Renal “Pot Pourri”:CKD, proteinuria, anaemia, bone disease and

stones

Cambridge Medical SeminarsDr Elaine Jolly

Consultant in Nephrology and Acute Medicine24 November 2018

Outline of talk

• Define CKD• eGFR calculation and interpretation

• Referral guidelines for CKD

• ACRs: how to interpret and when to act

• Potential scenarios on the medical take– Case vignettes

• Issues arising as a consequence of CKD– Anaemia management

– Renal bone disease

• Stone disease

Chronic kidney disease (CKD)

• Common: affects 5.5 - 8.5% of UK population• Expensive: £1.44 billion in 2009-2010 (NHSE)• Not a specific diagnosis - further assessment to

establish cause and individualise treatment• Asymptomatic in early stages

• Management has 4 key aims:– Manage risk factors for cardiovascular disease– Slow CKD progression– Detect and treat CKD-related complications (Stage 3b

onwards)– Allow timely preparation for renal replacement therapy

eGFR by CKD-EPI equation

Pitfalls in eGFR interpretation• Creatinine:

– Bias from tubular secretion

– Formation (muscle mass, catabolism, extreme physical activity, traumatic muscle damage, haemolysis, protein-rich diet)

• Not validated / less accurate at extremes of age

• No mass input

• Correction factor for low (<80 / 62 µmol/L) creat

Chronic Kidney Disease

Definition: Abnormalities of kidney function or structure present for > 3 months, with implications for health. This includes all people with markers of kidney damage and those with a GFR < 60 ml/min/1.73 m2 on at least 2 occasions separated by a period of at least 90 days (with or without markers of kidney damage).

Increasing risk

Incre

asing risk

CKD – Referral guidelines, NICE 2015

• People with CKD in the following groups should normally be referred for specialist assessment:

– GFR < 30 ml/min (CKD Stage 4 or 5)– ACR ≥ 70 mg/mmol, unless known to be caused by diabetes and

already appropriately treated– ACR ≥ 30 mg/mmol (A3), together with haematuria– sustained decrease in GFR of ≥ 25%, a change in GFR category or

sustained decrease in GFR of ≥ 15 ml/min within 12 months– hypertension that remains poorly-controlled (despite use of ≥ 4

antihypertensive drugs at therapeutic doses) – known or suspected rare or genetic causes of CKD– suspected renal artery stenosis

• May be possible for routine follow-up to take place at GP surgery• CKD with renal outflow obstruction should normally be referred to

urological services

ACR (albumin-creatinine ratio)

• Dipstick urine testing is only semi-quantitative and highly-dependent on urine concentration

• False positives: after iodinated contrast (<24 hrs), highly-alkaline urine, gross haematuria, some antiseptics (chlorhexidine)

• Persistent proteinuria requires quantification

• Spot urine ACR

• Reported as mg/mmol at CUH (range 0-2.5)

• A1 = normal, A2 = microalbuminuria, A3 = macroalbuminuria

• Limitations – extremes of muscle mass

Proteinuria

• Hallmark of glomerular disease

• Risk factor for progression of CKD

• Risk factor for development of cardiovascular disease

Even relatively mild proteinuria (+/- reduced GFR) associated with all-cause and CVS mortality, ESRD, AKI and progressive CKD)

Proteinuria

• Nephrotic-range: discuss with nephrology (renal biopsy usually indicated)

• Exclude post-renal proteinuria

• Non-nephrotic (isolated) proteinuria:

– Medical history and exam

– Measure serum creat / eGFR

– Exclude transient (fever, exercise, UTI, young) or orthostatic

– May reflect an underlying renal or systemic disorder:

• ANA, ANCA, C3/C4, immunoglobulins, hepatitis/HIV serology

• Urine for monoclonal light chains

• Renal US (reflux, ADPKD)

• Nephrology referral if A3

• Kidney biopsy usually indicated for non-nephrotic proteinuria with active urinary sediment or decreased GFR or if proteinuria persistently >1g/day or new NVH, hypertension, drop in GFR

Case 1 – CKD and Medication

• AB, 65Y, male

• 2/7 history of dysuria, fever, right loin discomfort

• PMH: IHD (PCI 2016, LVEF 45%), hypertension, CKD Stage 3a (baseline eGFR 45 ml/min, Creat 140), OA knees

• DH: aspirin, ramipril, amlodipine, frusemide, bisoprolol, (diclofenac)

• O/E: T 38.5, BP 95/60, HR 90 bpm, mild suprapubic and right renal angle tenderness

• Ix: WCC 15 (neutrophilia), CRP 247, Creat 165, lactate 3.1

Urine: Protein / blood / leucocytes / nitrites +

• Blood and urine cultures taken, IV fluids prescribed, IV augmentinand gentamicin (5mg/kg) given

What is your next step in management?https://designer.voxvote.com/Event/EditQuestion/78eb0fc1-0d29-437d-982c-a99a00dd93ca

• Continue regular medication unaltered

• Stop everything (just in case…)

• Stop the frusemide as giving IV fluids but continue everything else

• Stop ramipril and frusemide but continue bisoprolol and amlodipine

• Stop all antihypertensives and frusemide

• Stop ramipril, amlodipine and frusemide

• None of the above

ACEI / ARB

• Overwhelming evidence is positive (CKD / CCF / diabetes)

• Reduction in GFR is seen in some patients:

– Following the introduction / dose increase of RAS antagonists

– do not modify the dose if either:• GFR decrease is < 25% or

• Serum creatinine increase from baseline is < 30%

– May be severe in those with bilateral renal artery stenosis, hypertensive nephrosclerosis, heart failure, ADPKD or CKD

• May precipitate AKI in situations of reduced renal perfusion

PG synthesis increased in:-CKD-Volume depletion (diuretics, vomiting, diarrhoea)-Effective arterial volume depletion (HF, NS, cirrhosis)-Older age-Severe hypercalcaemia

Medication toxicity in CKD

Action of ACEI / ARB

X

Case 2 – CKD and Anaemia

• CD, 35Y, female• Referred to ambulatory care with tiredness, GP checked bloods 1

week previously: Hb 88• PMH: ADPKD, CKD Stage 4 (baseline eGFR 20 ml/min, Creat 250,

DNA’d last 2 nephrology clinic visits), frequent UTIs, hypertension• DH: ramipril, trimethoprim / cefalexin, ferrous sulphate

• O/E: BP 125/70, HR 72 bpm, slightly pale, no abdominal pain, DRE: no melaena

• Ix: Hb 90 (MCV normal), Creat 300, K 5.8Historical results (Hb >100 when last seen in clinic 4/12 previously)Pregnancy test: negative

• Iron studies / folate / Vit B12 / TSH / blood film taken• Serum iron 4.0 / ferritin 10.3 / transferrin 2.98 / transferrin

saturation: 7%

What is your next step in management?https://designer.voxvote.com/Event/EditQuestion/65c4dc32-2a47-468c-980b-a99a00e02814

• Arrange urgent blood transfusion as symptomatically anaemic

• Nothing - I have no idea how to interpret iron indices

• Change iron preparation from oral to IV infusion

• Check EPO level and consider starting ESA (recombinant erythropoeitin)

• Contact the renal unit for advice

• None of the above

Anaemia management in CKD

• Normocytic, normochromic, hypo-proliferative anaemia

• Mechanism:

– reduced production of erythropoetin (EPO) and shortened red cell survival, (uraemic-induced inhibitors of erythropoeisis, nutritional deficiencies)

• Increasingly common as eGFR < 60 ml/min (esp. diabetics)

• NHANES (90s) – prevalence of anaemia: 1% (eGFR=60)

9% (eGFR=30)

33-67% (eGFR=15)

• Why treat?

– QOL, increased cardiovascular disease / hospitalisations / cognitive impairment / mortality

• Don’t measure EPO levels – will be normal or even high, don’t always correlate with biological activity

• Try and avoid transfusion (sensitises patient which may limit potential transplantation options)

• EPO deficiency• Blood loss (frequent

phlebotomy, blood trapping “lost circuits”)

• Shorter RBC life span• Decreased BM responsiveness

to EPO• Vitamin deficiencies• Poor iron absorption (oral iron

no better than placebo?)• Uraemia-associated platelet

dysfunction• ESA use – depletes circulating

iron stores• [Aluminium toxicity impairing

RBC development (mainly dialysis / PO4 binders)]

• [Haemolysis (copper, chloramines)]

• Chronic inflammation

Why do CKD patients become iron-deficient?

NICE guidelines 2017 (CKD)

• Screening– eGFR < 60ml/min, 6-12 monthly– Assess iron status: % HRC (>6%) or reticulocyte haemoglobin content

(<29pg) or combination of transferrin saturation (<20%) and serum ferritin (<100 µg/L)

– Exclude non-renal causes of anaemia

• Management– Hb <110 g/L or symptoms, aiming to maintain Hb 100-120– Correct iron deficiency first: consider trial of oral iron before offering

IV iron (high-dose, low frequency)– Offer ESA if on-going anaemia despite iron sufficiency (eGFR <

30ml/min)– Correct hyperparathyroidism

–PIVOTAL trial

Case 3 – CKD and bone disease

• EF, 70Y, female

• 2/12 history of constipation, thirst, abdominal pain and nausea

• PMH: COPD, CKD Stage 4 (baseline eGFR 19 ml/min, Creat 220), PVD, hypertension

• DH: aspirin, amlodipine, bendroflumethiazide, doxazosin, seretide / salbutamol, alfacalcidol, sevelamer, aranesp

• O/E: BP 150/80, HR 95 bpm, clinically dry, mild generalised abdominal pain

• Ix: Creat 320, Ca 3.1, K 4.2, PO4 1.3, ALP 170

PTH 28 pmol/L

CXR: slightly prominent right hilum

What is your next step in management?https://designer.voxvote.com/Event/EditQuestion/ec6ee2a7-76f8-4aa6-a89a-a99a00e4e9de

• Consult a BNF………

• Check a serum ACE to confirm a putative diagnosis of sarcoidosis

• Rehydrate with IVI but continue all medication

• Rehydrate with IVI and stop alfacalcidol and bendroflumethiazide

• Rehydrate and prescribe pamidronate

• None of the above

Alfacalcidol - active vitamin D3 metabolite

X

Vitamin D and CKD

Vitamin D deficiency

• Low serum 25(OH)D (calcidiol) level <20 ng/ml (50nmol/L)

• Very common in general pop. (> 40% of adults, NHANES 2006)

• In CKD population – pretty well ubiquitous

• Routine use of Vit D in CKD for the past 30 years to try to prevent / reverse the impact of hyperparathyroidism on the skeleton

• But does replacing deficiency guarantee benefit?

• Supplementation generally increases Vit D levels (and suppresses PTH) but less focus on clinical end-points (fracture risk, hospitalisations, mortality)

• Unresolved issues:– what should we be measuring

– what replacement protocol works best

– which end-points to use for titration

– role of monitoring and screening

Vitamin D supplements in the management of CKD-MBD, NICE 2014

• “Detailed advice on the management of CKD–MBD is beyond the scope of this guideline. If uncertain, seek advice from your local renal service.”

• Do not routinely offer vitamin D supplementation to manage or prevent CKD–mineral and bone disorders

• Offer cholecalciferol or ergocalciferol to treat vit D deficiency in people with CKD and vit D deficiency (“Native” Vit D, eGFR >30 ml/min, Normal PTH/PO4)

• If vit D deficiency has been corrected and symptoms of CKD–MBD persist, offer alfacalcidol (1-alpha-hydroxycholecalciferol) or calcitriol (1-25-dihydroxycholecalciferol) to people with a GFR <30 (G4 or G5) (“Synthetic or active” Vit D, eGFR <30 ml/min)

• Monitor serum Ca2 + PO4 in people receiving alfacalcidol or calcitriolsupplements

Case 4 – Stone disease

• GH, 50Y, male

• 2/7 history of severe left loin discomfort, followed by the passage of “gritty” urine, on-going colicky pain

• PMH: obesity, hypertension, diet-controlled diabetes, gout, ?renal calculus 5 years previously (not investigated)

• DH: losartan, amlodipine, colchicine PRN

• O/E: Obs and clinical exam: NAD

• Ix: Creat 60, CRP <4 Ca 2.15 PO4 1.3

Urine: Protein + / blood +++

CTAP:

What is your next step in management?https://designer.voxvote.com/Event/EditQuestion/449e7e32-bf19-4d3e-897a-a99a00e99a21

• Contact urology

• 24 hour urine collections x2

• Measure serum urate

• Check urinary pH

• Consider switching antihypertensive medication

• Refer to renal stone clinic

• All of the above

Prevention Clinical approach• ~10% people will have a stone

episode

• > 50% will have > 1 episode

• Expensive

• Stone disease has been linked to hypertension, obesity, and diabetes

• Stone history - no. of episodes, surgical interventions (stone composition)

• Risk factors - gout, T2DM, obesity, malabsorption, distal RTA, sarcoidosis, hyperparathyroidism, genetic disorders

• Dietary history - calcium, animal protein, salt, fluid, fruits / vegetables

• Family history of stone disease

• Drugs - calcium supplements, vitamin C, carbonic anhydrase inhibitors, protease inhibitors

Investigations(Stones recurrent +/- < 30 years +/- family history +/- known syndrome)

• Bloods: venous biochemistry inc. bicarb, creat, calcium / phosphate, PTH, urate

• Urine: pH (fresh urine sample)

Culture

24 hour collection x2:

plain and acid

Electrolytes Calcium

Creatinine Phosphate

Urate Oxalate

Cystine Citrate

• Stone analysis

• Imaging: US / CT

Management of stone disease

• General:

– fluids; aim for >2L urine/day (i.e. 2.5-3L oral fluid)

– low salt, low oxalate, ‘vegan’ diet

– alkalinise urine:

potassium citrate 10 ml tds

sodium bicarbonate 1g tds

lemon juice in drinking water

• Consider in addition:

– Hypercalciuria: Thiazides

– Hyperuricosuria: Allopurinol

– Struvite: Rotating antibiotics

– Oxalate: Calcium supplements with meals, pyridoxine

– Cystine: Captopril, penicillamine, tiopronin

Summary

• CKD is a frequently-occurring comorbid condition and has wide-reaching clinical implications

• eGFR and ACR calculations - how to interpret and act on results

• Importance of medication management in CKD

• Anaemia and bone mineral disorder management in CKD

• Stone disease

Thank you!