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L15 Renal Chronic Kidney Disease

Chronic Kidney Disease (Mate tākihi)

What this lecture covers

A two-part lecture on chronic kidney disease (CKD). Part 1 deals with the definition and staging of CKD, its epidemiology in Aotearoa (with marked Māori and Pacific disparities), the mechanisms of progression, and the evidence-based interventions that slow progression while simultaneously reducing cardiovascular risk (BP control, RAS inhibition, SGLT2 inhibitors). Part 2 covers the extra-renal (systemic) manifestations of kidney failure — anaemia, CKD–mineral bone disease, acidosis — and the treatment options for established kidney failure (conservative care, dialysis, transplantation). A recurring theme is that most people with CKD die of cardiovascular disease, not of kidney failure itself, so the two risks must be managed together. The diabetic nephropathy case (Case 22) is used throughout as the integrating clinical thread.

Definition & Staging of CKD

  • Understand the definition of CKD: structural or functional abnormality of the kidneys present for ≥ 3 months, manifested by either:
    1. Kidney damage (with or without reduced GFR) — pathological abnormalities, markers of damage (proteinuria, renal tubular syndromes, imaging abnormalities), or a kidney transplant; OR
    2. GFR < 60 ml/min/1.73m² (with or without kidney damage).
  • The two-pronged definition is the key point: you can have CKD with a normal GFR if there is persistent damage (e.g. proteinuria), and you can have CKD with no overt damage if GFR is low enough.
  • Know the CGA classification — CKD is classified by Cause, GFR category, and Albuminuria category. The case label “CKD grade 3b A3” is the GFR + albuminuria shorthand from this system.
  • Know the 5 GFR stages (the clinical continuum):
    • Stage 1: GFR > 90 ml/min (damage present, e.g. proteinuria)
    • Stage 2: GFR 60–90 ml/min
    • Stage 3: GFR 30–60 ml/min (subdivided 3a / 3b)
    • Stage 4: GFR < 30 ml/min
    • Stage 5: kidney failure → RRT (renal replacement therapy = dialysis or transplant)
  • Understand the serum creatinine vs GFR relationship across the continuum: serum creatinine stays near-normal until late, then rises steeply as GFR falls. This is why creatinine is an insensitive early marker and eGFR is preferred.

Epidemiology & Risk Factors

  • Know the prevalence: CKD affects roughly 12% of the population (Otago/Southland figure). At a population level, ~1 in 3 adults are at increased risk, ~1 in 7 have CKD, and ~1 in 1400 are on dialysis or transplant.
  • Understand the ethnic disparities in Aotearoa (a central equity theme):
    • Māori odds ratio for CKD ≈ 1.56; Pacific OR ≈ 2.62.
    • Prevalence of CKD in Samoans in Auckland ≈ 33%; Māori ≈ 24%.
    • Across Pacific ethnicities, prevalence of CKD among those tested ran ~25–38%, far above the non-Māori/non-Pacific group (~13%).
  • Know the risk factors for CKD (≈1/3 of adults are at increased risk):
    • Age
    • Diabetes mellitus
    • Hypertension
    • Ethnicity (Māori, Pacific)
    • Socioeconomic deprivation
    • Gender (F > M for CKD, but M > F for ESKD)
    • Family history of CKD
    • Obesity
    • Prior episodes of AKI
  • Know the screening strategy: screen groups with well-accepted risk factors — hypertension, diabetes, cardiovascular disease, and Māori & Pacific aged > 25 years. Screening tests are urinalysis (proteinuria & haematuria) and eGFR (kidney function).

Mechanisms of Progression

  • Understand the general behaviour of progression: it occurs at a variable, unpredictable rate, and is driven largely by secondary haemodynamic and metabolic factors rather than the original underlying disease. This is why the same treatments help regardless of the initiating cause.
  • Understand the final common pathway: glomerulosclerosis (secondary FSGS) with associated proteinuria is the end-stage histological pathway for most progressive CKD.
  • Understand the self-perpetuating injury cycle (the key concept to be able to explain):
    1. Nephron loss → surviving nephrons undergo compensatory glomerular hypertrophy and hyperfiltration.
    2. This exposes them to higher intraglomerular pressures, causing endothelial and podocyte injury.
    3. Damaged filtration barrier → proteinuria, which itself directly injures tubular epithelial cells, driving interstitial fibrosis.
    4. The histological endpoints: arteriolosclerosis, interstitial fibrosis, glomerulosclerosis, and tubular atrophy.
  • Understand: hypertension is tightly associated with this cycle — raised systemic pressure transmits to the glomerulus and accelerates injury.

Slowing Progression — Modifiable Factors

Core principle

The factors that slow CKD progression (BP, proteinuria, glycaemia, lipids, smoking) are the same factors that reduce cardiovascular risk. Managing CKD and CVD is one integrated task, not two.

Hypertension

  • Know the burden: hypertension is present in 80–85% of CKD patients, and prevalence rises from ~65% to ~95% as GFR falls from 85 to 15 ml/min.
  • Understand the contributing mechanisms: sodium retention, RAAS activation, increased sympathetic neural activity, and altered nitric oxide / endothelin balance.
  • Understand that hypertension is both an independent predictor of renal disease and a driver of progression of existing disease — a bidirectional relationship.
  • Know the evidence and targets: BP control slows progression, reduces CV events, and reduces mortality. Guidelines suggest systolic < 140 mmHg; SPRINT/STEP suggest lower. Practical target is a sitting systolic in the 120–130s, and the greater the proteinuria, the lower the target.
  • Understand: lower mean arterial pressure correlates with a slower rate of GFR decline in both diabetics and non-diabetics.

Which antihypertensive agents

  • Know the agent hierarchy and why each is chosen:
    • ACEI & ARB — first choice. They reduce intraglomerular pressure directly (by dilating the efferent arteriole), over and above their systemic BP effect, and they reduce proteinuria. A fall in GFR of ~20% on starting is expected and indicates effectiveness.
    • SGLT2 inhibitors — now indicated for CKD (renal + cardiovascular protection).
    • Diuretics — important with ACEI/ARB; watch for rapid intravascular volume depletion.
    • Calcium channel blockers — lower BP (still useful) but do not directly modify GFR; variable long-term renal effect.
    • β-blockers — reduce renin; use where there is diastolic dysfunction.

Proteinuria

  • Understand why proteinuria is the single most important modifiable prognostic factor:
    • It is the strongest predictor of progressive kidney disease.
    • Its presence is almost a prerequisite for functional deterioration (disease-dependent).
    • Elevated BP is more harmful in the presence of proteinuria.
    • Initial level, degree of reduction with treatment, and residual level all correlate with outcome.
    • Note the clinical-practice gap: it is not routinely assessed in primary care.
  • Understand UACR (urine albumin:creatinine ratio) is both diagnostic for CKD and prognostic for CKD progression, heart failure and CVD outcomes. Risk rises across ACR bands (<3, 3–30, >30 mg/mmol).
  • Know the proteinuria management principles:
    • Lower BP target in proteinuric disease (< 120/80, or MAP ~92 mmHg).
    • ACEI/ARB are preferred and should be used even if normotensive in proteinuric kidney disease.
    • Use maximum tolerated doses; goal urine protein:creatinine ratio < 50 mg/mmol.
    • Established CKD is not a contraindication to ACEI/ARB.
    • Candesartan is the lecturer’s preference (greatest antiproteinuric + BP effect per dose; additional anti-fibrotic action via AT1 blockade on tubular epithelial cells).

RAS inhibition + SGLT2 inhibition (the modern evidence base)

  • Know the headline message: RASi and SGLT2i are the treatments with the strongest evidence base for delaying CKD progression.
  • Understand: DAPA-CKD post-hoc analysis showed SGLT2i benefit in delaying CKD progression irrespective of type 2 diabetes status — i.e. benefit is not confined to diabetics.
  • Understand the magnitude: trial data suggest a 50-year-old with albuminuric non-diabetic CKD treated with combined ACEI/ARB + SGLT2i may gain ~7.5 additional years free of kidney failure and death vs placebo.
  • Understand: in CKD with heart failure, SGLT2i confer benefit irrespective of albuminuria.

Full risk-management package

  • Know the proven-benefit interventions (Goal Directed Medical Therapy):
    • Smoking cessation
    • Antihypertensive therapy
    • ACEIs & ARBs
    • SGLT2 inhibitors
    • Mineralocorticoid receptor antagonists — finerenone
    • Lipid-lowering therapy (benefit in CKD but not in dialysis patients) — remember statins
    • Antiplatelet therapy
    • Exercise / weight control

Part 1 take-home points

  • Proteinuria and hypertension are the major prognostic factors and require aggressive treatment; both drive progression.
  • Most patients with CKD die of CVD, not of reaching dialysis.
  • Treatment is Goal Directed Medical Therapy combining BP, proteinuria, glycaemic, lipid and lifestyle control.

CKD and Cardiovascular Risk

  • Understand the central epidemiological fact: there is an independent, graded, inverse relationship between eGFR and cardiovascular risk — as eGFR falls, relative risk of any CVD, CV admission and CV death rises sharply (e.g. RR ~5.9 at eGFR <15 vs eGFR >60 in the Go et al. 1.1-million-adult cohort).
  • Understand the bidirectional relationship between CKD, heart failure and CVD: each worsens the others, which is why early diagnosis matters.
  • Know the cardiovascular complications of CKD, grouped as:
    • Cardiomyopathy — increased LV wall thickness (LVH), microvascular disease, myocardial fibrosis.
    • Vascular disease — arterial stiffness and calcification (e.g. femoral artery calcification).
  • Know the prevalence of LVH rises with declining renal function: ~17% general population → ~27% (mild) → ~31% (moderate) → ~45% (severe) → ~75% at dialysis start. LV disease predicts survival on dialysis.
  • Understand the dialysis-population mortality data (Parfrey/Foley): CV mortality is dramatically higher in dialysis patients than the age/race/gender-matched general population — a young dialysis patient may carry the CV risk of a much older person.

Extra-renal Manifestations (Part 2)

Why kidney failure becomes a multisystem disease

As nephron mass falls, the kidney loses not just excretory capacity but also its endocrine and metabolic regulatory roles. The systemic consequences follow directly:

  • ↓ excretion → uraemia, fluid/sodium overload → hypertension
  • ↓ endocrine function → anaemia (EPO) and disordered calcium/phosphate metabolism
  • ↓ metabolic regulation → metabolic acidosis
  • altered drug handling

Anaemia of CKD

  • Understand the type and mechanism: a normochromic, normocytic anaemia caused by:
    • Decreased erythropoietin (EPO) production by the failing kidney (the primary driver).
    • Decreased iron availability — inflammation raises hepcidin, which reduces iron absorption and recycling (functional iron deficiency).
  • Know the clinical impact (many “CKD symptoms” are really anaemia symptoms): poor exercise tolerance, cold intolerance / low metabolic rate, reduced libido, impaired cognition, impact on cardiac function.
  • Know the treatment:
    • Iron — maximise availability; aim for high ferritin (500–1000 µg/l). In CKD, ferritin < 200 µg/l = functional deficiency (PIVOTAL study).
    • Erythropoietin (rH-EPO) — a major advance; normalise Hb to 110–120 g/l (not higher).
    • Transfusion only for severe symptoms (carries transplantation sensitisation risk).
    • Stop unnecessary blood tests (iatrogenic blood loss).

CKD–Mineral Bone Disorder (CKD-MBD / “Renal Osteodystrophy”)

  • Understand the normal calcium–phosphate control system first (so the CKD derangement makes sense):
    • Parathyroids: sense Ca²⁺; low Ca²⁺ / low vit D3 / high PO₄³⁻ → PTH release. PTH → phosphate excretion (↓ Na-PO transporters), Ca²⁺ reabsorption, vit D3 activation, and bone remodelling.
    • Kidney: site of 1α-hydroxylation of vitamin D and of phosphate excretion via Na-PO transporters.
    • Bone: high PO₄³⁻ → FGF-23 release, which increases phosphate excretion and initially down-regulates PTH and 1α-hydroxylation (to limit bone mobilisation).
  • Understand the pathogenesis of secondary hyperparathyroidism in CKD (the key sequence to be able to explain):
    1. Loss of renal mass → impaired phosphate excretion → hyperphosphataemia (occurs early, around GFR 60).
    2. Reduced renal mass → ↓ 1α-hydroxylase → ↓ 1,25(OH)₂ vitamin D3.
    3. Low active vitamin D → ↓ intestinal Ca²⁺ absorption → hypocalcaemia.
    4. Hypocalcaemia + hyperphosphataemia → stimulate PTH synthesis and release.
    5. Loss of vitamin-D feedback inhibition allows PTH to keep rising unchecked → secondary hyperparathyroidism.
  • Understand the FGF-23 / Klotho axis in CKD: phosphate retention drives ↑ FGF-23, but loss of renal Klotho (its co-receptor) makes FGF-23 ineffective at promoting phosphaturia and at suppressing PTH — so phosphate stays high and PTH stays high.
  • Know the biochemical phenotype of secondary hyperparathyroidism:
    • Hypocalcaemia (low-normal)
    • Low 1,25(OH)₂ vitamin D3
    • Hyperphosphataemia
    • High PTH
    • Elevated (bone) alkaline phosphatase
    • Acidosis contributes to bone changes
  • Know the clinical / radiological consequences:
    • Increased bone resorption with active osteoid → osteitis fibrosa / osteomalacia.
    • Characteristic X-ray changes: subperiosteal resorption and Brown’s tumours.
    • Ectopic / vascular calcification when Ca × PO₄ > 4.5 — the main driver of premature mortality.
  • Understand vascular calcification mechanism: medial calcification occurs because vascular smooth muscle cells undergo a phenotypic shift to osteoblast-like cells; almost universal in advanced CKD.
  • Understand tertiary hyperparathyroidism: marked, refractory PTH oversecretion that becomes autonomous (parathyroid hyperplasia or monoclonal adenoma; reduced calcitriol-receptor density / loss of feedback responsiveness). Distinguished by hypercalcaemia not explained by Ca/calcitriol supplements.
  • Understand calciphylaxis: the extreme of metastatic calcification (Ca × PO₄ > 4.5), with high associated mortality.
  • Know the management of secondary hyperparathyroidism:
    • Dietary phosphate restriction.
    • Phosphate binders (Ca²⁺, Al³⁺) to cut dietary absorption.
    • PTH suppression — calcitriol; calcimimetics (block the calcium-sensing receptor).
    • Correct acidosis with sodium bicarbonate (helps both bone and CKD progression).
    • Good dialysis.
    • Early calcitriol supplementation rationale: prevention is easier than treating established disease; calcitriol suppresses PTH better than calcium alone; endpoint is PTH ~2–3× normal.
    • Parathyroidectomy indications: very high PTH with refractory hyperphosphataemia/hypercalcaemia limiting calcitriol use, bone pain, or risk of ectopic calcification.
    • (Note the lecturer flags dietary phosphate restriction and binders as an “evidence-free zone”.)

Metabolic acidosis

  • Understand that CKD causes metabolic acidosis, which both worsens bone disease and accelerates CKD progression — hence bicarbonate is used therapeutically.

Kidney Replacement Therapy (Kidney Failure Management)

  • Know the treatment options for established kidney failure:
    1. Active conservative care (non-dialytic supportive management).
    2. Haemodialysis or peritoneal dialysis.
    3. Kidney transplantation.
  • Know when to start: usually around eGFR 6–10 ml/min with associated symptoms. The IDEAL study (NEJM) showed no benefit from an early start.
  • Understand what dialysis does and its limits:
    • Maintains a state of controlled renal failure — clearance equivalent only to GFR ~10–20 ml/min.
    • Effective if done well (“the more the better”), but does not replace the kidney’s metabolic and endocrine functions.
    • Large impact on the individual’s lifestyle and family.
    • Two modalities: peritoneal dialysis and haemodialysis.
  • Understand transplantation as the preferred therapy for suitable recipients:
    • Offers full rehabilitation / near-normal kidney function.
    • Cost: lifelong immunosuppression and its side effects.
    • Donor sources: cadaveric vs living related donor (LRD).
    • Major equity-of-access issues; waiting list ~700 (2100).
    • Note: dialysis carries markedly higher mortality, with patients dying 10–15 years younger — reinforcing transplant preference.
  • Know the organ donation points: a “gift of life”, multi-organ donation possible (kidneys, heart/valves, liver, lung, pancreas, corneas, bone); importance of family discussion and awareness.

Overall lecture summary

  • CKD is common (~12% of population) with major Māori/Pacific inequities.
  • Cardiovascular risk is increased in CKD, and CVD is the usual cause of death.
  • Early identification and effective risk-factor control (BP, proteinuria, RASi, SGLT2i, lipids, smoking) both slow CKD progression and reduce CVD risk.

The integrating case — Case 22: Diabetic Nephropathy

Why this case is used

A 54-year-old woman with 8-year type 2 diabetes, hypertension (154/96), heavy proteinuria (ACR 125 mg/mmol; normal < 2.5), eGFR 31 → CKD grade 3b A3, dyslipidaemia, smoking, established micro- and macrovascular complications (retinopathy, neuropathy, claudication, ankle oedema) and a strong family history (father died of MI aged 53). She illustrates nearly every theme: the diabetes–kidney link, the dominance of cardiovascular risk, the role of ACEI/ARB + SGLT2i + glycaemic control, and the use of risk calculators. Quoted risk: ~30% chance of a major adverse cardiovascular event (MACE) or ESKD within 5 years, and the exercise of recalculating risk by changing ethnicity to Māori/Pacific to demonstrate inequity. The central exam-style question: “What is she most likely to die from?” → cardiovascular disease.

Self-test checklist

  • Can you state the full ≥3-month, two-pronged definition of CKD?
  • Can you explain what the CGA classification stands for and decode a label like “3b A3”?
  • Can you list the 5 GFR stages with their cut-offs and say why serum creatinine is a poor early marker?
  • Can you quote the approximate prevalence of CKD and explain the Māori/Pacific disparities (odds ratios)?
  • Can you list the major risk factors for CKD, including the F>M (CKD) vs M>F (ESKD) point?
  • Can you describe the screening strategy (who and which two tests)?
  • Can you explain the self-perpetuating injury cycle of progression (hyperfiltration → intraglomerular hypertension → proteinuria → fibrosis) and name the final common pathway?
  • Can you explain why ACEI/ARB are first-line and why a ~20% GFR drop on starting is reassuring?
  • Can you justify why proteinuria is the strongest prognostic factor and state the treatment goals (BP and PCR targets)?
  • Can you summarise the SGLT2i / RASi evidence, including benefit irrespective of diabetes status?
  • Can you list the components of Goal Directed Medical Therapy (and recall that statins help in CKD but not dialysis)?
  • Can you explain the inverse eGFR–cardiovascular risk relationship and why most CKD patients die of CVD?
  • Can you describe the cardiac (LVH, fibrosis) and vascular (stiffness, calcification) complications of CKD?
  • Can you explain the mechanism and treatment of anaemia of CKD (EPO, hepcidin/iron, target Hb)?
  • Can you walk through the pathogenesis of secondary hyperparathyroidism step by step?
  • Can you explain the role of FGF-23 and Klotho in CKD-MBD?
  • Can you state the biochemical phenotype of secondary hyperparathyroidism (Ca, PO₄, vit D, PTH, ALP)?
  • Can you distinguish secondary vs tertiary hyperparathyroidism and define calciphylaxis?
  • Can you list the management options for CKD-MBD (binders, calcitriol, calcimimetics, bicarbonate, parathyroidectomy)?
  • Can you explain why metabolic acidosis is treated in CKD?
  • Can you list the three KRT options, the eGFR threshold for starting dialysis, and what the IDEAL study showed?
  • Can you explain what dialysis cannot replace and why transplantation is preferred?

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