2. INTRODUCTION:
The Kidneys depend on systemic blood pressure (SBP) to maintain
adequate renal blood flow , adequate GFR, tubular function and overall
salt and water balance.
This explains the vulnerability of kidneys to diseases involving the renal
vasculature.
Vascular injury to kidneys is usually a manifestation of generalized
vascular pathology.
4. Thrombotic Microangiopathies
1. Hemolytic Uremic Syndrome (HUS)
2.Thrombotic Thrombocytopenic Purpura (TTP)
In both conditions, there is:
Microangiopathic hemolytic Anemia (MAHA), with anemia, RBCs
fragmentation, schistocytes, intravascular PLT clumping and hence
thrombocytopenia
Typical renal histological lesions include intraglomerular platelet and fibrin
thrombi, with ischemia and arteriolar lesions
5. Hemolytic Uremic Syndrome (HUS)
Commonest cause of AKI in children
Children (< 4 years) ------> 90 % of cases
It is loosely defined as presence of microangiopathic hemolytic angiopathy
and renal impairment.
6. Forms of HUS
1. Typical, or Diarrhea-associated (D+ HUS):
Onset is explosive, with AKI
Most cases below 5 years
Diarrohea, often bloody preceeds MAHA within 1 week in 80% cases
Abdominal pain, cramping and vomiting frequent whereas fever is typically absent.
Neurologic symptoms including dysphagia, hyperreflexia, blurred vision, memory
deficit, encephalopathy, preservation and agraphia may often develop.
SEIZURE and cerebral infarction may develop in severe cases.
7. PATHOGENESIS
Shiga toxin(Stx1 and Stx2) are referred as verotoxin. They are produced by E.coli and
shigella dysenteriae
Verotoxin-producing E.Coli O157:H7 (VTEC), with damage to the vascular
endothelium(largely confined to kidneys)
After entry into circulation Shiga toxin binds to glycolipid surface receptor
globotriaosylceramide (gb3) which is richly expressed in renal vasculature.
Upon entering into cell it induces inflammatory cytokines (IL-8), monocyte chemotactic
protein 1 and stromal cell derived factor 1 and chemokines (cxcr4 and cxcr7) this action
results in platelet aggregation and microangiopathic process.
8. 2. Atypical, or (D-HUS) :
It results from complement deregulation, may be congenital or acquired
Patient may have low C3 and a normal C4 characteristics of alternating pathway activation.
Factor H deficiency most common defect. Factor H competes with Factor B to prevent formation
of Cb3
A familial varient of aHUS -DEAP HUS ( Deficiency of CFHR plasma proteins and CFH AutoAb
Positve) when autoantibody to factor H is formed.
Older children and adults, most of them have no diarrhea
Familial, associated with factor H deficiency which limit cleavage of unusual large von Willebrand;
leading to continuing platelet activation
Poorer prognosis, death in > 50 % of cases
9. Thrombotic Thrombocytopenic
Purpura (TTP)
Tradiationally, TTP is characterized by the pentad: MAHA, Thrombocytopenia,
neurologic symptoms, fever and renal failure.
Pathophysiology involves accumulation of ultra-large multimers of Von
willebard factor as a result of absence or markedly decreased activity of
plasma protease ADAMTS 13,
These ultra large multimers forms clots and shear erythrocytes resulting in
MAHA;TTP
TTP is now defined as large MAHA associated with ADAMTS13 activity (less
then 5-10%), however only absence of ADAMTS13 alone may not produce TTP; often
triggering factors (infection, surgery, pancreatitis or pregnancy) is required to induce
clinical TTP
If untreated TTP has mortality rate exceeding 90 %, even with modern therapy 20 % die
within 1st month from complication of microvascular thrombosis.
10. In idiopathic TTP, the formation of an autoantibody to ADAMTS13 (IgG or IgM) either increases
its clearance or inhibits its activity.
Upshaw-Schülman syndrome is a hereditary condition characterized by congenital deficiency
of ADAMTS13.
TTP in these patients can start within the first weeks of life but in some instances may not
present until adulthood, especially during pregnancy.
Both environmental and genetic factors are thought to influence the development of TTP.
Plasma transfusion is an effective strategy for prevention and treatment.
Drug-induced TMA is a recognized complication of treatment with some chemotherapeutic
agents, immunosuppressive agents, and quinine.
11. HUS/TTP TREATMENT
Treatment should be based on pathophysiology.
Autoantibody-mediated TTP and DEAP HUS respond to the
combination of plasma exchange and prednisone. In addition to
removing the autoantibodies, plasma exchange with fresh-frozen
plasma replaces ADAMTS13.
Plasma infusion is usually sufficient to replace the ADAMTS13 in
Upshaw-Schülman syndrome.
Drug-induced TMA secondary to endothelial damage typically does not
respond to plasma exchange and is treated primarily by discontinuing
use of the agent and providing supportive care.
Plasma infusion/exchange is effective in certain types of aHUS as it
replaces complement-regulatory proteins.
12. RADIATION NEPHROPATHY
Either local or total body irradiation can produce microangiopathic injury.
The kidney is one of the most radiosensitive organs, and injury can result with as
little as 4–5 Gy.
Such injury is characterized by renal insufficiency, proteinuria, and hypertension
usually developing ≥6 months after radiation exposure.
Renal biopsy reveals classic TMA with damage to glomerular, tubular, and
vascular cells, but systemic evidence of MAHA is uncommon.
No specific therapy is available.
13. HIV RELATED TMA
HIV-related TMA is a complication encountered mainly before widespread use of
highly active antiretroviral therapy. It is seen in patients with advanced AIDS and
low CD4+ T cell counts although it can be the first manifestation of HIV infection.
The presence of MAHA, thrombocytopenia, and renal failure are suggestive, but
renal biopsy is required for diagnosis since other renal diseases are also
associated with HIV infection.
The mechanism of injury is unclear, although HIV can induce apoptosis in
endothelial cells. ADAMTS13 activity is not reduced in these patients.
Cytomegalovirus co-infection may also be a risk factor. Effective antiviral therapy
is key, while plasma exchange should be limited to patients who have evidence of
TTP.
14. SCLERODERMA (PROGRESSIVE
SYSTEMIC SCLEROSIS)
Kidney involvement is common (up to 52%) in patients with widespread scleroderma,
with 20% of cases resulting directly from scleroderma renal crisis.
Other renal manifestations in scleroderma include transient (prerenal) or medication-
related forms of acute kidney injury (e.g., associated with D-penicillamine, nonsteroidal
anti-inflammatory drugs, or cyclosporine).
Salt and water retention with microvascular injury can lead to pulmonary edema.
Cardiac manifestations, including myocarditis, pericarditis, and arrhythmias, denote an
especially poor prognosis.
15. Glomerulonephritis and vasculitis associated with antineutrophil cytoplasmic antibodies and
systemic lupus erythematosus have been described in patients with scleroderma. Anti-U3-RNP
may identify young patients at risk for scleroderma renal crisis.
Anticentromere antibody, in contrast, is a negative predictor of this disorder. Because of the
overlap between scleroderma renal crisis and other autoimmune disorders, a renal biopsy is
recommended for patients with atypical renal involvement, especially if hypertension is absent.
Scleroderma renal crisis occurs in 12% of patients with diffuse systemic sclerosis but in only 2%
of those with limited systemic sclerosis Mild proteinuria is usually present ± HTN
Sclerodermal renal crisis is most severe form characterized by-
Accelerated HTN ( Ratinopathy and Encephalopathy may follow Htn)
Rapid decline in renal function
Nephrotic range proteinuria
Hematuria
16. Systemic Sclerosis
Pathology:
Intimal proliferation of interlobular arteries, with deposition of mucoplysaccharides: Onion-Skin
appearance
Fibrinoid necrosis of afferent arterioles
Treatment:
Treatment with ACE inhibition is the first-line therapy unless contraindicated.
The goal of therapy is to reduce systolic and diastolic blood pressure by 20 mmHg and 10
mmHg, respectively, every 24 h until blood pressure is normal. Additional antihypertensive
therapy may be given once the dose of drug for ACE inhibition is maximized.
Both ACE inhibitors and angiotensin II receptor antagonists are effective.
Poor prognosis; Before the availability of angiotensin-converting enzyme (ACE) inhibitors,
the mortality rate for scleroderma renal crisis was >90% at 1 month. Introduction of renin-
angiotensin system blockade has lowered the mortality rate to 30% at 3 years.
Nearly two-thirds of patients with scleroderma renal crisis may require dialysis support, with
recovery of renal function in 50% (median time, 1 year). because of other organ
involvement, especially restrictive cardiomyopathy
17. ANTIPHOSPHOLIPID SYNDROME
Antiphospholipid syndrome can be either primary or secondary to systemic
lupus erythematosus and is mediated by antiphospholipid antibodies—
mainly anticardiolipin antibodies , lupus anticoagulant, or anti-β-2
glycoprotein I antibodies (antiβ2GPI).
TMA is commonly present in renal biopsies, although signs of MAHA and
platelet consumption are usually absent.
Hypertension is common.
Treatment
lifelong anticoagulation.
Glucocorticoids may be beneficial in accelerated hypertension.
Immunosuppression and plasma exchange may be helpful for catastrophic
episodes of antiphospholipid syndrome but by themselves do not reduce
recurrent thrombosis.
18. HELLP SYNDROME
HELLP (hemolysis, elevated liver enzymes, low
platelets) syndrome is a dangerous complication of
pregnancy associated with microvascular injury.
Occurring in 0.2–0.9% of all pregnancies and in 10–20% of
women with severe preeclampsia, this syndrome carries a
mortality rate of 7.4–34%.
Most commonly developing in the third trimester, 10% of
cases occur before week 27 and 30% post-partum.
Renal failure occurs in half of patients with HELLP
syndrome,.
19. Although renal failure is common, the organ that defines this syndrome is the liver.
Subcapsular hepatic hematomas sometimes produce spontaneous rupture of the liver
and can be life-threatening.
Neurologic complications such as cerebral infarction, cerebral and brainstem
hemorrhage, and cerebral edema are other potentially life-threatening complications.
Nonfatal complications include placental abruption, permanent vision loss due to
Purtscher-like (hemorrhagic and vaso-occlusive vasculopathy) retinopathy, pulmonary
edema, bleeding, and fetal demise.
A history of MAHA before pregnancy is of diagnostic value.
Serum levels of ADAMTS13 activity are reduced (by 30–60%) in HELLP syndrome but not
to the levels seen in TTP (<5%).
HELLP syndrome usually resolves spontaneously after delivery, although a small
percentage of HELLP cases occur post-partum. Plasma exchange should be considered if
hemolysis is refractory to glucocortcoids and/or delivery, especially if TTP has not been
ruled out.
20. POEMS Syndrome
POEMS syndrome is a systemic disease characterized by polyneuropathy,
organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes.
Peripheral neuropathy with severe motor sensory deficit is the hallmark of the disease.
Another characteristic is that >95% of monoclonal light chain is of the lambda isotype.
IgA also makes up about 50% of the monoclonal protein.
Organomegaly can involve any organ and often presents as lymphadenopathy. In the
kidney, the hypertrophy frequently is unilateral.
Most patients present with mild to moderate renal impairment and low grade
proteinuria.
Progression to end stage renal ds may occur.
21. SICKLE CELL NEPHROPATHY
Renal complications in sickle cell disease result from occlusion of the vasa recta in the renal
medulla.
The low partial pressure of oxygen and high osmolarity predispose to hemoglobin S
polymerization and erythrocyte sickling.
Sequelae include hyposthenuria, hematuria, and papillary necrosis (which can also occur in
sickle trait).
The kidney responds by increases in blood flow and glomerular filtration rate mediated by
prostaglandins.
Proteinuria is present in 20–30%, and nephrotic-range proteinuria is associated with
progression to renal failure.
Chronic kidney disease is present in 12–20% of patients.
Despite the frequency of renal disease, hypertension is uncommon in patients with sickle cell
disease.
23. Renal Artery Stenosis (RAS) and
Ischemic Renal Disease:
RAS
Prevalence:
2-4 % in general population
30-40 % in accelerated HTN and
renal insufficiency
Causes:
Atherosclerosis:(ARV D)
90 %
Elderly
Fibromuscular Dysplasia:
5-10 %
Young
Ischemic Renal Disease
Atherosclerosis of 1 or both renal
Artery
Elderly male
± HTN
Often with atherosclerotic PVD (68%)
IHD (45%)
CHF (33%)
History of stroke (28%)
Progressive loss of renal function
24.
25.
26. Atherosclerotic Reno-vascular
disease:
It accounts for >90% of all RVD, in patients > 55, or < 30 Years of age
Lesions of RAS are 90% ostial (within the1st one cm of renal artery origin)
It can be demonstrated in:
>10% of patients undergoing coronary angiography
>40% with peripheral vascular disease (PVD), with > 5 vessels
involvement
30% with congestive cardiac failure (CCF), aged >70 years
15-20 % with ESRD
It is increased with aging and is associated with common atherogenic risk factors:
Hypertension
Hypercholesterolemia
Smoking
Diabetes
27. Clinical Presentations:
Hypertension (HTN), with Chronic Kidney Disease (CKD), a pro-atherogenic state
make the incidental finding of ARVD, rather than being the cause of it..
Epi-gastric bruit
Hypokalemia and metabolic alkalosis
Flash pulmonary edema(5%):
Sudden onset of acute heart failure in absence of myocardial ischemic event
Commonly at night(due to posture-related redistribution of fluid or may be due to diurnal
variations of vasoactive peptides)
Mechanism may be due to reduced natriuretic ability, coupled with LVH and severe HTN in
patients with severe bilateral RAS
Acute Kidney Injury (AKI), due to arterial occlusion
28. Prognosis of ARVD:
Renal outcome is determined by the presence of parenchymal disease
giving the picture of ischemic nephropathy (intrarenal atheroma, or
cholesterol embolization)
The correlation between the severity of proximal lesions(degree of
stenosis or occlusion) and renal function is poor.
Poor prognosis (5-year survival<20 %)
29.
30.
31. Treatment of RAS:
Conservative medical management:
Cessation of smoking/weight loss/exercise
Strict Control of HTN
Lipid lowering agents
Aspirin
Revascularization, especially successful in significant RAS associated
AKI, or with flash pulmonary edema:
Percutaneous Transluminal Renal Angioplasty (PTRA), with stenting (PTRAS), in
>95% of cases
Surgical reconstruction: celiac, or mesenteric –to- Renal Bypass, in remainder of
cases
Balloon angioplasty:
Uncontrolled HTN
Success rate: 82-100 %
Recurrence rate: 10 % (follow-up with duplex U/S)
32. Fibromuscular Dysplasia (FMD):
It accounts for 10% of all RVD
Most commonly in young women (20-35 Ys)
The stenotic lesions are distal and appear like “string of beads”, at angiography
Clinically, presented with severe HTN, but renal failure is unusual
It is usually associated with other arterial lesions (carotid stenosis in 10% of
cases)
Revascularization cure the HTN and restores the kidney function completely;
because the kidney beyond the FMD, is usually healthy
Fibromuscular dysplasia of the renal artery, medial type (elastic tissue stain)
The media shows marked fibrous thickening, and the lumen is stenotic
33. Atheroembolic RVD:
Cholesterol embolisation syndrome (CES) is occurring in:
Elderly patients with widespread atherosclerosis (almost exclusively)
As complication of abdominal aorta/renal artery manipulation or surgery
As a consequence of angiography
Clinically:
Renal insufficiency &/or HTN
Livideo reticularis
Evidence of embolisation in other organs: Cerebrovascular events, retinal artery
occlusion, acute pancreatitis, ischemic bowels, gangrene of extremities
Urine analysis:
Cholesterol crystals (not usually present)
Increased cellularity
Proteinuria (mild)
Eosinophiluria
34.
35. Treatment of CES
Control HTN (avoid hypotension)
Adequate hydration
Anticoagulants may delay healing of ulcerated atherosclerotic lesions
Dialysis may be needed
36. Thromboembolic Occlusion of
Renal Arteries
Causes:
Intrinsic pathology in renal vessels:{In situ thrombosis}
Post-traumatic.. Young patients (blunt trauma, deceleration injury,..)
Atherosclerotic.. Old patients
Dissection/Aneurysm/Arteriography
Inflammatory: Takayasau, syphilis, systemic vasculitis, thrombangitis obliterans
Embolization: {originating in distant vessels}; much more common
(90%) and usually unilateral
Tumor/Fat emboli
Emboli from left heart (most common), as left mural thrombus following MI or AF, or bacterial
endocarditis, septic/aseptic valvular vegetations..
Paradoxical emboli, passing through patent foramen ovale or ASD
37. Clinical Manifestations Of
Thromboembolism
Difficult to diagnose, require high index of suspicion
Variable, depend on: extent/time course of occlusion and state of pre-
existing renal circulation
Acute renal thrombosis/infarction
Sudden onset of flank pain/tenderness (absent in 55 %)
Fever/nausea/vomiting
Hematuria (microscopic)
Deteriorated renal function: transient (unilateral), or severe (bilateral)
Hypertension, usually transient (renin release in peri-infarction zone)
Elevated TLC, AST, LDH, ALP (renal enzymes in infarction)
38. Clinical Manifestations Of
Thromboembolism
Gradual unilateral occlusion --> may go undetected
Patients with RAS & established collateral circulation have no symptoms
(little/no infarction)
Thus, the spectrum of clinical manifestations lies between some extremes
in different occasions:
ARF
Unexplained Progressive Azotemia (old patient ± refractory HTN)
HTN + Azotemia (renal transplant)
40. Clinical Manifestations of RVT
Depend on extent and rapidity of occlusion:
1. Acute:
Nausea/vomiting
Flank Pain
Hematuria
Leucocytosis
Compromised renal functions
Increased renal size on U/S
2. Chronic:
Dramatic ↑ of proteinuria
Tubular Dysfunction: Glucosuria, aminoaciduria, phosphaturia and impaired
urinary acidification
41. Diagnosis of RVT
Investigations:
Doppler U/S: more sensitive then USG alone
CT Angiogram- 100% sensitive
Magnetic Resonance Angiography is another good option but is more expensive.
Treatment:
Anticoagulation Therapy and treatment of underlying cause
Endovascular Thrombolysis may be considered in severe cases
Occasionally, neprectomy may be undertaken for life-threatning complication
Vena caval filters may be used to prevent migration of thrombi
