Advances in chronic kidney disease pathophysiology and management
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Focus | Clinical
Advances in chronic kidney
disease pathophysiology
and management
Tim Usherwood, Vincent Lee CHRONIC KIDNEY DISEASE (CKD; Box 1) haematuria with dysmorphic red cells
is a major health concern in Australia, and casts. The urine is often normal in
with a prevalence of 9% among hypertensive kidney disease, and it may
Background
Chronic kidney disease (CKD) is a
non-Indigenous adult Australians and also be normal in other conditions such as
major health concern in Australia, with a 18% among Aboriginal and Torres Strait polycystic kidney disease and interstitial
prevalence of 9% among non-Indigenous Islander people.1 Risk factors for CKD nephritis.
adult Australians and 18% among are listed in Box 2, while Figure 1 shows Although typically asymptomatic
Aboriginal and Torres Strait Islander the classification of stages of CKD by in its earlier stages, CKD tends to
people. CKD is a risk factor for glomerular filtration rate (GFR) and urinary progress and may result in end-stage
cardiovascular disease, kidney failure
albumin.2 CKD is not itself a diagnosis, kidney disease. CKD is also a risk factor
and other complications.
and a full assessment includes the three for cardiovascular disease and, in its
Objective elements shown in Table 1. Attempts later stages, is associated with various
The aim of this article is to outline recent should always be made to ascertain the complications that affect the patient’s
advances in CKD pathophysiology and underlying pathology as this helps guide
management, focusing on strategies
treatment. Recommended diagnostic
for slowing disease progression and
investigations in CKD are listed in Box 3; Box 1. Definition of chronic kidney
preventing cardiovascular and other
complications. these may be varied according to clinical disease2
findings and comorbidities (Table 2).3 • An estimated or measured glomerular
Discussion
Most people with CKD do not undergo filtration rate (GFR)Advances in chronic kidney disease pathophysiology and management Focus | Clinical
wellbeing. Management therefore for CKD progression and should be aminoglycosides, calcineurin inhibitors,
focuses on delaying progression, reducing addressed. Physical activity is beneficial, gadolinium, radiographic contrast
cardiovascular risk and preventing or and alcohol consumption should not agents, nonsteroidal anti-inflammatory
ameliorating complications. Kidney Health exceed National Health and Medical drugs and cyclooxygenase-2 inhibitors.
Australia, and many guideline bodies Research Council guidelines. With rare Trimethoprim can raise serum creatinine
internationally, recommend an approach exceptions, patients with CKD should be by inhibiting tubular secretion – thus
to management based on stage of GFR and encouraged to maintain a normal protein reducing estimated GFR (eGFR), which
albumin excretion (Figure 1).2 intake of 0.75–1 g/kg/day. Limiting is calculated using serum creatinine – but
sodium intake to no more than 100 mmol has no effect on actual GFR.5 A second
(6 g salt) per day will benefit both blood common reason for acute kidney injury is
Slowing progression of chronic pressure and albumin excretion.2,3 Patients hypotension, however caused.
kidney disease should be advised to choose low salt foods Patients with CKD stages 3–5
Strategies to delay progression of CKD and not add salt at the table. Referral to a are at increased risk of acute kidney
include lifestyle advice, prevention of dietician may be beneficial. injury;6 if they are ill and unable to
acute kidney injury, control of blood Acute kidney injury is diagnosed maintain adequate fluid intake (eg due
pressure and albuminuria, and disease- by either a sudden increase in serum to gastroenteritis), patients should be
specific interventions. Obesity and creatinine or a significant reduction advised to temporarily cease medications
smoking are significant risk factors in urine output when compared with that may increase the risk of decline
normal. Inadvertent use of nephrotoxic in kidney function or cause adverse
medications is a common cause of effects as a result of reduced clearance.
Box 2. Risk factors for chronic kidney acute injury; medications that should be A useful mnemonic for these drugs is
disease in the Australian population2 avoided or prescribed in reduced dose SAD MANS (Sulfonylureas, Angiotensin
in patients with CKD include lithium, converting enzyme [ACE] inhibitors,
Potentially modifiable:
• Obesity
• Hypertension
• Diabetes Albuminuria stage
• Smoking Kidney GFR Normal Microalbuminuria Macroalbuminuria
function (mL/min/1.73m2) (urine ACR mg/mmol) (urine ACR mg/mmol) (urine ACR mg/mmol)
• Established cardiovascular disease
stage Male:Focus | Clinical Advances in chronic kidney disease pathophysiology and management
greater sensitivity than proteinuria
Table 2. Investigations that may be indicated for patients with chronic kidney disease
testing for detecting most clinically
Patient factors Suggested investigations significant abnormalities. Therefore, the
recommendation is to use albumin-to-
Has or is at risk of diabetes Fasting blood glucose, glycated haemoglobin
creatinine ratio (ACR) as a standardised
Has eGFR 40 years Serum and urine electrophoresis
disease, conferring an increased risk at
Has rash, arthritis or features Antinuclear antibodies, extractable nuclear every stage of CKD.11 Reduction in the
of connective tissue disease antibodies, anti-dsDNA, complement components amount of albuminuria is associated with
(C3, C4) improved outcomes.12 Strategies include
reducing sodium intake and blood pressure,
Has pulmonary symptoms or Antiglomerular basement membrane antibody,
especially through prescription of an ACE
deteriorating kidney function Antineutrophil cytoplasmic antibody
inhibitor or ARB. Addition of spironolactone
Has risk factors for HBV, HCV or HIV HBV, HCV, HIV serology can also reduce albumin excretion; serum
potassium should be carefully monitored.
Has persistent albumin-to-creatinine Consider renal biopsy – refer to nephrologist
Persisting significant albuminuria
ratio >60–120 mg/mmol and/or
haematuria (with no urologic cause) (eg urine ACR ≥30 mg/mmol) is an
indication for referral to a nephrologist.
eGFR, estimated glomerular filtration rate; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human A number of diseases affecting
immunodeficiency virus
the kidneys, such as immunological
conditions or polycystic disease, need
specific treatments that lie outside the
Diuretics, Metformin, Angiotensin The currently recommended target scope of this article. However, one recent
receptor blockers [ARBs], Non-steroidal blood pressure in patients with CKD is important discovery is the potential
anti-inflammatories, Sodium–glucose consistently less than 130/80 mmHg.2 renal and cardiovascular benefits of
co-transporter-2 [SGLT2] inhibitors). Aiming for a lower systolic blood SGLT2 inhibition in patients with type 2
Hypertension is extremely common pressure of below 120 mmHg may be diabetes. Although originally developed
among patients with CKD because of appropriate in certain individuals at high to reduce blood glucose through inhibition
several interacting mechanisms.7 Control cardiovascular risk, but the increased of glucose resorption in the proximal
of blood pressure in many cases slows risk of falls, syncope, electrolyte convoluted tubule, this class of medication
progression of GFR decline and also abnormalities and acute kidney injury has wide-ranging effects in the body,
reduces cardiovascular risk. A significant needs to be considered.7 including acting as a mild diuretic,
proportion of patients with CKD have A single agent will not achieve blood increasing sodium and water excretion
so-called ‘masked hypertension’ with pressure control in many patients. Add-on and reducing blood pressure.13 Their
normal blood pressure in the clinic options should be considered in light of use in patients with CKD and diabetes
but elevation on ambulatory or home comorbidities and may include a thiazide is associated with fewer cardiovascular
monitoring, so such measurement should or thiazide-like diuretic, or a calcium events, reduced mortality and slowing
be considered. Lifestyle interventions to channel blocker. Difficulty achieving of decline in GFR; consequently,
reduce blood pressure should be discussed control may be due to poor medication SGLT2 inhibitors are now considered
with all patients with CKD. Reduction in adherence,9 high sodium intake or second-line agents in type 2 diabetes,
sodium intake is particularly important, obstructive sleep apnoea. If blood pressure after metformin.14
along with weight loss and a low-fat is not consistently below target with at
diet rich in fruit and vegetables (eg the least three anti-hypertensive agents,
Dietary Approaches to Stop Hypertension then referral to a nephrologist may be Reducing cardiovascular risk
[DASH] diet).8 beneficial. Further guidance on blood Cardiovascular disease is the most
Most patients with CKD and pressure control in CKD is available in frequent cause of death in people with
hypertension have elevated levels of the Kidney Health Australia handbook early stages of CKD, for whom the absolute
angiotensin II, which increases systemic Chronic kidney disease (CKD) management risk of cardiovascular events is similar
vascular resistance and hence blood in primary care.2 to that of people who have established
pressure through direct vasoconstriction. Although various proteins may be coronary artery disease. Reduced GFR
First-line medication for hypertension present in excess in the urine of patients and elevated urinary albumin are both
in CKD is therefore an ACE inhibitor or with CKD, testing for albuminuria has independent risk factors for cardiovascular
ARB. These should not be combined. better analytical precision and exhibits disease.11 Interventions to reduce this
190 Reprinted from AJGP Vol. 50, No. 4, April 2021 © The Royal Australian College of General Practitioners 2021Advances in chronic kidney disease pathophysiology and management Focus | Clinical
elevated risk include lifestyle change and the liver; these effects are mediated by in part by reducing renal conversion of
and blood pressure control, as discussed hepcidin, a protein produced by the liver calcitriol.22 Fasting levels of phosphate,
previously in this article. that is often elevated in patients with CKD. calcium and parathyroid hormone should
Statins also play an important Other contributors to anaemia in CKD may be monitored in all patients with CKD
part in cardiovascular risk reduction. include poor diet, blood loss and reduced stage 3 or higher, and vitamin D deficiency
Dyslipidemia is common in patients with erythrocyte survival. corrected. Management of mineral and
CKD and typically includes increased Anaemia should always be bone disorder is complex and should
triglyceride levels in conjunction investigated and not attributed to CKD be undertaken in consultation with a
with decreased levels of high-density without exclusion of other causes. nephrologist.2,23
lipoprotein. Cholesterol may not be Vitamin B12 and/or folate deficiency Other complications emerge as CKD
elevated, except in patients with marked may contribute, as may hypothyroidism progresses, especially once GFR falls below
proteinuria (nephrotic syndrome).15 or hyperparathyroidism. Iron studies may 30 mL/min/1.73m2. Although such patients
These abnormalities likely contribute to be misleading as CKD is an inflammatory should normally be cared for in partnership
the increased risk and may be partially state and therefore serum ferritin may with a nephrologist, general practitioners
reversed by a statin. A 2014 Cochrane be elevated as an acute phase reactant. continue to have a key role in supporting the
review found that statins consistently Iron deficiency can only be excluded if patient and their family; providing advice
lower the risk of death and major ferritin is >100 μg/L and the transferrin and information; encouraging healthy
cardiovascular events by approximately saturation is >20%.19 Patients with CKD diet, exercise and other behaviours;
20% in people with CKD who are not and anaemia should be prescribed iron, coordinating management; offering
receiving dialysis. The effects on stroke orally or parenterally, to maintain these preventive care; and screening for and
and kidney function were uncertain. The levels. If their haemoglobin remains below addressing comorbidities.2
review concluded that statins have an 100 g/L, they should also receive an
important role in primary prevention of erythropoietin analogue. Gastrointestinal
cardiovascular events and mortality in bleeding should always be considered a Key points
people who have CKD.16 National and possible cause of iron deficiency anaemia • CKD is not a diagnosis; attempts
international guidelines recommend and the patient referred for endoscopy. should always be made to ascertain the
statin or statin/ezetimibe combination Mineral and bone disorder in CKD underlying pathology as this helps guide
for all patients living with CKD and aged is characterised by altered calcium, treatment.
≥50 years, and for younger patients phosphate, parathyroid hormone and • Strategies to delay progression of CKD
who have additional risk factors for vitamin D homeostasis. The consequences include lifestyle advice, prevention of
cardiovascular disease.2,17 include diminished bone strength and acute kidney injury, control of blood
mineralisation (renal osteodystrophy), pressure and albuminuria, and disease-
soft tissue and vascular calcification, and specific interventions.
Other complications of chronic accelerated progression of cardiovascular • Inadvertent use of nephrotoxic
kidney disease disease.20,21 The changes of mineral and medications is a common cause of acute
Although CKD can be caused by a bone disorder typically start to occur once kidney injury.
variety of underlying pathologies, as it GFR falls below 60 mL/min/1.73m2. • Strategies to reduce cardiovascular risk
progresses, a consistent pathophysiological Metabolic acidosis may develop later and in CKD include healthy lifestyle, blood
syndrome emerges. This is characterised further exacerbate calcium loss from bone. pressure control and statins.
by hypertension, cardiovascular disease, Elevated serum phosphate, mainly due • Patients with renal anaemia, mineral
anaemia, mineral and bone disorder, to reduced urinary excretion, occurs early in and bone disorder, or advanced
volume overload and metabolic acidosis.18 the evolution of mineral and bone disorder. disease should normally be cared for
Hypertension and increased The kidney is responsible for converting in partnership with a nephrologist.
cardiovascular risk are discussed calcidiol (25-hydroxycalciferol) to calcitriol
previously in this article. Anaemia becomes (1,25-dihydroxycalciferol), the most potent
Authors
increasingly common at lower levels of form of vitamin D. Lower levels of calcitriol
Tim Usherwood BSc, MBBS, MD, FRCP, FRCGP,
GFR. Interstitial cells in the renal cortex impair vitamin D–dependent calcium FRACGP, Professor of General Practice, The
are the main source of erythropoietin in absorption from the gastrointestinal tract. University of Sydney, NSW
Vincent Lee MBBS, FRACP, PhD, Associate Professor,
adults; patients with CKD have a relative Elevated phosphate and lower calcium
Westmead Applied Research Centre, University of
deficiency in erythropoietin production.19 stimulate parathyroid hormone production Sydney, NSW
Erythropoiesis depends on adequate iron (secondary hyperparathyroidism), and Competing interests: None.
stores, and iron deficiency is common elevated parathyroid hormone increases Funding: None.
in CKD. An important cause is reduced bone turnover.20,21 Fibroblast growth Provenance and peer review: Commissioned,
externally peer reviewed.
iron absorption from the gut and reduced factor 23, a protein secreted by osteocytes, Correspondence to:
release of iron from storage in macrophages appears to play a key part in these processes, tim.usherwood@sydney.edu.au
© The Royal Australian College of General Practitioners 2021 Reprinted from AJGP Vol. 50, No. 4, April 2021 191Focus | Clinical Advances in chronic kidney disease pathophysiology and management
References 17. Wanner C, Tonelli M. KDIGO clinical practice
1. Australian Institute of Health and Welfare. Profiles guideline for lipid management in CKD:
of Aboriginal and Torres Strait Islander people Summary of recommendation statements and
with kidney disease. Cat. no. IHW 229. Canberra, clinical approach to the patient. Kidney Int
ACT: AIHW, 2020. 2014;85(6):1303–09. doi: 10.1038/ki.2014.31.
2. Kidney Health Australia. Chronic kidney disease 18. Bello AK, Alrukhaimi M, Ashuntantang GE,
(CKD) management in primary care. 4th edn. et al. Complications of chronic kidney disease:
Melbourne, Vic: Kidney Health Australia, 2020. Current state, knowledge gaps, and strategy for
action. Kidney Int Suppl (2011) 2017;7(2):122–29.
3. Johnson DW, Atai E, Chan M, et al. KHA-CARI
doi: 10.1016/j.kisu.2017.07.007.
guideline: Early chronic kidney disease: Detection,
primary prevention and management. Nephrology 19. Fishbane S, Spinowitz B. Update on anemia in
(Carlton) 2013;18(5):340–50. doi: 10.1111/ ESRD and earlier stages of CKD: Core curriculum
nep.12052. 2018. Am J Kidney Dis 2018;71(3):423–35.
doi: 10.1053/j.ajkd.2017.09.026.
4. ANZDATA Registry. ANZDATA 42nd annual report
2019 (data to 2018). Adelaide, SA: Australia and 20. Moorthi RN, Moe SM. CKD-mineral and
New Zealand Dialysis and Transplant Registry, bone disorder: Core curriculum 2011. Am J
2020. Available at www.anzdata.org.au/report/ Kidney Dis 2011;58(6):1022–36. doi: 10.1053/j.
anzdata-42nd-annual-report-2019 [Accessed ajkd.2011.08.009.
5 February 2021]. 21. Roberts DM, Singer RF. Management of renal
5. Delanaye P, Mariat C, Cavalier E, Maillard N, bone disease. Aust Prescr 2010;33:34–37.
Krzesinski JM, White CA. Trimethoprim, creatinine doi: 10.18773/austprescr.2010.016.
and creatinine-based equations. Nephron Clin 22. Waziri B, Duarte R, Naicker S. Chronic Kidney
Pract 2011;119(3):c187–c94; discussion c193–4. Disease-Mineral and Bone Disorder (CKD-MBD):
doi: 10.1159/000328911. Current perspectives. Int J Nephrol Renovasc Dis
6. James MT, Grams ME, Woodward M, et al. 2019;12:263–76. doi: 10.2147/IJNRD.S191156.
A meta-analysis of the association of estimated 23. Kidney Disease: Improving Global Outcomes
GFR, albuminuria, diabetes mellitus, and (KDIGO) CKD-MBD Update Work Group. KDIGO
hypertension with acute kidney injury. Am J 2017 clinical practice guideline update for the
Kidney Dis 2015;66(4):602–12. doi: 10.1053/j. diagnosis, evaluation, prevention, and treatment
ajkd.2015.02.338. of Chronic Kidney Disease-Mineral and Bone
7. Ku E, Lee BJ, Wei J, Weir MR. Hypertension in Disorder (CKD-MBD). Kidney Int Suppl (2011)
CKD: Core curriculum 2019. Am J Kidney Dis 2017;7:1–59. doi: 10.1016/j.kisu.2017.04.001.
2019;74(1):120–31. doi: 10.1053/j.ajkd.2018.12.044.
8. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects
on blood pressure of reduced dietary sodium
and the dietary approaches to stop hypertension
(DASH) diet. N Engl J Med 2001;344(1):3–10.
doi: 10.1056/NEJM200101043440101.
9. Usherwood T. Encouraging adherence to long-
term medication. Aust Prescr 2017;40(4):147–50.
doi: 10.18773/austprescr.2017.050.
10. Johnson DW, Jones GR, Mathew TH, et al. Chronic
kidney disease and measurement of albuminuria
or proteinuria: A position statement. Med J Aust
2012;197(4):224–25. doi: 10.5694/mja11.11468.
11. Currie CJ, Berni ER, Berni TR, et al. Major adverse
cardiovascular events in people with chronic
kidney disease in relation to disease severity and
diabetes status. PLoS ONE 2019;14(8):e0221044.
doi: 10.1371/journal.pone.0221044.
12. Bakris GL. Slowing nephropathy progression:
Focus on proteinuria reduction. Clin J Am Soc
Nephrol 2008;3 Suppl 1:S3–10. doi: 10.2215/
CJN.03250807.
13. Wilcox CS. Antihypertensive and renal
mechanisms of SGLT2 (sodium-glucose
linked transporter 2) inhibitors. Hypertension
2020;75(4):894–901. doi: 10.1161/
HYPERTENSIONAHA.119.11684.
14. The Royal Australian College of General
Practitioners. Management of type 2 diabetes:
A handbook for general practice. East Melbourne,
Vic: RACGP, 2020.
15. Keane WF, Tomassini JE, Neff DR. Lipid
abnormalities in patients with chronic kidney
disease: Implications for the pathophysiology
of atherosclerosis. J Atheroscler Thromb
2013;20(2):123–33. doi: 10.5551/jat.12849.
16. Palmer SC, Navaneethan SD, Craig JC, et al. HMG
CoA reductase inhibitors (statins) for people with
chronic kidney disease not requiring dialysis.
Cochrane Database Syst Rev 2014;(5):CD007784.
doi: 10.1002/14651858.CD007784.pub2. correspondence ajgp@racgp.org.au
192 Reprinted from AJGP Vol. 50, No. 4, April 2021 © The Royal Australian College of General Practitioners 2021You can also read
