Renal Flashcards

Question

Indications for renal biopsy in lupus nephritis and classic histopathological findings

Answer 1

- renal bx should be performed in most pts with SLE who develop renal involvement, to determine histologic class and therefore determine Mx - histologic class can change - therefore any clinical change may warrant consideration of bx IF / histopath - glomerular deposits that stain primarily for IgG, but also IgA, IgM, C3 and C1q "full house immunofluorescence pattern" Full house pattern also seen in HIV, IE, post strep GN - Glomerular deposits (mesangial, subendothelial, subepithelial) and extraglomerular deposits (tubular basement membrane, interstitium, vessels), tubuloreticular inclusions in glomerular endothelial cells Tubuloreticular inclusions also seen in HIV nephropathy (although this is typically collapsing FSGS) and people treated with alpha-interferon

Answer 2

Indications for renal biopsy - needed to confirm diagnosis, however, typically only performed in setting of rapidly progressive or severe disease - persistent proteinuria > 1g / day - new hypertension or significant rise over baseline BP - elevated creatinine IF - immune complex deposition (IgA or IgG in mesangium) Light microscopy - mesangial hypercellularity and matrix expansion Histopath - immune complex pattern, hypercellularity, glomerular sclerosis, interstitial fibrosis, formation of crescents due to proliferation of epithelial cells

Answer 3

- Occurs in up to 20% of pts with diffuse cutaneous systemic sclerosis - most comonly in first 5 years after diagnosis - underlying mechanism - thrombotic microangiopathy / vascular changes in small arteries of the kidney - intimal proliferation and thickening, narrowing and obliteration of vascular lumen, concentric onion-skin hypertrophy

Answer 4

- more common in first 5 years after diagnosis of diffuse cutaneous systemic sclerosis risk factors -> diffuse cutaneous systemic sclerosis, especially if rapidly progressive -> anti RNA polymerase III Abs -> glucocorticoid use - > 15mg prednisolone per day

Answer 5

- acute onset renal failure - abrupt onset moderate - marked hypertension in 90% patients, associated with headache & blurred vision, retinopathy (including haemorrhages and exudates), encephalopathy complicated by seizures - new diastolic hypertension (85%) - mean peak blood pressure of 180/100mmHg - urine sediment is usually normal. Proteinuria 0.5-1g/day may be present in pts with pre-existing hypertension. GN is not a feature of SRC - microscopic haematuria and cell casts are uncommon - 10% of SRC is normotensive, although BP may be higher than baseline. Worse prognosis due to delayed recognition. Normotension in SRC may suggest cardiac failure.

Answer 6

Must exclude MAHA first Mainstay of management is prompt BP control - return to baseline BP within 72 hrs - ACEi first line - captopril. Accept transient rise in creatinine due to relaxation of efferent arteriole and decrease in intraglomerular perfusion pressure (not a reason to cease therapy). Prognosis - if untreated, ESRF in 1-2 months and death within 1 year - with prompt BP control - renal function stabilises or improves in 70%, survival at 1 year is 80%

Answer 7

Approx. 50% of pts with SLE have renal involvement, lupus nephritis typically occurs within 6 - 36 months of diagnosis. 30% will develop renal impairment, but this is relatively uncommon within the first few years of diagnosis Risk factors for lupus nephritis - age <33 yrs at diagnosis - non-white ethnicity - black, hispanic, asian. More common & more sevre - male > females

Answer 8

Oliguria - < 400-500ml/day is common in AKI Anuria - <50-100mL is uncommon in AKI Causes of anuric renal failure: 1. Shock 2. Complete bilateral urinary tract obstruction - BPH most common cause in males - bladder or prostate Ca - clots 3. HUS 4. Renal cortical necrosis >50% cases are pregnancy-associated (abruption, infected abortion, eclampsia) Extreme ATN - significantly diminished perfusion of kidneys due to spasms of feeding arteries, microvascular injury or DIC 3. Bilateral renal arterial obstruction 4. RPGN - especially anti-GBM disease **diuretics do not prevent AKI or progression to CRRT. Can be used for short term volume control, but should not be used to delay dialysis.

Answer 9

- Loss of anti-thrombin, protein C and S in the urine => increased platelet activation & presence of more fibrinogen in the circulation - The lower the albumin, the higher the hypercoagulability - especially in membranous GN

Answer 10

- primary mesangial IgA nephropathy is the most common primary glomerular lesion. Most common cause of nephritic syndrome in <40 yrs - primary IgAN: Mesangial IgAN HSP - normally self-limiting, supportive Mx unless significant renal dysfunction or proteinuria -secondary IgAN 1. Liver cirrhosis - especially ETOH liver disease (associated with failure to clear IgA), also HBV and HCV 2. Celiac disease - about 1/3 pts have IgAN 3. IBD 4. Ankylosing spondylitis 5. Dermatitis herpetiformis 6. Mycosis fungoides 7. HIV infection - however, typically get collapsing FSGS 8. GPA - occurs when in remission after immunosuppressive therapy, pts present with haematuria but no other features of recurrent vasculitis

Answer 11

Treatment of proteinuria -RAAS blockade (ACEi/ARB) for proteinuria >1g/day, consider for proteinuria 0.5-1g/day, uptitrate to achieve <1g/day proteinuria Treat hypertension -if proteinuria >1g/day -> aim BP <125/75mmHg -if proteinuria <1g/day -> aim BP <130/80mmHg Role of SGLT2i -biggest positive trial in IgAN. Start empagliflozin or dapagliflozin if persistent proteinuria >500mg/day despite maximally tolerated doses of ACEi/ARB for at least 3-6 months. Reduces renal progression & risk of death Immunosuppression - role of corticosteroids is controversial, may be worth trying in pts with persistent proteinuria > 1g /day despite adequate trial of RAAS blockade - other immunosuppressive agents (on top of steroids) - increases chances of remission of proteinuria BUT does not slow progression of renal disease

Answer 12

Class I - minimal mesangial LN Class II - mesangial proliferative LN Class III - focal membranoproliferative LN Class IV - diffuse membranoproliferative LN Class V - membranous LN Class VI - advanced sclerosing lN Class I - minimal mesangial LN - normal light microscopy - rarely diagnosed because urine typically normal - may have mild proteinuria - normal renal function - no therapy, unless progresses to more sinister class Class II - mesangial proliferative LN - microscopic haematuria +/- haematuria - good prognosis; no need to treat unless progresses to more sinister class Class III - focal membranoproliferative LN -MOST common & MOST severe -microscopic haematuria + proteinuria +/- HTN +/- reduced eGFR +/- nephrotic syndrome -<50% glomeruli involved on light microscopy. Almost always SEGMENTAL involvement of each glom -needs immunosuppression Class IV - diffuse membranoproliferative LN - >50% glomerli involved on light microscopy - microscopic haematuria + proteinuria + HTN + reduced eGFR + nephrotic syndrome - low C3, high anti-dsDNA - segmental OR global involvement of each glomerulus - needs immunosuppression Class V - membranous LN - nephrotic syndrome +/- microscopic haematuria +/- HTN - normal or slightly elevated creatinine - may present with no other clinical signs of SLE and normal complement levels Class VI - advanced sclerosing LN - slowly progressive renal dysfunction & proteinuria. Usually no haematuria / no active GN. - global sclerosis > 90% glomeruli - old & scarred - given no active GN - immunosuppression unlikely to help

Answer 13

- rare genetic disorder - caused by a mutation in type IV collagen - type IV collagen is needed for normal function of kidneys, ears, eyes - three genes which may be involved - COL4 A3, A4, A5 - mutation in COL4 A5 is most common, is X-linked, and has the most severe phenotype - due to this mutation glycine is replaced by a larger amino acid -> collagen unable to pack tightly

Answer 14

Renal - haematuria - universal feature of Alport's syndrome since infancy - can be macroscopic. Milder phenotypes (associated with COL4 A3 and A4 mutations) may just have microscopic haematuria - proteinuria as renal impairment progresses Ears -sensorineural hearing loss, especially loss of hearing at higher frequencies -hearing typically normal at birth, but develops progressively - usually at stage where renal function is normal but there is proteinuria Eye - sight not typically affected - corneal erosions - lenticonus - keratoconus - cataracts - slit lamp exam - oil droplet reflex ; fundoscopy will show white / yellow flecks on retina

Answer 15

Anti-PR3 and MPO ANCA IgG activate neutrophils Neutrophils release mediators of acute inflammation Tissue destruction and cell death

Answer 16

Electron microscopy shows thinning of the basement membrane and basket-weave appearance of the basement membrane

Answer 17

Needs immunosuppression Induce remission 1L steroids or cyclophosphamide - PO cyclophosphomide is twice the cumulative dose of IV cyclophosphamide. No difference in time to remission, but less ADRs, less leukopenia AND increased risk of renal relapse with IV. No difference between PO and IV in terms of long term mortality and renal function / progression to ESRF. Plasma exchange for severe cases of ANCA associated renal vasculitis, or if pulmonary haemorrhage, concurrent anti-GBM Abs, severe renal failure PLEX associated with higher rates of remission Rituximab is as effective for induction & then maintanence as cyclophosphamide, BUT needs to be ANCA positive for PBS approval. For maintanence - options are AZA or MMF. AZA is better for ANCA vasculitis (as opposed to lupus nephritis where MMF is better).

Answer 18

- ACEi in proteinuric patients can slow deterioration of renal function - most patients rapidly progress to ESRF requiring dialysis in their 20s - consideration of transplantation (rarely develop Abs to type 4 collagen post transplant, resulting in progressive graft dysfunction secondary to Goodpasture syndrome)

Answer 19

In children (<12) - typically streptococcal URTI or skin infection (mostly URTI) In adults (>60) - typically staphylococcal infections. Can be skin, bone, heart, teeth, UT, lung, heart). In elderly & diabetic - skin most common source

Answer 20

Accept PTH levels 2-4 x upper limit normal - if exceeding this, need to suppress 1. Aim for phosphate level around 2 Calcium based phosphate binders - mainly calcium carbonate Non-calcium based phosphate binders - sevelamer and lanthanum are only available for patients on dialysis 2. Cholcecalciferol for vitamin D deficiency 3. If PTH does not normalise despite phosphate binders -> consider calcitriol (only if Ca levels are not elevated) 4. For tertiary refractory hyperparathyroidism - consider cinacalcet -> increases sensitivity of calcium sensing receptors. No evidence that cinacalcet decreases cardiovascular mortality

Answer 21

-Male predominance -Common in children (<12yo) - most common cause of acute nephritis in children -Immunocompromised - diabetics, elderly, ETOH, AIDs, malnourishment -TB -Synthetic valves -IVDU -Malignancy

Answer 22

Immune complex deposition Deposition of IgG Abs and C3

Answer 23

- hypercholesterolaemia - typically with HDL elevation and hypertriglyceridaemia - proteinuria => reduced plasma oncotic pressures => increased hepatic lipoprotein synthesis - hypertrigylceridaemia likely due to impaired metabolism - can also get lipiduria in nephrotic syndrome

Answer 24

Deterioration in renal function - typically weeks after infective precipitant - up to 95% of children will present with asymptomatic haematuria - can also present as nephritic syndome Hypertension 50-90% Generalised oedema - MOST common symptom - 66% of symptomatic children Red-brown urine - 30-50% AKI, acute renal failure and RPGN is rare

Answer 25

In infection-related GN, serum C3 +/- C4 levels are low in 90% patients As opposed to IgAN, where complement levels are normal or elevated

Answer 26

Progressive renal failure is the primary indication for renal bx in suspected infection-related GN Light microscopy - diffuse proliferative and exudative glomerulonephritis with prominent endocapillary proliferation and numerous neutrophils IF - diffuse granular pattern of C3 and IgG deposits (compared to IgAN where immune complex deposition is focal and patchy)

Answer 27

Antibiotics if infection still present Supportive management as prognosis typically excellent Frusemide 1mg/kg for mx of fluid status Treat hypertension - nifedipine

Answer 28

No. Prognosis of infection-related GN is excellent, especially in children. Most children will have normal or modestly reduced renal function up to 18 yrs. post. 20% could have persistently abnormal urinalysis. Some adults will develop HTN, recurrent proteinuria and renal impairment. This is associated with evidence of glomerulosclerosis on biopsy -> may actually represent membranoproliferative GN rather than infection-related

Answer 29

90% of pauci-immune GN is ANCA associated, 10% is ANCA negative. 1. Granulomatosis with polyangitis -90% are c-ANCA positive for proteinase-3 -associated with URTI & ocular symptoms -more likely to have relapsing disease 2. Microscopic polyangitis -70% are p-ANCA positive for myeloperoxidase -7% will interstitial lung disease 3. Eosinophilic granulomatosis with polyangitis -p-ANCA for myeloperoxidase

Answer 30

-urinary loss of cortisol binding globulin -serum cortisol concentrations may be reduced -however, percentage of unbound cortisol is increased, serum free cortisol concentrations are normal and symptomatic hypocortisolism does not occur

Answer 31

Sclerotic biopsy pattern is associated with worse prognosis

Answer 32

Urine dipstick is highly sensitive for glomerular proteinuria i.e. albumin. Therefore, usually negative in tubular proteinuria (i.e. proteins other than albumin) Glomerular proteinuria - filtration of high molecular weight protein (mostly albumin) Tubular proteinuria - low molecular weight protein. e.g. beta 2 microglobulin and light chains - filtered through glomerulus and meant to be reabsorbed by the PCT

Answer 33

Tolvaptan is a vasopressin 2 receptor antagonist - reduces aquaporin expression in collecting ducts, increasing diuresis and therefore reduces the urine osmolality Reduction in osmolality (aiming <280) is associated with reduced growth of cysts and reduced rate of decline in eGFR. Every 4 years on Tolvaptan, delays dialysis by 1 year ; therefore there are more benefits with early treatment

Answer 34

- nephrotic range proteinuria - >3500mg / 3.5g per 24 hours - spot PCR >3000mg/g or >3g - hypoalbuminaemia - serum albumin <35 - oedema Mechanism of proteinuria in nephrotic syndrome - glomerular proteinuria - primary mechanism is destruction of podocytes, effacement of podocyte foot processes, slit diaphragm disruption and loss

Answer 35

- typically affecting lower extremities, but can also get periorbital oedema on waking ; also anasarca, pulmonary oedema, pleural effusions - mechanisms include primary sodium retention - abnormally filtered proteins drive sodium reabsorption in collecting duct with subsequent volume expansion - secondary sodium retention - loss of albumin drives fluid out of vasculature, leading to underfilling and secondary sodium retention via RAAS activation Resistance to loop diuretics that are typically protein bound

Answer 36

Loss of albumin and hormone binding proteins leads to metabolic & endocrine derangements - urinary loss of thyroid binding globulin - low T3 and T4 levels - most patients with nephrotic syndrome are generally euthyroid because the physiologically important free T3 and T4 levels are normal, T3/T4 ratio is normal - membranous nephropathy is associated with Graves' disease and autoimmune thyroiditis (Hashimoto's)

Answer 37

Mutations in slit diaphragm molecules 1. NPHS2 (podocin) 2. TRPC6 Typically no response to steroids

Answer 38

-exact mechanism unknown -circulating factor which is toxic to podocytes and causes generalised podocyte effacement -potential culprit molecules: Soluble urokinase plasminogen activator receptor (suPAR) Cardiotrophin-like cytokine factor 1 (CLCF1) MicroRNas -explains >60% recurrence post transplant -typically causes diffuse podocyte effacement (as opposed to focal / segmental) -50% respond to immunosuppression / PLEX

Answer 39

1. Collapsing FSGS in HIV 2. Hepatitis C 3. Drugs - IFN, heroin, bisphosphanates 4. Reflux nephropathy 5. Massive obesity 6. Healed previous glomerular injury Can breakdown causes of secondary FSGS into virus or drug induced Pathogenesis of secondary FSGS - adaptive changes to glomerular hyperfiltration

Answer 40

- Primary FSGS typically causes diffuse podocyte effacement, secondary FSGS causes segmental effacement - Primary FSGS typically presents as acute onset nephrotic syndrome - proteinuria (70-100%), haematuria (50%), HTN (20%), AKI (25-50%) - Secondary FSGS typically presents as slowly progressive proteinuria and renal impairment. Either non-nephrotic proteinuria OR nephrotic range proteinuria without nephrotic syndrome - - Primary FSGS responds well to immunosuppression, whereas focus of Mx in secondary FSGS is underlying cause and supportive management with low protein, low salt diet and BP control

Answer 41

- classically collapsing FSGS - collapsing FSGS describes a histologic variant seen in HIV, other infections - COVID-19, parvovirus B19, drugs, lupus, haemophagocytic syndrome - characterised by collapse & sclerosis of the entire glomerular tuft (rather than segmental injury) - typically results in more severe nephrotic syndrome, worse renal impairment - frequently resistant to therapy with rapid progression to ESRF

Answer 42

Anti-GBM ANCA-associated GN / Pauci-immune GN Immune-complex mediated GNs : lupus nephritis, IgAN, infection-related GN, mixed cryoglobulinaemia

Answer 43

Anti-GBM (Goodpasture) disease Due to collagen IV deficiency, people with Alport syndrome do not really have a glomerular BM. Post transplant, introduction of new antigens -> production of anti-GBM Abs

Answer 44

Small vessel vasculitis Autoantibodies against the non-collagenous domain of the alpha 3 chain of type 4 collagen (typically IgG) Affecting the renal & pulmonary capillary beds Involves immune complex deposition (IgG and C3)

Answer 45

Genetic - HLA DR3 seen in 80% pts with anti GBM disease Some seasonal and geographic associations - not yet understood Association between smoking and risk of pulmonary haemorrhage Exposure to hydrocardbons e.g. petrol Alemtuzumab (anti CD 52 on B and T cells) - used for Rx of MS and CLL People with Alport syndrome are at increased risk of anti-GBM post transplant

Answer 46

In patients with diabetic kidney disease and albuminuria, non-steroid mineralocorticoid receptor antagonists improve cardiovascular outcomes and mortality Non-steroidal mineralcorticoid receptor antagonist (finerenone) should be started in patients with CKD with T2DM, normal K, eGFR >25, albuminuria >3g/mmol despite maximal tolerated dose of RAAS inhibitor FIGARO-DKD trial (NEJM) - among patients with stage 2-4 CKD and T2DM with moderately elevated albuminuria OR stage 1-2 CKD with severely elevated albuminuria, finerenone therapy improved CV outcomes (composite outcome of death from CV causes, non-fatal AMI, nonfatal stroke, or hospitalisation for heart failure)

Answer 47

1. Osteitis fibrosa cystica - increased bone turnover due to secondary hyperparathyroidism 2. Adynamic bone disease - decreased bone turnover, usually due to excessive suppression of PTH. Most common CKD related bone lesion in patients on dialysis 3. Mixed uraemic osteodystrophy - high or low bone turnover with abnormal mideralisation 4. Osteomalacia - rare. Low turnover & abnormal mineralisation. Previously associated with aluminium containing phosphate binders.

Answer 48

Positive anti-GBM IgG serology Urgent biopsy required if positive serology Histopath - severe necrotising and crescenteric pattern IF - strong linear / ribbon-like staining of IgG and C3

Answer 49

Aim to rapidly remove anti-GBM Abs through plasma exchange, steroids, cytotoxic therapy e.g. cyclophosphamide, supportive therapy / dialysis Prognosis is better if <30% crescents on biopsy, creatinine <300 & not on dialysis

Answer 50

1. AL amyloidosis or primary amyloid - light chain dyscrasia, fragments of monoclonal light chains form amyloid fibrils (lamba light chains are more amyloidogenic than kappa light chains) ; although this is a plasma cell dyscrasia with monoclonal paraprotein, typically does not meet criteria for MM -> classified as MGRS 2. AA amyloidosis - acute phase reactant serum amyloid A forms amyloid fibrils. Associated with chronic inflammatory disorders such as osteomyelitis and rheumatoid arthritis

Answer 51

-membranous nephropathy is the 2nd most common cause of primary nephrotic syndrome in Caucasian adults (after diabetic nephropathy ; FSGS globally 2nd most common - but more common in African Americans) -IgG4 deposition in the subepithelial space => disruption of barrier => proteinuria -LM: diffuse thickening of basement membrane ; "spike and dome" appearance Majority of membranous nephropathy in adults is PRIMARY (85%). Mostly due to **autoantibodies against phospholipase A2 receptor found on podocytes (anti-PLAR2 Abs) ** Secondary membranous nephropathy - only 15% in adults, more common in children - associated with chronic infections HBV, malaria - solid organ malignancies - lung Ca, colon Ca - drugs - penicillamine - class 5 lupus nephritis (membranous lupus nephritis)

Answer 52

Basement membrane thickening with little or no cellular proliferatio or infiltration Subepithelial electron dense deposits "spike and dome" appearance of the basement membrane

Answer 53

Patients with autosomal dominant polycystic kidney disease Age > 18 yrs CKD 2-3, eGFR 30-90 AND evidence of rapid progression - eGFR decline by >5ml/min in 1 year - rate of decline in eGFR >2.5 ml / min / year over 5 years Contraindications eGFR <30 Baseline hypernatremia (tolvaptan can make you more hypernatremic by increasing diuresis) Inability to respond to thirst - patients need to be drinking approx. 5 L fluid per day Hypovolemia Concomitant diuretic use Interactions with CYP3A4 inhibitors

Answer 54

Target HbA1c <6.5% to <8.0% - individualise target Non-pharmacological management - smoking cessation, physical activity, protein intake 0.8g/kg/day for non-dialysis patients. <2g sodium per day <5g salt / sodium chloride. Oral hypoglycaemic therapy: 1st line pharmacotherapy - metformin (cease if eGFR <30 or dialysis, reduce dose if eGFR <45), SGLT2i (start only if eGFR >20 & not on dialysis) 2nd line pharmacotherapy - add additional agent - GLP1 receptor agonist preferred Other drugs: RAAS blockade for hypertensive & proteinuria Moderate to high intensity statin if >50 yrs Non-steroidal mineralocorticoid antagonist (finerenone) if urine ACR >3mg/mmol despite RAAS blockade and eGFR >25 and K normal

Answer 55

Autoantibodies against the phospholipase A2 receptor in podocytes (anti PLA2R) - Anti PLA2R is detectable in serum even prior to onset of proteinuria - the greater the titre of anti PLA2R, the more active the disease - proteinuria may continue even when the immunologic phase of the disease has resolved with immunosuppression - use anti PLA2R to track disease activity. Can stop immunosuppression when Abs become negative, even if the proteinuria has not yet resolved.

Answer 56

-often self-limiting -supportive care and mx of proteinuria (RAAS blockade) -consider anticoagulation when albumin <25 Who needs immunosuppression? 1. Heavy proteinuria > 8g/day 2. Poor renal function 3. PLA2R Abs >150 Immunosuppression 1st line steroids rituximab cyclophosphamdie if high risk cyclosporin

Answer 57

- Most common cause of nephrotic syndrome in <10yo, peak incidence 2-6yo. Only represents 15% nephrotic syndrome in adults - exact pathogenesis unclear -> likely due to systemic T cell dysfunction => production of glomerular permeability factor => direct damage to glomerular capillary wall => foot process effacement => proteinuria - 30% patients with minimal change disease have autoantibodies against nephrin (an essential component of the glomerular slit diaphragm) Minimal change disease may be idiopathic; or associated with NSAIDs, or malignancy - most common Hodgkin's lymphoma

Answer 58

- light microscopy - typically NORMAL, or only mild mesangial proliferation - IF - no immune complex deposition - EM - diffuse effacement of foot processes

Answer 59

Supportive management - low salt diet - diuretics - RAAS blockade not required in normotensive pts with minimal change disease Glucocorticoids are the treatment of choice - lead to complete remission of proteinuria in > 85-90% of cases Have an antiproteinuric effect in addition to immunosuppressive effect Only 7-12% pts do not respond to steroids -> consider alternate diagnosis e.g. FSGS Steroid dose of 1mg/kg/day for minimum 8 weeks, max duration of 16 weeks Relapse is common - 50-75% steroid responsive adults will relapse => trial repeat course of pred Some pts will require continuous low-dose pred If not tolerating pred => cyclophosphamide, higher likelihood of sustained remission than cyclosporine. Cyclosporine if relapse after cyclophosphamide Rituximab if relapse after both cyclophosphamide and cyclosporine If appear to be glucocorticoid resistance - consider alternative diagnosis - repeat biopsy ? FSGS - ? inadequate steroid therapy - ensure not taking alkylating aluminium agents which reduce bioavailability of prednisolone

Answer 60

Target Hb 100-115 Clinical trials that assessed higher Hb targets (e.g. 135) - found increased CV events, hospitalisation for HF, death with higher Hb targets. Start EPO only if Hb <100 and transferrin saturation >25% and ferritin > 200, using the lowest possible ESA dose.

Answer 61

A - anaemia. Is Hb and ferritin on target? EPO dose adjustment needed? A- access. Is the current access adequate, what is the long term plan? B - bones. Is the Ca / PO4 / phosphate on target? C - cardiovascular risk. Are CV risk factors optimised? T - transplant. Is this patient a potential transplant candidate? Is the work up moving forwards?

Answer 62

- Intraglomerular hypertension - Tubulointerstitial disease - Systemic hypertension - Glomerular hypertrophy - Hyperlipidaemia

Answer 63

- BP control reduces progression to ESRF in patients with proteinuria - BP control reduces all-cause mortality in patients with CKD

Answer 64

Albuminuria independently increases risk of CVD and death from CV cause.

Answer 65

SGLT2i increase tubuloglomerular feedback and increase afferent arteriole tone => decreasing intraglomerular pressure. May initially cause decrease in eGFR, followed by stabilisation. Decrease albuminuria. Complimentary mechanism to RAAS blockade. ACEi/ARB decrease efferent arteriole tone and decrease intraglomerular pressure.

Answer 66

- RAAS activation - sodium retention, AT2 mediated vasoconstriction of efferent arteriole - Increased sympathetic activation - Hypertensive disease - e.g. hypertensive nephrosclerosis - Fluid overload - Vascular disease and stiffness - Secondary hyperparathyroidism -> increases intra-cellular calcium -> vasoconstriction - EPO analogues / stimulants -> incr. haematocrit -> HTN - Impaired NO synthesis and endothelin mediated vasodilatation

Answer 67

1. Klotho deficiency 2. Increased FGF-23 3. Decreased bone formation 4. Increased vascular calcification FGF23 levels increase in response to increased dietary PO4 load, PTH, increased calcitriol, Ca

Answer 68

As per KDIGO guidelines 2024 Aim SBP <120, unless frailty, high risk of falls & fractures, symptomatic postural hypotension, very limited life expectancy. Individualise targets.

Answer 69

ACEi/ARB Non-dihydropyridine CCBs - diltiazem, verapamil Spironolactone

Answer 70

- Consider addition of night-time medications as pts with CKD do not have a nocturnal decline in BP. Promoting nocturnal decline in BP is associated with reduced incidence of CV events and stroke. - Salt restriction <2g sodium per day or <5g salt per day - in proteinuric pts => start with ACEi/ARB, consider non DHP CCBs for their anti-proteinuric effects ACEi/ARB not superior in CKD patients without proteinuria -in oedematous patients, loop diuretics are preferred. Thiazide diuretics less effective when eGFR <30. Can consider addition of HCT to loop diuretics for sequential nephron blockade if refractory oedema.

Answer 71

1. IRON DEFICIENCY 2. Damage to EPO producing juxtaglomerular & peritubular fibroblasts (renal EPO predominates in adulthood) 3. Anaemia of chronic disease

Answer 72

- PTH levels are increased. Increased PTH is triggered by increased PO4, decreased serum free ionised Ca concentration, decreased calcitriol, increased FGF23, increased expression of vitamin D receptors, Ca sensing receptors, fibroblast growth factor receptors - PTH increases calcitriol levels, increased PO4 & Ca resorption from bone, increases Ca reabsorption from kidneys and PO4 excretion from kidneys - Calcitriol is suppressed by elevated PO4 levels & FGF23 - Calcitriol levels are reduced. Calcitriol normally increases Ca & PO4 absorption from GIT, increases Ca & PO4 resorption from bone and increases Ca reabsorption and PO4 excretion from kidneys - Calcitriol suppresses PTH - FGF23 main role is maintaining normal PO4 concentration - by inhibiting PO4 re-absorption in renal proximal tubule (via Klotho) and decreased calcitriol (which then decreases PO4 reabsorption from GIT)

Answer 73

If CKD + mod-severe albuminuria (I.e. >3mg/mmol per day), with or without diabetes

Answer 74

Continue unless rise in serum creatinine >30% within 4 weeks of initiating ACEi/ARB or increasing dose

Answer 75

- can cause progression of CKD through increase in mediators such as angiotensin 2, intra-renal ammonia and endothelin 1 & aldosterone that cause tubulointerstitial injury & fibrosis - metabolic acidosis can also lead to muscle breakdown / wasting, worsening of bone disease & osteomalacia, worsen insulin resistance

Answer 76

Contrary to previous theories, treatment of metabolic acidosis is likely NOT associated with delayed progression of CKD or improved mortality Consider treatment for metabolic acidosis if bicarb <18, aim for normal range 23 - 29 mmol / L 1. Dietary modification Reduce endogenous acid production through a base-producing diet (fruits & vegetables) 2. Sodium bicarbonate - side effects including bloating, belching, sodium loading can worsen fluid retention & HTN 3. Sodium citrate - risk of acute aluminium encephalopathy 4. Veverimer - new therapy. Selectively binds hydrochloric acid and excretes it via the GIT

Answer 77

- poor outcomes associated with K>6 and K<3 in CKD patients - dietary modification (reduce processed foods that are rich in bioavailable potassium) - Potassium binders 1. Resonium 2. Patiromer - non-absorbable polymer that exchanges K for Ca in the gut - side effects are constipation, abdominal pain, low Mg 3. Sodium zirconium cyclosilicate - selective cation that binds K in the gut, exchanges K for Na and H - works in 1-6 hours - can cause hypokalaemia

Answer 78

Aim BP 120-125/80 More intensive BP lowering reduces risk of progression to ESRF in patients with proteinuric CKD, and reduces mortality in CKD regardless of proteinuric or non-proteinuric.

Answer 79

Elevated serum phosphate in CKD increases CVD risk via 2 mechanisms: 1. Vascular calcification - phosphorous directly induces phenotypic changes in vascular smooth muscle cells by increasing transcription of proteins involved in bone formation and matrix mineralisation => increased calcification Arteriosclerotic disease -> calcium phosphate deposition in media Atherosclerotic disease -> cholesterol plaque in intima 2. Phosphate inhibits activated vitamin D via FGF-2 FGF-23 inhibits 1 alpha hydroxylase which converts 25-hydroxvitamin D to 1,25 dihydroxyvitamin D Activated vitamin D normally inhibits RAAS and therefore controls cardiomyocyte proliferation and hypertrophy

Answer 80

- CKD and proteinuria are independent risk factors for CVD - Patients with CKD are at higher risk of worse CAD, more likely to have atypical symptoms, increased mortality after ACS, PCI or CAGS in patients with CKD - Among patients with CKD, the risk of death, particularly due to CVD, is typically higher than the risk of eventually requiring renal replacement therapy Cardiovascular risk factors in CKD include traditional and non-traditional RFs - Traditional RFs are more important in early CKD - diabetes, HTN, hypercholesterolaemia, smoking, older age - Non-traditional CV risk factors in CKD Hyperphosphataemia Proteinuria / albuminuria Vascular calcification / increased calcium load Elevated FGF-23 levels Retention of uraemic toxins Anaemia Increased inflammatory / poor nutrition state Inflammation and elevated levels of certain cytokines

Answer 81

In CKD - typically secondary hyperparathyoidism. Provoked by increased PO4, increased FGF23, decreased Ca and decreased calcitriol. In ESRF - typically tertitary hyperparathyroidism

Answer 82

FGF-23 is produced by osteocytes and osteoblasts in response to increased dietary PO4 load, decreased calcitriol levels, PTH, Ca. FGF-23 acts via a co-transporter transmembrane protein known as Klotho FGF-23 is increased in CKD. It causes a rise in PTH, decrease in calcitriol, reduces PO4 re-absorption in proximal renal tubule and decreases PO4 absorption in GIT by decreasing calcitriol levels. Levels of FGF23 have been associated with cardiovascular risk

Answer 83

Calcitriol increases Ca & PO4 If Ca is rising with calcitriol, may need to switch to cinacalcet to suppress PTH

Answer 84

Transferrin saturation 25% or less AND ferritin 500ng/mL or less Always give IV iron Must make sure iron replete before giving EPO

Answer 85

1. Increasing age 2. Female sex - higher risk of diabetic kidney disease 3. Male sex - higher risk of progression to ESRF from late stage CKD 4. Hyperglycaemia 5. Hypertension 6. AKI 7. Obesity 8. Smoking 9. Race - African Americans, Latino, American Indians 10. Low socioeconomic status

Answer 86

Hyperglycaemia -> formation of advanced glycation end products & reactive oxygen species AGEs & ROS -> stimulate intracellular signalling for pro-inflammatory and pro-fibrotic gene expression 1. Increase in intraglomerular pressure / glomerular hyperfiltration -> decreased afferent arteriole tone, increased efferent arteriole tone. Diabetic products activate RAAS -> increased efferent arteriole tone Hyperglycaemia -> upregulation of SGLT1 and SGLT2 transporters in proximal tubule -> increased sodium reabsorption -> reduced sodium passing by macula densa -> reduced afferent arteriole resistance. Imbalance between tone of afferent and efferent arteriole => increased intra-glomerular pressure => sclerotic response *this is the mechanism for ACEi & SGLT2i renoprotective effects* 2. Oxidative stress & inflammation Hyperglycaemia, insulin resistance & dyslipidaemia => formation of advanced glycation end products => bind to AGE receptors (RAGE) on kidney cells => production of cytokines via NFkB TGF beta => mesangial cell hypertrophy & matrix accumulation TNF alpha => renal hypertrophy, podocyte and tubular cell injury 3. Interstitial fibrosis and tubular atrophy TGF beta => excess collagen and fibronectin deposition Accumulation of mesangial matrix forms Kimmelstiel-Wilson nodules

Answer 87

1. Autosomal dominant PCKD 2. Autosomal recessive PCKD - often leads to death in utero / as an infant 3. De Novo PCKD Autosomal dominant PCKD - >1000 mutations. Most are point mutations. Truncating mutations associated with more severe disease than non-truncating mutations. - MOST common (78%) - PKD1 mutation on chromosome 16, mutation of polycystin 1, affects cilia function in tubules, MORE severe phenotype (earlier age of onset, larger kidneys with more cysts, median age of ESRF 54 yrs.) "second hit hypothesis" in PKD1. Germline / inherited mutation present in ALL cells, however, cysts only in <10% of tubules. Cyst formation likely results from LOSS of normal haplotype in the presence of an abnormal PKD1 gene. Loss of heterozygosity with a somatic PKD1 mutation within individual PKD1 cysts. - PKD2 (15%) - on chromosome 4, mutation of polycystin 2, affects cilia function in the tubules, milder disease than PKD1, median age of ESRF 74 yrs. De-novo PCKD 10-15% do not have a family history De novo mutations Either no parental information or milder familial disease (PDK2 or non-truncating PKD1)

Answer 88

Microalbuminuria - 30-300mg / day Macroalbuminuria - >300mg / day Nephrotic range >3.5g/day

Answer 89

HbA1c is typically falsely LOW in CKD. Due to anaemia / EPO / iron.

Answer 90

1. Hydration - > 3L per day (if on Tolvaptan approx 5L per day). Aim to maintain urine osmolality <280. Reduced urine osmolality reduces rate of growth of cysts and slows decline in eGFR (similar extent to tolvaptan) 2. Salt restriction - 2-2.3g/day 3. Caloric restriction - protective effect in animal models 4. Lipid control 5. BP control - ACEi/ARB (RAAS blockade) is 1st line What are the benefits of RAAS blockade in PCKD? - reduces increase in total kidney size - reduces rate of decline in renal function - improves cardiovascular mortality (BP control improves CV mortality in PCKD than in non-PCKD causes of ckd Tolvaptan (vasopressin 2 receptor antagonist) for those who are eligible Eligibility criteria: age >18 yrs, CKD 2 or 3 (eGFR 30-90) AND evidence of rapid progression with eGFR decline of >5 ml / min in 1 year or rate of decline >2.5 ml / min / year over 5 yrs. Contraindicated if eGFR <30 Mechanism - reduces urine osmolality <280moscm/kg by reducing aquaporins in collecting duct & increasing diuresis.

Answer 91

All patients with T2DM and CKD should be started on SGLT2i as 1st line therapy, alongside metformin. SGLT2i have cardioprotective and renoprotective effects. DAPA-CKD trial - in patients with CKD, with or without diabetes, patients on dapagliflozin had significantly lower rates of composite outcome (sustained decline in eGFR of at least 50%, ESRF, death from renal or CV cause) compared to placebo. Start a SGLT2i for patients with CKD and T2DM with an eGF >20. Can continue even if eGFR <20, unless not tolerated or RRT. In the absence of diabetes, start an SGLT2i in CKD with eGFR >20 AND - urine ACR >20mg / mmol or 200mg/g - or eGFR 20-45 and urine ACR <20mg/mmol or 200mg/g - heart failure

Answer 92

Dulaglutide Liraglutide

Answer 93

Linagliptin Saxagliptin

Answer 94

Aim for BP <130 / 85. Intensive BP lowering reduces mortality, reduces CVD, and slows progression to ESRF in patients with severe albuminuria. 1st line agent is ACEi/ARB. Can add dihydropyridine CCBs as 2nd line. If increased albuminuria, can trial non DHP CCBs or diuretics as 2nd line.e

Answer 95

1. Male sex 2. PKD1 mutations, truncating mutations 3. Family history of ESRF before 55 yrs. 4. High caffeine intake 5. Low fluid intake 6. High BMI 7. Hypertension 8. Proteinuria / albuminuria 9. Kidney size 10. Early onset of symptoms 11. Elevated co-peptide (pre pro-hormone of vasopressin)

Answer 96

Screen with MRA without gadolinium ; or CTA if MRA is contraindicated Do not screen everyone - many small aneurysms without clinical significance may be detected Screen high risk patients only - prior history of aneurysmal rupture - family history of ICH / aneurysms - neurological symptoms - high risk jobs (e.g. airplane pilot) - prior to major surgery

Answer 97

Renal function typically remains intact till 4th decade of life Once it starts to decline, renal function starts to drop rapidly Roughly 4-6 ml/min/year 50% of patients reach ESRF by 60 yrs. Median age of ESRF with PKD1 mutations is 54 yrs. Median age of ESRF with PKD2 mutations is 74 yrs.

Answer 98

Renal manifestations - Hypertension - can occur before decline in eGFR - Haematuria - 35-50% of patients (more common than proteinuria) - Proteinuria - less common than haematuria, associated with worse prognosis - Renal failure - Flank pain secondary to cyst haemorrhage or cyst infection (urine MCS may be negative in cystic infection because cysts do not always communicate with collecting ducts. Quinolones have good penetration into renal cysts) - Calculi - UTI - Chronic pain syndrome Extra-renal manifestations of polycystic kidney disease 1. Hepatic cysts - occur in 80% of patients. Moderate - severe polycystic liver disease occurs in 15% patients More severe in postmenopausal patients Can present with early satiety, reflux, abdominal pain & bloating, ascites, oedema from IVC compression, chronic pain, cyst infection or rupture, biliary dilatation 2. Abdominal / inguinal hernia - 2nd most common extra-renal manifestations, 45% patients 3. Cerebral aneurysms -typically involve MCA, occur in 5% of young people, up to 20% of patients > 60 yrs -smoking cessation and BP & lipid control important 4. Cardiac Valvular disease - mitral prolapse, aortic regurgitation Cardiomyopathy, lVH, coronary aneurysms / dissection, aortic aneurysms / dissection. Consider addition of beta blockers to RAAS blockade. 5. Other Pancreatic cysts - up to 35% patients, associated with benign tumour IPMN Seminal vesicle cysts Colonic diverticular disease

Answer 99

USS show bilaterally enlarged kidneys with DIFFUSE cysts involving the cortex & medulla. MRI is more sensitive than USS, particularly in young patients. If positive family history - age 15 - 39 yrs. - need 3 or more cysts in total for diagnosis - age 40 - 59 yrs - 2 or more cysts in each kidney - >60 yrs - 4 or more cysts in each kidney If no family history - bilateral renal enlargement and >10 cysts in each kidney Exclusion of diagnosis is an important consideration for living related donors - no cysts on USS by age 40 yrs. - <5 cysts on MRI by age 40

Answer 100

1. Mild benign cysts - kidney size normal 2. Acquired renal cystic disease - history of lithium use, dialysis. Kidney size is small or normal 3. Autosomal dominant tubulointerstitial kidney disease - if cysts present will typically spare cortex, kidneys not enlarged 4. Autosomal recessive kidney disease - mutation in PKHD1, more severe - 30% fatal at birth, associated with congenital hepatic fibrosis and portal hypertension 5. Tuberous sclerosis - can be comorbid with PCKD, associated with earlier renal failure, can have cysts & angiomyelolipomas in kidneys, astrocytomas and seizures 6. VHL - risk of clear cell RCC that can develop from renal csysts 7. Multicystic dysplasic kidney - most common type of paediatric renal cystic disease

Renal Flashcards

(135 cards)