Fichas
Sept 28
Fichas del conjunto (83)
- 1Causes of CKD/ ESRDHypertension and diabetes (more) working together can cause chronic kidney disease
- 2why Microalbuminuria is imporanta manifestation of Endothelial cell injury
A risk marker for:
Hypertension progression
Cardiovascular disease
Chronic Kidney disease - 3Major histologic changes in diabteitc nephropathy:GBM thickening
Mesangial expansion
Kimmelstiel-Wilson lesion
Glomerular sclerosis - 4Clinical diagnosis of dibetic nephopthyDuration of diabetes
Uncontrolled diabetes
Proteinuria
Renal failure
Retinopathy and Neuropathy - 5Therapy - Slowing the Progression of CKDRAAS suppression/Albuminuria therapy
ACE inhibitors
Angiotensin Receptor Blockers
Hypertension Control
Diabetes Management (most imporant)
Hyperlipidemia Control
Discontinue smoking - 6ManagementTight glycemic control - HbA1C <7% (MOST EFFECTIVE at slowing CKD progression)
ACEI / ARB treatment - Proteinuria <500 mg/day
Additional antihypertensive therapy - BP <130/80 mm Hg (<125/75 mmHg in patients with proteinuria > 1.0 g/day)
Dietary protein restriction - 0.8 g/kg/day
Lipid lowering therapy - LDL cholesterol <100 mg/dL
Lifestyle modification - Smoking cessation, weight loss, salt restriction - 7Why are ace and arb goodGlycosolated is damigming afferent and efferent arteior which cause dilation and likiness and aff artiole which will underperfusion kindey which will increase RAAS system
Which will cause it damaged efferent arteriole and cause vaconstiction and back pressure on glomerulus which dmages ait even more and more leaky
Ace and arb will decrease efferent arteiolr vasocontrciton becus ace and arb will inhibit RAAS. Yes it will decrease GFR but sacrifice needs to be done - 8Pathology Hypertensive NephrosclerosisPartial hyalinization of glomerulus
Hylanization in artieal walls - 9Clinical features for hypetensive nephrocoloisisChronic hypertension
Left ventricular hypertrophy
Hypertensive retinopathy
Proteinuria (usually less than 1 gm/day)
Progressive renal insufficiency - 10mad cycleHyptension will damage ckd which will cause kindey to increase RAAS system which will even cause more hypertension
- 11Anemia of CKDUsually normochromic and normocytic
Erythropoietin due to renal mass
Must exclude all non-renal causes of anemia - 12Anemia of chronic diseaseDecrease release of iron from macrohpages and decrease of iron reab which will lead to anemia of chronic disease.
Just cant say its epo and sometimes pt needs iron - 13Mineral bone disordersVitamin D deficiency
Hypocalcemia
Hyperphosphatemia
Hyperparathyrodism - 14PTH releaseincrease phosporus
decrease calcium
decrease in vitamin D - 15Clinical featuresAsymptomatic
Bone pain
Proximal myopathy
Fractures
Vascular medial wall calcification
Soft tissue calcification
Calciphylaxis - 16TreatmentLow phosphate diet
Phosphate binders with meals
Vitamin D
Calcimimetic agents
Parathyroidectomy - 17HemodialysisSurgery that creates vein and arteries together (fistula)
But since we need right now we put central venous cather in internal jugular vein and tunnel it under collar bone.
usually on it 3x a weeks
Take blood out of body and tken into pump and goes thru dialyzer and then once u clean the blood it goes back to body - 18Peritoneal dialysisFluid is put in for hours and then use peitenoem to create ceoncentation gradient.
Bath has low k and and vessels are exposed to it and they will go down their coencentration gradient out into another bag - 19Renal transplantationWe don’t take out native kindey so u actually have 3rd kidney,
- 20What were the risk factors for progression of CKD for our patient?Uncontrolled Hypertension
Uncontrolled Diabetes
Heavy Proteinuria
Hyperlipidemia
Inconsistent Use ACEi/ARB
Anemia
Poor Follow-up & Follow-through - 21Austodomal dominaant polyscitic kidney disease has what?Two renal cysts unilaterally or bilaterally before age 30 years by renal ultrasound.
Two cysts in each kidney between the ages of 30 and 59 years by renal ultrasound.
Four or more cysts in each kidney after age 60 years by renal ultrasound. - 22Types of ADPKDPKD1 (more common)
PKD2 (less common)
difference bwteen 2 is done by genetic testing - 23Pathogenesis of ADPKDLoss of ciliary signaling which effects cell division
Cilia is filled with fluid thru aqp2 which leads to fluid filled cysts - 24Extra renal manifestationscysts in liver
valve abnormailites
diverticular disease in colon
anurysm in CNS - 25Progression of ADPKDThe more cyst u have the more decrease in kidney function
- 26Treatment of ADPKDdrugs that will block V2 receptors (antagonists) that can slow cysts being made
more studies need to be done - 27Screening for Intracrianl anuerymsPatients with a family history of SAH
High risk occupation such as pilots
Prior to major elective surgeries with anticipated hemodynamic instability. - 28Treatment of asymptomatic ICAUnder 10 mm in diameter - Observation and follow-up (at 6 months initially and then yearly)
For >10 mm - surgical clipping is indicated. - 29Differential Diagnosis of cystic kindey disease.
- 30Stages of CKDI
II
III
IV
V - 31IKidney Damage
GFR >90 - 32IImild
60-89 - 33IIImoderate
30-59 - 34IVsevere
15-29 - 35VEnd-Stage Renal Disease
<15 - 36End-Stage Renal Disease treatmentstransplant
dialysis
hospice - 37Diabetic Nephropathy in stage 1Hyperfunction & Hypertrophy
Glomerular Hyperfiltration
GFR
albumin excretion <30
timing: present at the time of diagnosis - 38DN in stage 2silent stage
Thickened BM & expanded mesangium
GFR
alumin excetion <30
timing: First Five years - 39DN in stage 3Incipient Stage
Microalbuminuria
GFR
album excretion 30-300
timing 6-15 years - 40DN in stage 4Overt Diabetic Nephropathy
Macroalbuminuria
GFR
album excre >300
timing 15-25 years - 41DN in stage 5Uremic
ESRD
GFR is 0
album ecretion decreasing
timing: 25-30 years - 42Microalbuminuria24 hr mcg/min
20-200
24 hr mg/day
30-300 - 43Macroalbuminuria24 hr mcg/min
>200
24 hr mg/day
>300 - 44Kindey USHyper-white/lighter/brighter due to scar tissue
Brighter then liver means CKD - 45hypertensive nephorsclerosis causesSalt can cause hypetension
Nsaids
Lower socionemoic status not having good food
Genetic
all can lead to end stage renal disease - 46Pathology Hypertensive NephrosclerosisPartial hyalinization of glomerulus
Hylanization in arterial walls - 47what can be found in stage 2hypertension
- 48what can be found in stage 3PTH
anemia
phosphorus - 49what can be found in stage 4acidosis
hyperkalemia - 50what can be found in stage 5uremic syndrome
- 51Co-Occurrences of CKDAlbuminuria
Anemia of CKD
CVD
CKD-MBD
Hyperglycemia
Hyperlipidemia
Hypertension - 52How do we measure Kidney FunctionEstimated GFR (ml/min/1.73m2) MDRD
Less accurate when GFR is less than 60
CKD-EPI GFR- Increased accuracy for eGFR evven when GFR 60< - 53Stage 1 and 2 is pretty normal GFR so to tell if you're actually in stage 1 or 2 u need tohave microscopic hematuria
proteinuria,
change in kidney US.
U need to have 1 of these things for 3 months to say of have chronic kidney disease that.
Unless you have GFR less than 30 then u don’t have to have any of these things - 54Polycystic Kidney Disease (PKD)Gradually developing clusters of non-cancerous fluid-filled sacs in the kidney (renal cysts)
Accounts for 5-10% of ESRD
Prevalence: 1 in 500-2000 (~0.5 M in US)
Multisystem disease with extrarenal manifestations
Predominantly genetic etiology in most patients - 55Multisystem disease with extrarenal manifestations:liver (hepatic cysts, fibrosis)
- blood vessels (intracranial aneurysm)
- heart valves - 56Large phenotypic variability in:age of onset
rate of progression to ESRD
extrarenal manifestations - 57Complications:hypertension
- loss of kidney function (CKD)
- pain in back or flank
- hematuria
- urinary tract infections - 58Genetic vs non-genetic (i.e. environmental) factors have variable contributions in the determination of traits and diseases. Non-genetic factors in PKD- toxic kidney injury
- smoking
- caffeine
- obesity - 59PKD is predominantly what type of genetic?monogenic
Single rare variant with strong effect causes disease - 60Autosomal Dominant PKD (ADPKD)More common and less severe form
(prevalence: 1 in 500-2,000)
Typically adult onset (“adult PKD”)
Hypertension in most adult patients
ICA in ~10% of patients
ESRD in 50% of patients by 60 y
Mutations in PKD1 (80%), PKD2 (15%)
and other genes (rare) - 61Autosomal Recessive PKD (ARPKD)Rare and more severe form
(prevalence: 1 in 20,000-30,000)
Typically pediatric onset (“juvenile
PKD”)
30-50% neonatal mortality
(due to pulmonary hypoplasia)
Hypertension in 75% of children
ESRD in 60% of patients by 20 y
Mutations in PKHD1 (>90%) and
other genes - 62Monogenic can be inherited bydominate or recessive fashion
in this case its mostly dominant - 63ADPKD is caused by mutations in thePKD1 (80% of cases) or PKD2 (15% of cases) genes or, in rare cases mutations in other genes. This demonstrates locus heterogeneity in ADPKD.
Locus heterogeneity: mutations at different loci (i.e. genes) result in the same phenotype/disease. - 64gentic effectPolycystin-1 (PC1, encoded by PKD1) and polycystin-2 (PC2, encoded by PKD2) are plasma membrane proteins and interact with each other to form a Ca2+-channel
- 65Impaired ciliary function in ADPKDCilia are microtubule-based cellular organelles protruding from the cell surface in most polarized cells types of the body. Their primary function is to transmit extracellular signals to the cell (“cells’ antennae”)
The PC1-PC2 complex is localized to cilia, and involved in cellular mechanosensation.
In normal cells, fluid-induced ciliary bending activates the PC1-PC2 complex and triggers Ca2+ influx and intracellular Ca2+ signaling, which regulates tissue morphogenesis. - 66PKD mutation effect on pc1 and pc2In PKD, impaired ciliary Ca2+ signaling results in disoriented cell divisions and cyst formation.
Diseases associated with impaired ciliary function, including PKD, are called ciliopathies. - 67PKD1 mutations cause more severe disease (ADPKD1, type 1) than mutations in PKD2 (ADPKD2, type 2):- more cysts at earlier age
- faster increase in total kidney volume
- earlier age of onset of ESRD
- less overall survival - 68major cause of phenotypic variability in ADPKD.Locus heterogeneity
- 69*In addition to in C-terminal truncation, premature termination codons (PTC) also cause mRNA degradation (except when PCT occurs within or close to the last exon). This mechanism is callednonsense-mediated mRNA decay (NMD). NMD leads to reduced protein expression.
coding variants - 70Allelic heterogenity in ADPKDAllelic heterogeneity: different mutations (i.e. alleles) within the same gene result in the same phenotype/disease.
The large number of PKD1 mutations (>2,000) in patients demonstrates allelic heterogeneity in ADPKD. Most mutations are private (i.e. only seen in 1 patient). PKD2 (not shown) has >200 mutations.
Extensive allelic heterogeneity suggests loss-of-function mechanism. - 71part 2The dominant inheritance of loss-of-function mutations indicates haploinsufficiency (1 wild-type allele is not sufficient for normal function).
Mutations in red lead to C-terminal truncation of the PKD1 protein. Protein-truncating (PT) mutations completely abolish PKD1 function (null-mutations). Non-truncating (NT) mutations shown in green result in incrementally reduced PKD1 function (hypomorphic mutations). - 72Patients with protein-truncating (PT) mutations in PKD1 (PKD1PT) exhibitmore severe phenotype than those with non-truncating (NT) mutations (PKD1NT).
Allelic heterogeneity is a major cause of phenotypic variability in ADPKD. - 73Variable expression in ADPKDVariable expression: variable phenotype/disease severity in patients with the same genotype (i.e. members of the same family)
Large intrafamilial variability in ADPKD phenotype (i.e. age of renal death) - 74Modifier genes in ADPKD lead toPhenotypic variability
Phenotypic variability is greater in non-twin siblings (~50% identical genome) than in monozygotic (MZ) twins (100% identical genome).
This indicates the effect of genes other than PKD1 (i.e. modifier genes) on the phenotype.
The identity of modifier genes in ADPKD remains poorly understood. - 75Somatic mutations in ADPKD lead tophenotypic variability
- 76Severity of the disease is determined bythe cellular amount of PKD1 activity.
Most patients carry an inherited hypomorphic (PKD1NT) or null-mutation (PKD1PT) on one allele of PKD1 (i.e. heterozygous).
An additional somatic mutation on the other PKD1 allele (compound heterozygosity) can further reduce cellular PKD1 activity and exacerbate the phenotype. - 77The presence/absence and nature (i.e. degree of hypomorphy) of somatic mutations is a source of phenotypic variability in ADPKD.
- 78Autosomal recessive PKD (ARPKD)>90% of patients have mutations in the Polycystic Kidney and Hepatic Disease 1 (PKHD1) gene.
In rare cases, mutations in other genes are responsible (locus heterogeneity).
Fibrocystin (the protein product of PKHD1) localizes to the ciliary membrane and forms a complex with PC1-PC2. The molecular function of fibrocystin remains unknown - 79Most ARPKD patients harborrare, compound heterozygous mutations.
- 80Large phenotypic variability in neonatal mortality (30%) and disease progression is due to:locus heterogeneity
- allelic heterogeneity (truncating mutations:
neonatal mortality (30-50%) vs non-truncatin mutations: milder presentation, survival) - 81Why do we want to know the genetic determinants of PKD in a patient?Provide better clinical prognosis
Assess risk of disease recurrence in families
Treat based on patient’s genotype
(“personalized medicine”) - 82Predicting Renal Outcomes in ADPKD (PROPKD)The PROPKD score allows the prediction of disease progression in ADPKD based on clinical and genetic characteristics.
Limitations: not informative in patients <35 y (unless earlier onset of HTN and urologic events); requires genetic testing - 83Risk of PKD recurrenceIn most cases (85%) of ADPKD, the patient has a positive family history (FH). In the absence of FH (15% of cases), ADPKD is due to a de novo mutation in the father’s sperm.
In populations with low level of consanguinity, patients with ARPKD have no FH.
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- Fichas sobre Sept 28, creado por Shylla T el 28/09/2020.
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- Shylla T
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