CKD Flashcards
Staging CKD + CrCl + ACR/PCR
CKD definition: Renal failure on >2 occasions in >3month period.
eGFR <60 + proteinuria (evidence of renal damage)
CKD stages:
I: GFR >or=90
II: 60–89
III: 30–59; IIIa: 45–59; IIIb: 30–44
IV: 15–29
V: <15
Measured GFR
Estimated GFR
Creatinine clearance ( CrCl ) is an estimate/surrogate of GFR; however, CrCl slightly overestimates true GFR because creatinine is secreted by the proximal tubule (in addition to being filtered by the glomerulus). The additional proximal tubule secretion falsely elevates the CrCl estimate of GFR
Cockcroft Gault
- Not recommended for assisting with drug dosing. Can over-estimate, as it hasn’t been expressed using standardised creatinine values
- Males CrCl = (140-age) x Weight (kg) / 0.814 x plasma creatinine (umol/L)
- Females CrCl = 0.85 x (140-age) x Weight (kg) / 0.814 x plasma creatinine (umol/L)
- GFR falls 0.5 per year over 30yo
MDRD (modification of diet in renal disease)
- not for AKI, only CKD
- may underestimate GFR by 29% in healthy ppl
- eGFR = 175 x serum creat^(-1.154) x age^(-203) x 0.742(if female) x 1.212(if black)
CKD-epi
- estimates GFR in CKD, not AKI. More accurate in ppl with normal or mildly reduced eGFR
- CKD-epi cystatin C equation (preferred in cirrhotics or ppl with low muscle mass)
- CKD-epi creatinine equation (used when cystatin C isn’t available)
- eGFR = 141 x min(SCr/κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993^(Age) x 1.018 [if female] x 1.159 [if Black]
IBW males = 50 + (2.3 x height [inches] - 60)
IBW females = 45.5 + (2.3 x height [inches] - 60)
Adjusted body weight (ABW) = IBW (kg) + 0.4 x (actual body weight - IBW)
Adjustments:
- if BMI <18.5, calculate using actual BW
- if BMI 18.5 - 24.9, use IBW
- if BMI >or=25 use adjusted body weight
ACR: urine albumin / urine creatinine
- normal total urine albumin is <30mg/day or <3.0mg/mmol (3-30mg/mmol moderately increased; >30mg/mmol severely increased)
PCR: urine protien (alb/light chains/globulins) / urine creatinine
- normal total urine protein is <150mg/day or <15mg/mmol (paediatric normal is <20mg/mmol; pregnant women N is <30mg/mmol)
- high PCR in relation to ACR is indicative of myeloma (indicates BJP in urine)
CKD management
CARI guidelines for CKD, dialysis, transplant: http://www.cari.org.au/CKD/ckd_guidelines.html
CKD and mortality
- *Mortality and CKD**
https: //www.ajkd.org/article/S0272-6386(10)01253-9/fulltext (CRIB study 2010) - Lab measures of renal f^n, cardiac f^n, age, sex, smoking hx, help to predict patient with CKD who are at highest risk of progressing to ESRD and death (all cause mortality).
- study had limited power. Cohort study
eGFR, albuminuria, mortality, ESRD
https: //www.ncbi.nlm.nih.gov/pmc/articles/PMC3917543/
- meta-analysis 21, 688ppl with CKD showed a lower eGFR (decrease by 15, from 45) and severe albuminuria was associated with significantly higher mortality and ESRD.
HTN - cause/pathophys
Caused by disturbance in RAAS
- leads to increased uptake of Na+ and H2O –> volume expansion/fluid overload
- activation of sympathetic nervous system –> vasoconstriction
- loss of nocturnal “dip” in blood pressure
Diagnosis
- ambulatory BP monitoring is required to detect masked hypertension and “non-dipping” (absense of naturally occuring BP decline during sleep)
Hypertension in CKD & T2DM pharmacotherapy
BP reduction is most potent CVD risk reducer. BP control is crucial for slowing progression of CKD.
Principles of HTN mx in CKD
- target BP < or= 140/80 (without albuminuria)
- target BP < or =130/80 (with albuminuria)
- sBP <120mHg has shown no consisten benefit, even if well tolerated, but can be considered in pts whom stroke prevention is a priority.
- nocte antihypertensive improves BP control with CKD
- elderly: start low go slow. if >75yo, no benefit in sBP<120mmHg unless has T2DM
Pharmacotherapy
- To achieve BP targets, an ACEI or ARB can be combined with a thiazide diuretic or loop diuretic, and, if necessary, a CCB or a β-blocker can be added.
- RAAS blockade with ACE-I reduces proteinuria and CKD progression; OR ARB (“sartan”) also renoprotective and cardioprotective. Uptitrate to maximal tolerated dose (dual RAAS blockade is not recommended)
- Diuretics: thiazide diuretics for mild/mod reduced GFR (but still >40); loop diuretic for more severely reduced GFR (<40)
- Ca-chann blocker: Dihydropyridines (amlodipine, nifedipine) increase proteinuria when used alone, but not when in combination w ACE-I/ARB
- Salt restricted diet to 2g/day; low K+ diet in CKD 4.
- Holistic pharmacotherpy to reduce CVD risk: commence statin, advise smoking cessation, aerobic activity 30mins 5days per wk, limit EtOH (1per day F; 2 per day M)
Treatment resistent HTN
- Pathogenesis of HTN in CKD is multifactorial - sodium retention, increased activity of the RAAS, and enhanced activity of the sympathetic nervous system. Hyperladosteronism is an important fx in Rx resistant HTN.
If BP still >140mmHg with 3-4 classes (ACE/ARB, diuretic, CCB) of meds by 4-6months, should evaluate for:
- medication and salt restriction adherence
- ceasing meds that may aggrevate HTN (ciclosporin, tac, cocaine, amphetamines, tobacco, COX2-I, EPO, steroids, MAO-I, OCP, SSRI)
- OSA, hypo/hyperthyroidism, pheochromocytoma, PCOS, primary aldosteronism, cushing’s syndrome
Then commence 4th/5th line agents:
- SARA (selective aldosterone receptor antagonist) inc spironolactone 25mg daily, epelonone can be used as add on therapy to ACE-I/ARB; but be wary of SARA induced hyperK+, so not recommended when CrCl <30 (or even <45) or K >5. PATHWAY2 trial states it’s preferred over b1 blocker or a1 blocker
- beta blockers: Inferior to spironolactone as 4th line. used in pts with previous MI. Use carvedilol, nebivolol, labetolol are vasodilating b-blocker, but reduces insulin sensitivity so should be avoided in pts with T2DM. Longer-acting b-blocker (e.g. metoprolol) can be used if phx MI or poor glycemic control. Improves survival in heart failure.
- alpha1 receptor blocker: prazosin, doxazosin. Caution in elderly as can cause postural HTN.
- centrally acting sympatholytic / alpha 2 blocker: clonidine, methyldopa, moxonidine (activate a2 receptors in brainstem/hypothalamus –> reduce peripheral sympathetic tone). Moxonidine newer and less SE’s than clonidine/methyldopa. Can be used in resistant HTN. Unwanted SE’s inc sedation, dry mouth, impotence
- peripheral vasodilator: hydralazine or minoxidil. Contra-indicated in pts with IHD. SE’s fluid retention, tachycardia. Significant SE’s are common. Often need co-administration of diuretic or b-blocker to compound SE’s
- direct renin inhibitors (aliskiren) as add-on to ACE/ARB. Prevents formation of angiotensin 1 and 2.
- long acting nitrates for isolated systolic HTN needs more studies
- Endothelin receptor antagonists (avosentan. For resistant HTN)
- Percutaneous transluminal sympathetic denervation of renal artery (done under local a) for Rx resistant HTN
Resistant hypertension approach 2015. Stepwise. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4408700/
- 4th line spiro if eGFR/K+ permits; 5th line b blocker (if cardiac Hx/MI) or a1 blocker (prazosin)
Resistent HTN 2017. https://link-springer-com.journals.library.austin.org.au/content/pdf/10.1007/s11906-017-0728-z.pdf
- mentions all drugs, but doesn’t clearly state 4th/5th line
SPRINT trial (Systolic BP intervention trial)
- 9361 ppl >50yo, high CVD risk, sBP >130. Excluded pts with T2DM
- patients treated to target sBP <120mmHg had fewer CVD events (MI, ACS, CVA, HF, death) than patients with target sBP <140
ONTARGET study. 2008. Lancet - Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(08)61236-2/fulltext
- In people at high vascular risk, telmisartan’s (ARB) effects on major renal outcomes are similar to ramipril (ACE-I) monotherapy. Combination therapy reduces proteinuria to a greater extent than monotherapy, but it worsens major renal outcomes.
- ARB’s and ACE-I are known to reduce proteinuria. ?combination more effective than either treatment alone. Study looked at the renal effects of ramipril vs telmisartan vs combination in pts >or=55yo with established atherosclerotic vascular disease or with diabetes with end-organ damage.
- 25 620 participants randomly assigned ramipril 10 mg daily, telmisartan 80 mg day, or combination of both (median follow-up 56 months), and renal function and proteinuria were measured. The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death.
(Combined Angiotensin Inhibition for the Treatment of Diabetic Nephropathy. NEJM 2013) https://www.nejm.org/doi/full/10.1056/nejmoa1303154
- CONCLUS: combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy.
- Combination therapy with ACE-I and ARB decreases proteinuria; however, its safety and effect on progression of CKD is uncertain.
- Patients with T2DM, urine ACR >or= 300, eGFR 30-89.9, and on losartan 100 mg daily, were randomly assigned to lisinopril 10-40 mg daily vs placebo.
- 1’ end point was first occurrence of a change in eGFR (decline ≥30 if the initial eGFR was ≥60; or a decline of ≥50% if the initial eGFR was <60), end-stage renal disease, or death.
- 2’ end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury.
ACCOMPLISH trial 2008 NEJM.
- ACE-I and Ca-chann blocker is superior to ACE-I and HCT diuretic in reducing CVD outcomes in pts with HTN.
ACCORD study
- some CVD benefit in targeting sBP <120 compared with sBP <140mmHg in pts with HTN and T2DM
Sources: https://spectrum.diabetesjournals.org/content/21/1/30 (2008, Mx HTN in T2DM, CKD)
https: //www.heartfoundation.org.au/images/uploads/publications/PRO-167_Hypertension-guideline-2016_WEB.pdf (HTN guidelines 2016)
https: //www.nature.com/articles/hr2012157 (antiHTN drugs in CKD)
https: //www.hindawi.com/journals/ijhy/2013/929183/ (resistant HTN 2013)
Resistant HTN image
resistant HTN image 2
https://www.ahajournals.org/doi/10.1161/HYP.0000000000000084#
Resistant Hypertension: Detection, Evaluation, and Management. 2018. From AHA.
Diabetic kidney disease
Diabetic kindey disease:
- Defined as the presence of albuminuria and/or decreased eGFR in patient with diabetes —— moderately increased albuminuria (prev called microalbuminuria) is 30-300mg/day; severely increased albuminuria is >300mg/day
- natural history: It was thought that moderately increased albuminuria was the earliest detectable clinical biomarker of classical diabetic glomerulopathy, which would then progress to severely increased albuminuria, followed by a decline in eGFR; and that patients w T1DM usu have normal or elevated GFR (hyperfiltration) in the setting of hyperglycemia initially. However, recent studies have shown that eGFR may progress before the onset of albuminuria in patients w T1DM. So now, “rapid eGFR decline” is considered to have greater prognostic importance, given it has been found to occur before or in parallel with onset of albuminuria. [https://www.ncbi.nlm.nih.gov/pubmed?term=23939543]
- kidney biopsy is gold standard to distinguish type of DKD, but this is often not warranted
- prognosis is worse with severe albuminuria due to risk of ESRD / CVD events
- becoming more common cause of DKD due to increased # of ppl with diabetes worldwide
Diabetic nephropathy (subtype of DKD)
- Pathophys: glomerular BM thickening, endothelial damage, mesangial expansion, podocyte loss
- mostly likely cause of diabetic kidney disease in type 1 diabetics with >5years of albuminuria
- not necessarily the cause of diabetic kidney disease in all type 2 diabetics
Tubulointerstitial disease (subtype of DKD)
Diabetic kidney disease - trial graph image
(see image attached)
Renal artery stenosis and stenting vs medical therapy
CORAL trial. Renal artery stenosis and stenting vs medical therapy. NEJM 2014. https://www.nejm.org/doi/full/10.1056/NEJMoa1310753
- the usefulness of stenting in atherosclerotic renal-artery stenosis for the prevention of major adverse renal and cardiovascular events is uncertain
- 947 participants who had atherosclerotic renal-artery stenosis, and either systolic HTN (taking two or more antihypertensive drugs) or CKD. They were randomised to medical therapy plus renal-artery stenting vs medical therapy alone.
- outcomes: adverse cardiovascular and renal events (a composite end point of death from cardiovascular or renal causes, MI, stroke, hospitalization for CCF, progressive renal insufficiency, or the need for RRT).
- Renal-artery stenting did not confer a significant benefit in preventing clinical events when added to comprehensive, multifactorial medical therapy, in patients with atherosclerotic renal-artery stenosis and HTN or CKD.
CKD and SGLT2 inhibitors
SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes. Lancet 2019. https://www.thelancet.com/journals/landia/article/PIIS2213-8587(19)30256-6/fulltext
- SGLT2 inhibitors reduced the risk of dialysis, transplantation, or death due to kidney disease in individuals with type 2 diabetes and provided protection against AKI. These data provide substantive evidence supporting the use of SGLT2 inhibitors to prevent major kidney outcomes in people with T2DM.
- effects of SGLT2 inhibitors on kidney failure, particularly the need for dialysis or transplantation or death due to kidney disease, is uncertain
- systematic review and meta-analysis of randomised, controlled, cardiovascular or kidney outcome trials of SGLT2 inhibitors that reported effects on major kidney outcomes in people with type 2 diabetes.
Also good source to read: SGLT2 inhibitors in T2DM and CKD. Current evidence. https://www.tandfonline.com/doi/full/10.1080/00325481.2019.1601404?scroll=top&needAccess=true
CKD and SGLT2 inhibitors (2)
Empagliflozin and Kidney Function Decline in Patients with Type 2 Diabetes: A Slope Analysis from the EMPA-REG OUTCOME Trial. JASN 2018. https://jasn.asnjournals.org/content/jnephrol/29/11/2755.full.pdf
- Empagliflozin slowed the progression of CKD in patients with T2DM and cardiovascular disease in the EMPA-REG OUTCOME Trial. In a prespecified statistical approach, we assessed treatment differences in kidney function by analyzing slopes of eGFR changes.
- The hemodynamic effects of empagliflozin, associated with reduction in intraglomerular pressure, may contribute to long-term preservation of kidney function
CKD and SGLT2 inhibitors (3)
(refer to image - SGLT2 inhibitors greatest effect on reducing albuminuria in patients with macroalbuminuria)
SGLT2 inh. & euglycemic DKA
Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. NEJM 2019. https://www.nejm.org/doi/full/10.1056/NEJMoa1811744
- CONCL: patients with T2DM and CKD, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years. Relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group
- Rates of diabetic ketoacidosis were low but higher in the canagliflozin group than in the placebo group (2.2 vs. 0.2 per 1000 patient-years). The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee.
- RCT. Assigned patients with T2DM and albuminuric CKD to receive canagliflozin (SGLT2 inhibitor) 100 mg daily vs placebo.
- primary outcome was a composite of ESKD (dialysis, transplantation, or a sustained eGFR of <15 ml), a doubling of the serum creatinine, or death from renal or cardiovascular causes.
SGLT2 inhibitors and renoprotection
Renal Hemodynamic Effect of Sodium-Glucose Cotransporter 2 Inhibition in Patients With Type 1 Diabetes Mellitus. https://www.ahajournals.org/doi/full/10.1161/circulationaha.113.005081
- determine the effect of 8 weeks of empagliflozin 25 mg QD on renal hyperfiltration in subjects with type 1 diabetes mellitus
- After 8 weeks of treatment, empagliflozin significantly lowered GFR by 33, in patients with T1DM and hyperfiltraton, under euglycemic conditions (baseline: 172±23, 8 weeks: 139±25; P<0.01)
- CONCL: short-term treatment with SGLT2 inh empagliflozin attenuated renal hyperfiltration in subjects with T1D, to near normal levels, likely by affecting tubular-glomerular feedback mechanisms.
- In humans, the prevalence of renal hyperfiltration in subjects with type 1 diabetes mellitus (T1D) has been reported to be as high as 60%, and this condition is accompanied by a significantly increased risk for development of diabetic nephropathy in many studies. The pathogenesis of hyperfiltration involves changes in both neurohormonal/vascular factors (the vascular hypothesis) as well as tubuloglomerular feedback mechanisms (TGF; the tubular hypothesis
- The tubular hypothesis is based on an increase in proximal tubular glucose delivery attributable to chronic hyperglycemia in diabetes. This leads to a maladaptive increase in glucose reabsorption along with sodium via the sodium-glucose cotransporter 2 (SGLT2) in the proximal tubule. As a result, distal sodium chloride delivery to the macular densa is decreased. This distal tubular condition is sensed as a low effective circulating volume stimulus at the level of the juxtaglomerular apparatus, causing an afferent renal vasodilatory response. The consequence of this altered TGF results in supranormal glomerular filtration rate (GFR) values and hyperfiltration range.
CKD and statin therapy
SHARP trial - Effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (SHARP trial). Lancet. 2011. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2811%2960739-3/fulltext
- Reduction of LDL cholesterol with simvastatin 20 mg + ezetimibe 10 mg daily safely reduced the incidence of major atherosclerotic events in a wide range of patients with advanced CKD.
- effects of lowering LDLs in ppl with moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the efficacy and safety of the combination of simvastatin plus ezetimibe on reducing the risk of MI, ischaemic stroke, and the need for coronary revascularisation
- RCT. 9270 patients with CKD (3023 on dialysis and 6247 not) with no known phx MI or coronary revascularisation. Randomly assigned to simvastatin 20 mg + ezetimibe 10 mg daily vs matching placebo.
- outcome: first major atherosclerotic event (non-fatal MI or coronary death, non-haemorrhagic stroke, or any arterial revascularisation procedure).
