Case 1: Glomerular Vascular Syndromes Flashcards
ATHEROSCLEROTIC NEPHROPATHY
● Aging in the developed world is commonly associated with the occlusion of coronary and systemic blood vessels.
● The reasons for this include obesity, insulin resistance, smoking, hypertension, and diets rich in lipids that deposit in the arterial and arteriolar circulation, producing local inflammation and fibrosis of small blood vessels.
● When the renal arterial circulation is involved, the glomerular microcirculation is damaged, leading to chronic nephrosclerosis. Patients with GFRs mL/min have more cardiovascular events and hospitalizations than those with higher filtration rates.
● Several aggressive lipid disorders can accelerate this process, but most of the time atherosclerotic progression to chronic nephrosclerosis is associated with poorly controlled hypertension.
● Approximately 10% of glomeruli are normally sclerotic by age 40, rising to 20% by age 60 and 30% by age 80.
● Serum lipid profiles in humans are greatly affected by apolipoprotein E polymorphisms; the E4 allele is accompanied by increases in serum cholesterol and is more closely associated with atherogenic profiles in patients with renal failure.
● Mutations in E2 alleles, particularly in Japanese patients, produce a specific renal abnormality called lipoprotein glomerulopathy associated with glomerular lipoprotein thrombi and capillary dilation.
HYPERTENSIVE NEPHROSCLEROSIS
● Uncontrolled systemic hypertension causes permanent damage to the kidneys in about 6% of patients With elevated blood pressure.
● As many as 27% of patients with end-stage kidney disease have hypertension as a primary cause.
● Although there is not a clear correlation between the extent or duration of hypertension and the risk of end-organ damage, hypertensive nephrosclerosis is fivefold more frequent in African Americans than Caucasians.
● Associated risk factors for progression to end-stage kidney disease include age, sex, race. smoking, hypercholesterolemia, duration of hypertension, low birth weight, and pre-existing renal injury. Kidney biopsies in patients with hypertension, microhematuria, and moderate proteinuria demonstrate arteriolosclerosis, chronic nephrosclerosis, and interstitial fibrosis in the absence of immune deposits.
● Today, based on a careful history, physical examination, urinalysis, and some serologic testing, the diagnosis of chronic nephrosclerosis is usually inferred without a biopsy.
● Treating hypertension is the best way to avoid progressive renal failure; most guidelines recommend lowering blood pressure to <130/80 mmHg if there is preexisting diabetes or kidney disease.
● In the presence of kidney disease, most patients begin therapy with two drugs, classically a thiazide diuretic and an ACE inhibitor; many will require three drugs.
● There is strong evidence in African Americans with hypertensive nephrosclerosis that therapy initiated with an ACE inhibitor can slow the rate of decline in renal function independent of systemic blood pressure.
● Patients with lower levels of hypertension are usually started on a thiazide diuretic or an ACE inhibitor alone. Malignant acceleration of hypertension can complicate the course of chronic nephrosclerosis, particularly in the setting of scleroderma or cocaine use.
● The hemodynamic stress of malignant hypertension causes fibrinoid necrosis of small blood vessels, thrombotic microangiography, a nephritic urinalysis, and acute renal failure. In the setting of renal failure, chest pain, or papilledema, the condition is treated as a hypertensive emergency.
● Slightly lowering the blood pressure often produces an immediate reduction in GFR that improves as the vascular injury attenuates and autoregulation of blood vessel tone is restored
CHOLESTEROL EMBOLI
● Although individuals with SA-hemoglobin are usually asymptomatic, most will gradually develop hyposthenuria due to subclinical infarction of the renal medulla, thus predisposing them to volume depletion.
● Patients with homozygous SS-sickle cell disease develop chronic vaso occlusive disease in many organs. Polymers of deoxygenated SS-hemoglobin distort the shape of red blood cells.
● These cells attach to endothelial and obstruct small blood vessels, producing frequent, random, and painful sickle cell crises over time. Vessel occlusions in the kidney produce glomerular hypertension, FSGS, interstitial nephritis, and renal infarction associated with hyposthenuria, microscopic hematuria, and even gross hematuria; some patients also present with MPGN.
● By the second or third decade of life, persistent vaso occlusive disease in the kidney leads to varying degrees of renal failure, and some patients end up on dialysis.
● Treatment is directed to reducing the frequency of painful crises and administering ACE inhibitors in the hope of delaying a progressive decline in renal function.
● Sickle cell patients can have transplantations, and renal graft survival is comparable to African Americans given transplantations for other reasons.
SICKLE CELL DISEASE
● Although individuals with SA-hemoglobin are usually asymptomatic, most will gradually develop hyposthenuria due to subclinical infarction of the renal medulla, thus predisposing them to volume depletion.
● Patients with homozygous SS-sickle cell disease develop chronic vaso occlusive disease in many organs. Polymers of deoxygenated SS-hemoglobin distort the shape of red blood cells.
● These cells attach to endothelial and obstruct small blood vessels, producing frequent, random, and painful sickle cell crises over time. Vessel occlusions in the kidney produce glomerular hypertension, FSGS, interstitial nephritis, and renal infarction associated with hyposthenuria, microscopic hematuria, and even gross hematuria; some patients also present with MPGN.
● By the second or third decade of life, persistent vaso occlusive disease in the kidney leads to varying degrees of renal failure, and some patients end up on dialysis.
● Treatment is directed to reducing the frequency of painful crises and administering ACE inhibitors in the hope of delaying a progressive decline in renal function.
● Sickle cell patients can have transplantations, and renal graft survival is comparable to African Americans given transplantations for other reasons.
THROMBOTIC MICROANGIOPATHIES
● Thrombotic thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome (HUS) represent a spectrum of thrombotic microangiopathies.
● TTP and HUS share the general features of idiopathic thrombocytopenic purpura, hemolytic anemia, fever, renal failure, and neurologic disturbances.
● When patients have more evidence of renal injury, their condition tends to be called HUS, and when there is more neurologic disease, it is considered to be TTP.
● In adults there is often a mixture of both, which is why they are often called TTP/HUS. On examination of kidney tissue there is evidence of glomerular capillary endotheliosis associated with platelet thrombi, damage to the capillary wall, and formation of fibrin material in and around glomeruli
● These tissue findings are similar to what is seen in preeclampsia/HELLP (hemolysis, elevated liver enzymes, and low platelet count syndrome), malignant hypertension, and the antiphospholipid syndrome.
● TTP/HUS is also seen in pregnancy; with the use of oral contraceptives or quinine; in renal transplant patients given OKT3 for rejection; in patients taking the calcineurin inhibitors cyclosporine and tacrolimus or in patients taking the antiplatelet agents ticlopidine and clopidogrel; or following HIV infection.
● Although there is no agreement on how much they share a final common pathophysiology, two general groups of patients are recognized: childhood HUS associated with enterohemorrhagic diarrhea and TTP-HUS in adults.
● Childhood HUS is caused by a toxin released by Escherichia coli 0157:H7 and occasionally by Shigella dysenteriae.
● This Shiga toxin (verotoxin) directly injures endothelial, enterocytes, and renal cells, causing apoptosis, platelet clumping, and intravascular hemolysis by binding to the glycolipid receptors (Gb3).
● These receptors are more abundant along endothelium in children compared to adults. In familial cases of adult TTP/HUS, there is a genetic deficiency of the ADAMTS13 metalloprotease that cleaves large multimers of von Willebrand’s factor. Absent ADAMTS13, these large multimers cause platelet clumping and intravascular hemolysis.
● An antibody to ADAMTS13 is found in many sporadic cases of adult TTP/HUS, but not all; many patients also have antibodies to the thrombospondin receptor on selected endothelial cells in small vessels or increased levels of plasminogen-activator inhibitor I (PAI-I ).
● The treatment of childhood HUS or adult TTP/HUS is daily plasmapheresis, which can be lifesaving.
● Plasmapheresis is given until the platelet count rises, but in relapsing patients it may need to be continued well after the platelet count improves, and in resistant patients twice-daily exchange may be helpful.
● Most patients respond within 2 weeks of daily plasmapheresis. Since TTP/HUS often has an autoimmune basis, there is an anecdotal role in relapsing patients for using splenectomy, steroids, immunosuppressive drugs, or anti-CD20 antibody Patients with childhood HUS from infectious diarrhea are not given antibiotics, as antibiotics are thought to accelerate the release of the toxin and the diarrhea is usually self-limited.
