Glomerulonephritis (e.g., lupus nephritis, post-streptococcal)

The Comprehensive Medical Guide to Glomerulonephritis (e.g., Lupus Nephritis, Post-Streptococcal)

1. Comprehensive Introduction & Overview

Glomerulonephritis (GN) represents a diverse group of kidney diseases characterized by inflammation of the glomeruli, the intricate filtering units within the kidneys. These microscopic structures are responsible for filtering waste products and excess fluid from the blood to form urine. When the glomeruli become inflamed, their ability to perform this vital function is compromised, leading to a spectrum of clinical manifestations ranging from asymptomatic urinary abnormalities to rapidly progressive kidney failure.

GN can be classified as primary, where the disease is confined to the kidneys, or secondary, where it arises as a manifestation of a systemic disease affecting other organs. The underlying causes are predominantly immune-mediated, involving the deposition of antibodies or immune complexes within the glomeruli, or direct immune cell attack.

This guide will provide an exhaustive overview of glomerulonephritis, focusing on its clinical definition, intricate pathophysiology, diverse etiologies, diagnostic approaches, therapeutic strategies, and long-term prognosis. We will specifically highlight two prominent examples: Lupus Nephritis, a common and severe renal complication of Systemic Lupus Erythematosus (SLE), and Post-Streptococcal Glomerulonephritis (PSGN), an acute form of GN triggered by a preceding streptococcal infection. Understanding these conditions is paramount for early diagnosis and effective management to mitigate the risk of irreversible kidney damage and progression to End-Stage Renal Disease (ESRD).

2. Deep-Dive into Technical Specifications / Mechanisms

2.1. Clinical Definition

Glomerulonephritis is defined as an inflammatory process primarily affecting the glomeruli, which are networks of tiny blood vessels (capillaries) located at the beginning of each nephron in the kidney. This inflammation can lead to structural damage, impairing the glomeruli's filtration barrier. Consequently, substances that should normally be retained in the blood (like proteins) can leak into the urine (proteinuria), and substances that should not be present in significant amounts (like red blood cells) can also appear in the urine (hematuria). The severity and type of inflammation dictate the clinical syndrome, which can range from mild, asymptomatic urinary changes to severe, acute kidney injury or chronic kidney disease.

2.2. Etiology (Causes)

The causes of glomerulonephritis are diverse and broadly categorized:

• Primary Glomerulonephritis: These forms are idiopathic or intrinsic to the kidney, with no identifiable systemic cause. Examples include:
  • IgA Nephropathy (Berger's Disease): Most common primary GN worldwide.
  • Focal Segmental Glomerulosclerosis (FSGS): Characterized by scarring of some glomeruli in segments.
  • Membranous Nephropathy (MN): Thickening of the glomerular basement membrane.
  • Minimal Change Disease (MCD): A common cause of nephrotic syndrome in children.
  • Membranoproliferative Glomerulonephritis (MPGN): Characterized by mesangial and endothelial cell proliferation.
• Secondary Glomerulonephritis: These forms are a manifestation of a systemic disease.
  • Autoimmune Diseases:
    • Lupus Nephritis (LN): Renal involvement in Systemic Lupus Erythematosus (SLE). Autoantibodies (e.g., anti-dsDNA) deposit in the glomeruli.
    • ANCA-Associated Vasculitis: Microscopic polyangiitis, granulomatosis with polyangiitis (Wegener's), eosinophilic granulomatosis with polyangiitis (Churg-Strauss).
    • Goodpasture's Syndrome (Anti-GBM Disease): Antibodies target the glomerular basement membrane (GBM) and often lung basement membranes.
  • Infections:
    • Post-Streptococcal Glomerulonephritis (PSGN): Occurs 1-3 weeks after pharyngeal or 3-6 weeks after cutaneous infection with nephritogenic strains of Group A Beta-Hemolytic Streptococcus. Immune complexes containing streptococcal antigens deposit in glomeruli.
    • Infectious Endocarditis: Immune complex deposition.
    • Hepatitis B & C: Can cause membranous or membranoproliferative GN.
    • HIV-Associated Nephropathy (HIVAN): A specific form of FSGS.
  • Other Systemic Diseases:
    • Diabetic Nephropathy: While distinct, severe diabetes can lead to glomerular damage.
    • Amyloidosis: Deposition of abnormal proteins in glomeruli.
    • Cryoglobulinemia: Immune complex deposition associated with certain infections (e.g., Hepatitis C) or lymphoproliferative disorders.

2.3. Pathophysiology

The underlying mechanism of glomerular injury in most forms of GN is immune-mediated, leading to an inflammatory cascade:

• Immune Complex Deposition:
  • Circulating Immune Complexes: Antigens (e.g., streptococcal antigens in PSGN, nuclear antigens in lupus nephritis) combine with antibodies in the circulation to form immune complexes. These complexes then deposit in the glomeruli, often in the subendothelial or subepithelial space.
  • In Situ Immune Complex Formation: Antibodies may bind directly to antigens already present within the glomerular structures (e.g., planted antigens) or to intrinsic glomerular antigens (e.g., anti-GBM disease).
• Complement Activation: The deposited immune complexes activate the complement system, leading to the generation of potent inflammatory mediators (e.g., C3a, C5a) that attract and activate inflammatory cells.
• Cellular Infiltration & Cytokine Release: Neutrophils, monocytes, macrophages, and T-lymphocytes are recruited to the glomeruli. These cells release pro-inflammatory cytokines, chemokines, and reactive oxygen species, which directly damage glomerular cells (podocytes, endothelial cells, mesangial cells).
• Glomerular Structural Damage:
  • Podocyte Injury: Leads to effacement of foot processes, compromising the filtration barrier and causing proteinuria.
  • Endothelial Cell Damage: Can lead to thrombosis and reduced blood flow.
  • Mesangial Cell Proliferation and Matrix Expansion: Can narrow capillary lumens.
  • Glomerular Basement Membrane (GBM) Changes: Thickening, splitting, or rupture, further disrupting filtration.
• Consequences: These changes collectively impair glomerular filtration, leading to:
  • Hematuria: Leakage of red blood cells through the damaged barrier.
  • Proteinuria: Leakage of proteins, ranging from mild to nephrotic range.
  • Reduced Glomerular Filtration Rate (GFR): Decreased kidney function, leading to azotemia (elevated BUN and creatinine).
  • Sodium and Water Retention: Contributing to edema and hypertension.

2.4. Clinical Staging/Grading (Focus on Lupus Nephritis)

While some types of GN are described by their histopathological features, Lupus Nephritis (LN) has a well-established classification system vital for prognosis and treatment. The International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification (updated in 2018) identifies six classes based on renal biopsy findings:

• Class I: Minimal Mesangial Lupus Nephritis: Minimal mesangial immune deposits, no significant mesangial hypercellularity by light microscopy. Clinically often asymptomatic.
• Class II: Mesangial Proliferative Lupus Nephritis: Mesangial hypercellularity with mesangial immune deposits. Clinically presents with microscopic hematuria and/or proteinuria, often non-nephrotic.
• Class III: Focal Lupus Nephritis: Endocapillary or extracapillary glomerulonephritis affecting <50% of glomeruli. Can be active (proliferative) or chronic (sclerotic). Manifests with hematuria, proteinuria (often nephrotic range), hypertension, and renal insufficiency.
• Class IV: Diffuse Lupus Nephritis: Endocapillary or extracapillary glomerulonephritis affecting ≥50% of glomeruli. This is the most common and severe form, often leading to significant renal impairment. Subdivided into Class IV-S (segmental) and Class IV-G (global), reflecting the extent of glomerular involvement. Presents with severe nephritic and/or nephrotic syndrome, hypertension, and rapid decline in GFR.
• Class V: Membranous Lupus Nephritis: Characterized by subepithelial immune deposits and diffuse thickening of the glomerular capillary walls. Can occur alone or in combination with Class III or IV. Typically presents as nephrotic syndrome.
• Class VI: Advanced Sclerotic Lupus Nephritis: ≥90% of glomeruli are globally sclerosed, indicating end-stage damage. Poor prognosis, often requiring renal replacement therapy.

3. Extensive Clinical Indications & Usage

3.1. Standard Presentation (Clinical Manifestations)

The clinical presentation of GN is highly variable and depends on the specific type, severity, and chronicity of the inflammation. Common syndromes include:

• Nephritic Syndrome: Characterized by:
  • Hematuria: Often microscopic, but can be macroscopic (gross hematuria, "cola-colored" or "smoky" urine), with dysmorphic red blood cells and red blood cell casts on urinalysis.
  • Proteinuria: Usually non-nephrotic range (<3.5 g/day).
  • Hypertension: Due to fluid retention and activation of the renin-angiotensin system.
  • Edema: Periorbital swelling, facial puffiness, peripheral edema, due to fluid retention.
  • Azotemia/Oliguria: Elevated blood urea nitrogen (BUN) and creatinine, indicating reduced GFR and decreased urine output.
  • Classic for PSGN, IgA nephropathy, and acute flares of lupus nephritis.
• Nephrotic Syndrome: Characterized by:
  • Massive Proteinuria: >3.5 g/day, leading to foamy urine.
  • Hypoalbuminemia: Low serum albumin due to protein loss.
  • Severe Edema: Generalized edema (anasarca), ascites, pleural effusions, due to reduced oncotic pressure.
  • Hyperlipidemia and Lipiduria: Due to compensatory hepatic lipoprotein synthesis.
  • Classic for minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy; also seen in lupus nephritis Class V.
• Rapidly Progressive Glomerulonephritis (RPGN): A severe, aggressive form characterized by a rapid decline in GFR (over days to weeks), often associated with crescent formation on renal biopsy. Presents with features of nephritic syndrome and can quickly lead to ESRD. Seen in anti-GBM disease, severe ANCA-associated vasculitis, and severe lupus nephritis.
• Asymptomatic Urinary Abnormalities: Isolated microscopic hematuria or proteinuria detected incidentally on routine urinalysis. Common in early IgA nephropathy or mild lupus nephritis.

3.2. Differential Diagnosis

Distinguishing GN from other kidney conditions and identifying the specific type of GN is crucial for appropriate treatment.

• Causes of Hematuria: Urinary tract infection (UTI), kidney stones (nephrolithiasis), benign prostatic hyperplasia (BPH), trauma, malignancy (bladder, kidney), polycystic kidney disease, thin basement membrane disease.
• Causes of Proteinuria: Diabetic nephropathy, hypertensive nephrosclerosis, orthostatic proteinuria, pre-eclampsia (in pregnancy), amyloidosis.
• Acute Kidney Injury (AKI): Prerenal azotemia (dehydration, heart failure), acute tubular necrosis (ATN), acute interstitial nephritis (AIN), urinary tract obstruction.
• Systemic Diseases with Renal Involvement: Diabetes, hypertension, vasculitis, multiple myeloma, amyloidosis.

3.3. Key Diagnostic Tests

A systematic approach to diagnosis involves laboratory tests, imaging, and ultimately, renal biopsy.

• Urinalysis with Microscopy:
  • Hematuria: Presence of red blood cells. Dysmorphic RBCs and RBC casts are highly suggestive of glomerular bleeding.
  • Proteinuria: Quantified by urine protein-to-creatinine ratio or 24-hour urine collection.
  • Leukocyturia/Casts: White blood cells and white blood cell casts (suggestive of inflammation/infection).
• Blood Tests:
  • Renal Function Panel: Serum creatinine, BUN, estimated GFR (eGFR) to assess kidney function.
  • Electrolytes: Sodium, potassium, chloride, bicarbonate.
  • Complete Blood Count (CBC): Anemia (common in chronic kidney disease), leukocytosis (infection/inflammation).
  • Complement Levels (C3, C4): Often low in immune complex-mediated GN (e.g., lupus nephritis, PSGN, cryoglobulinemia) due to consumption.
  • Autoantibody Panel:
    • Antinuclear Antibodies (ANA) & anti-dsDNA: For Systemic Lupus Erythematosus and lupus nephritis.
    • Anti-Neutrophil Cytoplasmic Antibodies (ANCA): For ANCA-associated vasculitis (c-ANCA/PR3, p-ANCA/MPO).
    • Anti-Glomerular Basement Membrane (Anti-GBM) Antibodies: For Goodpasture's syndrome.
  • Infection Markers:
    • Anti-Streptolysin O (ASO) titer, Anti-DNase B: For recent streptococcal infection (PSGN).
    • Hepatitis B & C serology, HIV testing: To rule out viral causes of secondary GN.
  • Serum Protein Electrophoresis (SPEP) & Immunofixation Electrophoresis (IFE): To screen for monoclonal gammopathies (e.g., multiple myeloma, amyloidosis).
• Renal Ultrasound: Assesses kidney size, cortical thickness, presence of hydronephrosis (obstruction), and can guide biopsy.
• Renal Biopsy (Gold Standard): Essential for definitive diagnosis, classification, assessment of disease activity and chronicity, and guiding specific treatment. Tissue is examined by:
  • Light Microscopy: Reveals cellular proliferation, sclerosis, crescent formation, and other structural changes.
  • Immunofluorescence Microscopy: Detects and localizes immune deposits (IgG, IgA, IgM, C3, C1q, fibrinogen).
  • Electron Microscopy: Provides ultrastructural details, such as the location of immune deposits (subepithelial, subendothelial, mesangial) and podocyte effacement.

3.4. Treatment Approaches

Treatment aims to halt the inflammatory process, preserve kidney function, manage symptoms, and prevent complications.

• General Supportive Care:
  • Blood Pressure Control: ACE inhibitors or ARBs are often first-line, as they also reduce proteinuria. Target <130/80 mmHg.
  • Fluid and Electrolyte Management: Diuretics for edema and hypertension.
  • Dietary Modifications: Low sodium for edema/hypertension; low protein diet if severe uremia.
  • Statins: For hyperlipidemia.
• Immunosuppressive Therapy: Cornerstone for many forms of GN.
  • Corticosteroids (e.g., Prednisone, Methylprednisolone): High-dose oral or intravenous pulse therapy for induction of remission, followed by tapering.
  • Cytotoxic Agents:
    • Cyclophosphamide: Potent immunosuppressant for severe, rapidly progressive forms (e.g., severe lupus nephritis, vasculitis). Administered intravenously.
    • Mycophenolate Mofetil (MMF): Effective for induction and maintenance therapy, especially in lupus nephritis.
    • Azathioprine: Used for maintenance therapy, often after cyclophosphamide.
  • Calcineurin Inhibitors (e.g., Tacrolimus, Cyclosporine): Used in specific forms like membranous nephropathy or as an alternative in lupus nephritis.
  • Biologics (e.g., Rituximab): Anti-CD20 monoclonal antibody, used in refractory cases of lupus nephritis, membranous nephropathy, and ANCA-associated vasculitis.
• Specific Treatments:
  • Lupus Nephritis: Often involves an induction phase (high-dose steroids + cyclophosphamide or MMF) followed by a maintenance phase (MMF or azathioprine).
  • Post-Streptococcal Glomerulonephritis (PSGN): Primarily supportive. Antibiotics for ongoing streptococcal infection (though not proven to prevent GN once established). Diuretics and antihypertensives for fluid overload and hypertension. Immunosuppression is rarely indicated.
  • Anti-GBM Disease: Plasma exchange (plasmapheresis) to remove circulating antibodies, combined with high-dose corticosteroids and cyclophosphamide.
• Dialysis and Kidney Transplantation: For patients who progress to End-Stage Renal Disease (ESRD).

3.5. Long-term Prognosis

The long-term prognosis of glomerulonephritis is highly variable and depends on several factors:

• Specific Type of GN: Some types, like PSGN in children, typically have an excellent prognosis with full recovery. Others, like severe lupus nephritis or rapidly progressive GN, carry a high risk of progression to ESRD.
• Severity at Presentation: The degree of proteinuria, GFR at diagnosis, and presence of hypertension are critical prognostic indicators.
• Histological Findings: The extent of active inflammation versus chronic scarring (fibrosis/sclerosis) on renal biopsy significantly impacts prognosis. A higher chronicity index indicates poorer long-term outcomes.
• Response to Treatment: Early and effective response to immunosuppressive therapy can improve outcomes.
• Complications:
  • End-Stage Renal Disease (ESRD): Requires dialysis or kidney transplantation.
  • Cardiovascular Disease: Increased risk due to hypertension, dyslipidemia, and chronic inflammation.
  • Infections: Immunosuppressive therapy increases susceptibility to various infections.
  • Recurrence: Some forms of GN can recur in a transplanted kidney (e.g., FSGS, IgA nephropathy, membranoproliferative GN).

4. Risks, Side Effects, or Contraindications (of Treatments)

Immunosuppressive therapies, while crucial for managing GN, carry significant risks and side effects:

• Corticosteroids (e.g., Prednisone):
  • Side Effects: Hyperglycemia (diabetes), hypertension, osteoporosis, weight gain, Cushingoid features, cataracts, glaucoma, mood disturbances, increased appetite, increased risk of infection, gastric ulcers.
  • Contraindications: Active untreated infection, uncontrolled severe psychiatric conditions (relative).
• Cyclophosphamide:
  • Side Effects: Bone marrow suppression (leukopenia, anemia, thrombocytopenia), hemorrhagic cystitis (bladder inflammation/bleeding), infertility (dose-dependent), increased risk of secondary malignancies (bladder cancer, lymphoma), nausea, hair loss.
  • Contraindications: Severe bone marrow suppression, active severe infection.
• Mycophenolate Mofetil (MMF):
  • Side Effects: Gastrointestinal upset (nausea, vomiting, diarrhea), bone marrow suppression (leukopenia), increased risk of infection (especially viral), teratogenicity (contraindicated in pregnancy).
  • Contraindications: Pregnancy, severe GI disorders (relative).
• Calcineurin Inhibitors (e.g., Tacrolimus, Cyclosporine):
  • Side Effects: Nephrotoxicity (kidney damage), hypertension, tremors, neurotoxicity, hyperglycemia, hirsutism (cyclosporine), gingival hyperplasia (cyclosporine), increased infection risk.
  • Contraindications: Uncontrolled hypertension, severe renal impairment (relative).
• Rituximab:
  • Side Effects: Infusion reactions (fever, chills, rash), increased risk of infection (especially viral, e.g., PML), B-cell aplasia.
  • Contraindications: Active severe infection, severe cardiac disease (relative).
• General Risks of Immunosuppression:
  • Increased Susceptibility to Infections: Bacterial, viral, fungal, and opportunistic infections are common. Prophylactic antibiotics or antiviral agents may be required.
  • Cancer Risk: Long-term use of certain immunosuppressants can increase the risk of certain cancers, particularly skin cancers and lymphomas.
  • Cardiovascular Risk: Many treatments can exacerbate hypertension and dyslipidemia.

5. Massive FAQ Section

Q1: What exactly is glomerulonephritis?
A1: Glomerulonephritis is an inflammation of the glomeruli, which are tiny filters in your kidneys. This inflammation can damage the filters, causing them to leak protein and blood into your urine, and impairing their ability to remove waste products from your blood.

Q2: What causes glomerulonephritis?
A2: Glomerulonephritis is most often caused by an immune system malfunction. It can be primary (originating in the kidneys) or secondary (part of a systemic disease). Common causes include autoimmune diseases like lupus (leading to lupus nephritis), infections like strep throat (leading to post-streptococcal glomerulonephritis), and certain viruses.

Q3: Is glomerulonephritis contagious?
A3: No, glomerulonephritis itself is not contagious. However, some infections that can trigger glomerulonephritis, such as strep throat, are contagious.

Q4: What are the common symptoms of glomerulonephritis?
A4: Symptoms can vary but often include blood in the urine (hematuria, making urine look cola-colored or smoky), foamy urine due to high protein (proteinuria), swelling (edema) in the face, hands, and feet, high blood pressure, and fatigue due to anemia or impaired kidney function.

Q5: How is glomerulonephritis diagnosed?
A5: Diagnosis typically involves a combination of tests:
* Urinalysis: To detect blood, protein, and casts in the urine.
* Blood Tests: To check kidney function (creatinine, BUN, eGFR), complement levels, and specific autoantibodies (e.g., ANA, anti-dsDNA, ANCA, anti-GBM) to identify the cause.
* Renal Biopsy: The gold standard, where a small piece of kidney tissue is examined under a microscope to determine the specific type, severity, and chronicity of the inflammation.

Q6: What is the difference between lupus nephritis and post-streptococcal glomerulonephritis?
A6: Both are types of glomerulonephritis, but their causes differ.
* Lupus Nephritis: Is a kidney complication of Systemic Lupus Erythematosus (SLE), an autoimmune disease where the body's immune system attacks its own tissues, including the kidneys.
* Post-Streptococcal Glomerulonephritis (PSGN): Develops after an infection with certain strains of Group A Streptococcus bacteria (e.g., strep throat or skin infection), usually after a latency period of 1-3 weeks. It's an immune reaction to the infection.

Q7: Can glomerulonephritis be cured?
A7: The possibility of a "cure" depends on the specific type of glomerulonephritis. Some forms, like PSGN in children, often resolve completely. Others, like lupus nephritis, are chronic conditions that require long-term management to control inflammation and prevent progression, but may not be fully cured. Early diagnosis and aggressive treatment are key to achieving remission and preserving kidney function.

Q8: What is the treatment for glomerulonephritis?
A8: Treatment strategies are tailored to the specific type and severity of GN. They often include:
* Immunosuppressive Medications: Such as corticosteroids, cyclophosphamide, mycophenolate mofetil, or biologics, to suppress the immune system and reduce inflammation.
* Blood Pressure Control: Using medications like ACE inhibitors or ARBs.
* Diuretics: To manage fluid retention and edema.
* Dietary Modifications: Low sodium, and sometimes low protein, to ease the burden on the kidneys.
* Dialysis or Kidney Transplant: For patients who progress to End-Stage Renal Disease.

Q9: What is the long-term outlook for someone with glomerulonephritis?
A9: The prognosis varies widely. Some individuals, especially children with PSGN, make a full recovery. Others, particularly those with more aggressive or chronic forms like diffuse lupus nephritis, are at higher risk of developing chronic kidney disease or progressing to end-stage renal disease (ESRD), requiring dialysis or a kidney transplant. Regular monitoring and adherence to treatment are crucial for the best possible long-term outcomes.

Q10: Are there any specific dietary restrictions for glomerulonephritis?
A10: Dietary recommendations are individualized based on the stage of kidney disease and specific symptoms. Common restrictions may include:
* Sodium (Salt) Restriction: To help control blood pressure and reduce fluid retention/edema.
* Protein Restriction: May be recommended if kidney function is significantly impaired, but this should be guided by a doctor or dietitian.
* Potassium and Phosphorus Restriction: May be necessary if blood levels of these electrolytes become too high due to kidney dysfunction.

Q11: Can glomerulonephritis lead to kidney failure?
A11: Yes, if left untreated or if it's a severe, aggressive form, glomerulonephritis can lead to progressive kidney damage and eventually End-Stage Renal Disease (ESRD), which requires dialysis or a kidney transplant for survival.

Q12: How often do I need follow-up appointments if I have glomerulonephritis?
A12: The frequency of follow-up appointments depends on the severity of your condition, the type of glomerulonephritis, and your response to treatment. Initially, visits may be frequent (e.g., monthly) to monitor kidney function, blood pressure, and medication side effects. Once stable, appointments may become less frequent, but lifelong monitoring is often necessary for chronic forms of the disease.

Related Clinical Integration

In the modern clinical management of glomerulonephritis, such as lupus nephritis or post-streptococcal variants, a multidisciplinary approach is essential for accurate diagnosis and long-term disease control. Clinicians must first establish a baseline and monitor disease progression through Kidney function tests (e.g., serum creatinine, BUN, urinalysis) / اختبارات وظائف الكلى (3095) (خدمات رعاية عامة), often necessitating a Renal biopsy / خزعة الكلى (949e) (خدمات رعاية عامة) to determine histological classification and guide therapeutic intensity. Pharmacological intervention typically involves immunosuppressive strategies, utilizing Prednisone / بريدنيزون 5 mg for acute inflammation alongside Antiproliferative agents (e.g., Mycophenolate Mofetil, Azathioprine) / العوامل المضادة للتكاثر (مثل مايكوفينولات موفيتيل، أزاثيوبرين) Standard to maintain remission and prevent progressive renal failure. Furthermore, because systemic inflammatory conditions often present with musculoskeletal comorbidities, practitioners should remain informed on broader systemic management, including the Surgical Management of Rheumatoid Arthritis: A Comprehensive Orthopaedic Guide, Calcium Pyrophosphate Dihydrate (CPPD) Deposition Disease (Pseudogout): Orthopedic Epidemiology & Biomechanics, Hemophilic Arthropathy: Understanding Joint Damage, Pathophysiology & Orthopedic Considerations, AAOS Guidelines for VTE: Elective Total Hip with DVT History, and