L21 Renal In-course Renal essay feedback

Overview

Feedback on the in-course renal assessment, worked through four clinical cases plus one short-answer question. The material covers diabetic nephropathy presenting with nephrotic-range proteinuria and the renal pharmacology of SGLT2 inhibitors and ARBs; ischaemic acute kidney injury after cardiac arrest, with the neurohormonal response to low perfusion and the tubular handling and mechanism of loop diuretics; acute post-streptococcal glomerulonephritis, its histology, immunopathology and complement basis; advanced chronic kidney disease with its metabolic complications including CKD-MBD; and pre-renal AKI from ileostomy losses with hyperkalaemia and metabolic acidosis. The unifying thread is glomerular haemodynamics: how afferent and efferent arteriolar tone, driven by tubuloglomerular feedback and angiotensin II, determines filtration pressure, GFR and proteinuria, and how drugs deliberately manipulate it.

Case 1: diabetic nephropathy with nephrotic-range proteinuria

Presentation: 58 year old man, type 2 diabetes for 10 years, on metformin 850 mg twice daily. BP 160/90 mmHg, JVP 3 cm, cardiomegaly (apex in 6th intercostal space, displaced to anterior axillary line), chest clinically clear, mild ankle oedema. Urinalysis 4+ protein; urine protein/creatinine ratio 213 mg/mmol (normal <20). Normal sodium and potassium, urea 12 mmol/L, creatinine 163 umol/L, plasma albumin 25 g/L (normal 38 to 42), normal LFTs, HbA1c 87 mmol/mol (normal <40).

Description of the presentation:

• Diabetic nephropathy presenting with nephrotic-range proteinuria: peripheral oedema, heavy proteinuria, low serum albumin.
• Hypertension due to Na+ retention.
• JVP is not elevated, so this is not heart failure. The cardiomegaly is due to hypertension.

Clinical review and examination in diabetes

The question asks for examination findings, not investigations. Investigations are not examination.

Macrovascular complications:

• Cerebrovascular, cardiovascular and peripheral vascular disease.
• PVD involves all arteries, not just a femoral bruit. Demonstrate this clearly, along with cold peripheries.

Microvascular complications:

• Retinopathy, peripheral neuropathy, autonomic neuropathy.
• Link PVD and neuropathy to diabetic foot disease.

SGLT2 inhibitors

Empagliflozin 10 mg with metformin 500 mg twice daily was added for glycaemic control.

Mechanism and expected effects:

• Blocks proximal tubular uptake of Na+ and glucose.
• Increased glucose excretion improves glycaemic control and gives a diuretic effect. No risk of hypoglycaemia.
• Weight loss and a blood pressure effect.
• Afferent arteriolar constriction, reducing filtration pressure and so reducing proteinuria.
• Additional cardiovascular and kidney protection related to a change in metabolism, with more efficient energy utilisation.
• Interactions with blood pressure medications and diuretics.

Natriuresis and tubuloglomerular feedback (the mechanism chain):

1. SGLT2 inhibition blocks Na+/glucose cotransport in the proximal tubule.
2. More Na+ is delivered to the macula densa.
3. Increased tubuloglomerular feedback causes afferent arteriolar constriction.
4. Intraglomerular hypertension falls.
5. Consequences: reduced proteinuria, reduced blood pressure, reduced arterial stiffness, plus reduced weight and reduced HbA1c from urinary Na+ and glucose loss.

Patient education (sick day rule):

• Starvation ketosis.
• Excessive volume depletion.
• Glycosuria leading to infection.

Practical guide to starting an SGLT2 inhibitor in T2DM with CKD

A three-domain checklist, each domain moving from assessment to intervention to follow-up.

Patient selection:

• Assessment: eligible patients eGFR >= 30 mL/min/1.73 m2 (annotated in red on the slide); high-priority features are uACR >= 200 mg/g and heart failure; potential contraindications are genital infection risk, diabetic ketoacidosis, foot ulcers and immunosuppression.
• Intervention: a low-dose SGLT2 inhibitor with proven benefit (canagliflozin 100 mg, dapagliflozin 10 mg, empagliflozin 10 mg), plus education on sick day protocol, perioperative care and foot care.
• Follow-up: assess adverse effects, review knowledge, and anticipate an acute drop in eGFR, which is generally not a reason to stop the SGLT2 inhibitor.

Glycaemia:

• Assessment of hypoglycaemia risk: insulin or sulfonylurea use, history of severe hypoglycaemia, HbA1c at or below goal.
• If risk is high: educate on hypoglycaemia symptoms and glycaemia monitoring, consider insulin or sulfonylurea dose reduction.
• Follow-up: ask about hypoglycaemia, reduce sulfonylurea or insulin if needed.

Volume:

• Assessment of volume depletion risk: concurrent diuretic use, tenuous volume status, history of AKI (annotated in red on the slide).
• If risk is high: educate on volume depletion symptoms, consider diuretic dose reduction.
• Follow-up: re-assess volume, reduce concomitant diuretic if needed.

Warning

The eGFR >= 30 criterion and the “history of AKI” item carry red strike-through/underline annotations by the lecturer; the slide does not state what the strike-through is intended to mean.

ARBs in diabetic kidney disease

Candesartan was started for longer-term management.

Systemic indications: hypertension and expanded intravascular volume, with effects on the heart and circulation, lowering blood pressure and improving cardiac function.

Kidney-specific actions:

• Preferential arteriolar vasodilation, efferent greater than afferent, reducing glomerular hydrostatic pressure and so reducing proteinuria.
• Reduced angiotensin II stimulated sodium and water uptake, giving natriuresis and diuresis.
• Anti-inflammatory and anti-fibrotic effects from blocking angiotensin II in tubular epithelial cells.

Action of ACEI/ARB in CKD (from the glomerular schematic): single-nephron GFR is $SNGFR=K_f\cdot NFP$. ACEI/ARB reduce angiotensin II mediated tone on both afferent and efferent sides, efferent more than afferent, increasing $K_f$ in the glomerulus, with pressure highly sensitive to vessel radius ($P\propto 1/r^4$), producing a fall in GFR.

Interpreting the 4 week follow-up

Repeat findings: oedema substantially improved, BP 132/80, JVP 1 cm, urine protein/creatinine ratio now 86, plasma albumin now 39 g/L, but plasma creatinine now 187 umol/L and eGFR 35 mL/min.

Mechanisms for the observed changes:

• Reduction in systemic blood pressure and intravascular volume reduces eGFR, because autoregulation is lost and renal perfusion falls (he has CKD).
• SGLT2 inhibitor: increased Na+ to the macula densa activates tubuloglomerular feedback, causing afferent arteriolar vasoconstriction and reducing glomerular filtration pressure.
• ARB: the main effect is blockade of angiotensin II induced afferent and efferent arteriolar vasoconstriction, with efferent vasodilation greater than afferent, reducing glomerular hydrostatic pressure, lowering GFR and reducing proteinuria.
• These effects are additive.

Important

All of these changes are beneficial: the fall in eGFR reflects the drugs working, not progressive CKD.

SGLT2 inhibitor versus ARB/ACEI on glomerular pressure

In type 2 diabetes the glomerulus sits at high pressure (wide afferent, narrow efferent arteriole), causing increased glomerular injury and increased proteinuria. The SGLT2 inhibitor acts by:

• Increased TGF activity via adenosine, giving preglomerular vasoconstriction.
• Increased prostaglandin release, giving preglomerular vasodilation.
• Blocking the effect of RAS activity via angiotensin II.
• Prostaglandin-induced post-glomerular vasodilation also occurs.

Net effect: GFR falls while renal vascular resistance is unchanged, and the glomerulus returns to normal pressure with reduced filtration. This is compared to a patient on an ARB, where the protection comes from preventing the angiotensin II mediated increase in efferent vasoconstriction.

Essay 1: AKI after cardiac arrest

Case: 44 year old man collapsed on George Street; a passing nurse started CPR, continued by ambulance officers; CPR lasted about 10 minutes before a rhythm was re-established. In ED: pulse 108/min, BP 80/50 mmHg lying, JVP 6 cm, bilateral basal crepitations consistent with pulmonary oedema. ECG confirmed anterior myocardial infarction. Urgent coronary artery revascularisation, then admitted to CCU. Catheterised with 175 mL of urine in the bladder.

Biochemistry: Na+ 135 mmol/L (N 136 to 142), K+ 5.9 mmol/L (N 3.5 to 5.0), urea 16 mmol/L (N 3 to 7), creatinine 210 umol/L (N 65 to 110). ABG: pH 7.2, pO2 94 mmHg (on 6 L/min O2), pCO2 33 mmHg, HCO3- 15.

Why he has AKI and is oliguric:

• Acute reduction in cardiac output and systemic blood pressure stimulates central baroreceptors, activating RAAS, the sympathetic nervous system and AVP.
• There is also a marked stress response at the level of the juxtaglomerular cells of the afferent arterioles, with local renin and angiotensin II release.

Neurohormonal pathway to salt and water retention (used in Essays 1 and 4)

Sequence of events leading to renal salt and water retention and renal dysfunction:

1. Low intravascular volume is sensed by baroreceptors, giving a threatened or low blood pressure.
2. Unloading of high-pressure baroreceptors.
3. Three parallel branches follow: increased AVP, increased sympathetic output, increased renin-angiotensin.
4. Increased AVP increases distal nephron Na reabsorption.
5. Increased sympathetic output reduces renal blood flow, which reduces GFR, which increases proximal tubular reabsorption, giving Na and water reabsorption.
6. Increased renin-angiotensin increases aldosterone, which increases distal nephron Na reabsorption.
7. All branches converge on oliguria and then AKI.

Alongside this: activation of JG cells with local renin and angiotensin II, and vasoconstriction of afferent arterioles.

Warning

Two boxes at the top of this flowchart are blank/uncaptioned in the rendered slide (on both occurrences of the diagram).

Urine biochemistry, acidosis and hyperkalaemia in AKI

Expected urine findings:

• Initially low urinary sodium and high urine osmolality.
• With established ATN, urinary sodium losses increase and the kidney is less able to concentrate urine.

Why he is acidotic, and the link to potassium:

• Profound tissue hypoxia from the cardiac arrest forces anaerobic metabolism, producing lactate and 2 H+.
• Intracellular buffering of H+ leads to K+ extrusion from cells.
• AKI means the kidney cannot regenerate sufficient HCO3- or excrete the excess K+.

Frusemide: mechanism and renal handling

Clinical trigger: on the ward round after angioplasty and stenting he has acute breathlessness overnight, JVP 6 cm, pulmonary oedema and BP now 150/96. Frusemide is added.

Mechanism:

• Blocks the NKCC cotransporter on the apical surface of the thick ascending limb of the loop of Henle.
• Blocking Na reabsorption increases delivery to the distal tubule, exceeding its capacity to reabsorb, so there is net loss of Na and water.

Pharmacokinetics and delivery to its site of action:

• Highly protein bound (98%), so frusemide is not filtered.
• It enters the urinary space via tubular secretion.

Tubular handling of diuretics:

• Diuretics are secreted by the proximal tubule.
• They are weak organic anions.
• Peritubular uptake is an active process driven by Na/K-ATPase (basolateral uptake via OAT in countertransport with alpha-ketoglutarate).
• They are secreted across the luminal membrane via voltage-driven OAT or a counter-transporter (exchanging with OH- or urate-).
• Probenecid inhibits the OAT transporter. Membrane potential shown as $E_K=-65$ mV.

Thick ascending limb cell detail:

• Apical Na+/2Cl-/K+ (NKCC2) cotransporter, blocked by frusemide.
• K+ back-leak into the lumen generates the lumen-positive voltage.
• Basolateral 3Na+ out and 2K+ in via Na/K-ATPase, plus K+/Cl- cotransport out to blood.
• The paracellular pathway for Na+, K+, Ca2+ and Mg2+ depends on that lumen-positive driving force and is therefore also blocked.
• Immunohistochemistry confirms NKCC2 localisation in thick ascending limb epithelium.

Other medications after myocardial infarction with AKI

ARB or ACEI:

• Indications: hypertension, heart failure, long-term reduction of cardiovascular risk.
• Actions: systemic vasodilation, reduced cardiac afterload, natriuresis and diuresis, reduced filtration pressure giving kidney protection, anti-fibrotic actions.

Spironolactone: improves cardiac outcomes; reduces the anti-inflammatory actions of aldosterone.

SGLT2 inhibitors: main indication here is reduction of cardiovascular risk and of the development or progression of heart failure.

Aspirin or clopidogrel: antiplatelet actions and endothelial protection; reduce the risk of thromboembolic complications and stent occlusion.

Statins: HMG-CoA reductase inhibitors; lipid lowering for cardiovascular protection.

Essay 2: acute post-streptococcal glomerulonephritis

Case: 18 year old man living in South Auckland brought to ED by family. Two episodes of macroscopic haematuria over 24 hours and passing much less urine than usual. Recurrent red crusty skin sores on hands and face (crusted honey-coloured lesions around mouth and chin, consistent with impetigo). Periorbital oedema noticed by family. In ED: low-grade fever 37.5 C, BP elevated at 152/100 mmHg.

Investigations:

Test	Patient	Normal range
Serum creatinine	164 umol/L	55 to 95
eGFR	54 mL/min/1.73m2	>90
Electrolytes (Na+, K+)	normal
White cell count	16.5 x 10^9/L	3.5 to 8.5
Neutrophils	14.8 x 10^9/L	2 to 8
Urinalysis dipstick	4+ blood, 1+ protein
Urinalysis	RBC >100 x 10^6/mL

Answers:

• Presentation: acute nephritic syndrome.
• Most likely cause: post-streptococcal glomerulonephritis.
• Confirmatory investigations: complement levels, post-streptococcal antibodies (IgM for acute), swabs of the skin lesions, and kidney biopsy.

Histology and immunofluorescence in APSGN

• Light microscopy: acute proliferative pattern, with mesangial expansion and occlusion of capillary loops, along with neutrophils.
• Immunofluorescence: granular pattern along the capillary loops with IgG and C3.

Immunopathology of acute glomerulonephritis

Acute post-streptococcal glomerulonephritis (APSGN):

• Triggered by recent infection with specific strains of group A beta-haemolytic streptococcus.
• It is an immune complex disease, triggering complement activation and inflammation.
• Immune complexes arise either in situ, from deposition of streptococcal antigens within the glomerular basement membrane with antibody binding, or by glomerular trapping of circulating immune complexes. Binding of multiple IgM or IgG antibodies to soluble antigen forms an insoluble complex that deposits at the tissue surface.
• This triggers complement activation (C3 degradation) by the classical pathway.
• Inflammation follows.

Sequence in the clinical case:

1. Activated immune complexes and/or nephritogenic antigens circulate from the streptococcal infection.
2. They attract and activate complement, with injury as the complexes contact the endothelium.
3. Chemotaxis via C3a and C5a recruits neutrophils.
4. Proteases are activated.
5. The result is a proliferative form of glomerulonephritis.

Complement activation as it applies to glomerulonephritis

Three activation pathways converging on C3 and C5:

• Classical: IgG1, IgG3, IgM with C1q, C2, C4, forming the C4bC2a classical pathway C3 convertase.
• Lectin: MBL and MASPs, triggered by microbial surfaces, agalactosyl IgG, IgG4, IgA, SpeB, also forming C4bC2a.
• Alternate: spontaneous C3 tickover, damaged cells, LPS, IgA, with C3b plus properdin and complement factor B forming the C3bBb alternative pathway C3 convertase.

Both converge on C3, then on the C5 convertases (C4bC2aC3b and C3bBbC3b), which cleave C5 to give:

• C5a, a chemotactic factor and key mediator.
• C5b,6,7,8,9, the membrane attack complex.

Complement regulatory proteins (key checkpoints):

• Circulating: factor H (CFH), factor I (CFI), membrane cofactor protein (MCP), which regulate the convertases.
• Cell-bound: CD59, which regulates MAC formation.

Treatment of APSGN

• Treat the infection with penicillin.
• Supportive management of acute nephritic syndrome, including blood pressure management.
• The disease is self-limiting.
• Immunosuppressive therapy is not indicated.

Essay 3: advanced chronic kidney disease

Case: 45 year old woman with known CKD who had not attended clinics for several years, presenting to ED with tiredness, lethargy, decreased appetite and associated nausea especially in the morning. BP 158/96 mmHg, JVP 4 cm, small amount of ankle oedema but no pulmonary oedema, left ventricular hypertrophy on ECG.

Blood test	Patient	Normal range
Na+	140 mmol/L	138 to 142
K+	5.1 mmol/L	3.5 to 5.2
HCO3-	18 mmol/L	22 to 28
Creatinine	240 umol/L	55 to 95
eGFR	20 mL/min/1.73m2	>90
Albumin	32 g/L	36 to 42
Alkaline phosphatase	285 IU/L	<120
Ca2+	2.05 mmol/L	2.2 to 2.6
PO4 3-	2.3 mmol/L	0.8 to 1.6
Serum urate	0.54 mmol/L	<0.35
Hb	92 g/L	>135
MCV	95 fL	75 to 95
MCH	28 pg	24 to 28
PTH	68 pmol/L	2 to 7
Plasma ferritin	50 ug/L	20 to 120
UACR	85 mg/mmol	<3.5
Urinalysis	>10^6/L RBCs	normal, no cells
Cholesterol	5.8 mmol/L	3 to 5.5
LDL cholesterol	3.4 mmol/L	<1.8
Glucose	5.6 mmol/L	4 to 7
HbA1c	41 mmol/mol	<40

Abnormalities and their pathophysiological basis:

• Stage 4 CKD, not requiring dialysis.
• Normocytic normochromic anaemia of CKD: decreased EPO, inflammation, and decreased iron availability (functional iron deficiency).
• Urinalysis and UACR consistent with chronic glomerulonephritis.
• Hyperuricaemia from decreased excretion, with increased risk of gout and increased cardiovascular risk.
• Low albumin reflects decreased nutrition.
• The raised HbA1c does not mean she is diabetic; it reflects the low Hb.

CKD-MBD and secondary hyperparathyroidism

Biochemical picture:

• Hypocalcaemia (low-normal values).
• Low levels of 1,25(OH)2 vitamin D3.
• Hyperphosphataemia.
• High concentration of PTH.
• Elevated (bone) alkaline phosphatase.
• Acidosis may also contribute to the bone changes.

Pathogenesis (progressive loss of renal mass impairs renal phosphate excretion, raising serum phosphorus):

1. Chronic kidney disease with loss of nephrons means an inability to excrete excess phosphate.
2. Phosphate retention raises FGF23.
3. FGF23 increases urinary Pi excretion (a compensatory response) and decreases 1,25(OH)2D.
4. Reduced 1,25(OH)2D lowers Ca2+ and raises PTH; the low Ca2+ also raises PTH directly.
5. The result is secondary hyperparathyroidism, which feeds back to alter Ca2+, Pi and FGF23, forming a self-reinforcing loop.

Management of advanced CKD

• Anaemia: iron infusion, EPO injections.
• Hyperuricaemia: no treatment if asymptomatic; allopurinol if gout.
• Cholesterol (cardiovascular risk): statins.
• Albumin: nutrition.
• Metabolic bone disease: calcitriol (active D3), dietary measures with phosphate binders, and for severe hyperparathyroidism surgery or calcium receptor blockers.
• Acidosis: sodium bicarbonate.
• Proteinuria and hypertension: ARB.

Essay 4: pre-renal AKI from ileostomy losses

Case: Mrs Jean Smith, 65 year old woman, presents to ED with several episodes of syncope over 24 hours. Discharged 7 days ago after colectomy for carcinoma of the colon with formation of an ileostomy. Large losses of watery faeculent material from the ileostomy, about 1500 mL a day. Supine BP 100/70 mmHg dropping to 90/60 on sitting (usual BP 140/90). JVP not visible even lying flat. Weight on admission 72 kg, weight on discharge 75 kg. Only 100 mL of urine passed in the last 12 hours.

Test	Result	Normal range
Serum creatinine (admission)	350 umol/L	65 to 100
Serum creatinine before surgery	115 umol/L
eGFR before surgery	55 mL/min/1.73m2	>90
Serum potassium (admission)	6.3 mmol/L	3.5 to 5.2
pH	7.18	7.35 to 7.45
pCO2	28 mmHg	35 to 45
HCO3-	12 mmol/L	22 to 28

Diagnosis:

• Low perfusion (pre-renal) acute kidney injury due to profound intravascular volume depletion superimposed on existing CKD: low BP, low JVP, 4 kg weight loss, with increased risk because of the CKD.
• Associated metabolic acidosis with respiratory compensation.

Pathophysiology:

• The oliguria is an appropriate physiological response.
• Both systemic and kidney-specific responses must be described: activation of RAAS, AVP and the sympathetic nervous system via central baroreceptors, plus local activation via juxtaglomerular cells in the afferent arterioles (the same pathway diagram as Essay 1).

Hyperkalaemia and metabolic acidosis in Essay 4

• The key driver of the metabolic acidosis is loss of bicarbonate in ileostomy fluid.
• Low intravascular volume causes generalised tissue hypoperfusion, forcing a change to anaerobic metabolism producing lactate and 2 H+.
• H+ is buffered inside cells, so K+ is extruded out.
• The failing kidneys cannot regenerate sufficient bicarbonate or excrete the excess H+ or K+.

Immediate and longer-term management of Essay 4

Immediate:

• Rapid IV fluid resuscitation with normal saline; IV NaHCO3 could also be used.
• The 3 kg weight loss corresponds to a 3 L fluid deficit.
• Rapid correction of intravascular volume should restore tissue perfusion and correct the metabolic acidosis and hyperkalaemia.
• Consider other treatments for hyperkalaemia if ECG changes progress.

Important

Do not give an ACEI or ARB in this clinical setting.

Longer-term follow-up plan:

• Education on the sick day rule.
• Adequate fluid intake.
• Slow gut motility with loperamide or codeine.
• She has CKD, the biggest risk factor for AKI: assess UACR.
• Increased risk of progressive CKD and associated cardiovascular risk, so start an ARB or ACEI once blood pressure is restored, and not before.
• SGLT2 inhibitor.
• Consider statins.

Self-test

1. Describe the clinical features in Case 1 that establish nephrotic-range proteinuria rather than heart failure, and explain what accounts for the cardiomegaly.
2. List the macrovascular and microvascular complications to look for on examination of a patient with diabetes, and state the one thing that does not count as examination.
3. Describe the steps by which an SGLT2 inhibitor reduces intraglomerular hypertension and proteinuria.
4. List the potential side effects an SGLT2 inhibitor patient must be educated about under the sick day rule.
5. What are the three potential contraindications plus the infection-related risk listed for SGLT2 inhibitor patient selection, and what eGFR threshold is given for eligibility?
6. A patient started on an SGLT2 inhibitor has an acute drop in eGFR at follow-up. Explain how this should be handled and why.
7. Explain the kidney-specific mechanisms by which an ARB reduces proteinuria.
8. In Case 1 at 4 weeks, proteinuria and albumin improved but creatinine rose and eGFR fell to 35 mL/min. Explain the three contributing mechanisms and say whether this represents progressive CKD.
9. Distinguish how an SGLT2 inhibitor and an ARB each normalise glomerular pressure in type 2 diabetes.
10. Describe the sequence of events from low intravascular volume to oliguria and AKI, naming the three neurohormonal branches and the effect of each.
11. What urine sodium and osmolality would you expect early in pre-renal AKI, and how do they change once ATN is established?
12. Explain why a patient after a 10 minute cardiac arrest is both acidotic and hyperkalaemic.
13. Describe the mechanism of action of frusemide and explain why a drug that is 98% protein bound still reaches its site of action.
14. Explain why frusemide also reduces paracellular reabsorption of Ca2+ and Mg2+.
15. Describe how diuretics are handled by the proximal tubule, and predict the effect of probenecid.
16. List the additional medications indicated after anterior MI with AKI, with the main reason for each.
17. Define acute nephritic syndrome as it presents in Essay 2, listing the clinical and laboratory features shown in that case.
18. Describe the light microscopy and immunofluorescence findings expected on biopsy in acute post-streptococcal glomerulonephritis.
19. Describe the immunopathological mechanism of APSGN from streptococcal infection to proliferative glomerulonephritis.
20. Name the three complement activation pathways, their C3 convertases, and the two key products generated downstream of C5.
21. What treatment is given for APSGN, and explain why immunosuppression is not indicated.
22. Explain why the Essay 3 patient has a normocytic normochromic anaemia, and why her HbA1c of 41 mmol/mol does not indicate diabetes.
23. Describe the pathogenesis of secondary hyperparathyroidism in CKD, starting from loss of nephrons.
24. List the management of the metabolic bone disease, anaemia and acidosis in stage 4 CKD.
25. Explain why Mrs Smith is acidotic, distinguishing the main driver from the contributing mechanism.
26. Predict what would happen if an ACEI were given to Mrs Smith on admission, and state when it should be started instead.
27. Integrative: in Case 1 a fall in eGFR after starting an ARB is described as beneficial, whereas in Essay 4 an ACEI is contraindicated. Explain the difference in terms of glomerular haemodynamics.

Answers

Reveal answers

1. Peripheral oedema, heavy proteinuria (4+ protein, urine protein/creatinine ratio 213 mg/mmol against a normal <20) and a low serum albumin of 25 g/L give nephrotic-range proteinuria from diabetic nephropathy. The JVP is 3 cm and so not elevated, which excludes heart failure. The cardiomegaly is due to hypertension, and the hypertension itself is due to Na+ retention.
2. Macrovascular: cerebrovascular, cardiovascular and peripheral vascular disease, where PVD involves all arteries and must be demonstrated clearly rather than by a femoral bruit alone, along with cold peripheries. Microvascular: retinopathy, peripheral neuropathy and autonomic neuropathy, linking PVD and neuropathy to diabetic foot disease. Investigations are not examination.
3. It blocks proximal tubular Na+/glucose cotransport, so more Na+ reaches the macula densa, which increases tubuloglomerular feedback, causing afferent arteriolar constriction, which lowers intraglomerular hypertension and therefore reduces proteinuria. Blood pressure, arterial stiffness, weight and HbA1c also fall.
4. Starvation ketosis, excessive volume depletion, and glycosuria leading to infection.
5. Contraindications: diabetic ketoacidosis, foot ulcers and immunosuppression, plus genital infection risk. Eligibility is given as eGFR >= 30 mL/min/1.73 m2, though the lecturer annotated this criterion in red without stating what the annotation means.
6. Anticipate it at follow-up; it is generally not a reason to stop the SGLT2 inhibitor.
7. Preferential arteriolar vasodilation, efferent greater than afferent, reduces glomerular hydrostatic pressure and therefore proteinuria. It also reduces angiotensin II stimulated sodium and water uptake, giving natriuresis and diuresis, and has anti-inflammatory and anti-fibrotic effects from blocking angiotensin II in tubular epithelial cells.
8. First, the reduction in systemic blood pressure and intravascular volume reduces eGFR because autoregulation is lost and renal perfusion falls, and he has CKD. Second, the SGLT2 inhibitor delivers more Na+ to the macula densa, activating tubuloglomerular feedback and constricting the afferent arteriole. Third, the ARB blocks angiotensin II mediated arteriolar vasoconstriction with efferent vasodilation exceeding afferent, lowering glomerular hydrostatic pressure. The effects are additive and all beneficial: the drugs are working, this is not progressive CKD.
9. The SGLT2 inhibitor acts preglomerularly: increased TGF activity via adenosine causes preglomerular vasoconstriction, increased prostaglandin release causes preglomerular vasodilation, and the RAS/angiotensin II effect is blocked, with the net result that GFR falls while renal vascular resistance is unchanged. The ARB acts postglomerularly, preventing the angiotensin II mediated increase in efferent vasoconstriction. Both return the diabetic glomerulus from high pressure to normal pressure with reduced filtration.
10. Low intravascular volume is sensed by baroreceptors as a threatened or low blood pressure, unloading high-pressure baroreceptors. Three branches follow: increased AVP, which increases distal nephron Na reabsorption; increased sympathetic output, which reduces renal blood flow, hence GFR, hence increases proximal tubular reabsorption of Na and water; and increased renin-angiotensin, which increases aldosterone and hence distal nephron Na reabsorption. There is also local JG cell activation with renin and angiotensin II and afferent arteriolar vasoconstriction. All converge on oliguria and AKI.
11. Initially low urinary sodium and high urine osmolality. With established ATN, urinary sodium losses increase and the kidney becomes less able to concentrate the urine.
12. Profound tissue hypoxia from the arrest drives anaerobic metabolism producing lactate and 2 H+. That H+ is buffered intracellularly, which extrudes K+ out of cells. The AKI means the kidney cannot regenerate sufficient HCO3- or excrete the excess K+.
13. It blocks the NKCC cotransporter on the apical surface of the thick ascending limb of the loop of Henle, blocking Na reabsorption so that delivery to the distal tubule exceeds its reabsorptive capacity, giving net loss of Na and water. Being 98% protein bound it is not filtered, so it reaches the urinary space by tubular secretion in the proximal tubule.
14. Blocking NKCC2 removes the K+ back-leak into the lumen that generates the lumen-positive voltage, and that voltage is the driving force for paracellular reabsorption of Na+, K+, Ca2+ and Mg2+.
15. Diuretics are weak organic anions secreted by the proximal tubule. Peritubular (basolateral) uptake is an active process driven by Na/K-ATPase, via OAT in countertransport with alpha-ketoglutarate, and they are then secreted across the luminal membrane by voltage-driven OAT or a countertransporter exchanging with OH- or urate-. Probenecid inhibits OAT, so it would block this secretion.
16. ARB or ACEI for hypertension, heart failure and long-term cardiovascular risk reduction, acting by systemic vasodilation, reduced afterload, natriuresis and diuresis, reduced filtration pressure and anti-fibrotic actions. Spironolactone to improve cardiac outcomes by reducing the anti-inflammatory actions of aldosterone. SGLT2 inhibitor to reduce cardiovascular risk and the development or progression of heart failure. Aspirin or clopidogrel for antiplatelet action and endothelial protection, reducing thromboembolic complications and stent occlusion. Statins, HMG-CoA reductase inhibitors, for lipid lowering and cardiovascular protection.
17. Acute nephritic syndrome: macroscopic haematuria, reduced urine output, periorbital oedema and hypertension (152/100), with impaired renal function (creatinine 164 umol/L, eGFR 54), a neutrophil leucocytosis (WCC 16.5, neutrophils 14.8) and urinalysis showing 4+ blood with 1+ protein and RBC >100 x 10
18. Light microscopy shows an acute proliferative pattern with mesangial expansion, occlusion of capillary loops and neutrophils. Immunofluorescence shows a granular pattern along the capillary loops with IgG and C3.
19. Recent infection with specific strains of group A beta-haemolytic streptococcus triggers immune complex disease. Complexes form either in situ, from streptococcal antigens deposited in the glomerular basement membrane with antibody binding, or by glomerular trapping of circulating complexes. These activate complement by the classical pathway with C3 degradation, causing injury as complexes contact the endothelium; C3a and C5a chemotaxis recruits neutrophils, proteases are activated, and the result is a proliferative glomerulonephritis.
20. Classical (IgG1, IgG3, IgM with C1q, C2, C4) and lectin (MBL and MASPs, triggered by microbial surfaces, agalactosyl IgG, IgG4, IgA, SpeB) both form the C4bC2a C3 convertase; the alternate pathway (spontaneous C3 tickover, damaged cells, LPS, IgA) forms C3bBb with C3b, properdin and factor B. Both converge on C3 and then C5 convertases (C4bC2aC3b, C3bBbC3b), generating C5a as a chemotactic factor and C5b-9, the membrane attack complex.
21. Penicillin to treat the infection, plus supportive management of the acute nephritic syndrome including blood pressure management. Immunosuppressive therapy is not indicated because the disease is self-limiting.
22. The anaemia of CKD reflects decreased EPO, inflammation, and decreased iron availability, a functional iron deficiency (her ferritin is within the normal range at 50 ug/L). The HbA1c is raised because her Hb is low, not because she is diabetic.
23. Progressive loss of renal mass (loss of nephrons) impairs renal phosphate excretion, so serum phosphate rises. Phosphate retention raises FGF23, which increases urinary Pi excretion as a compensation but also lowers 1,25(OH)2D. Falling 1,25(OH)2D lowers Ca2+ and raises PTH, and the low Ca2+ raises PTH directly. Secondary hyperparathyroidism results and feeds back on Ca2+, Pi and FGF23 in a self-reinforcing loop.
24. Anaemia: iron infusion and EPO injections. Metabolic bone disease: calcitriol (active D3), dietary phosphate binders, and for severe hyperparathyroidism surgery or calcium receptor blockers. Acidosis: sodium bicarbonate. (Also hyperuricaemia: no treatment if asymptomatic, allopurinol for gout; statins for cholesterol; nutrition for albumin; ARB for proteinuria and hypertension.)
25. The key driver is loss of bicarbonate in the ileostomy fluid. Contributing to it, the low intravascular volume causes generalised tissue hypoperfusion and a switch to anaerobic metabolism producing lactate and 2 H+, with the failing kidneys unable to regenerate bicarbonate or excrete the excess H+ or K+.
26. It would be harmful and is explicitly contraindicated in this setting of profound volume depletion and pre-renal AKI. An ARB or ACEI should be started only once blood pressure has been restored, as part of longer-term management to reduce progression of CKD and cardiovascular risk.
27. In Case 1 the patient is volume expanded with intraglomerular hypertension, so ARB-induced efferent vasodilation lowers glomerular hydrostatic pressure, reduces proteinuria and protects the kidney; the modest fall in eGFR is the intended haemodynamic effect. In Essay 4 the patient is profoundly volume depleted with renal perfusion already low, and filtration is being maintained by angiotensin II mediated efferent vasoconstriction; blocking it removes that support and worsens the AKI. Restore intravascular volume first, then start the ARB or ACEI.