Management of Type 2 Diabetes Mellitus and Kidney Failure in People with HIV-Infection in Africa: Current Status and a Call to Action

Figures & data

Figure 1 HIV-related and traditional risk factors influencing the development and progression of CKD in PWH.

Notes: Reproduced with permission. Swanepoel CR, Atta MG, D’Agati et al Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney international. 2018;93(3):545–559. © 2017 International Society of Nephrology. Published by Elsevier Inc. Creative Commons CC-BY-NC-NDlicense.¹²

Abbreviations: APOL1, apolipoprotein L1; ABCC, ATP-binding cassette transporter proteins; ART, antiretroviral therapy; CKD, chronic kidney disease, FSGS (NOS) focal segmental glomerulosclerosis, not otherwise specified; GN, glomerulonephritis; HIVAN, HIV-associated nephropathy.

Table 1 Similarities and Differences in the Clinical Presentation of CKD in HIV and DKD

	DM and CKD	HIV and CKD
HPT	Often HPT before onset of CKD	HPT is usually not associated with HIVAN. Prior to CKD only HPT if known with pre-existing HPT
Phenotype	Frequently metabolic phenotype (T2DM)	BMI often not raised.
Oedema	Oedema often present	± Oedema If CKD due to HIVAN – oedema unlikely Only oedematous if nephrotic syndrome or advanced CKD
Accompanying features	Other Target organ damage: Retinopathy (50–60% will have proteinuria) Peripheral neuropathy Macrovascular complications: IHD, CVA, PVD	Often multiple pathologies on kidney biopsy ± Evidence of intercurrent illness May have no specific features (HIVAN and ICGN can occur with any CD4 count)
Urine dipstick	Classical presentation: Usually albuminuria ± blood	Variable: Bland or Proteinuria ± blood (if ICGN, AIN or TB)
Natural history	Gradual onset of: Pre DKD: Hyperfiltration (Increased GFR) Incipient DKD: Microalbuminuria and HPT Overt DKD: Proteinuria, nephrotic syndrome and GFR decreasing. ESKF	Presentation of kidney disease is varied depending on underlying cause.
Progression of disease	With poorly controlled HPT and DM eGFR can drop 10mL/min/year	HIVAN: without treatment can progress to ESKF in 3/12 Decline more rapid
Rapid decline in eGFR, what to consider?	AKI on CKD AIN (due to drug) PIGN or other GN	Untreated HIVAN ICGN – can decline rapidly if crescentic AIN due to drug Intercurrent opportunistic infections: eg TB or IRIS

Abbreviations: HPT, Hypertension; CKD, chronic kidney disease; DM, diabetes mellitus; T2DM, type 2 diabetes mellitus; BMI, body mass index, HIVAN, human immunodeficiency virus associated nephropathy; KF, kidney failure; IHD, ischaemic heart disease; CVA, cerebrovascular accident; PVD, peripheral vascular disease; GN, glomerulonephritis; ICGN, immune complex mediated GN; Hb, haemoglobin; eGFR, estimated glomerulofiltration rate; DKD, diabetic kidney disease; PIGN, post infectious glomerulonephritis, ESKF: end stage kidney failure, AIN: acute interstitial nephritis; AKI, acute kidney injury; TB, tuberculosis; IRIS, immune reconstitution syndrome.

Table 2 Similarities and Differences in the Investigation of CKD in HIV and DKD

	DM and CKD	HIV and CKD
Laboratory Investigations
Microscopy	Bland microscopy	Active urine on microscopy if ICGN
Urea	Urea – get symptomatic at a lower urea than normal population	Due to low muscle mass – Urea and creatinine may underestimate degree of KF. Cystatin C currently best measurement of eGFR.
Anaemia	Anaemia develops earlier in CKD	Anaemia likely multifactorial
Markers of MBD	MBD develops earlier in DKD	Tenofovir associated osteomalacia
UPCR	Absence of albuminuria does not exclude DKD Decreasing trend of albuminuria being associated with lower eGFR. Albuminuria may reflect a dynamic, fluctuating condition rather than a linear progression	Variable- depending on cause: Nephrotic range proteinuria (HIVAN) Nephrotic syndrome (Membranous GN/or other GN) Sub nephrotic + blood (ICGN)
Special Investigations
Ultrasound	Increased kidney size despite reduced eGFR	Increased kidney size despite reduced eGFR in HIVAN
Renal biopsy	Classification of DKD histological features: Mild non-specific light microscopy changes and EM showing thickened basement membrane Mesangial expansion: mild Mesangial expansion: severe Nodular sclerosis (Kimmelstiel-Wilson lesions) Advanced diabetic glomerulosclerosis	Multiple pathologies can be found: Glomerular dominant: podocytopathy: Overt Nephrotic syndrome: membranous GN, HIVAN IC mediated GN disease: example, PIGN Tubulointerstitial disease Vascular dominant Other: in setting of HIV: (HPT nephrosclerosis, DKD)
Indication for biopsy	Proteinuria with no retinopathy Onset of proteinuria rapid or onset of proteinuria <5 years in T1DM Macroscopic haematuria or active urine sediment Unexplained rapid decline in KF	Spectrum of kidney disease is broad - Low threshold for biopsy Significant proteinuria (increasing trend or nephrotic range) Haematuria or active urine sediment Unexplained decline in kidney function

Abbreviations: CKD, chronic kidney disease; DM, diabetes mellitus; MBD, mineral bone disease; HIVAN, human immunodeficiency virus associated nephropathy; KF, kidney failure; IHD, ischaemic heart disease; CVA, cerebrovascular accident; PVD, peripheral vascular disease; GN, glomerulonephritis; ICGN, immune complex mediated GN; Hb, haemoglobin; eGFR, estimated glomerulofiltration rate; DKD, diabetic kidney disease; EM, electron microscopy; PIGN, post infectious glomerulonephritis, ESKF: end stage kidney failure, AIN: acute interstitial nephritis; AKI, acute kidney injury; TB, tuberculosis; IRIS, immune reconstitution syndrome.

Table 3 Adjustment of Diabetes Treatment in Chronic Kidney Disease

	Dose Adjustment for CKD 3–5 (*eGFR <30 ml/Min/1.73m^2)
Metformin	Contraindicated
Insulin	Insulin uptake, metabolism and elimination is reduced. Less insulin is required – titrate to need: eGFR 60–15: 25% reduction^# eGFR <15: 50% reduction^#
Sulphonylureas
Gliclazide	eGFR < 30, use under specialist supervision
Glipizide	No dose adjustment based on eGFR [start conservatively (2,5 mg orally daily) and titrate up slowly in CKD]^#
Glimepiride	eGFR <30: reduce dose to 1 mg orally daily eGFR < 15: not recommended
Glibenclamide	Use not recommended
SGLT2 inhibitors
Canagliflozin	eGFR > 60: 100 mg daily, can titrate up to 300 mg orally daily eGFR 30–60: 100 mg orally daily eGFR < 30: Not recommended for initiation  ● May continue for reducing risk of decline eGFR, ESKD, CV death and admission for HF
Dapagliflozin	eGFR > 45: no dose adjustment eGFR 25–45: 10 mg orally daily^# eGFR < 25^#: Not recommended for initiation  ● May continue for reducing risk of decline eGFR, ESKD, CV death and admission for HF
Empagliflozin	eGFR > 30 no dose adjustment (A) CKD: eGFR > 20: 10 mg orally daily (may have a beneficial effect on CV health and reducing risk of decline eGFR) (B) For Glycaemic Control with No CVD or CVD Risk Factors eGFR < 30: Use not recommended (C) Heart Failure eGFR ≥ 20: No adjustment necessary eGFR < 20: Insufficient data to support a dosing recommendation in this population
Ertugliflozin	eGFR > 45: no dose adjustment eGFR < 45: use not recommended
Thiazolidinediones
Pioglitazone	No dose adjustment required
Alpha-glucosidase inhibitors
Acarbose	eGFR < 30: use not recommended
Miglitol	eGFR < 25: use not recommended

Table 4 Adjustment of Incretin Treatment in Chronic Kidney Disease

	Dose Adjustment for CKD 3–5 (*eGFR <30ml/min/1.73m^2)
GLP- 1 RA
Dulaglutide	No dose adjustment
Exenatide	CrCl 30–50: caution with initiating or increasing the dose CrCl < 30: use not recommended If using a once weekly preparation: eGFR < 45: use not recommended
Liraglutide	No dose adjustment
Lixisenatide	eGFR 30–60: no adjustment necessary eGFR 15–29: monitoring of kidney function and gastrointestinal side effects is recommended eGFR < 15: use not recommended
Semaglutide	No dose adjustment
DPP-4 inhibitors
Alogliptin	CrCl 30 −59: decrease to 12.5 mg orally daily CrCl < 30: decrease to 6.25 mg orally daily
Linagliptin	No dose adjustment required
Saxagliptin	eGFR < 45: decrease to 2.5 mg orally daily
Sitagliptin	eGFR 30–45: decrease to 50 mg orally daily eGFR < 30: decrease to 25 mg orally daily

Notes: *eGFR, estimated glomerular filtration rate in ml/min/1.73m².

Abbreviations: GLP-1 RA, glucagon-like peptide 1 receptor agonist; CrCl, creatinine clearance; DPP-4, dipeptidyl peptidase IV; mg, milligrams.

Table 5 Adjustment of Diabetes Treatment for Kidney Failure-Dialysis Requiring

Metformin	Contraindicated
Insulin	No specific dose adjustment is required.
Sulphonylureas
Gliclazide	Discontinue and replace with insulin
Glipizide	Discontinue and replace with insulin
Glimepiride	Discontinue and replace with insulin
Glibenclamide	Discontinue and replace with insulin
SGLT2 inhibitors
Canagliflozin	Contraindicated at present
Dapagliflozin	Contraindicated at present
Empagliflozin	Contraindicated at present
Ertugliflozin	Contraindicated at present
GLP- 1 RA
Dulaglutide	Use with caution in ESKD, monitor kidney function closely in patient with gastrointestinal side effects
Exenatide	Contraindicated at present
Liraglutide	Use with caution in ESKD, when initiating or escalating doses in patients with renal impairment
Lixisenatide	Contraindicated at present
Semaglutide	Use with caution, monitor for side effects CrCl<15 requiring dialysis: Contraindicated**
DPP-4 inhibitors
Alogliptin	6.25 mg orally daily; administer without regard to timing of haemodialysis
Linagliptin	No dose adjustment required
Saxagliptin	2,5 mg orally daily post dialysis
Sitagliptin	25 mg orally daily without regard to timing of dialysis
Thiazolidinediones
Pioglitazone	No dose adjustment required
Alpha-glucosidase inhibitors
Acarbose	Contraindicated at present
Miglitol	Contraindicated at present

Notes: **Advice from therapeutic index: South African Medical Formulary.

Abbreviations: SGLT2, sodium glucose co-transporter-2; GLP-1 RA, glucagon-like peptide 1 receptor agonist; DPP-4, dipeptidyl peptidase IV; CrCl, creatinine clearance; ESKD, end stage kidney disease; mg, milligrams.

Figure 2 Choice restricted conservative kidney management.

Abbreviations: CKD, chronic kidney disease; UTI, urinary tract infection; eGFR, estimated glomerular filtration rate; KRT, kidney replacement therapy; NGO, non-government organisation; NSAIDs, non-steroidal anti-inflammatory drugs.

Swanepoel CR, Atta MG, D’Agati VD, et al. Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: improving Global Outcomes (KDIGO) controversies conference. Kidney Int. 2018;93(3):545–559. doi:10.1016/j.kint.2017.11.007

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