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VOLUME
Vol.05 Issue03 2025
PAGE NO.
31-35
10.37547/ijmscr/Volume05Issue03-06
Renal problems in scleroderma: pathogenesis, clinical
manifestations, and modern treatment methods
Pulatova Sh.B.
Tashkent Medical Academy, Tashkent, Uzbekistan
Allamurodova N.A.
Tashkent Medical Academy, Tashkent, Uzbekistan
Received:
29 January 2025;
Accepted:
28 February 2025;
Published:
31 March 2025
Abstract:
Systemic sclerosis (SSc) is an autoimmune disease of connective tissue characterized by fibrosis of the
skin and internal organs, vascular damage, and immunological changes. One of the most severe complications is
renal involvement, particularly scleroderma renal crisis (SRC). Renal crisis is one of the most serious complications
of SSc and often occurs in diffuse SSc. This article discusses the pathogenesis, clinical manifestations, diagnostic
methods, and modern approaches to treatment of renal involvement in SSc.
Keywords:
Systemic sclerosis, scleroderma renal crisis, chronic kidney disease, renovascular hypertension,
antifibrotic therapy.
Introduction:
SSc is an autoimmune disease
characterized by impaired collagen turnover and
progressive fibrosis of connective tissues. The disease
affects various internal organs, including the
cardiovascular system, lungs, digestive system, and
kidneys. Renal involvement in SSc is a serious
complication that significantly impacts the patient's
quality of life and prognosis. Sclerodermic renal
involvement, related to SSc, is a pathological process
that develops slowly and manifests as progressive
kidney failure [1, 8]. This condition is observed in a
significant portion of patients with SSc and is mainly
associated with fibrosis of the renal glomeruli,
interstitial tissue, and blood vessels. Due to its slow
progression, sclerodermic renal involvement often
does not manifest clinically in the early stages and can
only be detected through laboratory tests. Another
form of renal damage in SSc is SRC, which presents with
sudden onset of severe hypertension, kidney failure,
and microangiopathic hemolytic anemia. SRC is
distinguished by its acute and severe progression, while
sclerodermic renal involvement is a chronic and slowly
progressing process. According to some researchers,
scleroderma renal crisis occurs in 5-20% of patients
with systemic sclerosis. The disease mainly develops
within the first 3-5 years. Among patients with
scleroderma renal crisis, 40-50% lose their ability to
work due to long-term complications. The mortality
rate is 10-20%. In systemic sclerosis, various clinical and
morphological forms of nephrological diseases occur,
and although their development depends on several
factors, all of them affect kidney function. In cases of
proteinuria or mild kidney dysfunction, the glomerular
filtration rate (GFR) is 60-90 ml/min/1.73m². With the
onset of scleroderma renal crisis, the GFR rapidly
decreases and may drop below 30 ml/min/1.73m²,
leading to the development of chronic kidney disease
[2]. SSc is a rare but severe systemic disease
characterized by endothelial dysfunction, tissue
fibrosis, and abnormal immune responses. Renal
involvement occurs in 20-50% of patients, and in 10-
15% of cases, kidney failure develops, which is a life-
threatening condition. This article provides an
overview of the pathogenesis, clinical manifestations,
and treatment of renal complications in SSc.
Clinical Features
Hypertension: This is a common problem in patients
with SSc. Blood pressure remains consistently high,
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International Journal of Medical Sciences And Clinical Research (ISSN: 2771-2265)
leading to impaired kidney function. Proteinuria:
Kidney damage causes protein loss in the div, which,
in turn, leads to nephrotic syndrome. Increased
Creatinine and Urea Levels: Due to worsening kidney
function, kidney dysfunction can result in the
accumulation of toxic substances in the div. Azotemia
and Uremia: These conditions are characterized by an
increased concentration of nitrogenous compounds in
the blood, which occur when kidney filtration function
is impaired. If kidney function fails, nitrogenous waste
products accumulate, leading to poisoning of the div.
Pathogenesis of Renal Involvement in SSc Scleroderma
Renal Crisis is the most dangerous and acute
manifestation of renal involvement, typically occurring
in the diffuse form of systemic sclerosis. This condition
is observed in 10-20% of patients and can lead to severe
kidney failure [3]. Main Features of SRC: Severe
Hypert
ension (≥180/100 mmHg): This appears as a
hypertensive crisis. Headache, Visual Impairment:
Damage to the eye blood vessels may occur due to
hypertension. Nausea, Vomiting: These symptoms arise
from decreased kidney function. Proteinuria (protein in
urine): Caused by impaired kidney filtration.
Microangiopathic Hemolytic Anemia: Destruction and
breakdown of blood cells. Oliguria or Anuria: Reduced
urine output or complete cessation of urine
production. Rapidly Progressive Kidney Failure: If
treatment is delayed, kidney function can completely
cease within a few days [4].
Slowly progressive kidney failure. In some patients,
kidney damage develops slowly and may remain
unnoticed for a long period. Main Clinical Features:
Normal or Slightly Elevated Blood Pressure: Unlike
acute SRC, blood pressure does not increase sharply.
Proteinuria (protein in urine) and Hematuria (blood in
urine): Mild or moderate in severity. Decreased Kidney
Filtration Function: Creatinine and urea levels gradually
increase. Edema (swelling): More prominent in the
face, hands, and feet. Oliguria or Anuria: Reduced urine
output or complete cessation of urine production.
Chronic Kidney Disease (CKD): This can develop over
several years [5]. Chronic Renal Failure (CRF): A
pathological condition where kidney function gradually
deteriorates due to prolonged kidney diseases. This
disease decreases the kidneys' ability to filter blood,
leading to the accumulation of toxins and excess fluid
in the div. Causes of CRF: CRF often develops as a
result of other chronic diseases. Main Causes of CRF:
Diabetes (Diabetic Nephropathy) Hypertension (High
Blood Pressure) Glomerulonephritis (Inflammation of
the kidney glomeruli) Polycystic Kidney Disease
Autoimmune Diseases (such as scleroderma, lupus)
Frequent
Recurring
Pyelonephritis
Medications
(NSAIDs, some antibiotics, and toxic substances) [6].
Stages of CRF: CRF develops gradually and may be
unnoticed in the early stages. However, as the disease
progresses, the following symptoms may appear:
Fatigue and weakness itchy and dry skin, loss of
appetite, nausea, and vomiting swelling in the arms and
legs. Increased blood pressure sensation of tightness
and shortness of breath sleep disturbances and
difficulty concentrating. Diagnosis of CRF: to diagnose
CRF, the following tests and examinations are
conducted: Blood tests: Creatinine, urea, electrolytes
(Na, K, Ca, P) Calculation of Glomerular Filtration Rate
(GFR)Urine tests: Proteinuria, microalbuminuria,
erythrocytes. Kidney ultrasound (US) and biopsy (if
necessary) [7]. Treatment Methods for CRF: Although
CRF cannot be completely cured with specific
medications, the progression of the disease can be
slowed, and symptoms can be managed. Pressure
Control: ACE inhibitors (captopril, enalapril, ramipril)
ARB drugs (losartan, valsartan) Diet and Fluid
Restrictions: Reduce salt intake (≤ 3
-5 g per day). Limit
animal protein. Avoid potassium and phosphorus-rich
foods. Electrolyte balance monitoring: If hyperkalemia
(elevated potassium levels) occurs, potassium intake
should be restricted. Use phosphate binders to reduce
phosphate levels. Anemia Treatment: Erythropoietin
preparations iron and vitamin B12 supplements Dialysis
or kidney transplantation: If GFR < 15 ml/min, initiate
hemodialysis
or
peritoneal
dialysis
kidney
transplantation is the most effective method [8].
Main pathogenetic mechanisms of kidney damage in
SSc: Endothelial dysfunction: in systemic sclerosis,
autoimmune inflammation leads to damage of
endothelial cells, resulting in vasoconstriction, platelet
activation, microthrombosis, and inflammation.
Hypercoagulability and microthrombosis: In SSc, there
is an increased tendency to thrombosis, which leads to
the development of thrombosis in the kidney capillaries
and arterioles. This results in ischemic damage to the
kidneys. Microangiopathic Hemolytic Anemia: Damage
to the inner layer of blood vessels causes the
breakdown of erythrocytes. Fibrosis and interstitial
changes: In SSc, excessive activation of fibroblasts and
collagen accumulation lead to the hardening of the
kidney interstitial tissue. Glomerulosclerosis: damage
to the kidney filtration system [3, 9]. Tubulointerstitial
Fibrosis: Atrophy of the renal tubules and loss of
function. Vascular fibrosis: overactive fibroblasts
produce collagen, leading to thickening of the
glomerular, interstitial tissue, and vessel walls, which
decreases renal blood flow and causes hypertension.
Increase in angiotensin II and endothelin: The elevated
levels of angiotensin II and endothelin lead to excessive
narrowing of the renal blood vessels, which results in
decreased GFR and kidney ischemia. Hyperactivation of
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International Journal of Medical Sciences And Clinical Research (ISSN: 2771-2265)
the Renin-Angiotensin-Aldosterone System (RAAS):
This hyperactivation contributes to an increase in blood
pressure and worsens renal blood supply, further
impairing kidney function. Immunopathogenesis and
Autoimmune Attack: Since SSc is an autoimmune
disease, antifospholipid antibodies and other
autoantibodies can damage the kidney blood vessels.
Inflammatory cytokines (such as TNF-
α, IL
-6, TGF-
β)
exacerbate inflammation and fibrosis in the kidney
tissues [10]. Activated macrophages and lymphocytes
release inflammatory mediators, leading to progressive
damage to the glomeruli Arterial Hypertension and
Renal Crisis: In SRC, severe and acute arterial
hypertension develops due to the narrowing of renal
vessels, which reduces the GFR. This further increases
the production of angiotensin II. Persistent high blood
pressure can lead to nephrosclerosis and chronic
kidney failure. Kidney involvement in SSc can manifest
in several forms: 1. SRC
–
This is one of the most severe
and
life-threatening
complications
of
SSc,
characterized by sudden onset of severe arterial
hypertension, rapidly progressing kidney failure,
microangiopathic
hemolytic
anemia,
and
thrombocytopenia. 2. CKD
–
This develops gradually
and is related to fibrosis of the renal vessels, typically
observed in patients with a long history of SSc. Clinical
signs include: fatigue and weakness, swelling in the feet
and hands, dry and itchy skin, decreased appetite,
nausea,
proteinuria,
arterial
hypertension,
osteoporosis, and bone pain (due to impaired kidney
function). This condition generally progresses slowly
over the years and leads to nephrosclerosis.
Management includes controlling blood pressure,
using ACE inhibitors to reduce proteinuria, monitoring
kidney function, and considering dialysis or kidney
transplantation [11]. Proteinuria and Nephrotic
Syndrome
are
less
common
manifestations.
Proteinuria refers to the excretion of high amounts of
protein in the urine, indicating dysfunction of the
kidney filtration system. If proteinuria is very high (> 3.5
g/day), it is called Nephrotic Syndrome. Nephrotic
Syndrome is characterized by significant protein loss
due to damage to the kidney glomeruli, leading to
edema and metabolic disturbances. Main Symptoms of
Nephrotic Syndrome: Proteinuria > 3.5 g/day.
Hypoalbuminemia (< 30 g/L). Diffuse edema (fluid
accumulation in the face, feet, and abdominal cavity).
Hyperlipidemia (elevated cholesterol and triglyceride
levels). Fat droplets and hyaline casts in the urine.
Primary Causes: Minimal Change Disease (common in
children). Focal segmental glomerulosclerosis (FSGS).
Membranous Nephropathy. Diabetic nephropathy
Amyloidosis and systemic autoimmune diseases (such
as SLE and SSc) [12].
Diagnosis
The diagnosis of kidney damage in SSc includes several
tests and evaluations. The frequency of renal crisis
development in patients with SSc is assessed through
various subjective, anamnestical, and objective clinical
criteria,
including:
Urinalysis:
Zimnitsky
test,
nechiporenko test, and general urine protein levels.
Renal Function Tests: blood urea nitrogen (BUN),
creatinine, and uric acid levels are measured.
Autoantibodies: Testing for scleroderma-specific
antibodies such as Scl-70, anticentromere antibodies.
Other laboratory tests: Increased residual nitrogen and
its components (urea, creatinine, uric acid), decreased
glomerular filtration rate (GFR), proteinuria, and
microangiopathic anemia are assessed. These tests
help in the evaluation and monitoring of kidney
function in patients with systemic sclerosis.
Immunological Tests: Antinuclear Antibodies (ANA):
Specific to SSc. Anti-topoisomerase I (Scl-70) and Anti-
RNA Polymerase III Antibodies: Found in severe forms
of SSc. Complement System (C3, C4): Can sometimes be
decreased. Anti-RNA Polymerase III and antinuclear
antibodies: Their presence can indicate the severity
and progression of the disease [5, 8].
Instrumental Methods
Electrocardiogram
and
Radiography
(excretory
urogra¬phy of joints). Kidney Ultrasound: Used to
examine kidney shrinkage, fibrosis, and impaired blood
flow. Doppler Ultrasound of Renal Vessels: Detects
narrowing or changes in renal arteries. Kidney Biopsy:
Rarely performed, but can be used to assess
microangiopathy and fibrosis of glomeruli, confirm SRC
or other nephropathies in complex cases [11,12].
Modern Approaches to treatment
the main goal of treatment is to preserve kidney
function, control blood pressure, and slow down the
fibrotic processes. SRC is a life-threatening condition
characterized by severe arterial hypertension and
kidney failure. If treatment is delayed, the risk of
dialysis or death increases.
1. Hypertensive Therapy. ACE Inhibitors (ACEI)
–
First-
line treatment. Captopril, Enalapril, Lisinopril. These
medications block the renin-angiotensin system,
reducing blood pressure within the kidneys. They are
fundamental for treating pulmonary heart disease,
improving prognosis, and reducing mortality. ACE
inhibitors should be started immediately upon the
onset of SRC.
2. Calcium Channel Blockers (Amlodipine, Nifedipine).
If ACE inhibitors are insufficient, calcium channel
blockers are used to further reduce blood pressure.
3. Diuretics (Furosemide, Spironolactone). Used to
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International Journal of Medical Sciences And Clinical Research (ISSN: 2771-2265)
reduce edema and fluid retention. Caution is required
if GFR <30 ml/min.
4. Statins (Atorvastatin, Rosuvastatin). Used to reduce
hyperlipidemia and lower cardiovascular risk.
5. Immunomodulatory and Antifibrotic Therapy Since
SSc is an autoimmune disease, immunomodulatory
drugs are key in treatment. Rituximab (anti-CD20
monoclonal antibodies): Suppresses the immune
system by depleting B lymphocytes, which helps reduce
fibroblast activity and fibrosis. Mycophenolate Mofetil
(MMF)
–
An immunosuppressive and antifibrotic drug
that
can
help
prevent
kidney
damage.
Cyclophosphamide
–
Used in severe autoimmune
diseases but has a risk of nephrotoxicity.
Corticosteroids
–
Used cautiously in SSc as high doses
can increase vasospasm and worsen the condition.
Tocilizumab
–
An IL-6 inhibitor used in resistant forms
of the disease.
6. Antifibrotic Therapy
–
Since SSc involves fibroblast
activation and collagen accumulation, antifibrotic
medications play an essential role in treatment.
Nintedanib
–
An antifibrotic and antiangiogenic agent
that can slow down kidney fibrosis. Pirfenidone
–
Reduces collagen synthesis and helps stop the
proliferation of fibroblasts. Angiotensin-converting
enzyme inhibitors (ACEIs)
–
One of the most effective
drugs for preventing SRC and providing antifibrotic
effects (e.g., captopril, enalapril) [7, 11].
7. Additional Approaches: Endothelin receptor
antagonists (bosentan, ambrisentan)
–
Used to dilate
blood vessels and reduce fibroblast activity.
Antithrombotic and anticoagulant drugs
–
Used to
prevent microthrombosis. Hypertension management
–
blood pressure control using ACE inhibitors or
angiotensin receptor blockers [13].
Chronic Kidney Disease Treatment
Treatment of SRC and CKD focuses on controlling blood
pressure, preventing further fibrosis, and improving
kidney function monitoring. Treatment Principles: 1.
Blood Pressure Control: ACEIs or angiotensin receptor
blockers (ARBs) are the first choice for treatment (e.g.,
captopril, enalapril). These medications dilate renal
blood vessels, lower blood pressure, and slow the
progression of kidney failure. 2. Caution with Steroids:
High doses of steroids (e.g., prednisone) can trigger
SRC, so their use should be restricted. 3.Support Kidney
Function: Maintain sodium and fluid balance. Low-
sodium (salt-free) and low-protein diet. Monitor
potassium levels. 4. Dialysis or Kidney Transplantation:
If the disease reaches its final stages, hemodialysis or
peritoneal dialysis may be required. In some cases,
kidney transplantation may also be considered. 5.Treat
the underlying Cause: Address the primary cause of the
disease
to
prevent
further
complications.
Immunosuppressive
Medications
for
SSc:
Immunosuppressive drugs (such as mycophenolate
mofetil, cyclophosphamide) may be prescribed for SSc.
Immunosuppressive Therapy: To reduce the activity of
SSc, immunosuppressive medications like azathioprine,
methotrexate, and mycophenolate are used [1, 8].
Complications
Monitoring blood pressure and adhering to a sodium-
restricted diet. ACE inhibitors or angiotensin receptor
blockers (ARB) are helpful in lowering blood pressure
and reducing proteinuria [12]. Treatment of
Complications: Anemia: Treated with erythropoietin
and iron supplements. Electrolyte Imbalances:
Appropriate medications are used to treat conditions
like hyperphosphatemia or hyperkalemia.
Prognosis and Outcomes: The prognosis for kidney
damage depends on early diagnosis and treatment.
Without therapy, SRC is associated with a high
mortality rate, but using ACE inhibitors significantly
improves survival. CKD develops slowly, but continuous
monitoring and treatment are required.
CONCLUSION
Kidney damage in SSc remains a serious issue that
requires a comprehensive approach. Chronic kidney
failure in systemic sclerosis primarily develops due to
vascular damage, fibrinoid necrosis, fibroblast
activation, and immune mechanisms. In particular, SRC
progresses rapidly and can lead to acute kidney failure.
Early diagnosis, blood pressure control, attention to
laboratory indicators, and immunosuppressive therapy
are essential to slow the progression of CKD and
improve the overall condition of the patient. The
pathogenesis of SRC is linked to microangiopathy and
excessive activation of the RAAS. Effective treatment
measures can help improve quality of life and prevent
the development of kidney failure. Modern treatment
methods may improve prognosis; however, further
research in antifibrotic therapy and individualized
patient care is needed.
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