Mednotes

L15 Renal Chronic Kidney Disease

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tagsrenal, lecture
aliasesL15 Renal Chronic Kidney Disease

40 min read

Overview

Chronic kidney disease is defined by structural or functional kidney abnormality lasting at least 3 months, and is staged by the CGA/KDIGO system on eGFR and albuminuria. The lecture runs in two parts. Part 1 covers who gets CKD (12% prevalence locally, with a large Māori and Pacific excess), why it progresses (a final common pathway of glomerulosclerosis and proteinuria driven by haemodynamic and metabolic factors rather than the original disease), and how to slow it: blood pressure control, proteinuria reduction with RAS blockade, SGLT2 inhibitors, and increasingly combination “pillar” therapy, all alongside cardiovascular risk reduction because most people with CKD die of cardiovascular disease rather than reaching dialysis. Part 2 covers the extra-renal manifestations of failing kidneys (anaemia, CKD-MBD and vascular calcification, acidosis, altered drug handling) and the treatment options for kidney failure: conservative care, dialysis and transplantation, with New Zealand registry data showing who receives what.

Case anchors

Case 22, diabetic nephropathy, is the clinical spine of Part 1.

  • 54-year-old woman, type 2 diabetes diagnosed 8 years ago at a routine occupational health check; hypertensive 170/100 and random BSL 9.2 mmol/L at diagnosis.
  • Current: smokes 15/day, no regular exercise, claudication at 200 m, persistent ankle oedema, numbness of fingers and toes, 6-monthly eye checks with laser therapy.
  • Strong family history: father and 2 older siblings with diabetes; father died of MI aged 53.
  • Medications: quinapril 10 mg/day, simvastatin 20 mg/day, metformin 850 mg twice daily.
  • Examination: weight 87 kg, height 1.65 m, waist 98 cm, BP 154/96 (large cuff), cardiomegaly, ankle oedema to lower third of leg, reduced posterior tibial and dorsalis pedis pulses, stocking sensory loss to light touch, pin prick and vibration to the ankles.
  • Investigations: urinalysis 4+ protein, ACR 125 mg/mmol (normal <2.5), creatinine 160 µmol/L, eGFR 31 mL/min/1.73 m², so CKD grade 3b A3. Cholesterol 6.1, HDL 0.9, LDL 3.4 mmol/L, HbA1c 68 mmol/mol.
  • Using the NZSSD CVD and renal risk calculator (nzssd.org.nz/cvd_renal), she has a 30% chance of MACE or ESKD within 5 years. The calculator takes age, diabetes duration, sex, smoking, systolic BP, HbA1c, ethnicity, previous CVD, total cholesterol, HDL, urine ACR, serum creatinine and BP-lowering medication, and returns 5-year CVD, MI and ESRD risks. The exercise is to switch ethnicity to Māori or Pacific and see the risk change.
  • Learning questions posed: impact of diabetes on community and individual, cardiovascular risk, management to slow progression, the role of ACEI/ARB, SGLT2 inhibitors and GLP-1 receptor agonists for BP, proteinuria and cardiorenal protection, the role of glycaemic control, and what she is most likely to die from.

Kidney failure case (Part 2): 45-year-old man with chronic glomerulonephritis for 10 years, presenting with lethargy, anorexia, pruritus, impaired sensation, restless legs and a metallic taste; hypertension, LVH, red eyes, excoriations, bronze complexion. Investigations: Hb 81 g/L (MCV 85, MCH 92), creatinine 850 µmol/L, eGFR 7 mL/min/1.73 m², urea 44 mmol/L, Ca²⁺ 2.01 mmol/L (2.1 to 2.6), PO₄³⁻ 2.9 mmol/L (0.7 to 1.5), ALP 440, PTH 54 pmol/L (2 to 7). CXR shows cardiomegaly and vascular calcification.

Diabetic kidney disease sits within a wide constellation of diabetic complications: cognitive impairment, depression and anxiety, periodontal disease, eye disease, erectile dysfunction, neuropathy, bladder dysfunction, foot disease, peripheral vascular disease, diabetic cardiomyopathy, coronary heart disease and cerebrovascular disease.

Definition, staging and the clinical continuum

CKD is structural or functional abnormality of the kidneys for at least 3 months, manifested by either:

  1. Kidney damage, with or without decreased GFR, defined by pathological abnormalities; markers of kidney damage (urinary abnormalities such as proteinuria, blood abnormalities such as renal tubular syndromes, imaging abnormalities); or kidney transplantation.
  2. GFR <60 mL/min/1.73 m², with or without kidney damage.

CKD is a clinical continuum rather than discrete events. Plotting GFR against stage: stage 1 is kidney damage or mild GFR reduction with proteinuria and GFR >90; stage 2 GFR 60 to 90; stage 3 GFR 30 to 60; stage 4 GFR <30; stage 5 requires renal replacement therapy (dialysis or transplant). Serum creatinine stays low through stages 1 to 3 and only rises sharply in stages 4 to 5, so creatinine is an insensitive marker until GFR has already fallen substantially.

KDIGO 2012 CGA staging combines eGFR and albuminuria.

  • eGFR categories (mL/min/1.73 m²): G1 normal or high >90; G2 mildly decreased 60 to 89; G3a mildly to moderately decreased 45 to 59; G3b moderately to severely decreased 30 to 44; G4 severely decreased 15 to 29; G5 kidney failure <15.
  • Albuminuria categories by urine ACR (mg/mmol): A1 normal (male <2.5, female <3.5); A2 microalbuminuria (male 2.5 to 25, female 3.5 to 35); A3 macroalbuminuria (male >25, female >35).
  • Risk rises moving down the table (falling eGFR) and to the right (rising albuminuria). Only G1 and G2 with A1 are low risk; most G3b to G5 combinations and all A3 combinations are high or very high risk.

Monitoring frequency follows the same matrix (KDIGO, de Boer et al. 2022, using A1 <30 mg/g or <3 mg/mmol, A2 30 to 299 mg/g or 3 to 29 mg/mmol, A3 ≥300 mg/g or ≥30 mg/mmol): low risk once a year or less; moderately increased at least once a year; high risk at least twice a year; very high risk three to four times a year and treat in agreement with a nephrologist. Actions escalate from monitor, to treat, to treat and consult.

Epidemiology and risk factors

  • Prevalence of CKD in Otago Southland is 12%. Māori odds ratio for CKD 1.56; Pacific 2.62. Prevalence of CKD in Samoans in Auckland 33%, Māori 24% (AusDiab data).
  • Population funnel (Kidney Health Australia, Australia or NZ): about 1 in 3 healthy adults are at increased risk, 1 in 7 have CKD, and 1 in 1400 are on dialysis or transplanted.
  • Tafuna’i et al. (Nephrology 2022) examined two Auckland Pacific health providers. Prevalence of CKD among those tested varied widely by ethnicity: non-Māori non-Pacific 12.9%, NZ Māori 22.6%, Fijian 25.1%, Tongan 32.4%, Cook Island Māori 32.5%, Tokelauan 33.3%, Samoan 36.0%, Niuean 36.2%, other Pacific Island 38.4%. Testing rates were only about 40 to 53% across all groups.
  • Risk factors for CKD (roughly one third of adults are at increased risk): age, diabetes mellitus, hypertension, ethnicity, living in areas of socioeconomic deprivation, gender (female >male for CKD, male >female for ESKD), family history of CKD, obesity, and episodes of AKI.

Screening strategy: screen groups with well-accepted risk factors, namely hypertension, diabetes and/or cardiovascular disease, and Māori and Pacific people over 25 years. Screen with urinalysis (proteinuria and haematuria) and kidney function (eGFR). Diabetes and hypertension are bidirectionally linked (40 to 80% of diabetics have hypertension; diabetics are twice as likely to develop hypertension) and share end-organ targets: microvascular (>70% of ESRD in the US attributed to hypertension or diabetes, increased retinopathy), heart (3x CHD, 2x LVH, 3x CHF), peripheral vascular (2 to 4x with diabetes), and brain (2x stroke).

Why CKD progresses

  • Progression occurs at a variable and unpredictable rate.
  • It is largely driven by secondary haemodynamic and metabolic factors rather than the underlying disorder.
  • Glomerular sclerosis (secondary FSGS) with associated proteinuria is the final common pathway.

Histological and mechanistic sequence: nephron loss leads to compensatory glomerular hypertrophy; repeated exposure to higher intraglomerular pressures produces more injury; endothelial and podocyte injury occurs; proteinuria directly injures tubular epithelial cells causing fibrosis. The end result seen on biopsy is interstitial fibrosis, glomerulosclerosis and tubular atrophy, together with arteriolosclerosis. There is a strong association with hypertension.

Management across the disease trajectory

Care shifts from conventional to supportive as GFR falls through hyperfiltration, albuminuria, declining GFR, rising uraemia and loss of residual kidney function (Lancet 2021).

  • Diet and lifestyle: plant-dominant low-protein diet, low salt intake, physical activity, weight loss, smoking cessation. Reassess risk factors every 3 to 6 months.
  • Pharmacotherapy for disease progression: RAAS blockers, SGLT2 inhibitors, MR antagonists, disease-specific drugs.
  • Pharmacotherapy for cardiovascular risk: BP-lowering, glucose-lowering and lipid-lowering drugs, diuretics.
  • Pharmacotherapy for other comorbidities: acidosis management, potassium binders, anaemia management, bone health.
  • Infection control and AKI prevention, then incremental transition to dialysis, and renal replacement therapy (dialysis or transplantation).
  • Supportive care appears progressively: kidney-preserving care (slow progression, prevent or delay dialysis, improve cardiovascular risk), symptom management, and at the lowest GFR palliative care (stopping, reducing frequency of, or not starting dialysis). Preservation of residual renal function matters at the low-GFR end.

The modifiable levers asked about explicitly are hypertension, proteinuria and dietary modification, with cardiovascular risk modified at the same time.

Hypertension in CKD

  • Hypertension is present in 80 to 85% of patients with CKD, and prevalence rises from 65% to 95% as GFR falls from 85 to 15 mL/min.
  • Contributing factors: sodium retention, renin-angiotensin-aldosterone activation, sympathetic neural activity, altered nitric oxide and endothelin activity.
  • It is an independent predictor of renal disease and drives progression of existing renal disease.
  • BP control slows progression of kidney disease, reduces cardiovascular events, reduces mortality, and reduces proteinuria.
  • Multiple trials, meta-analyses and guidelines suggest a systolic BP <140 mmHg; SPRINT and STEP suggest lower. Patient age and similar factors are not well adjusted for.
  • Meta-analysis (Bakris et al. AJKD 2000): lower mean arterial pressure gives slower GFR decline in both diabetics and non-diabetics, r = 0.69, P <0.05. Untreated hypertension (MAP about 119) is associated with GFR decline of about -12 mL/min/year.
  • Target (level 1): sitting systolic BP in the 120s to 130s. The greater the proteinuria, the lower the target blood pressure.

Guideline comparison (Bakris et al. JACC 2019), ACC/AHA vs ESC/ESH thresholds defining hypertension: office/clinic ≥130/80 vs ≥140/90; daytime mean ≥130/80 vs ≥135/85; night-time mean ≥110/65 vs ≥120/70; 24-hour mean ≥125/75 vs ≥130/80; home mean ≥130/80 vs ≥135/85. Treatment targets: <130/80 (ACC/AHA) vs systolic <140 and close to 130 (ESC/ESH). Initial single-pill combination is advised when >20/10 mmHg above goal (ACC/AHA) or at ≥140/90 (ESC/ESH). Both agree on home BP monitoring (twice each morning and evening in the week before clinic, annual machine validation), restricting beta-blockers to patients with comorbidities, initial single-pill combination, and follow-up that detects poor adherence, with telemonitoring and digital health recommended.

Choice of agent:

  • ACEI and ARB are first choice. They reduce intraglomerular pressure directly, over and above their systemic BP effect, and reduce proteinuria. A fall in GFR of about 20% is indicative of effectiveness.
  • SGLT2 inhibitors are now indicated for CKD.
  • Diuretics have an important role in conjunction with ACEI/ARB; rapid intravascular volume depletion is a possible adverse effect.
  • Calcium channel blockers do not modify GFR and have variable impact on long-term kidney function, but they lower BP and are still important.
  • Beta-blockers reduce renin; use when there is evidence of diastolic dysfunction.

Evidence that ACEI/ARB reduce progression and kidney failure: in RENAAL (Brenner et al. NEJM 2001) ESRD reached about 35% on placebo vs about 26% on losartan over 48 months, a 28% risk reduction, P = 0.002. Meta-analysis odds ratios for kidney failure (Xie et al. AJKD 2016) all favour treatment: ACEI vs placebo 0.61 and 0.55; ARB vs placebo 0.70 and 0.82; ACEI vs active control 0.65 and 0.71; ARB vs active control 0.75 and 0.67.

SPRINT (NEJM 2015;373:2103): randomised open-label multicentre trial, age ≥50, systolic 130 to 180 mmHg, ASCVD risk >10%, no diabetes, no stroke. Intensive target systolic <120 (n = 4678) vs standard <140 (n = 4683). First occurrence of MI, ACS, stroke, HF or CV death 5.2% vs 6.8% (HR 0.75, 95% CI 0.64 to 0.89, P <0.001); death from any cause 3.3% vs 4.5% (HR 0.73, 95% CI 0.60 to 0.90, P = 0.003).

Proteinuria

Historically recognised: “bubbles appearing on the surface of the urine indicate renal disease with a prolonged course.”

  • Proteinuria is the strongest predictor of progressive kidney disease.
  • Its presence is almost a prerequisite for renal function deterioration (disease dependent).
  • Elevated blood pressure is more relevant in the presence of proteinuria.
  • Initial proteinuria, the degree of reduction achieved, and the residual level all correlate with outcome.
  • It is unfortunately not routinely assessed in primary care.

Prognostic meta-analysis (Matsushita et al. Lancet 2010; Gansevoort et al. Kidney Int 2011): for all-cause mortality, cardiovascular mortality, ESRD, AKI and progressive CKD, adjusted hazard ratios show a U- or J-shaped relationship with eGFR, rising steeply as eGFR falls below about 60, and rising further at each higher ACR band (ACR <3, 3 to 30, and >30 mg/mmol). Higher ACR sits above lower ACR across almost the whole eGFR range. Reduced eGFR and raised ACR carry a similar risk for cardiovascular disease.

Targets and agents in proteinuric disease:

  • Kidney protection in proteinuric individuals requires a lower target blood pressure, <120/80 or MAP 92 mmHg.
  • Preferred agents on meta-analysis are ACEI and/or ARB, in all forms of proteinuric kidney disease. They are safe to use in CKD, and established CKD is not a contraindication.
  • Use ACEI or ARB for proteinuric kidney disease even if the patient is normotensive (level 1).
  • The lecturer’s preference is candesartan: greatest anti-proteinuric and BP-lowering effect for a given dose, with additional anti-fibrotic effects through blocking the AT1 receptor on tubular epithelial cells and reducing pro-inflammatory actions.
  • Use maximum recommended doses if tolerated. Goal is a urinary protein/creatinine ratio <50 mg/mmol.
  • Antiproteinuric response and residual proteinuria are predictive of long-term outcome.
  • Add SGLT2 inhibitors for renal and cardiovascular protection.

uACR pathway (Bozkurt et al. Eur J Heart Fail 2025): measure uACR early and regularly in people with diagnosed CKD and in people without it who have diabetes, heart failure or CVD. If uACR ≥30 mg/g, retest in 3 months; if still ≥30 mg/g, diagnose CKD once albuminuria has persisted ≥3 months, then manage to prevent progression (RAS blockade, SGLT2i, ns-MRA such as finerenone, GLP-1 RA), and screen at least annually thereafter. uACR is diagnostic for CKD and prognostic for CKD progression, heart failure and CVD outcomes; it is simple, non-invasive, cost-effective and available, and should be tested at least annually alongside eGFR. Global prevalence: CKD 844 million, CVD 620 million, bidirectionally linked, with severe outcomes (kidney failure, hospitalisation, death).

SGLT2 inhibitors and combination “pillar” therapy

DAPA-CKD (Heerspink et al. NEJM 2020): randomised, double-blind, placebo-controlled, 386 sites in 21 countries, n = 4304, GFR 25 to 75 mL/min, 67.5% type 2 diabetes, ACR 200 to 5000 mg/g. Dapagliflozin 10 mg/day vs placebo: primary composite 9.2% vs 14.5%; composite kidney outcome (≥50% GFR decline, ESKD, renal death) 6.6% vs 11.3%; composite cardiovascular outcome (HF hospitalisation, CV death) 4.6% vs 6.4%; death from any cause 4.7% vs 6.8%; all P <0.001 to 0.009.

EMPA-KIDNEY (NEJM 2022): 241 centres, 8 countries, double-blind, 6609 patients, eGFR 20 to 45 regardless of albuminuria or eGFR 45 to 90 with uACR >200, after a 15-week placebo run-in. Empagliflozin 10 mg/day vs placebo: CKD progression or CV death 13.1% vs 16.9% (HR 0.72, 0.64 to 0.82, P <0.001); hospitalisation from any cause 24.8 vs 29.2 per 100 patient-years (HR 0.86, 0.78 to 0.95, P = 0.003); HF hospitalisation or CV death 4.0% vs 4.6% (HR 0.84, 0.67 to 1.07, P = 0.15); death from any cause 4.5% vs 5.1% (HR 0.87, 0.70 to 1.08, P = 0.21).

Post hoc DAPA-CKD analysis (Madero, Chertow and Mark, Kidney Med 2024) shows benefit irrespective of type 2 diabetes status: eGFR decline of about -4.13 and -3.22 mL/min/year on placebo, reaching eGFR ≤10 at roughly 6 years, versus about -1.48 and -1.99 on dapagliflozin, reaching the same threshold roughly 11 years later.

Lifetime benefit of RAAS plus SGLT2 inhibition in albuminuric non-diabetic CKD (Vart et al. CJASN 2022;17:1754): trial-level estimates from REIN, the Guangzhou trial and DAPA-CKD, combination therapy (ACEi/ARB n = 690 plus SGLT2i n = 1398) vs no therapy for the composite of creatinine doubling, kidney failure and death: aHR 0.35 (0.30 to 0.41). Event-free survival from age 50 to 75 was 17.0 years (12.4 to 19.6) with combination vs 9.6 years (8.4 to 10.7) with placebo, a gain of 7.4 years (6.4 to 8.7); assuming lower adherence and efficacy the gain is about 5.3 to 5.8 years.

DAPA-HF (McMurray et al. NEJM 2019): 20 countries, 410 centres, 4744 patients with NYHA II to IV heart failure and EF ≤40%, 45% with type 2 diabetes, median follow-up 18.2 months. Dapagliflozin vs placebo: primary composite of worsening HF or CV death 16.3% vs 21.2% (HR 0.74, 0.65 to 0.85); CV death or HF hospitalisation 16.1% vs 20.9% (HR 0.75); death from any cause 11.6% vs 13.9% (HR 0.83, 0.71 to 0.97). Benefit occurred with or without type 2 diabetes.

Evidence summary across trials (Kang and Jardine, Nat Rev Nephrol 2021): for the kidney outcome, HR 0.51 (0.38 to 0.69) in people without diabetes and 0.63 (0.57 to 0.69) in people with diabetes, overall 0.62 (0.57 to 0.67). For HF hospitalisation or CV death, 0.75 (0.65 to 0.87) without diabetes and 0.76 (0.72 to 0.81) with diabetes, overall 0.76 (0.72 to 0.80). In people with CKD and heart failure, SGLT2i confer benefit irrespective of albuminuria.

The four pillars act on three interacting central processes (metabolic dysregulation, haemodynamic perturbations and inflammation):

  1. RAS blockers: decrease efferent arteriolar tone, hyperfiltration, endothelial dysfunction and cardiac remodelling.
  2. SGLT2 inhibitors: increase afferent arteriolar tone, improve tubuloglomerular feedback, decrease hyperfiltration, proteinuria and oxidative stress, increase anti-inflammatory and anti-fibrotic effects.
  3. Finerenone (ns-MRA): decreases inflammation, fibrosis, endothelial dysfunction, tissue remodelling and proteinuria.
  4. GLP-1 receptor agonists (potential pillar 4): decrease weight, dyslipidaemia, oxidative stress and endothelial dysfunction.

In diabetic kidney disease all four (RASi, SGLT2i, ns-MRA, GLP-1 RA) are disease-specific targeted therapies on a base of comprehensive lifestyle modification. In non-diabetic kidney disease RASi and SGLT2i are established, while ns-MRA and endothelin A receptor antagonists are not yet established. Combining them gives additive benefit (addressing multiple mechanisms, larger anticipated improvements in albuminuria and eGFR decline, enhanced cardioprotection) and enhanced tolerability: SGLT2i plus RASi reduces hospitalisation, AKI and hyperkalaemia; SGLT2i plus ns-MRA reduces hyperkalaemia; SGLT2i plus ETA-RA reduces diuretic initiation or intensification (Neuen et al. NDT 2025).

Hazard ratios for CKD progression by combination (Neuen et al. Circulation 2024): SGLT2i 0.63 (0.53 to 0.77); GLP-1 RA 0.86 (0.72 to 1.02); ns-MRA 0.77 (0.67 to 0.88); GLP-1 RA plus ns-MRA 0.66 (0.53 to 0.83); SGLT2i plus GLP-1 RA 0.54 (0.42 to 0.70); SGLT2i plus ns-MRA 0.49 (0.38 to 0.61); triple therapy SGLT2i plus ns-MRA plus GLP-1 RA 0.42 (0.31 to 0.56). All favour combination over conventional care, with triple therapy lowest.

Standard of care and risk management

Management pathway: a lifestyle base layer (healthy diet, physical activity, stop tobacco, weight management, risk factor reassessment every 3 to 6 months), then first-line drug therapy for most patients: SGLT2i continued until dialysis or transplant, aim for systolic BP <120 mmHg with a RAS inhibitor at maximum tolerated dose if hypertensive, and statin-based therapy (moderate or high intensity) based on ASCVD risk and lipids. Then targeted therapies for complications: manage hyperglycaemia per the KDIGO diabetes guideline including GLP-1 RA where indicated; ns-MRA in people with diabetes and an indication; dihydropyridine CCB and/or diuretic if needed to reach BP target; steroidal MRA for resistant hypertension if eGFR ≥45; antiplatelet agent for clinical ASCVD; ezetimibe or PCSK9i by ASCVD risk and lipids (same principles as people without CKD, including AF management); and management of anaemia, CKD-MBD, acidosis and potassium abnormalities.

Risk management strategies of proven benefit: smoking cessation; antihypertensive therapy; ACEI and ARB; SGLT2 inhibitors; mineralocorticoid receptor antagonists (finerenone); lipid-lowering therapy in CKD but not in dialysis; antiplatelet therapy; exercise and weight control.

Risk-guided architecture for cardio-kidney-metabolic care: clinical goals are to reduce CKD progression, reduce cardiovascular events, reduce hospitalisations, and improve survival and quality of life. Therapy differs by diabetes status (CKD with diabetes: RAASi, SGLT2i, ns-MRA, GLP1-RA; without diabetes: RAASi, SGLT2i) with decision modifiers for heart failure (ARNI, MRA), obesity (incretin-based therapy) and ASCVD (statin plus PCSK9i). Integrated risk estimation using kidney and CV risk equations sorts patients into high, intermediate and low risk tiers, driving intensive guideline-directed medical therapy escalation for higher risk with ongoing re-evaluation, all resting on foundational lifestyle care. Alongside this the lecture presents Te Whare Tapa Whā (Mason Durie), the Māori health model of a wharenui with four walls, taha wairua (spiritual), taha hinengaro (mental and emotional), taha tinana (physical) and taha whānau (family and social), all supporting hauora (well-being) and resting on whenua (land, roots).

Take-home points of Part 1: proteinuria and hypertension are major prognostic factors, contribute to CKD progression, and require more aggressive treatment. Most patients with CKD die of cardiovascular disease. Goal-directed medical therapy is needed, and “remember statins.”

Therapeutic convergence between heart failure and CKD: HFrEF uses ARNI, beta-blocker, MRA, SGLT2i; HFpEF uses SGLT2i, MRA, ARNI (where LVEF is below normal, <60%) and GLP-1 RA (to improve symptoms in overweight or obese patients); CKD uses ACEI/ARB, SGLT2i, ns-MRA and GLP1-RA (the last only in type 2 diabetes with CKD).

CKD and cardiovascular disease

  • Dialysis patients have dramatically higher annual mortality than the general population at every age, with the largest relative excess at younger ages and narrowing beyond 85 years (Parfrey et al. JASN 1999).
  • Cardiovascular risk rises inversely and independently with eGFR (Go et al. NEJM 2004, n = 1,120,295, median follow-up 2.8 years). Relative risk of any CVD, admission and death all rise as eGFR falls; for death, RR is about 1 at eGFR >60, 1.2 at 45 to 59, 1.8 at 30 to 44, 3.2 at 15 to 29, and 5.9 at <15.
  • Incidence per 100 person-years, eGFR <60 vs >60 (Jankowski, Circulation 2021): major cardiovascular events about 6.9 vs 4.2; cardiovascular death about 3.4 vs 1.4; all-cause mortality about 5.5 vs 2.3, all P <0.0001.

Mechanisms linking CKD to cardiac injury (Mathew et al. Kidney Int 2017):

  1. Increased salt and water retention raises blood pressure and myocardial wall tension.
  2. Increased phosphorus load raises FGF23 and reduces Klotho, promoting myocardial fibrosis.
  3. Mediators drive medial calcinosis and endothelial dysfunction, including coronary microcirculatory dysfunction.
  4. Increased angiotensin II raises blood pressure and promotes renal and myocardial fibrosis.

Cardiovascular complications fall into cardiomyopathy (increased LV wall thickness, reduced microvasculature, increased fibrosis, seen grossly as a hypertrophied fibrotic heart with a thickened LV wall and small chamber) and vascular disease (increased stiffness, increased calcification, for example femoral artery calcification visible on plain X-ray).

Prevalence of LVH rises with worsening renal function (Levin et al. AJKD 1999): general population 17%; mild insufficiency (CCr 75 to 50) 27%; moderate (50 to 25) 31%; severe (<25) 45%; at the start of dialysis 75%. LV disease predicts survival on dialysis over 72 months: normal about 0.7 survival probability, concentric LVH and LV dilatation about 0.25 to 0.4, systolic dysfunction worst at about 0.1 (Parfrey and Foley 1999).

CKD and hypertension jointly drive cardiac risk in a self-reinforcing cycle (Middleton et al. Kidney Int 2010). Diminished GFR leads on one arm to disordered mineral metabolism, metabolic acidosis, systemic inflammation, electrolyte disturbances and anaemia, which cause cardiovascular disease; and on the other arm to autonomic dysregulation, sodium retention, nephrosclerosis, endothelial dysfunction, lost arterial compliance and hyperuricaemia, which raise blood pressure and, via increased vascular resistance, LVH, arterial occlusion and ventricular remodelling, also cause cardiovascular disease, which then feeds back to worsen GFR.

Extra-renal manifestations: the framework

Failing kidneys produce a predictable set of systemic consequences:

  • Decreased nephron mass, with reduced GFR and excretory capacity.
  • Altered sodium and water homeostasis leading to hypertension.
  • Altered endocrine function affecting calcium metabolism and causing anaemia.
  • Altered metabolic function causing acidosis.
  • Altered drug handling.

Anaemia of CKD

Symptoms attributable to anaemia include poor exercise tolerance, lower metabolic rate with feeling cold, reduced libido, impaired cognitive ability, and an impact on cardiac function.

Mechanism (Babbitt JASN 2012): a normochromic normocytic anaemia arising from decreased EPO production by the kidney (further affected by uraemic inhibitors) and decreased iron availability. Inflammation raises hepcidin, which is also less cleared by the failing kidney; hepcidin acts on the duodenum to reduce iron absorption and on macrophages to reduce iron recycling, shrinking the iron pool available to the bone marrow. Red cell survival is shortened and blood loss further depletes iron.

Treatment:

  • Iron therapy to maximise availability, aiming at high ferritin concentrations of 500 to 1000 µg/L (PIVOTAL, NEJM 2019;380:447). A ferritin <200 µg/L represents functional deficiency in CKD.
  • Stop unnecessary blood tests.
  • Transfusion only for severe symptoms, given the risks in relation to future transplantation.
  • Erythropoietin, a major advance: recombinant human EPO to normalise Hb to 110 to 120 g/L.

CKD-MBD and renal bone disease

Changes in bone mineral metabolism and bone structure are universal associations of progressive renal disease. Phosphate metabolism changes occur early, from GFR around 60 mL/min/1.73 m².

Normal regulation, by organ:

  • Parathyroids sense calcium and have vitamin D3 receptors and respond to phosphate. Low Ca²⁺ and low D3, or high PO₄³⁻, raise PTH. Raised PTH increases phosphate excretion by decreasing Na-PO transporters and reducing tubular uptake, and raises vitamin D3 with increased calcium absorption from gut and release from bone, driving remodelling. (Remember this pattern for primary hyperparathyroidism.)
  • Kidney carries the Na-PO transporters and performs 1α-hydroxylation of vitamin D.
  • Bone: a phosphate load raises FGF23, which increases phosphate excretion, initially downregulates PTH (to reduce bone mobilisation), and reduces 1α-hydroxylation of vitamin D (reducing gut absorption of calcium and phosphate and D3 effects on bone remodelling).

Phosphate handling in numbers: dietary intake about 1500 mg/day, of which about 900 mg is absorbed via the gut NaPi2b transporter and about 600 mg/day excreted in faeces; serum phosphate 0.65 to 1.45 mmol/L; renal handling via NaPi2a. Urinary phosphate excretion falls with CKD stage: stage 1 to 2, 900 mg/day; stage 3, 700 mg/day; stage 4, 600 mg/day; stage 5 and 5D, 0 to 500 mg/day.

The regulatory loop: FGF-23 from bone downregulates PTH production, stimulates phosphaturia and downregulates 1,25-dihydroxyvitamin D at the kidney; PTH inhibits calciuria, promotes phosphaturia and upregulates 1,25D; 1,25D increases intestinal calcium and phosphate absorption, increases bone resorption, raises Ca²⁺ (which lowers PTH), and accelerates its own degradation.

What goes wrong in CKD:

  1. Progressive loss of renal mass impairs renal phosphate excretion, so serum phosphorus rises.
  2. Phosphate retention raises FGF23 (the predominant driver of the FGF23 rise is the phosphate load) and has direct effects on PTH, modulating kidney Na-PO4 transporters.
  3. Decreased renal mass reduces 1α-hydroxylase activity, so 1,25(OH)₂D synthesis falls. Deficiency of 1,25(OH)₂D decreases intestinal calcium absorption, causing hypocalcaemia.
  4. Hypocalcaemia and hyperphosphataemia stimulate PTH release and synthesis; the lack of 1,25(OH)₂ vitamin D removes feedback inhibition of PTH synthesis, so PTH production continues to rise. This is secondary hyperparathyroidism.
  5. CKD also reduces Klotho. Without klotho, FGF23-mediated suppression of PTH secretion is ineffective and FGF23-mediated phosphaturia is impaired, so PTH release overrides FGF23 suppression while FGF23 levels keep rising.
  6. Raised PTH increases bone turnover but mineralisation is reduced, giving osteomalacia and osteitis fibrosa. Acidosis may also contribute to the bone changes.
  7. When the calcium-phosphate product exceeds 4.5, ectopic calcification is promoted (the Part 2 case gives 2.1 x 2.9 = 6.09).

Order of biochemical change as GFR falls (Isakova et al. JASN 2015): FGF23 rises earliest and most steeply (approaching 1000 RU/mL by GFR 15); PTH begins rising around GFR 45 to 60; 1,25 vitamin D stays roughly flat then falls from about GFR 45 downwards; phosphate stays flat until GFR about 30 to 15 and only then rises.

FGF-23 regulates mineral metabolism through direct effects on renal phosphate excretion, 1,25-dihydroxyvitamin D3 synthesis and PTH secretion. Normally it increases phosphate excretion, decreases 1-alpha-hydroxylase and increases 24-hydroxylase in the kidney, and decreases PTH secretion. In the CKD setting its action on the heart is uncertain, with possible roles in cardiac remodelling and vascular calcification (Larsson NDT 2010).

Biochemical and clinical phenotype of secondary hyperparathyroidism/CKD-MBD:

  • Hypocalcaemia (low normal values)
  • Low 1,25(OH)₂ vitamin D3
  • Hyperphosphataemia
  • High PTH concentration
  • Elevated (bone) alkaline phosphatase
  • Enhanced ectopic calcification, particularly vascular
  • Characteristic X-ray changes, with increased bone resorption and active osteoid (osteitis fibrosa, osteomalacia). Radiological signs include subperiosteal resorption along the phalanges and Brown’s tumours (lucent phalangeal lesions).

Warning

One CKD-MBD radiology slide is unlabelled: the images show a mottled “salt-and-pepper” appearance and a lateral spine film, but the anatomical region and specific findings are not stated on the slide.

Vascular calcification: alterations in bone mineral metabolism result in extraskeletal calcification, particularly vascular, through medial calcification as vascular smooth muscle cells undergo a phenotypic shift to osteoblast-like cells. It is almost universal in advanced CKD and is the main driver of premature mortality (Hutchison, Nat Rev Nephrol 2011). Femoral artery calcification is visible as linear calcification on plain X-ray.

Tertiary hyperparathyroidism: marked, refractory oversecretion of PTH with hypercalcaemia not related to calcium supplements or calcitriol, due to hyperplasia or a monoclonal parathyroid adenoma. It relates to decreased calcitriol receptor density and/or loss of responsiveness to feedback stimuli, so the cells become autonomous.

Important

Calciphylaxis is the extreme of altered mineral metabolism: metastatic calcification with a Ca x PO product >4.5 signalling calcification risk, presenting as dark necrotic ulcerated skin lesions and carrying high mortality.

Management of secondary hyperparathyroidism:

  • Dietary phosphate restriction (marked as an evidence-free zone)
  • Phosphate binding with Ca²⁺ or Al³⁺ to reduce dietary absorption (also an evidence-free zone)
  • PTH suppression with calcitriol and newer agents, including calcimimetics acting at the calcium-sensing receptor
  • Treating acidosis with sodium bicarbonate, for both bone and CKD progression
  • Good dialysis

Early calcitriol supplementation: the rationale is that calcitriol is superior to calcium alone in suppressing PTH, and prevention of hyperparathyroidism is more readily achievable than treatment of established disease. The end point is a PTH of 2 to 3 times normal.

Parathyroidectomy: considered because of the risk of ectopic calcification. Indications are high PTH, refractory hyperphosphataemia and/or hypercalcaemia that limits calcitriol administration, and bone pain.

Metabolic acidosis in CKD

Bicarbonate supplementation slows progression of CKD and improves nutritional status (de Brito-Ashurst et al., JASN). Acidosis also matters for bone metabolism, and its correction is part of secondary hyperparathyroidism management.

Kidney replacement therapy

Options are active conservative care, haemodialysis or peritoneal dialysis, and kidney transplantation. Dialysis is usually started around an eGFR of 6 to 10 mL/min with associated symptoms; the IDEAL study (NEJM) showed no benefit from an early start.

Dialysis therapy maintains a state of controlled renal failure, with clearance equivalent to a GFR of 10 to 20 mL/min. Done well it can be very effective, and more is better. Its limitations are in metabolism and endocrine function, and it has a large impact on the individual’s lifestyle and family. Peritoneal dialysis exchanges fluid across the peritoneum via an indwelling catheter with inflow and outflow bags; haemodialysis uses an extracorporeal circuit with a dialyser cartridge.

Kidney transplantation is the preferred therapy for suitable recipients, with 700 (2100) on the list, offering full rehabilitation and effectively normal kidney function. Drawbacks are the side effects of immunosuppressive medications, dependence on organ donors (cadaveric vs living related donor), and issues of equity of access. The graft is placed in the iliac fossa rather than replacing the native kidneys.

Organ donation is a gift of life. Multi-organ donors alter many lives (2 kidneys, heart and heart valves, liver, lung, pancreas, corneas, bone). Awareness and discussion with family matter (www.donor.co.nz).

New Zealand kidney failure data (ANZDATA)

2023 summary for Aotearoa New Zealand:

  • Transplant: 175 new transplants (33 pmp), up 1% on 174 in 2022; 74 live donor (up 6%), 101 deceased donor (down 3%). Deceased donor subtypes include ABO-incompatible 7, non-directed 9, multi-organ 5 (pancreas-kidney 3, liver-kidney 2), paired kidney exchange 17; 93 donated after brain death and 8 after cardiac death. Pre-emptive transplants over the preceding 5 years totalled 166, of which 151 non-Māori and 15 Māori.
  • Overall: 5572 people treated for kidney failure (1064 ppm, vs 5429 in 2022); 2374 living on dialysis (453 ppm, vs 2315); 725 living with a transplant (138 ppm, vs 703); 3198 people started kidney replacement therapy (611 ppm, vs 3114).
  • Dialysis: 700 new dialysis patients (vs 680 in 2022), comprising 211 peritoneal dialysis and 489 haemodialysis. Prevalent numbers include facility haemodialysis 2063 and home haemodialysis 389, automated PD 486 and CAPD 260. Location: home 1135 (217 pmp) vs facility 2063 (394 pmp).

Warning

Some numeric labels in the ANZDATA infographic (for example the peritoneal dialysis figures of 235 ppm vs 40 ppm) are laid out ambiguously in the original and were transcribed as legible.

Trends and equity:

  • Incidence of KRT 1994 to 2023 rose from 248 patients (69 pmp) in 1994 to 725 (138 pmp) in 2023, through intermediate points of 369 (97), 460 (114), 496 (116), 559 (126) and 628 (128), while the NZ population grew from about 3.4 to 5.2 million. Incidence has therefore risen faster than population.
  • Primary cause of kidney disease in new KRT patients, 2023, NZ vs Australia: diabetic kidney disease about 49% vs 36% (much the largest cause in NZ), glomerular disease 17% vs 19%, hypertension/renal vascular 8% vs 12%, familial/hereditary 6% vs 7%, tubulointerstitial 5% vs 7%, other systemic diseases 3% vs 2%, miscellaneous 8% vs 15%, not reported 1% vs 2%.
  • Incidence by ethnicity 2019 to 2023 (new patients pmp): Pacific Peoples rose from 373 to 478 (with a dip to 388 in 2022); Māori fell from 253 to 205; non-Māori non-Pacific stayed flat at 78 to 82.
  • Modality by ethnicity, 2023: non-Māori non-Pacific about 58% haemodialysis, 35% PD, 8% pre-emptive transplant; Māori about 62% HD, 33% PD, 1% pre-emptive transplant; Pacific Peoples about 82% HD, 18% PD, 0% pre-emptive transplant. Māori and Pacific patients have far lower access to pre-emptive transplantation.
  • Relative incidence of treated kidney failure in Māori compared with non-Māori non-Pacific (reference rate 1) peaks at roughly 5 to 6 times in the 35 to 64 age range for both sexes, then declines somewhat but stays elevated. Rates are higher 10 to 15 years younger than in the reference population.
  • Incidence by age group 2014 to 2023: the 65 to 74 group is consistently highest (about 290 to 440 pmp), then 55 to 64 and 75 to 84 (about 200 to 310); the 0 to 24 and 25 to 34 groups stay below about 70 pmp.
  • Comorbidities at end of year, 2013 to 2023: coronary disease highest throughout, falling from about 33% to 29%; peripheral vascular from about 19% to 14%; lung disease stable about 17 to 19%; cerebrovascular from about 14% to 11%. Most comorbidities show a gradual decline over the decade.
  • Diabetes as a comorbidity in prevalent patients, 2013 to 2022: highest in Pasifika and Māori on dialysis (rising from about 68 to 70% to about 71 to 73%), then transplant Pasifika (39% to 50%), transplant Māori (31% to 42%), dialysis non-Māori non-Pasifika (32% to 41%), and lowest transplant non-Māori non-Pasifika (20% to 22%).
  • Diabetes status at KRT entry, 2013 to 2023: in Australia non-diabetic and type 2 diabetes both sit around 45 to 50% with type 1 at 5 to 6%; in New Zealand type 2 diabetes is consistently highest, rising from about 55% to 56%, non-diabetic falls from about 41% to 38%, and type 1 stays at 4 to 6%.
  • KRT modality by country, 2023: Australia transplant 47%, facility HD 41%, PD 9%, home HD 4%; New Zealand transplant 43%, facility HD 37%, PD 13%, home HD 7%. Among dialysis patients only: Australia facility HD 76%, PD 17%, home HD 7%; New Zealand facility HD 65%, PD 23%, home HD 12%. New Zealand uses relatively more PD and home HD.

Summary points

  • Chronic kidney disease is common, affecting 12% of the population.
  • Cardiovascular risk is increased in CKD.
  • Early identification and effective control of risk factors are important for improved outcomes, both slowing progression of CKD and reducing the risk of CVD.

Self-test

  1. State the two alternative criteria by which CKD is defined, including the required duration.
  2. List the six eGFR categories (G1 to G5) of the KDIGO classification with their numerical ranges.
  3. Define the three albuminuria categories by urine ACR in mg/mmol, giving male and female thresholds.
  4. Explain why serum creatinine is an unreliable early marker of falling GFR.
  5. Describe the final common pathway of CKD progression and the mechanistic steps that lead to it.
  6. List six risk factors that place an adult at increased risk of CKD, and state which groups should be screened and with what two tests.
  7. Distinguish the roles of ACEI/ARB and SGLT2 inhibitors in terms of their effects on the glomerular arterioles.
  8. What fall in GFR after starting an ACEI or ARB indicates that the drug is working?
  9. State the blood pressure target in CKD and how it changes with proteinuria, and give the target urinary protein/creatinine ratio.
  10. Explain why proteinuria is described as the strongest predictor of progressive kidney disease, listing the features of proteinuria that correlate with outcome.
  11. Describe the uACR-based pathway for diagnosing CKD in someone without a prior diagnosis.
  12. Summarise the DAPA-CKD trial population and its primary composite outcome result.
  13. Summarise the EMPA-KIDNEY primary result and state which secondary outcomes did not reach significance.
  14. List the four therapeutic pillars in diabetic kidney disease and one mechanism of action for each.
  15. Which drug combination gives the lowest hazard ratio for CKD progression, and what is that hazard ratio?
  16. List four mechanisms by which CKD produces cardiac injury.
  17. Describe how the prevalence of LVH changes across renal insufficiency categories, and which pattern of LV disease predicts the worst dialysis survival.
  18. Explain the mechanism of anaemia in CKD, including the role of hepcidin.
  19. State the treatment targets for iron and haemoglobin in the anaemia of CKD.
  20. Describe the sequence of biochemical abnormalities in CKD-MBD as GFR falls, in the order in which they appear.
  21. Explain the pathogenesis of secondary hyperparathyroidism in CKD, from loss of renal mass to sustained PTH elevation.
  22. What is the role of Klotho, and what happens to FGF23 signalling when it is lost in CKD?
  23. Distinguish secondary from tertiary hyperparathyroidism.
  24. List the biochemical features of CKD-MBD and two characteristic radiological findings.
  25. Describe the pathogenesis of vascular calcification in CKD and state its clinical significance.
  26. List five management strategies for secondary hyperparathyroidism, noting which are labelled evidence free, and give the indications for parathyroidectomy.
  27. At what eGFR is dialysis usually started, and what did the IDEAL study show about starting earlier?
  28. What clearance does dialysis provide, and what are its main limitations?
  29. What is the commonest primary cause of kidney disease in new KRT patients in New Zealand, and how does this compare with Australia?
  30. Describe the ethnic inequities in kidney replacement therapy in New Zealand, covering incidence and modality.
  31. A 54-year-old woman with type 2 diabetes has BP 154/96, ACR 125 mg/mmol, eGFR 31 mL/min/1.73 m², LDL 3.4 mmol/L, HbA1c 68 mmol/mol and smokes 15/day. Classify her CKD, state what she is most likely to die from, and outline the drug classes she should be on.
  32. Integrative: explain how a single pathological process, phosphate retention, links reduced nephron mass to premature cardiovascular death in CKD.

Answers

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