What a Rheumatologists needs to know about Nephrology

Dr Louise Moist University of Western Ontario Louise/[email protected]

May 2014 Disclosures

• Advisory board Amgen, Leo Pharma, Roche Learning Objectives

• Update in recent trends in nephrology pertinent to the rheumatologists in: • Proteinuria/eGFR • Lupus nephritis • Gout in CKD • Pain control in CKD • Drugs in CKD

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Kidney Disease 101

Damage Function – Microalbuminuria is – Measure Cr a marker of – Interpret with age, vascular/ sex, weight endothelial damage – eGFR – Microalbuminuria – If abnormal consider is a risk factor CVD other kidney function and CKD – Lytes, Ca, Phos, Hb,acid base, clearance (urea) Rate per 1,000 Patient Years Proteinuria predicts progression to ESRD> than Creatinine Hemmelgarn

et.al. 2010;303(5):423 JAMA. et.al. 100x> risk of Dialysis

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Rate per 1,000 Patient Years Proteinuria predicts death>creatinine Hemmelgarn et.al. 2010;303(5):423 JAMA. et.al. Almost 10X > 10X> Almost risk

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KEY POINT

When you see this...

High albumin to creatinine ratio Or proteinuria on dip stick

Think this... HIGH CVD RISK GFR(mL/min/1.73m2) > 90 60-89 30-59 15-29 <15 Stage 1 2 3 4 5 Kidney Severe Failure Moderate  GFR Kidney  GFR damage Kidney with mild Description damage  GFR with normal or  GFR

Endstage Kidney Disease (ESKD) = Dialysis or Transplantation

Stages of CKD GFR

Hypertension* Hemoglobin < 12.0 g/dL Unable to walk 1/4 mile Serum albumin < 3.5 g/dL Serum calcium < 8.5 mg/dL Serum phosphorus > 4.5 mg/dL 90 80 70 60 50 40 30 20

10 Proportion of population (%) of population Proportion 0 15-29 30-59 60-89 90+ Estimated GFR (ml/min/1.73 m2)

*>140/90 or antihypertensive medication p-trend < 0.001 for each abnormality Abnormalities in Uremia “Uremia” & the Uremic Toxin

Membrane permeability & Intracellular Ca2+ integrity PTH (9000 daltons) Protein catabolism Soft tissue calcification

Alters/mitochondrial pathways/ ATP generation abN phospholipid turnover Brain Platelets Glucose Pancreas Myocardium intolerance When you see this...

Creatinine 145 umol/L eGFR == 35ml/min consistent with stage 3 CKD

Think this... HIGH CVD RISK Impaired Immunity

Early CKD: altered cellular & humoral immunity Alterations in PMN leukocytes – CHO metab, ATP generation, endothelial cell adherance, ROS generation – Impaired chemotaxis, phagocytosis, intracellular bacterial killing Moderate lymphocytoepenia (circulating T cells) Interferon production Pt more susceptible to infections e.g. T.B., bacteremias, cancers, response to Hep B vaccinations

Mortality: The Facts

Stages 1-4 – Risk of death from CVD >>> renal disease – 40% of patients with CKD will have CVD related death – Approximately: Each 10 umol/L  SCr  •  39% mortality •  59% CVD related death • Normotensive patients with MI

Mortality: Stage 5

Cardiac events in ESRD 3.5-50 times GP Annual mortality on dialysis 15-20% Cardiac causes of death 45% Post MI – 1 year mortality = 59% – 5 year mortality =90%

CKD Management

Reduce CKD progression – BP control – Regression of proteinuria – Use of ACEI/ARB – Smoking cessation

Cardiovascular risk reduction – Depends on stage of CKD

Nephrology vs Rheumatology

• Experienced, dedicated, committed Dr. • Stage 4 CKD for sure • Management of CVS risk s • Comanagement Patient Subsets Population vs. Patient

MS LN ( Lupus nephritis)

26 yo Creat 260 eGFR 30 (?),protein 2 g24 h, unwell Anti dna 800, rash, leukopenia, Biopsy Class IV LN Steroids MMF or Cyclophosphamide

Common Mistakes in Treating Lupus

1. Assuming Cyclophosphamide is the gold standard

Am J Kidney Dis. 63(4):667-676 2014

MMF vs CYC for LN-Results of the ALMS Trial

Black, MixedBlack, Hispanic,

•The ALMS trial did not achieve its primary endpoint •ALMS was NOT a non-inferiority trial •However MMF has increasingly become the SOC Appel, et al., JASN, 2009; Isenberg, et al, Rheumatol, 2010 MMF vs CYC for SEVERE LN Defined as LN presenting with renal insufficiency

Rovin et al., CJASN, 2012 Common Mistakes in Treating Lupus

3. NOT USING ANTIMALARIAL AGENTS ROUTINELY • decrease the frequency of lupus flare

• improves kidney outcomes

• increased probability of remission in membranous nephritis treated with MMF when combined with hydroxychloroquine

• lowers probability of decrease in kidney function if used prior to the onset of lupus nephritis

• probability of receiving an antimalarial agent is only 50% if their primary lupus physician is a nephrologist

Am J Kidney Dis. 63(4):667-676 2014 Common Mistakes in Treating Lupus

4. USING URINARY SEDIMENT FOR RESPONSE CRITERIA

• ACR recommends using urinary sediment for assessing response

• improvement defined as changing from active urinary sediment to inactive urinary sediment (5 RBCs, 5 WBC, and noRBCs and no WBCs

• the quantity of cells or casts is influenced by the duration of centrifuge time

• mesangial proliferation (class II nephritis) can be associated with RBCs and casts and these lesions do not require immunosuppressive

• using urinary sediment for response criteria can be misleading and result in unnecessary use of potentially toxic therapies.

Am J Kidney Dis. 63(4):667-676 2014 Common Mistakes in Treating Lupus

NOT REDUCING OR MINIMIZING IMMUNOSUPPRESSIVE EXPOSURE IN PATIENTS WITH ADVANCED KIDNEY DISEASE • CKD 4 or 5 D , a renal-limited flare might not warrant immunosuppressive tx

• significant scarring in the kidney

• very little or no benefit from another course of therapy.

• immunotherapy guided by extrarenal manifestations.

• dialysis pt immunosuppressive dose should be minimized high risk of infection.

Am J Kidney Dis. 63(4):667-676 Common Mistakes in Treating Lupus

WHEN to do A BIOPSY

• Abnormal renal function • Careful in young people Creat 50 increases to 90

• Proteinurea • 1 gram may be masked if on ACEI ARB

• Consider if marked change in presentation

• Fibrosis scarring vs active disease

• Risk vs Benefit

Case -Clinical History

51 y.o. female SLE presented with microscopic hematuria  creatinine 80 to 115 mol/L over 2 years • Positive ANA (1:640) with anti-Smith antibodies • C3 level low normal C4 level • UA: large blood, 1+ protein, and 20 RBCs/ HPF, • Urine protein-creatinine ratio was 0.5 • positive lupus anticoagulant What additional information would you like? MS LN ( Lupus nephritis)

6 months later MMF 1250 gm bid prednisone 15mg ,ramipril 5mg, Plaquenil Creat 120 eGFR 60 ,protein .5g24 h

• 2mo later returns creat 190, alb/cr 50

Lupus nephritis

Rule out other causes of rise in creatinine • Volume status • Drugs NSIADs, ACEI, ARB,DRI • Predisone ( urea) • Septra • ACEi ARB DRI Repeat Cr follow up

Lupus nephritis

Pregnancy • Education risks • Remission 6mo • Lupus anticoaulant before BCP • Switch to azothioprine and stable • Off ramipril • Stay on hydroxychloroqine • Prognosis based on renal function Cr 160 • Co manage high risk OB

Gout in CKD

MR Tophi 65 yo HT, Creat 162 eGFR 42ml/min Ramipril, HcT, ASA 81mg. Statin Boys weekend ( moose meat, booze) Acute gout, treated wih NSAID, 3 days later to emerg Creat 640 uric acid 800

Mr Tophi

Cause of AKI? ACEI / NSAID combo dehydration

Time to recovery • Renal mass

Need for prophylaxis? dose of Allopurinol exacerbation of gout

Gout in CKD

Treatment Prevention

• NSAIDS • Colchicine • 20% excreted kidneys • neuropathy, myopathy, BM • Colchicine • No if eGFR < 15ml • 1-2 0.6mg per day • 15-30 ml q 3days • Caution statins • Allopurinol • Steroids • Dose reductions? • Slow titration

• Uloric

• No role for uricosurics < 60ml

Drugs In CKD and Rheumatology

Victim Accessory

Gentamycin Disruption of Functions Acyclovir NSAIDs Indinavir Thiazide diuretics Sodium phosphate TMP-SMX Pamidronate Cisplatin Prolonged Effects Hetastarch Benzodiazapines Calcineurin inhibitors Methotrexate Gold Glyburide NSAIDs Beta-lactams

Drug Use in CKD Drug use in CKD Septra and CKD

Dose-response • SS TMP-SMX, OR = 3.4 (1.6 – 7.4) • DS TMP-SMX, OR = 6.6 (3.5 – 12.6) Hyperkalemia • 14% of patients had electrolyte testing after Rx • Absolute risk of hyperkalemia = 6.9/1000 TMP-SMX Rx Mortality • 26/189 (14%) died during admission • Absolute risk of death (21 day) = 26.2/1000 TMP-SMX Rx

Slide courtesy of Matt Weir Pain Control and CKD

. Modified WHO analgesic ladder in patients with chronic kidney

Parmar MS, Parmar KS. 2013 [v3; ref status: indexed, http://f1000r.es/10f] F1000Research 2013, 2:28 (doi: 10.12688/f1000research.2-28.v3) Pain Control in CKD Metabolic Bone DiseASE

Renal Osteodystrophy Diagnosis of Osteoporosis in CKD

• hip fracture risk women > 65 • eGFR of 45 to 59 mL/minute (HR 1.57, 95% CI 0.89-2.76) • eGFR <45 mL/minute (HR 2.32, 95% CI 1.15-4.68) • FRAX no eGFR • DXA measures areal BMD, rather than volumetric BMD • cannot distinguish cortical and trabecular bone • cannot assess bone microarchitecture/ bone turnover

• DXA eGFR > 30 hyperparathyroidism, hyperPO4 • Oral bisphosphonate • DXA <30 is not routinely performed • Only under special circumsances Summary

• CKD secondary to factors related to Rheum is multifactorial and multidisciplinaery

• Each stage has associated multi-system morbidities

• Management of the Rheum Dx

• Prevent progression with aggressive BP and proteinuria control

• Prevent CVD using CKD specific risk factor modification

Thank You!