 and 110 patients with SRC, respectively, the majority of whom (91 and 98% respectively) were treated with ACE inhibitors and/or angiotensin receptor antagonists (ARA), reported survival rates from 71–82% at 1 year, 59–60% at 5 years, and 42–47% at 10 years [19, 47]. Other anti-hypertensive agents may be considered for management of refractory hypertension in conjunction with an ACE inhibitor in SRC, including ARA, calcium channel blockers, doxazosin, and clonidine [1, 49]. Beta-blockers are not appropriate, as they affect peripheral circulation.

It can be summarized that survival benefit was shown with the use of ACE inhibitors in patients with SRC. Experts recommend immediate use of ACE inhibitors in the treatment of SRC [17].

**55**

warranted.

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

A patient with SRC is, from a definition, the one with acute kidney injury and should be managed in cooperation with a nephrologist. Thus, recommendation for acute kidney injury should be applied including regular monitoring of kidney function, minimization of nephrotoxic medication, etc. During first days of SRC treatment, serum creatinine levels usually increase. This is an anticipated decrease in glomerular filtration that should not discourage us from intensive blood pressure

Renal replacement therapy should be initiated if necessary. Both hemodialysis and peritoneal dialysis are possible alternatives. However, hemodialysis is a preferred option. ACE inhibitor treatment should continue long term, even in patients on chronic renal replacement therapy, especially in patients with possible recovery

In chronic hemodialysis patients, kidney transplantation has to be considered. There are two particular details in SSc patients that should be discussed: first, there is a possibility of late recovery of kidney function and, second, there is historically reported bad outcome of transplanted SSc patients. Indeed, patients with SRC may recover renal function up to 3 years after the crisis, most often within 12–18 months [50]. Thus, many authors recommend that decision to transplant should not be made before 2 years after SRC onset [17]. Patients after SRC on hemodialysis treatment should therefore be regularly checked for signs of recovery of kidney function. But in general, postponing kidney transplant in hemodialysis patients could worsen their prognosis. It seems prudent that in patients without significant residual renal function, without signs of kidney recovery and unfavorable findings on kidney biopsy (if done) such as vascular thrombosis and glomerular ischemic

collapse, we consider kidney transplant in 6 months from SRC [51].

have shown excellent patient and graft survival [52].

transplantation has to be considered [53].

1–2 years after transplantation [53, 54].

at high risk of SRC development [52].

described risk factors [53–55].

Older studies reported bad outcome of SSc patients after kidney transplant compared to patients with other causes of kidney failure. However, recent studies

Generally, on the other hand, long-term dialysis increases the risk of death. Independent of the underlying disease, dialysis increases the risk of infection (in patients undergoing peritoneal dialysis) and, over the long term, enhances the risk of vascular calcification and atherosclerosis. In patients on chronic dialysis, kidney

In a series of 260 SSc patients who underwent renal transplantation in the United States, their 5-year graft-survival rate was 56.7% [53]. In that study, the risk of SRC recurrence was higher for patients with early renal insufficiency following SRC onset. Recurrent SRC in the allograft may be predicted by the same previously

For those with recurrent SRC, the time of onset following transplantation is not known. Recurrence usually happens within the first few months to the first

Kidney transplantation should therefore be considered in all SSc patients with the need of renal replacement therapy. What has not changed over the last decade is that only small percentage of patients with SSc is transplanted due to severe extrarenal disease. Thorough work-up before enrolling a patient on waiting list is

Both recurrence of SRC after kidney transplantation and graft loss due to SRC recurrence have been reported. Recurrence rate is fortunately low (8.8%) and patients after kidney transplant should be monitored similarly to patients with SSc

*2.10.3.2 Acute kidney injury*

control [27].

of renal function.

### *2.10.3.2 Acute kidney injury*

*New Insights into Systemic Sclerosis*

most studies and its short-acting character enables good titration at the start of the treatment. It is usually necessary to use very high doses. Blood pressure should be

*Management of scleroderma renal crisis, adapted from Lynch et al. [50]. ACEi, angiotensin-converting enzyme inhibitor; AKI, acute kidney injury; ARB, angiotensin receptor blocker; DBP, diastolic blood pressure; HDU, high dependency unit; ITU, intensive therapy unit; MAP, mean arterial pressure; SBP, systolic blood pressure.*

ACE inhibitors have complex effect and decrease blood pressure and plasma

Several cohort studies showed benefit in survival with the use of ACE inhibitors in patients with SRC. The experts recommend immediate use of ACE inhibitors in the treatment of SRC [11, 17–19, 29, 43–48]. Prospective analysis of 108 patients with SRC has suggested that patients on ACE inhibitors (captopril in 47 and enalapril in 8) had a significantly better 1 year survival rate (76%) and 5 years (66%) compared to patients without ACE inhibitors (15% at one and 10% at 5 years, respectively). Treatment with ACE inhibitors was significantly associated with better survival in SRC, after adjustment for age and blood pressure (p < 0.001) [29, 49, 50]. Two recent retrospective studies including 91 and 110 patients with SRC, respectively, the majority of whom (91 and 98% respectively) were treated with ACE inhibitors and/or angiotensin receptor antagonists (ARA), reported survival rates from 71–82% at 1 year, 59–60% at 5 years, and 42–47% at 10 years [19, 47]. Other anti-hypertensive agents may be considered for management of refractory hypertension in conjunction with an ACE inhibitor in SRC, including ARA, calcium channel blockers, doxazosin, and clonidine [1, 49]. Beta-blockers are not appropri-

It can be summarized that survival benefit was shown with the use of ACE inhibitors in patients with SRC. Experts recommend immediate use of ACE inhibi-

renin activity. The dramatic response to therapeutic inhibition of the reninangiotensin system in SRC implicates renin overproduction as a central part of the

brought back to normal levels within 2–4 days.

ate, as they affect peripheral circulation.

tors in the treatment of SRC [17].

pathogenesis of SRC [1, 42].

**Figure 7.**

**54**

A patient with SRC is, from a definition, the one with acute kidney injury and should be managed in cooperation with a nephrologist. Thus, recommendation for acute kidney injury should be applied including regular monitoring of kidney function, minimization of nephrotoxic medication, etc. During first days of SRC treatment, serum creatinine levels usually increase. This is an anticipated decrease in glomerular filtration that should not discourage us from intensive blood pressure control [27].

Renal replacement therapy should be initiated if necessary. Both hemodialysis and peritoneal dialysis are possible alternatives. However, hemodialysis is a preferred option. ACE inhibitor treatment should continue long term, even in patients on chronic renal replacement therapy, especially in patients with possible recovery of renal function.

In chronic hemodialysis patients, kidney transplantation has to be considered. There are two particular details in SSc patients that should be discussed: first, there is a possibility of late recovery of kidney function and, second, there is historically reported bad outcome of transplanted SSc patients. Indeed, patients with SRC may recover renal function up to 3 years after the crisis, most often within 12–18 months [50]. Thus, many authors recommend that decision to transplant should not be made before 2 years after SRC onset [17]. Patients after SRC on hemodialysis treatment should therefore be regularly checked for signs of recovery of kidney function. But in general, postponing kidney transplant in hemodialysis patients could worsen their prognosis. It seems prudent that in patients without significant residual renal function, without signs of kidney recovery and unfavorable findings on kidney biopsy (if done) such as vascular thrombosis and glomerular ischemic collapse, we consider kidney transplant in 6 months from SRC [51].

Older studies reported bad outcome of SSc patients after kidney transplant compared to patients with other causes of kidney failure. However, recent studies have shown excellent patient and graft survival [52].

Generally, on the other hand, long-term dialysis increases the risk of death. Independent of the underlying disease, dialysis increases the risk of infection (in patients undergoing peritoneal dialysis) and, over the long term, enhances the risk of vascular calcification and atherosclerosis. In patients on chronic dialysis, kidney transplantation has to be considered [53].

In a series of 260 SSc patients who underwent renal transplantation in the United States, their 5-year graft-survival rate was 56.7% [53]. In that study, the risk of SRC recurrence was higher for patients with early renal insufficiency following SRC onset. Recurrent SRC in the allograft may be predicted by the same previously described risk factors [53–55].

For those with recurrent SRC, the time of onset following transplantation is not known. Recurrence usually happens within the first few months to the first 1–2 years after transplantation [53, 54].

Kidney transplantation should therefore be considered in all SSc patients with the need of renal replacement therapy. What has not changed over the last decade is that only small percentage of patients with SSc is transplanted due to severe extrarenal disease. Thorough work-up before enrolling a patient on waiting list is warranted.

Both recurrence of SRC after kidney transplantation and graft loss due to SRC recurrence have been reported. Recurrence rate is fortunately low (8.8%) and patients after kidney transplant should be monitored similarly to patients with SSc at high risk of SRC development [52].

Immunosuppression given to SSc patients after kidney transplant alters the course of the disease. Most of the patients after kidney transplant have stable disease or even improve symptoms. Regarding immunosuppressive regimens after kidney transplant, it is difficult to make any evidence-based conclusions. Most patients were treated with high-dose steroids at the time of transplantation followed by long-term low doses in combination with calcineurin inhibitors and mycophenolate mofetil. A significant number of patients were weaned from steroids with reasonable outcome, but recommendations cannot be made due to limited number of patients [52].

### *2.10.3.3 Plasma exchange*

Plasma exchange, which has been proposed for thrombotic microangiopathy, has not demonstrated efficacy and should not be prescribed, with the exception of the rare SRC patients who might develop thrombotic microangiopathy associated with anti-ADAMTS-13 antibodies [54]. There are no clinical trial data for use of plasma exchange in SRC.

### **3. Nonscleroderma renal crisis involvement of kidney in systemic sclerosis**

### **3.1 Intersticial kidney changes/disease**

Clinically relevant renal involvement (non-SRC) in SSc is uncommon [55]. Asymptomatic and slowly progressive renal involvement is present in 60–80% of SSc patients. In more than half of asymptomatic SSc patients, renal function demonstrates clinical markers of renal damage (proteinuria, elevation of serum creatinine, hypertension, etc.) [32, 56–58]. These patients presented with evidence of underlying chronic renal disease but without confounding illnesses such as diabetes or hypertension existing prior to the onset of their SSc. Histological findings showed expressions of fibrillar collagens. In some SSc cases, drug exposure may explain interstitial kidney changes [6]. It is unclear whether SSc cases are more susceptible to this, but interstitial nephritis remains an important differential diagnosis.

### **3.2 Glomerulonephritis**

Glomerulonephritis occurs in the context of overlap connective tissue disease or systemic vasculitis. In other words, SSc should be associated with other immunopathological diseases presented by glomerulonephritis, mainly systemic lupus erythematosus and ANCA-associated glomerulonephritis [59].

Circulating antimyeloperoxidase antibodies have been reported in several patients with dcSSc associated with necrotizing and crescentic glomerulonephritis [1, 58]. A study of 81 SSc patients with renal impairment found 2 patients with lcSSc with perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) along with circulating IgG and IgM antimyeloperoxidase antibodies. After screening for ANCA in SSc by indirect immunofluorescence, the levels of IgM and IgG anti-MPO antibodies in 8 patients (8%) with SSc were determined by ELISA [60]. In conclusion, the presence of ANCA in SSc patients should predict ANCA-associated vasculitis. The treatment of these associated glomerulonephritis is managed according to the principles of treatment of the overlapping renal diseases (**Figure 8**).

**57**

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

**4. Conclusion**

**Figure 8.**

*University.*

therapeutic possibilities are needed.

**Acknowledgements**

AZV-16-33542A.

SRC is a rare manifestation with dramatic clinical picture and high morbidity and mortality. Current strategies to reduce the associated morbidity and mortality include identification of at-risk patients to aid early diagnosis. Caution should be exercised in diagnosis of SSc cases with serological features of renal disease including anti-RNA polymerase III autoantibodies, for non-SRC renal disease SLE serology and ANCA positivity. ACE inhibitor therapy should be lifelong in all SRC patients. Prompt initiation of ACE inhibitors stays a key point in SRC therapy. New

*Normotensive patient with systemic sclerosis and acute renal failure underwent renal biopsy. End-stage kidney disease: crescentic glomerulonephritis showing fibrous crescents. A mixed mononuclear cell infiltrate and considerable tubular loss are shown. Hematoxylin-eosin staining, magnification 200 times. Courtesy of Miroslav Podhola, MD., PhD., Department of Pathology, Faculty of Medicine in Hradec Kralove, Charles* 

This work was supported by MH CZ—DRO UHHK, grant number 00179906; Charles University research projects [PROGRES Q40-15]; and MHCR 023728 and *Renal Involvement in Systemic Sclerosis DOI: http://dx.doi.org/10.5772/intechopen.87187*

### **Figure 8.**

*New Insights into Systemic Sclerosis*

of patients [52].

exchange in SRC.

**sclerosis**

diagnosis.

**3.2 Glomerulonephritis**

**3.1 Intersticial kidney changes/disease**

*2.10.3.3 Plasma exchange*

Immunosuppression given to SSc patients after kidney transplant alters the course of the disease. Most of the patients after kidney transplant have stable disease or even improve symptoms. Regarding immunosuppressive regimens after kidney transplant, it is difficult to make any evidence-based conclusions. Most patients were treated with high-dose steroids at the time of transplantation followed by long-term low doses in combination with calcineurin inhibitors and mycophenolate mofetil. A significant number of patients were weaned from steroids with reasonable outcome, but recommendations cannot be made due to limited number

Plasma exchange, which has been proposed for thrombotic microangiopathy, has not demonstrated efficacy and should not be prescribed, with the exception of the rare SRC patients who might develop thrombotic microangiopathy associated with anti-ADAMTS-13 antibodies [54]. There are no clinical trial data for use of plasma

**3. Nonscleroderma renal crisis involvement of kidney in systemic** 

Clinically relevant renal involvement (non-SRC) in SSc is uncommon [55]. Asymptomatic and slowly progressive renal involvement is present in 60–80% of SSc patients. In more than half of asymptomatic SSc patients, renal function demonstrates clinical markers of renal damage (proteinuria, elevation of serum creatinine, hypertension, etc.) [32, 56–58]. These patients presented with evidence of underlying chronic renal disease but without confounding illnesses such as diabetes or hypertension existing prior to the onset of their SSc. Histological findings showed expressions of fibrillar collagens. In some SSc cases, drug exposure may explain interstitial kidney changes [6]. It is unclear whether SSc cases are more susceptible to this, but interstitial nephritis remains an important differential

Glomerulonephritis occurs in the context of overlap connective tissue disease or systemic vasculitis. In other words, SSc should be associated with other immunopathological diseases presented by glomerulonephritis, mainly systemic lupus

Circulating antimyeloperoxidase antibodies have been reported in several patients with dcSSc associated with necrotizing and crescentic glomerulonephritis [1, 58]. A study of 81 SSc patients with renal impairment found 2 patients with lcSSc with perinuclear anti-neutrophil cytoplasmic antibodies (p-ANCA) along with circulating IgG and IgM antimyeloperoxidase antibodies. After screening for ANCA in SSc by indirect immunofluorescence, the levels of IgM and IgG anti-MPO antibodies in 8 patients (8%) with SSc were determined by ELISA [60]. In conclusion, the presence of ANCA in SSc patients should predict ANCA-associated vasculitis. The treatment of these associated glomerulonephritis is managed according to

the principles of treatment of the overlapping renal diseases (**Figure 8**).

erythematosus and ANCA-associated glomerulonephritis [59].

**56**

*Normotensive patient with systemic sclerosis and acute renal failure underwent renal biopsy. End-stage kidney disease: crescentic glomerulonephritis showing fibrous crescents. A mixed mononuclear cell infiltrate and considerable tubular loss are shown. Hematoxylin-eosin staining, magnification 200 times. Courtesy of Miroslav Podhola, MD., PhD., Department of Pathology, Faculty of Medicine in Hradec Kralove, Charles University.*

### **4. Conclusion**

SRC is a rare manifestation with dramatic clinical picture and high morbidity and mortality. Current strategies to reduce the associated morbidity and mortality include identification of at-risk patients to aid early diagnosis. Caution should be exercised in diagnosis of SSc cases with serological features of renal disease including anti-RNA polymerase III autoantibodies, for non-SRC renal disease SLE serology and ANCA positivity. ACE inhibitor therapy should be lifelong in all SRC patients. Prompt initiation of ACE inhibitors stays a key point in SRC therapy. New therapeutic possibilities are needed.

### **Acknowledgements**

This work was supported by MH CZ—DRO UHHK, grant number 00179906; Charles University research projects [PROGRES Q40-15]; and MHCR 023728 and AZV-16-33542A.

*New Insights into Systemic Sclerosis*

### **Author details**

Tomas Soukup1 \*, Jan Toms1 , Sabina Oreska<sup>2</sup> , Eva Honsova<sup>3</sup> and Roman Safranek4

1 Division of Rheumatology, 2nd Department of Gastroenterology, Charles University, Hradec Kralove, Czech Republic

2 Department of Rheumatology, Institute of Rheumatology, Charles University, Prague, Czech Republic

3 Department of Clinical and Transplant Pathology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic

4 Division of Nephrology, Haemodialysis Centre, Charles University, Hradec Kralove, Czech Republic

\*Address all correspondence to: tomas.soukup@fnhk.cz

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**59**

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

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