Renal Study Guide: Chronic Kidney Disease (CKD) PDF

Chronic Kidney Disease (CKD) Kidney dysfunction for ³ 3 months 1 of 4 criteria § GFR < 60 Definition...

Chronic Kidney Disease (CKD) Kidney dysfunction for ³ 3 months 1 of 4 criteria § GFR < 60 Definition § Structural damage § Urine cast § Albuminuria (Ualb/UCr > 30) Risk factor Black race ancestry Most common cause Diabetes > HTN § Small (< 9 cm) In diabetes patient, kidney increases in size early on (hypertrophy of the glomeruli but damage and shrink after) Ultrasound § Increased echogenicity (fibrosis) § Loss of corticomedullary diEerentiation § Waxy cast (Tamm-Horsfall protein retained in a dilated tubule before excretion) § Microalbuminuria (usually 5 years post DM) à early injury to glomerulus Urinalysis o Spot Ualb/UCr 30 – 300 mg o Nephrotic range proteinuria DOES NOT occur > ESKD Stage 5 CKD requires dialysis/transplant § Stroke, Afib, CHF (deposition of CaPO4 in vascular smooth muscle § GFR < 10 cc/min cell à stiE heart muscle à hypertrophy) Immediate dialysis if CKD and pericarditis/CHF/metabolic acidosis/neurological symptoms Renal osteodystrophy § Secondary hyperparathyroidism à osteitis fibrosa cystica – § Serum: ¯ Ca, ­ phosphate, ¯ 1,25-OH vit D (normal inactive vitamin D3) à compensatory ­ PTH + ­FGF-23 high-turnover (test with alkaline phosphatase) o ¯ phosphate reabsorption in proximal tubule + ­ excretion à main reason for ­ PTH § Vitamin D deficiency à osteomalacia – low-turnover o Free Ca binds phosphate in blood à ¯ serum Ca (also ¯ 1,25-OH vit D) à ¯ reabsorption of Ca § X-ray findings o FGF-23 made by osteocytes o Subperiosteal resorption (middle phalanges and tips of fingers) § ­ renal phosphate excretion à brown tumor (bone cyst) § Inhibit 1a-hydroxylase à ¯ 1,25-OH Vitamin D o Rugger-jersey spine § ¯ PTH secretion, ­ 24-OH of PTH o Salt and pepper skull – alternating areas of sclerosis and lucency § Trade-oE hypothesis: every ­ phosphate is countered by ­ PTH à high PTH with normal [Ca] and [phosphorous] Complications due to activation of osteoclast à also seen in myeloma § DiEuse parathyroid nodular hyperplasia § Loss of inner and outer skull tables definition + ground-glass appearance + spotty deossification Serum phosphorous < 5.5 mg/dl § ¯ dairy products – milk/cheese, meats § Intestinal phosphate binders – calcium based, non-calcium based, aluminum-based antacids Preventions Vitamin D treatment (active form) Calcitriol (1,25-OH D3) Calcimimetics Sensipar - Bind Ca receptor à mimic high [Ca] à turn oE PTH  Anemia of CKD Secondary to erythropoietin deficiency § Produced by specialized peritubular capillary EC that become fibrotic § Prevalent at stage 4 § Contribute to left ventricular hypertrophy Check iron stores, vitamin B12, folic acid Normal concentration of Fe, B12, folate. Normal shape and size but too few à normocytic normochromic anemia Work up Iron deficiency à hypochromic microcystic anemia B12 deficiency à megaloblastic anemia Human recombinant erythropoietin (EPO) Target Hgb 11.5 à higher results in HTN and mortality Treatment SGLT2 inhibitors seem to help preventing EPO loss Pericarditis Di]use widespread concave ST elevation and PR depression ECK Reciprocal ST depression and PR elevation in aVR Sinus tachycardia CXR Water bottle sign à pericardial eEusion Friction rub Physical exam Ewart sign à pericardial eEusion compresses surround lung tissue à lack of air Hyperkalemia Loss of p wave (sinus node failure) Widening of QRS (slow conduction) Sine wave pattern (cardiac arrest) EKG Peaked T waves IV Calcium Increase threshold potential Treatment Insulin, Beta-2 agonist Stimulate Na/K/ATPase Chronic interstitial nephritis (CKD) Etiology § AIN (drug induced, infection) § AIN – treatable § Directly without AIN § CIN – not amenable to therapy Characteristics § No inflammation – minimal infiltrate § Activated T, fibroblast, macrophages § Tubular atrophy and dilation § Epithelial cell loss of brush border and ­ basement membrane + fibrosis § Thyroidization – Tamm-Horsfall protein and waxy cast Drug induced Unknown – Mesoamerican Analgesic therapy Calcineurin inhibitors Lithium Aristolochic acid (herbal) Heavy metals Nephropathy § Phenacetin ± acetaminophen § Tacrolimus, cyclosporin § Enter tubules via ENAC – § Common herbal therapy (China) § Lead, Cadmium, Mercury, § India, Sri Lanka, Central § ASA or ca]eine § Most important in collecting duct principal cell § Group I human carcinogen Arsenic America, Egypt § NSAIDS maintaining § Average 20 years use § Balkan nephropathy – aristolochia § Industrial pollution of food § Young men 3rd – 5th decade Characteristics § No AIN but straight to chronic immunosuppression § ­ CKD risk with concomitant clematis grows in wheat fields along supply and herbal therapy § Agricultural workers § Inhibit IL2 production and T use of diuretics (­ Na and Li Danube River (sugarcane) cell proliferation uptake by ENAC) § Low altitude § Do not aEect bone marrow § High ambient temperatures § Female 60 – 85% Can also cause Also cause nephrogenic DI – Nephrotoxicity can occur years after Lead § Minimal HTN § Age > 30 yo § HTN hypernatremia exposure à dose dependent eEect § HTN § Absence of significant § Analgesic dependency – headache, § Diabetes § Gout proteinuria muscle pain § Malignancy (lymphoma) Cadmium § Band urinary sediment Clinical features § Personality disorders § Industrial use – electronic § Addictive habits waste § Dose dependent § By-product of zinc smelting § Renal – sterile pyuria, CIN § Herbal therapy o Minimal HTN § HTN  o Non nephrotic proteinuria § Malignancy (transitional o ¯ net acid secretion and renal cell) o Papillary necrosis – renal Herbal therapy colic/gross hematuria § Heavy metals arise from o Salt wasting polluted soil, deliberate addition, improper manufacturing § Ayurveda (lead, copper, arsenic, gold, sulfur) – India (Samskaras) § Intra-renal conversion to reactive Nephrotoxic over long periods § Hypocellular chronic interstitial fibrosis § Absorption at proximal tubule § Tubulointerstitial origin oxidizing metabolites à of use § Lesion in proximal tubule via divalent cation channels § Persistent and recurrent medulla/papillae o ­ excretion of B2 microglobulin, (DMT1) à proximal tubular episodes of volume § Papillary necrosis retinol binding protein, neutral injury + ­ accumulation and depletion + o Blunting of calyces endopeptidases build up in the interstitium à environmental/genetic Pathogenesis o Calcified papillae § Extensive AA-DNA adduct formation interstitial fibrosis exposure à ­ CKD risk o Renal colic/obstruction (biomarker) à non-reparable genomic § Small shrunken kidney o Small contracted kidney lesion § Minimal cellular infiltrate o Loss of concentration ability § Lifelong oncogenicity à high grade § Minimal tubular proteinuria transitional cell (uro-epithelial) Concomitant use of amiloride Lead à Chelation therapy Prevention/Treatment Cadmium à no chelation therapy ESRD Treatment Transplantation Hemodialysis Peritoneal dialysis § CVD is still #1 cause of death § A – acidosis (pH > AV graft Use peritoneal membrane as filter membrane o Active malignancies – at least 2 years after successful treatment § AV fistula – high arteriole pressure dilates the § Line the walls of the abdominal cavity o Active/chronic infection vein à increase flow à spot for dialysis § Surface area = 1.75 ± 0.5m2 à ­ when infused Patient o Active ischemic heart disease/PVOD catheter with dialysate selection o Noncompliance history o Require good collateral flow, else steal § Contain large pore (25mm), small pores (5mm), o Active autoimmune kidney disease syndrome = blood flow to vein instead of and ultra small pores (water transport) § HIV recipients eligible if on therapy – can be matched with HIV donors supply tissue à ischemia § Permanent external catheter Requirements Living Cadaveric Tunneled catheter is used for vascular access § Living related § Donation after brain death (still have heartbeat via artificial until proper access can be created § Living unrelated resuscitation) § Tunneled, cuEed doubled lumen catheter in Donors § Paired exchange § Donation after cardiac death (irreversible CNS injury unable to maintain internal jugular vein ventilatory and BP support) § Least desirable à infection, § HepC+ donors thrombosis/stricture, ineEicient dialysis § Required request in the US vs presumed consent Diet and fluid intake restricted Transplanted kidney is heterotopic – in the groin Di]usion >> Convection (ultrafiltration) § Old kidney stays in § 2 compartment with semi-permeable § Porous membrane Anatomy § Vascular supply of the kidney comes from iliac artery Clearance membrane and concentration gradient § Positive pressure/negative suction drives flow methods § Clearance directly related to volume of fluid removed MHC/HLA is coded for by chromosome 6 Human kidney – only ultrafiltration (convection) § 3 alleles – A, B, D à 6 major HLA antigens/2 haplotypes per person Hollow fiber dialyzer – 2 compartments (blood Similar dialysate to hemodialysis Matching o D region most important – influence lymphocyte reactivity Technique vs. dialysate) separated by semi-permeable § Sit in the peritoneum and allow diEusion across § Co-dominant inheritance membrane. Dialysate blood vessels into peritoneal cavity  § Class I HLA presented on all nucleated cells (not RBC) à CD8 cytotoxic T cell activation § High HCO3 à diEusion into blood à § Drainage of dialysate and replacement with fresh § Class II are restricted to APCs, DC, B cells and activated T cells à activate CD4 helper T cells neutralize acidosis batch à removal of uremic toxins § Transplantation is based on matching as many HLA antigens as possible à lower risk of rejection à § Adjustable K § Risk of PD peritonitis at site of catheter insertion crossmatch § Isotonic NaCl § O can be used as universal donor § No creatinine and urea à diEusion out of 10-15% TP experience a rejection episode blood and into the dialysate § Flow rate 800cc/min § 3-4h, 3 times/week CCPD CAPD § Decrease BUN by > 65% each treatment § Continuous cycling § Continuous § Creatinine is no longer used as a marker for § Cycle at night 8-10h ambulatory renal function § 4-6 exchanges § 4 exchanges/day 30- § 10L exchanged 40’ Regimen § 2L fill volume § 2-2.5L/exchange § No machine and blood access needed Rejection § Least preferred Acute – T cell or humoral (B cell) mediated Hyperacute – IgG mediated modality § Infiltration of interstitium and tubules by § Ab against donor HLA antigens ready in blood Thrombosis – patency of HD access Maintaining eEectiveness of peritoneum – fibrosis cytotoxic T cells à tubulitis (hallmark of (sensitized) due to prior exposure (blood GFR = 20cc/min à move from stage 5 CKD to No survival benefit over hemodialysis rejection) transfusions, pregnancy, previous TP) Stage 4 CKD à does not correct CKD Risk of bowel obstruction and hernia § Type IV hypersensitivity reaction – T cells § IgG bind HLA on donor cell à immediate § Fever + enlarged, tender kidney thrombosis à infarction of kidney Infection risk but higher with PD catheter § Type II hypersensitivity à prevent with Decrease CV morbidity and mortality slightly compared to CKD but still loss of 60-70% expected crossmatch (recipient serum + donor survival compared to general population lymphocytes + complement à positive à sensitized) Problems Induction therapy (IV) Anti-T cell antibodies (IgG) IL2R Inhibitors § T cell depleting § Non-T cell depleting § Directed against mature T cell § No bone marrow suppression § Polyclonal – thymoglobulin (rabbit) § Basiliximab o serum sickness (1 week after) à type III hypersensitivity o cytokine release sickness (with first dose) § Monoclonal – OKT3 (mouse) Maintenance therapy (oral) § Prevent re-population of T cells § Monotherapy/discontinuation à rejection à lifelong therapy § Most used: calcineurin + purine inhibitor § Steroids are optional Post TP § mTOR inhibitors used selectively for intolerance to other drugs Immuno- Corticosteroids Calcineurin inhibitors Purine synthesis mTOR inhibitors suppression inhibitors § Prednisone § Tacrolimus/cyclosporin § Second most important § Sirolimus/Everolimus § Inhibit IL1 § Most important § Mycophenolic acid § Inhibit intracellular production by T § Inhibit production of IL2 § Azathioprine signaling after cells and T cell proliferation § Prevent cell replication binding of IL2 § ¯ T number § Metabolized by CYP450 (ALL proliferating cells, § No ¯ T number à avoid using with but cells other than nondihydropyridine CCB lymphocytes have and grapefruit juice pathway to SALVAGE à (inhibit CYP450) somewhat lymphocyte specific) § HTN § HTN § GI inflammation § Pneumonitis Side e]ects § Diabetes § Diabetes § Ulcers § Hyperlipidemia § Weight gain § Hyperlipidemia § Skin cancer § Poor wound healing  § Hyperlipidemia § Malignancy – B cell § No nephrotoxicity § Osteoporosis – lymphoma § Diabetes inhibit vit D § AKI/CKD – nephrotoxic § ¯ risk of malignancy § Osteomalacia à interstitial fibrosis § AVN – avascular necrosis No No Yes Yes A]ect BM Malignancy § Squamous cell skin cancer § B cell lymphoma (elimination of T cells allow B cell proliferation without inhibition) § EBV related § Solid tumors – breast, lung, colon, prostate (slight increase in risk) Complication Infection TP patients receive prophylactic pneumonia vaccination/lifelong abx/anti-viral prophylaxis § Viral – Herpes group family (CMV, EBV) à fever/pneumonia/hepatitis/colitis à fatal o CMV à Owl eyes + bat wing CXR (pneumonitis) § Fungal – aspergillosis, cryptococcus, TB § Bacterial – pneumococcal Hereditary and Congenital Kidney Diseases Cystic Diseases of the Kidney Glomerulopathies Storage disease Kidney stones ADPCKD ARPCKD Medullary sponge kidney Alport’s syndrome Fabry’s disease Cystinuria Classification Hereditary – genotype but phenotype Congenital – genotype + Congenital X-linked (80%), autosomal dominant X-linked recessive Autosomal recessive expressed later in life phenotype at birth (5%) or autosomal recessive (15%) Characteristics § Most common genetic abnormality of § Rare § NO loss of GFR § 2% of all dialysis patients § More severe in man kidneys § No cyst on surface § Hereditary nephritis if only renal § Median death – 41 years § Always bilateral ­ in size involvement without therapy (CAD) § 100% penetrant (may be clinically § AD + chronic microhematuria + no silent) ESRD + renal only à thin basement § 5-10% patients of dialysis patients membrane nephropathy (TBM) Genetic PKD1 – chromosome 16 (85%) and PKD2 Fibrocystin on chromosome Disorder of collagen type IV (6 chains) Deficiency of a galactosidase Dibasic amino acid transport – chromosome 4 (15%) 6 § Absence of a5 chain – X-linked A enzyme (cleave defect – COLA § Primary cilia glycoproteins § Primary cilia dominant form of AS glycosphingolipids into sugar § Cystine § Cilia projects from rental tubular cell § Cell adhesion, repulsion, § Absence of a3 or a4 chain – AR or AD and ceramide) § Ornithine into urinary space à sense urine flow proliferation form of AS § Lysine § Regulate cell growth and proliferation, § Arginine migration, and interactions with other cells à influence cell-cell interaction/adhesion § cAMP second messenger Location All tubules à both Dilation of Dilation of terminal collecting medullary and collecting ducts in pre-calyceal region of renal cortex duct – pyramids (ectasia) à medullary § < 10% of all 1 medullary cysts only million nephrons only! involved with cystic change § Secretory pump reversal à complete detachment from tubules à cysts fill with fluid Pathogenesis § All cells in kidney acquire germline Embryologic defect in Formation of small and large Thickening and thinning of the Accumulation of ceramide § Staghorn calculi – cystine defect ureteric bud formation medullary cysts that are often basement membrane trihexaside in blood stones § Second somatic mutation à focal cyst diEuse § Lamellation (weave of type 4 vessels/nerves/organs § Benzene ring – cystinuria development collagen)  § Abnormal cellular diEerentiation, § Zebra maturation and apoptosis body § ­ fluid secretion into the cyst § Foamy § Displacement of Na/K/ATPase pump to luminal side (from basolateral side) à pumping Na § Negative IF for collagen a3-4-5 chains into the lumen à enlarge cysts in aEected males, mosaicism in § > 250mg/gm creatinine carrier females lysosomes § Acid urine § Radiopaque § Honeycombing Renal § Hypertension – renin mediated § Cysts begin in utero § Usually asymptomatic § Micro/macrohematuria Deposits of glycosphingolipids Stone presentation phenotype § Gross/microscopic hematuria § Fusiform dilatation of § Nephrolithiasis/nephrocalcinosis § Dysmorphic RBCs à abnormal are found in lysosomes of § 2nd and 3rd decade § Non dysmorphic RBCs (normal collecting duct § Calcium oxalate or calcium GBM § Mesangial § Bilateral GBM) § Inadequate amniotic fluid phosphate stone formers § Non nephrotic proteinuria and HTN cells/podocytes/endothelial § Staghorn § Infection à oligohydramnios § Recurrent UTI later in life à progressive CKD cells § Cause renal failure § Kidney stones – uric acid § Enlarged kidney § No risk of ESRD § ESRD in 100% males § Tubular – distal tubule and § 30% coexist with calcium § ESRD (PKD1 >> PKD2) § Elevated diaphragm + § Normal kidney size loops of Henle oxalate stone formation (­ § NO malignant potential small chest cavity § Highest risk in deletion mutations § Interstitial cells risk in heterozygote carriers) § Vascular endothelium Normal kidney size Nephrotic syndrome Progressive CKD External § Cysts in other organs – liver, pancreas § Liver – congenital hepatic § Cochlear defects/deafness § Skin: angiokeratoma manifestations (asymptomatic) fibrosis § Ocular defects/anterior lenticonus corporum di]usum § Liver synthetic function normal – § Portal hypertension universalis AST/ALT/Bilirubin § Splenomegaly § Nerves: acroparesthesias, § Elevated alkaline phosphatase à § Potter sequence – anhidrosis aEect bile ducts mechanical eEects of § Heart: LVH with congestive § Mitral valve prolapse oligohydramnios cardiomyopathy, § Intracranial aneurysms (­ if family § Physical deformities arrhythmias, premature history) § Pulmonary hypoplasia coronary artery disease § Berry aneurysms – most common § Potter facies – flat § Eye: corneal opacities at bifurcation of the anterior cerebral nose, folds under eyes, § Kidney: nephrotic syndrome artery and anterior communicating receding chin, low-set artery ears § Hernias and colonic diverticula § Wide hands § Rocker-bottom feet Diagnosis § Genetic testing Blush pattern on § Ultrasound – anechoic cysts lobulated CT – contrast structures pulling in dilated § 20% have no family history CD Treatment § Kidney transplantation § Paint brush sign Transplantation Enzyme replacement § Urinary alkalinization § Cyst hemorrhage: fluid intake and § Bouquet of Risk for anti-GBM glomerulonephritis § Fabryzyme – IV infusion q2 o Maintain urine pH 6.5-7 analgesia flowers sign (type II hypersensitivity) weeks over 2 hours o Citrate salts > bicarbonate § Infection: abx with good penetrability § The body never sees a3,4,5 antigens o K salt necessary to prevent § Hypertension: ACEI, avoid diuretics à risk of rejection hypercalciuria from sodium § Diuretics: make cyst grow faster due load – require bedtime dose to fluid accumulation § D-penicillamine § Intracranial aneurysms: surgery if o BB – dimethyl-cysteine 10mm diameter or greater (free sulfhydryl group) o Reduce cystine (dimer) excretion by binding  § Vaptans (ADH inhibitor) slow cysteine (monomer of progression of cyst growth à target cystine) cAMP o Required when urinary cystine level > 500mg o Renal toxicity § Chelation Renal Embryogenesis Pronephros Mesonephros Metanephros 4 weeks – intermediate mesoderm § Begin after regression of pronephros at 4-5 weeks § Form from the most distal portion of the mesonephric duct (ureteric bud) nonfunctional § Forms a functional glomerulus and produces an o Interact with metanephric blastema/mesenchyme (portion of ultrafiltrate intermediate mesoderm) à form ureter/renal pelvis/collecting ducts § Pronephric duct is called mesonephric duct o Metanephric blastema forms the rest of tubular system § Begin to regress by 12 weeks § Development at 5 weeks § Metanephric kidneys – kidneys form in renal pelvis, rotate and ascend up to T12-L3 around week 5-9 § Complete after 10-12 weeks § Final stage of human renal development § Prone to teratogenic injury o Avoid ACEI/ARB during pregnancy (highly teratogenic) Congenital Renal Malformations Bilateral renal agenesis – Unilateral renal Pelvic kidney Duplication of renal Horseshoe kidney Nutcracker kidney – Renal vein Reflux pyelonephritis Potter syndrome agenesis pelvis and ureter entrapment syndrome Renal Absence of both kidneys § Ureteric bud failed to § Failure of § Most common § Most common fusion anomaly of kidney § Compression of left renal § Retrograde propulsion of urine up presentation § Failure of the ureteric connect to the metanephric physical § Male/female 2:1 vein by superior mesenteric into the kidney with bladder bud to interact with the metanephric blastema kidney to malformation § Fusion of lower poles of 2 normal kidneys artery contraction metanephric blastemal § Absence of 1 kidney ascend § Premature splitting of across midline o Congenital malposition of § Vesico-ureteral reflux (VUR) bilaterally § Compensatory the ureteric bud o At the level of inferior mesenteric artery the left renal vein lying § Etiology § Incompatible with life hypertrophy of the § 1 ureter enters the o Kidneys are lower – L3-L5 anterior instead of posterior o Boy – posterior urethral valves contralateral kidney + bladder via the lateral § Fusion site = isthmus to the aorta o Girl – congenital abnormality of slight ­ risk of HTN and orifice à reflux § ­ risk of obstruction – ureteral kinking/stricture § Tall and thin patient à when the insertion of the ureter into the CKD § Kidney stones losing weight, losing the bladder support fat § Result in chronic pyelonephritis – small, contracted, poorly functional scarred kidney External Oligohydramnios § Usually asymptomatic § Occasionally § Higher risk of § Infection § Abdominal pain manifestation sequence § Frequently associated associated infection/stones § Malignancy § Flank pain § Potter facies with other genetic with HTN, o Wilms’ tumor – isthmus § Hematuria § Pulmonary hypoplasia syndromes and urologic infections o Transitional cell cancer § Left sided varicocele à respiratory abnormalities (reflux) § Associated with § Pelvic pain – women insuEiciency (neonatal o Trisomy 18 – Edward syndrome death) o Turner’s syndrome – XO § Wide hands § Rocker-bottom feet Treatment Artificial amniotic fluid à survival to 1 yo then transplant  Primary Hypertension BP = CO x SVR à longer duration + higher pressure à greater target organ damage § Acceleration of atherosclerosis D à narrow lumen § Distal vascular ischemia Chronic hypertension Acute malignant hypertension § Medical emergency – systolic > 180mmHg or diastolic > 120mmHg with end organ damage o Encephalopathy, papilledema, AKI, acute cardiac decompensation, aortic dissection, stroke Kidney pathology § Hypertensive (benign) nephrosclerosis § Flea-bitten surface § Symmetric atrophy, always bilateral § Pinpoint petechial hemorrhage – ruptured capillaries § ¯ cortical thickness § Finely granular/cobblestone (leather-like) surface o Retraction of the cortex from ischemic scar formation in the interstitium o Collapse of the cortex from fibrosis § Thyroidization § Glomerulosclerosis § Tubular atrophy Renal autoregulation Remodeling – constrict aEerent blood vessels and narrow the lumen à eEective between 140-180mmHg Above 180mmHg, autoregulation cannot maintain GFR/RBF à rupture of capillaries Vasculature § Deposition of hyaline-like material into the damaged, more permeable arteriolar § Fibrinoid necrosis wall à prevent transmission of high pressure into the fragile capillaries and o Disruption of vascular endothelium à plasma glomerulus (rupture risk) constituents entering vascular wall o Hyaline arteriosclerosis à small arteries o Hyaline arteriolosclerosis à arterioles § Homogenous eosinophilic thickening § Loss of cellular detail § ¯ luminal caliber (deposition of basement membrane material and plasma proteins from lumen leakage) § Medial hyperplasia § Necrotizing arteriolitis § Fibroblastic intimal thickening o Acute inflammatory infiltrate in the arteriolar § Progressive ¯ blood flow to the glomerulus and tubules à irreversible ischemic injury wall § No immune complexes/complement activation § Hyperplastic arteriolosclerosis o Proliferation of myointimal cells à onion-skin with luminal narrowing Secondary Hypertension – Kidney Disease Primary hyperaldosteronism § Severe or resistant HTN – evidence of target organ damage – BP > 140/90 on § Loss of GFR à Na retention à high BP § Clinical presentation exactly like RAS 3 medications § Renal stenosis à renal ischemia à ­ renin secretion, AngII, o HTN refractory >140/90 on 3 drugs § New onset HTN < 30 or stage 2 HTN after age 55 aldosterone o Hypokalemic metabolic alkalosis – urine K > 20 meq/L § Acute rise in BP over a previously stable value § Metabolic alkalosis § Lab § Asymmetry renal size >1.5 cm diEerence between kidneys or a unilateral § Hypokalemia o Plasma aldosterone >10 ng/dl kidney < 9cm o ­ renin à ­ aldosterone à ­ Na/K/ATPase on principle cells à ­ H o Plasma renin < 1 ng/ml/hr § Unilateral or bilateral flank bruit (systolic/diastolic bruit) secretion o ­ aldosterone/renin ratio > 20 § Acute elevation in plasma creatinine – unexplained or after ACEI/ARB § Aldosterone/renin < 15 § No abdominal bruit § Caucasians >> Black 3:1 § ACEI/ARB is contraindicated in bilateral renal artery stenosis § Kidney size equal § Diagnosis – ultrasound doppler, MRA, CT angiography o Stenosis + dilation by ACEI/ARB à ¯ perfusion à loose function of § Minimal edema – aldosterone escape à ­ ANP § Confirmation – renal arteriography – intra-arterial digital subtraction aEected kidney § Mild hypernatremia – resetting of ADH osmostat angiography o If unilateral à other kidney increases blood flow and hypertrophy à § Treat with stent and/or medication renal function stay 80% normal Fibromuscular dysplasia Atherosclerosis Prevalence 10-20%, 80-90% in women 80-90%, age > 50, men >> women Progression in 50%, often to total occlusion  75% cases – internal carotid, vertebral, externa carotid artery, coronary, mesenteric Age onset 14-50 y/o Higher risk for dissection/aneurysm formation Pathogenesis Abnormal growth of layers of blood vessels à stenosis Intimal narrowing secondary to atherosclerosis – extension of aortic § Autonomous hypersecretion of aldosterone from adrenal gland cortex § Medial 90% atherosclerosis § Solitary adenoma – benign proliferation of aldosterone-producing cells Non inflammatory, non-atherosclerosis (35% of cases) – zona glomerulosa § Bilateral hyperplasia – dysregulation of aldosterone synthesis (aldosterone synthase gene) – 60% of cases Location Mid-distal segment Proximal 2 cm - ostium Adrenal cortex Histology/Scan Multifocal FMD – medial FMD § Cholesterol clefts Adrenal mass on CAT scan § String of beads § Renal artery stenosis (RAS) § Post-stenotic dilation – indicator of RAS severity Focal FMD – intimal FMD  Metabolic acidosis § pH < 7.35 + [HCO3] < 22 meq/L § AG = Na – (HCO3 + Cl) § Negative inotropic e.ects on heart à CHF § Normal AG = 6 (3 – 10) ­ anion gap ¯ anion gap § Vasodilation + tachycardia à hypotension § Unmeasured cations – Ca, Mg, IgG, Li unmeasured ­ ¯ § Impaired glucose metabolism à hyperglycemia § Unmeasured anions – phosphorous, anion High phosphate - AKI or CKD § ¯ protein synthesis à malnutrition proteins (albumin), organic acids, sulfates ­ organic acids § ­ bone resorption à osteoporosis § Low AG 10 cation High Ca – malignancy, hyperparathyroidism § Compensation formula: ¯ High Mg – IV Mg for pre-eclampsia, oral ingestion pCO2 =(1.5 x HCO3) +8 ± 2 High IgG - myeloma Anion Gap Metabolic Acidosis § ­ H+ generation due to organic acid à ¯ HCO3 as it bu\ers the H + add an unmeasured anion § Electrical neutrality is maintained by accumulation of an organic anion bound to Na § True HAGMA à AG ³ 10 § Osmolar gap = 2Na + glucose/18 + BUN/3 à alcohol present Ketoacidosis Lactic acidosis Pyroglutamic acid Ethylene glycol Methanol Salicylate Non-diabetic euglycemic Inhalation abuse DKA EDKA Type A Type B (5-oxoproline) ketoacidosis Source Anti-freeze § Antifreeze § Aspirin § Diabetes § Starvation § Alcohol § SGLT2 § Hemodynamic § Drug induced § Chronic ingestion § Toluene (30%) § Automobiles (windshield wiper § Oil of wintergreen inhibitors § Hypoxic § Biguanide oral of acetaminophen § Glue § Air conditioners fluid) § Pepto-Bismol § Precipitate § Sepsis shock hypoglycemic § Prolonged § Shoe/nail polish § Brake fluid § Solvent d by stress § Organ/limb medication - depletion of § Whipped cream Plastic products § Fuel event ischemia phenformin, glutathione dispenser § Bottles § Adulterated alcohol (infection, secondary to metformin § Lighter fluid § Resins pregnancy, atherosclerosis § Reverse § Room fresheners Adulterated alcohol trauma) transcriptase § Spray inhibitor for HIV – paint/lacquers/thinn NRTI ers § Iron overdose § Isoniazid § Propofol - sedative § Propylene glycol – preservative (diazepam, Ativan) Qualities § Odorless § Sweet odor § Fruity smell breath (acetone excretion by lung) § Lipid soluble (CNS) § Colorless § Colorless § Volatile § Sweet taste § Sweet taste § Readily absorbed Uremic acidosis through pulmonary bed § Sweet smell § Colorless Toxicity/ Stage 1 – intoxication (CNS) § Methanol à § Metabolized in liver § Impaired glucose availability/utilization Glucose à pyruvate à lactate Retention of sulfur, § Form hippuric acid Metabolism § Ethylene glycol à formaldehyde into toxic anions § ­ lipolysis for energy (anaerobic metabolism by LDH) phosphorous, lactic à non resorbable glycolaldehyde (catalyzed by § Free FA metabolism à ketone bodies (acetoacetic acid, b-hydroxybutyric acid à low GFR and anion (secreted and § Catalyzed by alcohol alcohol acid, acetone) impaired tubular filtered) dehydrogenase (rate dehydrogenase) § Acetone (not ketone bodies) excreted via lung à fruity smell function § Catalyzed/metaboliz limiting) § Acetoacetic acid, b-hydroxybutyric acid à renal excretion ed § 0-12h o liver CYP450 § Delirium / Ataxia / Nausea o alcohol / Vomiting dehydrogenase Stage 2 – metabolism § Formaldehyde à § Disrupt § Glycolaldehyde à formate (catalyzed mitochondria/mi glycolate à oxalate by aldehyde crosomal § Catalyzed by aldehyde dehydrogenase) function dehydrogenase § Propylene glycol § 12-36h à D/L lactic acid § Production of metabolic (metabolized by acids alcohol and § Hemodynamic collapse  Stage 3 – AKI § Formate à formic aldehyde § 24-72h acid dehydrogenase) § ATN + calcium oxalate urinary crystals (radiopaque) § Directly related to breakdown of ethylene glycol by alcohol and aldehyde dehydrogenase Labs/ Positive ketone test § Lab measures L-lactic acid à Imaging § Urine – nitroprusside reaction à detect ONLY acetoacetic acid >> acetone elevated except with D-lactic acidosis § Blood – specifically detect b-hydroxybutyric acid § Negative urinary ketones No osmolar gap Urine dipstick underestimate severity of ketoacidosis Needle-shaped prisms Acids § Glycolic acid (majority) § Formic acid § Salicylic acid § Acetoacetic acid (10-20%) § D-lactic acid (only with propylene § Hippuric acid § Oxalic acid (majority) § Lactic acid § b-hydroxybutyric acid (80-90%) glycol and certain type of bariatric § Lactic acid § Lactic acid surgery) § L-lactic acid for the rest Osmolar Yes Yes No No No except with propylene glycol and No No gap D-lactic acid production Diagnosis/ § CNS changes § No nephrotoxicity § Tinnitus § Type I – no § Prolonged § Constant source § Normal to § Normal blood lactic acid in D-lactic § Volume depletion Clinical § Undetectable blood § Vision loss § Nausea/vomiting insulin protein/calorie of carbohydrates low blood acid associated disease (hippuric acid bind presentatio alcohol § Hyperemia/edema § Can couple with production malnutrition à for energy due to glucose o Propylene glycol Na) n § Urine fluorescence respiratory o ­ glucagon lipolysis for alcoholism à eat § Depletion o Short bowel syndromes – intact § Hypokalemia § Compare measured alkalosis – direct o hyperglycemia energy much less protein of glycogen colon but short small bowels (hippuric acid bind (freezing point depression) stimulation of § Type II – § Fad diets – § Gastritis/pancre stored in § Jejunal-ileal bypass (bariatric K) vs. calculated serum medullary peripheral insulin extremely low atitis and cannot liver à weight loss surgery) § Non anion gap osmolarity à osmolar respiratory center resistance à calorie/low carb eat/drink lipolysis § Resection of small bowels acidosis (hippuric gap ³ 10 hyperosmolar (Adkins/South § Normal to low secondary to trauma/ischemia acid bind NH4) à § Measured serum but not ketoic! beach diets) blood glucose + § ­ carb delivery to colon à chronic (more osmolarity = 2Na + § Normal to low no energy source metabolized into D-lactic acid by common) glucose/18 + BUN/3 + blood glucose à fat and muscle gram + anaerobes (lactobacilli) § Serum hippuric acid ethylene glycol breakdown § Ataxia/confusion/disorientation/slu is undetectable rred speech § AKI/CKD in acute anion gap metabolic acidosis Treatment § Stable BP § Inhibit alcohol § Forced diuresis – § Hydration § Carbohydrates § Hydration § Alternative § Improve circulatory hemodynamics § HCO3 infusion § If osmolar gap present à dehydrogenase HCO3 rich solution § IV insulin § Food § Nutrition (IV diabetes § Normalize oxygenation and delivery to § K replacement prevent enzymatic (alcohol, (D5W with dextrose à therapy peripheral tissues conversion à treat with fomepizole) if 150meq/L NaHCO3) carbohydrate) § HCO3 as needed to maintain pH > 7.2 alcohol or fomepizole osmolar gap present § Urinary § Must address underlying causes (inhibit alcohol § IV folic acid alkalinization – dehydrogenase) (metabolize formic convert to ionic form § HCO3 + D5WENA infusion acid to inactive of salicylic acid à ­ § Hemodialysis if kidney metabolites) renal elimination injury is present § Hemodialysis (if § Lactated Ringers (like NS vision loss) but alkalinizing) § Bicarbonate drip Hyperchloremic Non-Anion Gap Metabolic Acidosis § Loss of HCO3 à ­ Cl to maintain electrical neutrality à hyperchloremia § Retention of HCl Additional causes Early kidney injury Dilutional (massive IV fluids) Toluene (hippuric acid) § Impaired NH3 production (proximal tubule) § 0.9 NS (except lactated ringers) has a pH of 6.5 with very high levels of Cl § Present with chronic use § Secretion defect of HCl (distal tubule) § Administration of large quantities of 0.9 NS will dilute down and replace the § Accumulation of HCl à consumption of HCO3 + ­ serum Cl HCO3 and ­ Cl retention Renal tubular acidosis (RTA) Diarrhea Urinary diversion  Type I Type II Type IV Location defect Cortical collecting tubule Proximal tubule Cortical collecting duct Colon Relevant § NH3 is made in proximal tubule via amino acid § Carbonic anhydrase on villi of proximal tubule cells Aldosterone stimulates Na+ reabsorption and H+ excretion in § Colon absorbs HCO3 rich fluid § Artificial urine storage physiology metabolism (glutamine) converts H2O and CO2 to H2CO3 for HCO3 reabsorption principal and a-intercalated cell à negative potential lumen from pancreas structure made from ileum § a-intercalated cell of CD secreted H+ in urine § Microvilli damage or CA inhibition à loss of HCO3 with drives K+ secretion (mostly from Na reabsorption) § Diarrhea à NaHCO3 loss in and colonic segments (stimulated by aldosterone), bu\ered by NH3 Na in urine (predominantly as KHCO3 or NaHCO3) § Inhibition of aldosterone à prevent H secretion + causes stool o In pelvis at original bladder § Disequilibrium acidosis § Equilibrium acidosis hyperkalemia § Volume contraction acidosis à neobladder o Reclaim HCO3 but cannot excrete H o Normal H excretion à not accumulating acid § Hyperkalemia à cell moves K inside in exchange for H à § Normal renal tubular function o In anterior abdomen à o ­ blood H à require extensive bone dissolution o Hold on to HCO3 that leaks in proximal tubule high blood H à acidosis extracellularly but alkalosis o Acidic urine reservoir (carbonate converted to HCO3) o Acidotic but do not require extra bu\er from bone intracellularly à further reduce NH3 production o Urine Na < 20 meq/L § Contact of urine and bowel o Bone also provides Ca and PO4 filtered in urine à (ammoniagenesis) à H retention and acidosis with normal o FENA < 1% segments à Cl hypercalciuria + hyperphosphaturia + alkaline anion gap reabsorption and HCO3 urine à stones § Accumulating acid is HCl secretion à acidosis K level Hypokalemic Hyperkalemia Hypokalemia – high aldosterone Causes Damage to cell membrane of principal or a- Inhibitors of CA Drugs/diseases causing hyperkalemia (distal tubular cells § Infectious/secretory § Bladder cancer – intercalated cell of CD § Acetazolamide (Diamox) / Methazolamide (Neptizane) remain intact) (inflammatory) enteritis cystectomy Drugs o Glaucoma therapy Drugs § Occult laxative abuse § Radiation injury § Amphotericin B – antifungal agent § Topiramate (Topamax) § NSAIDS § Villous adenoma § Neurogenic bladder o Dose dependent damage to cell membrane o Anti-convulsant § Bactrim – trimethoprim acts as amiloride exclusively of the distal tubule o Migraines treatment § ACEI/ARB § Lithium – manic-depression treatment § Nonselective beta blocker Autoimmune diseases Hereditary Fanconi’s syndrome Systemic diseases Ileostomy – short bowel § SLE § Cystinosis § PCT damage § Diabetes – sclerosis of the macula densa syndrome Unique findings § Wilson’s disease § Type II RTA § Resection of the majority or all § Nephrolithiasis – calcium phosphate – alkaline § Glycogen storage disease § Tubular proteinuria + of the colon pH, radio opaque Multiple myeloma overflow proteinuria § Unable to absorb any § k light chains § Hypophosphatemia pancreatic HCO3 rich secretion Ifosfamide secondary to § Daily losses of large volumes § chemotherapy hyperphosphaturia of NaHCO3 Heavy metals § Hypouricemia secondary § High risk of volume depletion § lead/cadmium to hyperuricosuria and non-anion gap acidosis § Nephrocalcinosis – secondary to hypercalciuria HAART § Hypokalemia secondary and hyperphosphaturia § reverse transcriptase to distal NaHCO3 delivery o Calcium and phosphate inhibitors (NNRTI) - § Glycosuria (normal precipitation within kidney tenofovir serum glucose) interstitium à calcification à fibrosis and progressive kidney disease Diagnosis Most serious – high risk of bone loss, kidney stones, § Clinical history and laboratory findings and nephrocalcinosis § Cannot be diagnosed with biopsy § History of drug exposure and presence/absence of Fanconi’s are crucial Treatment § Oral HCO3 to match daily H production § Supplemental oral HCO3 – extremely high amount Treat hyperkalemia – must normalize K before acidosis can get Supplemental oral HCO3 Supplemental oral HCO3 § Can be fully corrected § Ine.ective to completely correct acidosis – HCO3 will better constantly leak into the urine § Discontinue implicated drugs § K supplements – else will worsen hypokalemia § Add a diuretic