Kidney Disease: Diagnosis

	eGFRi
	≥60 mL/min	30-59 mL/min	<30 mL/min
UP/Ciii <50	Regular Follow-up	Check risk factors for CKDx and nephrotoxic medicines including ARTiv,x Discontinue or adjust drug dosages where appropriatev Perform renal ultrasound If haematuria present with any level of proteinuria refer to a nephrologist Refer to a nephrologist if new CKD or progressive decline in eGFR	Check risk factors for CKD and nephrotoxic medication including ARTiv Discontinue or adjust drug dosages where appropriatev Perform renal ultrasound Urgent referral to nephrologist
UP/Ciii 50-100
UP/Ciii >100

Management of HIV-associated Kidney Disease^vi

Prevention of progressive renal disease	Comment
1.Antiretroviral therapy	Start ART immediately where HIV-associated nephropathy (HIVAN)vii or HIV immune complex disease strongly suspected. Immunosuppresive therapy may have a role in immune complex diseases. Renal biopsy to confirm histological diagnosis recommended
2.Start ACE inhibitors or angiotensin-II receptor antagonists if: a.Hypertension, and/or b.Proteinuria	Monitor eGFR and K+ level closely on starting treatment or increasing dose a) Blood pressure target: <130/80 mmHg
3.General measures: a.Avoid nephrotoxic drugs b.Life style measures (smoking, weight, diet) c.Treat dyslipidaemiaviii and diabetesix d.Adjust drug dosages where necessary	CKD and proteinuria are independent risk factors for CVD

ⁱFor eGFR: Use CKD-EPI formula based on serum creatinine, gender, age and ethnicity because eGFR quantification is validated > 60 mL/min. The abbreviated modification of diet in renal disease (aMDRD) or the Cockcroft-Gault (CG) equation may be used as an alternative; see http://www.hivpv.org/. Definition CKD: eGFR < 60 ml/min for > 3 months (see http://kdigo.org/home/guidelines/ckd-evaluation-management). If not previously known to have CKD, confi rm pathological eGFR within 2 weeks. Use of DTG, COBI and RTV boosted PIs is associated with an increase in serum creatinine/reduction of eGFR due to inhibition of proximal tubular creatinine transporters without impairing actual glomerular filtration: consider new set point after 1-2 months

ⁱⁱUrinalysis: Use urine dipstick to screen for haematuria. To screen for proteinuria, use urine dipstick and if ≥1+ check urine protein/creatinine (UP/C), or screen with UP/C. Proteinuria defined as persistent if confirmed on ≥ 2 occasions > 2-3 weeks apart. If UP/C not available, use urine albumin/creatinine (UA/C), see iii

ⁱⁱⁱUP/C in spot urine is preferred to UA/C as detects total urinary protein secondary to glomerular and tubular disease. UA/C largely detects glomerular disease and can be used for screening for HIV-associated renal disease where UP/C is not available, but is not appropriate for screening for tubular proteinuria secondary to drug nephrotoxicity (e.g. TDF). If both UP/C and UA/C are measured, UP/C > UA/C suggests tubular proteinuria.Screening values for UA/C are: < 30, 30-70 and > 70. UA/C should be monitored in persons with diabetes. UPC ratio is calculated as urine protein (mg/L) / urine creatinine (mmol/L); may also be expressed as mg/mg. Conversion factor for mg to mmol creatinine is x 0.000884

^ivRepeat eGFR and urinalysis as per screening table, ERA 1

^vSee Dose Adjustment of ARVs for Impaired Renal Function

^viJoint management with a nephrologist

^viiHIVAN suspected if black ethnicity & UP/C > 100 mg/mmol & no haematuria

^viiiSee ERA 3

^ixSee ERA 3

^xDifferent models have been developed for calculating a 5-years CKD risk score while using different nephrotoxic ARVs integrating HIV-independent and HIV-related risk factors

ART: Drug-associated Nephrotoxicity

Renal abnormality*	Antiretroviral Drug	Managementvi
Proximal tubulopathy with any combination of: Proteinuria: urine dipstick ≥1, or confirmed increase in UP/C >30 mg/mmoli Progressive decline in eGFR and eGFR <90 mL/minii Phosphaturiaiii: confirmed hyophosphataemia secondary to increased urine phosphate leak	Tenofovir	Assessment: Tests for proximal renal tubulopathy/renal Fanconi syndromeiii Consider renal bone disease if hypophosphataemia of renal origin: measure 25(OH) vitamin D, PTH, DXA Consider stopping tenofovir if: Progressive decline in eGFR and no other cause Confirmed hypophosphataemia of renal origin and no other cause Osteopenia/osteoporosis in the presence of increased urine phosphate leak
Nephrolithiasis Crystalluria Haematuriaiv Leucocyturia Loin pain Acute renal insufficiency	Indinavir Atazanavir (Darunavir)	Assessment Urinalysis for crystalluria/stone analysis Exclude other cause for nephrolithiasis Renal tract imaging including CT scan Consider stopping atazanivir/indinavir if: Confirmed renal stones. Recurrent loin pain +/- haematuria
Interstitial nephritis: Progressive decline in eGFRii Tubular proteinuriaiii/ haematuria Eosinophiluria (if acute) Leucocyte casts	Indinavir Atazanavir	Assessment: Renal ultrasound Refer to nephrologist Consider stopping Indinavir/Atazanavir if: Progressive decline in eGFR and no other cause
Progressive decline in eGFR, but none of the abovev	Tenofovir Ritonavir boosted protease inhibitors	Complete assessment: Risk factors for CKDv (see Kidney Disease: Diagnosis and Management) PRT, UA/C, UP/C (see Kidney Disease: Diagnosis and Management and Indications and Tests for Proximal Renal Tubulopathy (PRT) Renal tract ultrasound Consider stopping ARVs with potential nephrotoxicity if: Progressive decline in eGFR and no other causev

^* Use of Cobicistat (COBI), Dolutegravir (DTG), Rilpivirine (RPV), and also PI/r is associated with an increase in serum creatinine/reduction of eGFR due to inhibition of proximal tubular creatinine transporters without impairing actual glomerular filtration: Consider new set point after 1-2 months

ⁱUP/C in spot urine detects total urinary protein including protein of glomerular or tubular origin. The urine dipstick analysis primarily detects albuminuria as a marker of glomerular disease and is inadequate to detect tubular disease.

ⁱⁱFor Estimated Glomerular Filtration Rate (eGFR): Use Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. The abbreviated MDRD (Modification of Diet in Renal Disease) or the Cockcroft-Gault (CG) equation may be used as an alternative, see http://www.hivpv.org/

ⁱⁱⁱSee Indications and Tests for Proximal Renal Tubulopathy (PRT)

^ivMicroscopic haematuria is usually present.

^vDifferent models have been developed for calculating a 5-years CKD risk score while using different nephrotoxic ARVs integrating HIV-independent and HIV-related risk factors

Indications and Tests for Proximal Renal Tubulopathy (PRT)

Indications for proximal renal tubulopathy tests	Proximal renal tubulopathy testsiv, including	Consider stopping tenofovir if
Progressive decline in eGFRi & eGFR <90 mL/min & no other cause and/or Confirmed hypophosphataemiaii and/or Confirmed increase in UP/Ciii Renal insufficiency even if stable (eGFR <60 mL/min) Tubular proteinuriav	Blood phosphate and urinary phosphate excretionvi Blood glucose and glucosuria Serum bicarbonate and urinary pHvii Blood uric acid level and urinary uric acid excretionviii Serum potassium and urinary potassium excretion	Confirmed proximal renal tubulopathy with no other cause

ⁱFor eGFR: Use CKD-EPI formula. The abbreviated MDRD (Modifi cation of Diet in Renal Disease) or the Cockcroft-Gault G) equation may be used as an alternative, see http://www.hivpv.org/

ⁱⁱSerum phosphate < 0.8 mmol/L or according to local thresholds; consider renal bone disease, particularly if alkaline phosphatase increased from baseline: measure 25(OH) vitamin D, PTH

ⁱⁱⁱUP/C in spot urine: Detects total urinary protein, including protein of glomerular or tubular origin. The urine dipstick analysis primarily detects albuminuria as a marker of glomerular disease and is inadequate to detect tubular disease

^ivIt is uncertain which tests discriminate best for tenofovir renal toxicity. Proximal tubulopathy is characterised by proteinuria, hypophosphataemia, hypokalaemia, hypouricaemia, renal acidosis, and glucosuria with normal blood glucose level. Renal insufficiency and polyuria may be associated. Most often, only some of these abnormalities are observed

^vTests for tubular proteinuria include retinol binding protein, ?1- or ?2-microglobulinuria, urine cystatin C, aminoaciduria

^viQuantified as fractional excretion of phosphate (FEPhos): (PO4 (urine)/PO4 (serum))/(Creatinine (urine)/Creatinine (serum)) in a spot urine sample collected in the morning in fasting state. Abnormal >0.2 (>0.1 with serum phosphate <0.8 mmol/L)

^viiSerum bicarbonate <21 mmol/L and urinary pH >5.5 suggests renal tubular acidosis

^viiiFractional excretion of uric acid (FE UricAcid): (UricAcid (urine)/UricAcid (serum)) / (Creatinine (urine) /Creatinine (serum)) in a spot urine sample collected in the morning in fasting state; abnormal >0.1

Reference

EACS Guidelines, Version 8.0 – October 2015