Mednotes

L20 Renal RENAL CLINICAL DAY

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tagsrenal, lecture
aliasesL20 Renal RENAL CLINICAL DAY

33 min read

Overview

A case-based integration day for the renal module, working through five clinical
threads: renal colic and stone disease, urinary tract infection (including the
awkward “do you treat?” scenarios), haematuria and its two possible homes
(urological versus nephrological, with IgA nephropathy as the worked
example), hyponatraemia as a disorder of water rather than salt (leading into
SIADH and the cardio-renal syndrome), and cardiovascular/renal risk in
type 2 diabetes with the drug classes that modify it. The unifying message of
the module summary is that clinical presentations are renal physiology and
pathophysiology made visible, and that drugs work by correcting that
pathophysiology.

Renal colic and stone disease

Presentation: sudden onset, severe, intense colicky flank pain radiating to the
groin, with haematuria on passing urine after the pain starts. In the case of a
44 year old male with this picture the differential offered was renal cancer,
urinary tract infection, first presentation of benign prostatic hypertrophy, or
renal calculus.

Imaging options considered were plain abdominal X-ray, renal ultrasound, both
together, or CT of the kidneys, ureters and bladder (CT-KUB). The slides show a
plain abdominal X-ray labelled as a right ureteric calculus, an axial CT with a
calculus near the right kidney/ureter, and a renal ultrasound showing an
echogenic focus with shadowing. The summary slide gives the diagnostic test for
renal stone as CTU (emphasised in red on the slide).

Stone types and frequencies

  • Calcium oxalate 36-70%
  • Calcium phosphate (hydroxyapatite) 6-20%
  • Mixed calcium oxalate and phosphate 11-30%
  • Struvite (magnesium ammonium phosphate) 6-20%, associated with infection
  • Uric acid 6-17%, radiolucent
  • Cysteine 0.5-3%

Mechanism of formation. Precipitation of crystals in a concentrated
solution, illustrated by rock candy crystallising on a string. Candidate major
contributors put to the class were dietary calcium, excess uric acid excretion,
excess urinary oxalate excretion, excess urinary calcium excretion and
concentrated urine.

Management of renal colic (summary slide): alpha blocker (emphasised) plus
analgesic. Definitive treatment depends on site and size.

  • Renal stones: ESWL or ureteroscopy, or percutaneous approach.
  • Ureteric stones: under 5 mm discharge to GP; 5-6 mm follow up; 7 mm and above
    acute operation.

CARI guideline pathway at the acute stone event. Three parallel strands at
presentation.

  1. Pain management: NSAIDs, paracetamol or opioids, all short-acting therapies,
    with rescue therapies prepared.
  2. Imaging: first suspected or complicated stones get non-contrast CT; recurrent
    uncomplicated stones get ultrasound. Complicated stones are those associated
    with urinary obstruction, infection, or risk of damage to the kidney or
    urinary tract.
  3. Stone retrieval, which may need urine straining for 48 hours, then stone
    analysis.

Post-stone event, in the patient’s usual environment and lifestyle: first-time
stone formers get a basic metabolic evaluation (medical history, blood test,
initial midstream urine); recurrent or high-risk formers get a comprehensive
evaluation (24 hour urine analysis, ideally about two collections; initial
midstream urine with cystine screen for unknown stone types; stone analysis as
required for unusual patterns of recurrence or unexpected treatment response).

Stone investigations. History should cover bowel disease, because oxalate
handling by the gut involves absorption in the small bowel and excretion in the
large bowel. Investigations: stone analysis; serum calcium, phosphate and uric
acid, with electrolytes and pH considered; 24 hour urinary excretion of calcium,
oxalate, phosphate and uric acid, with total volume helpful. Dietary review
covers dietary calcium (needs to be high normal), salt intake (needs to be low),
oxalate-rich foods, excess vitamin C and vitamin D supplementation.

Stone prevention.

  • Fluids above all: dilute urine, more than 2.5 litres.
  • Non-opaque (uric acid) stones: fluids, alkalinisers, allopurinol, surveillance.
  • Calcium oxalate stones: high normal dietary calcium, reduce oxalate sources,
    low dietary salt; consider allopurinol because of uric acid levels and possible
    seeding.
  • Potassium citrate can be considered for recurrent stone formers.
  • Hypercalciuria: thiazides, but of limited value.

CARI dietary guidance. Overall: healthy eating patterns and optimised fluid
intake to raise daily urine output. For recurrent or high-risk stones, do stone
analysis, metabolic evaluation and urinalysis, determine stone type, then
dietitian-led nutrition therapy, with simultaneous pharmacological therapy where
needed (potassium citrate for profound hypocitraturia, thiazide diuretics for
severe hypercalciuria). For calcium-based stones specifically: urine output at
least 2.5 L/day; sodium under 2300 mg/day (100 mmol/day) to lower urine calcium;
calcium 1000-1200 mg/day according to age and sex; limit non-dairy animal
protein to reduce acid load and urine calcium; diet rich in fruit and vegetables
to reduce acid load and raise urine citrate. Calcium oxalate stones: a low
oxalate diet is not recommended, instead pair calcium-rich foods with oxalate
foods at meals if urine oxalate is high. Calcium phosphate stones: avoid high
alkali diets that raise urine pH above 7. Track progress with repeat 24 hour
urinalysis and refine the intervention.

Urinary tract infection

Index case: 31 year old woman with her third UTI, symptoms of urinary frequency
and dysuria, asymptomatic after treatment. The teaching questions probed whether
the commonest organism is Staph. saprophyticus, whether most lower UTIs are due
to gut flora, whether poor toilet hygiene is the main cause, and whether Ural
sachets alkalinising the urine treat the infection; a further set asked whether
7 days of antibiotics is needed to prevent recurrence, whether single-dose
therapy works in uncomplicated UTI, whether nitrofurantoin is safe in stage 3
CKD, and whether trimethoprim or nitrofurantoin are the usual first choices; and
a third asked whether she needs urgent ultrasound, urgent CT KUB, no
investigation, or whether she caught it from her partner.

Organisms

  • Community acquired: E. coli 60-70%; Staph. saprophyticus 20-30%; Enterococcus
    (Strep. faecalis); Proteus mirabilis.
  • Hospital acquired: Enterococcus (Strep. faecalis), Klebsiella, Proteus,
    Pseudomonas sp., Enterobacter sp.

Uncomplicated UTI treatment. Single dose therapy or 3 day therapy.

  • Trimethoprim 600 mg (2 tablets) or 300 mg daily
  • Co-trimoxazole 2.8 g (3)
  • Nitrofurantoin 50-100 mg BD (NICE guidelines)
  • Norfloxacin 800 mg (2), or ciprofloxacin 500 mg, not first line because of
    resistance concerns
  • Caution with amoxicillin-clavulanic acid

Non-pharmacological treatments are symptomatic but not bactericidal, and
alkalinisation of the urine negates the efficacy of nitrofurantoin.

Antibiotic prophylaxis. Indicated for recurrent UTI, defined as more than 2
in 6 months or more than 3 in 12 months, and in at-risk individuals such as
pregnancy and transplant. Regimens: trimethoprim 150 mg (half tablet),
norfloxacin 200 mg (caution per NICE), nitrofurantoin 50 mg (normal GFR, caution
with long term use). Duration up to 6 months; NNT to prevent any recurrence in
one year is 1.85. In post-menopausal women, topical oestrogens reduce episodes
(0.5 versus 5.9 episodes per patient year) by reducing vaginal colonisation with
E. coli. Cranberry juice has no good clinical evidence, from 2 RCTs against
placebo or against TMP-SMX.

The “do you treat?” case series. Each is a yes/no decision on the same kind
of urine result in a different patient.

  1. 75 year old woman in a rest home, routine GP review, asymptomatic. Urine
    10-50 WBC, no RBC, squamous epithelial cells present, 10^6 organisms
    predominantly E. coli.
  2. 24 year old woman, 16 weeks pregnant, asymptomatic, routine antenatal MSU:
    10-40 WBC, 5x10^6 E. coli on culture.
  3. 72 year old woman, stable CKD with eGFR 45 mL/min, mild dysuria; urine 10-50
    WBC, no RBC, squamous epithelial cells present.
  4. The same 72 year old, but dysuria intermittent over 3-4 weeks and the culture
    negative. Treatment options raised here: exclude vaginal thrush, consider
    oestrogen status, and what other important questions to ask.
  5. The same 72 year old, living with her husband and fully independent, CKD due
    to hypertension, on candesartan, dysuria for 3-4 days, urine WBC over
    100x10^6/L, culture E. coli, treated with trimethoprim; repeat kidney function
    shows eGFR fallen from 45 to 37 mL/min. The options were acute kidney injury,
    an allergic or adverse drug reaction, stopping the candesartan, or an effect
    of the trimethoprim therapy.

Recurrent UTI and structural disease

Case: repeat UTIs about 4-6 weeks apart with urine culture growing Proteus
mirabilis, and the question of whether to investigate. The imaging options put
were plain abdominal X-ray alone, renal tract ultrasound with plain abdominal
X-ray, CT KUB without contrast, or CT KUB with contrast. The linked images show
renal calculi in recurrent Proteus UTI: a plain abdominal X-ray, an
intraoperative open kidney with a large staghorn calculus in the renal pelvis,
and several removed staghorn calculi. The point to hold: recurrent Proteus
infection and stone disease travel together (struvite stones are the
infection-associated type from the stone list above).

Haematuria

Case 1: 56 year old male with one week of intermittent macroscopic haematuria,
ex-smoker, controlled hypertension, no loin pain, no weight loss, no urinary
tract symptoms. The options were reassurance with re-presentation if it recurs,
urgent CT, dipstick plus urinalysis including cytology first, or empirical
antibiotics for presumed asymptomatic UTI.

Approach. Haematuria is either nephrological or urological. Baseline: MSU and
cytology, urea and creatinine. Then by age:

  • Under 40: renal ultrasound; if normal, nothing further from the urological
    side, otherwise nephrology referral to rule out glomerulonephritis.
  • 40 to 80: renal CT and cystoscopy.
  • Over 80: renal ultrasound and cystoscopy.

Remember the smoking risk.

Risk factors raising suspicion of significant urological disease: history of
recurrent visible haematuria; age over 40; current or recent smoking; recurrent
UTI or other urological disorders; occupational exposure to chemicals or dyes;
previous pelvic irradiation; excessive analgesic use; treatment with
cyclophosphamide.

Guideline work-up pathway. Split first into non-visible and visible
haematuria. Non-visible splits into asymptomatic and symptomatic, then by age
(under 40 versus over 40). The nephrological arm means considering nephrological
causes: measure blood pressure, test creatinine (eGFR), ACR/PCR, and request
urine microscopy for dysmorphic red cells and urinary casts, then ultrasound of
the urinary tract. Visible haematuria (and the symptomatic/age-driven pathway)
goes to urinary tract imaging where direct access permits, for example IVU,
ultrasound or CTU, which is either positive or negative. Positive imaging leads
to cystoscopy/urology referral, from which a cause is either found or not.
Negative imaging asks whether the patient is over 40 or has positive urine
cytology: yes goes to cystoscopy/urology referral, no goes to monitoring for a
urological cause. Cystoscopy should also be considered below age 40 if risk
factors for urothelial cancer are present.

Both monitoring arms sit in primary care.

  • Monitor for nephrological cause: annually with urine dipstick, BP, eGFR and
    ACR/PCR while haematuria persists. Refer to nephrology if eGFR under 30
    mL/min/1.73m²; eGFR under 45 with diabetes; eGFR declining by more than 10
    mL/min at any stage in the last five years or more than 5 mL/min in the last
    year; proteinuria ACR at least 30 mg/mmol or PCR at least 50 mg/mmol; or
    uncontrolled blood pressure (140/90 mmHg).
  • Monitor for urological cause: annually for two years with urine dipstick,
    eGFR, ACR/PCR and cytology. Refer back to urology if haematuria persists, urine
    cytology is positive, or urinary tract symptoms develop or increase.

Case 2: 26 year old male with an upper respiratory tract infection, then
macroscopic haematuria 1-2 days later, that is synpharyngitic haematuria, with
non-specific malaise and lethargy; three days later the haematuria persists and
he has an episode of right-sided loin pain. Investigations show normal renal
function, normal blood pressure, normal haematology, negative auto-antibody
screen and normal renal ultrasound. The options were post-streptococcal GN,
renal calculus, nephritic syndrome, need for cystoscopy, or consistency with a
glomerulonephritis.

Important

Haematuria with proteinuria and no UTI symptoms (culture negative) is
glomerulonephritis until proven otherwise. Haematuria without urological
findings should always prompt consideration of GN, and warrants nephrological
review and discussion. In this case a renal biopsy is warranted.

IgA nephropathy

Worldwide the most common form of primary glomerulonephritis.

Glomerular pattern of injury. Mesangial: mesangial hypercellularity and
matrix accumulation resulting from mesangial immune complex accumulation
(recall the fenestrated endothelium within the glomerulus). The histology shows
mesangial hypercellularity and matrix on PAS, hypercellularity on H&E, and
positive mesangial staining on immunofluorescence consistent with IgA/immune
complex deposition.

Warning

The transcript flags that the specific stains on the histology slide were not
labelled and were inferred from appearance.

Presenting patterns by age (from the incidence-versus-age graph, four
overlapping curves):

  • Henoch-Schonlein purpura, peaking early, around age 10
  • Recurrent macroscopic haematuria, peaking around age 15-20
  • Proteinuria with microscopic haematuria, peaking around age 30-35
  • Hypertension, nephrotic syndrome or chronic renal failure, a broad peak around
    age 30-40 and the most persistent pattern at older ages

Four-hit hypothesis for primary IgA nephropathy.

  1. Aberrant production of galactose-deficient IgA1 (Gd-IgA1) secreted by B cells
    and plasma cells, triggered by gut or upper respiratory tract mucosal
    infection or an altered microbiome.
  2. Gd-IgA1 enters the systemic circulation, where IgG or IgA autoantibodies
    recognising Gd-IgA1 are formed.
  3. Formation of immune complexes containing Gd-IgA1.
  4. Deposition of those immune complexes in the glomerular mesangium.

A possible role is proposed for the gut microbiota enzymatically removing
galactose moieties from the IgA hinge region; the hinge region diagram shows
O-glycan-specific antibodies binding the Gd-IgA1 hinge at amino acid positions
225-236 (a Pro/Ser/Thr sequence). The fuller pathogenesis schematic runs:
antigen crosses the mucosal barrier, dendritic cell presents to B and T cells in
a Peyer patch via BAFF-R, TACI, BAFF, APRIL, BCMA and CD40/CD40L, generating
CD38+ IgA1 plasma cells and IgA1; Gd-IgA1 and anti-Gd-IgA1 IgG/IgA immune
complexes rise in the circulation and deposit in mesangial cells, with
proteinuria, complement activation, RAAS activation, ET-1/ETA receptor
activation and SGLT2 involvement at the nephron.

Compared with a healthy glomerulus (Bowman space, podocyte, arteriole,
glomerular capillary lumen), the IgAN glomerulus shows Gd-IgA1 immune complex
deposition in the mesangium, mesangial hypercellularity, endocapillary
hypercellularity, crescent formation and podocyte injury.

Natural history and where therapy acts. Over the disease course from early
to late, the contribution of immune complex-mediated nephron loss falls, while
the intrarenal response to nephron loss (glomerular hyperfiltration,
tubulointerstitial response to proteinuria, systemic hypertension) rises; nephron
number declines throughout. Therapy maps onto this timeline. Immune-directed
therapy acts early: systemic steroids, targeted steroids, and inhibitors of
immune activation. Agents that slow progression act on the nephron-number arm:
RAAS inhibitors, SGLT2 inhibitors and ET-1 receptor antagonists.

Hyponatraemia: a water problem

Case 1: 25 year old in neurosurgical ICU with a head injury, plasma Na+ 125
mmol/L (normal 140) three days after admission; blood pressure 136/80, JVP 2 cm,
no oedema.
Case 2: 44 year old woman admitted at the end of a half marathon with
confusion and unsteadiness; BP 120/80, JVP 3 cm, normal examination, Na+ 122
mmol/L, K+ 4.2 mmol/L, urea 4.2 mmol/L, creatinine 85 µmol/L.

In both, the class was asked whether plasma Na+ reflects total body sodium,
whether it means sodium wasting or dehydration, whether renal impairment is
required, and (case 2) whether she has drunk excess water.

The four-question framework, answered as the slides build:

  1. What does the hyponatraemia mean? It reflects body water: is the plasma sodium
    diluted, or have there been severe losses of salt and water?
  2. What clinical information do you need? Assessment of volume status: is the
    patient volume deplete, volume excess, or is intravascular volume apparently
    normal?
  3. What investigations sort out the mechanism? The options offered were repeating
    the plasma sodium, plasma osmolality alone, urine osmolality alone, urine and
    plasma osmolality together, or measuring plasma AVP; with the added question
    of what urine sodium would do in case 1 versus case 2.
  4. How would we treat it?

Water regulation. AVP release is driven by the thirst centre and
osmoreceptors in the hypothalamus signalling release from the pituitary, giving
very tight minute-to-minute control of plasma osmolality at 274-284 mosm/kg. Low
plasma osmolality gives low AVP and loss of water, raising plasma osmolality;
high plasma osmolality gives high AVP and water reabsorption, lowering
osmolality, which matters for cell volume and integrity. A stress response with
sympathetic nerve input increases AVP release and so increases water reabsorbed
in the collecting duct. Angiotensin II also feeds back on to the hypothalamic
thirst centre.

Results in both cases: urine osmolality high at 700-800 mosm/kg with plasma
osmolality low at 260 mosm/kg.

SIADH. The management principle is to correct the driver of excessive AVP
release.

  1. Case 1: head injury and pain give excess AVP as a stress response.
  2. Case 2: excess fluid intake while running, plus extreme exercise activating
    the sympathetic nervous system (AVP release) and RAAS, with renal perfusion
    reduced during exercise.

Other causes: drugs (ecstasy and rave parties), CNS drugs, pneumonia. Treatment:
fluid restrict and correct very slowly, letting the kidney and brain do the
correction themselves.

Cardio-renal syndrome

Case: 76 year old man with known congestive heart failure admitted with acute
pulmonary oedema. BP 110/70, JVP 6 cm, peripheral as well as pulmonary oedema.
Plasma Na+ 122 mmol/L, K+ 5.2 mmol/L, urea 13.5 mmol/L, creatinine 175 µmol/L,
eGFR 32 mL/min, against a previous baseline creatinine 120 µmol/L and eGFR 50
mL/min. The options were intravascular volume depletion, low urine osmolality,
elevated urine osmolality, urinary sodium wasting, or suppressed plasma AVP.

Definition. Disorders of the heart and kidney whereby acute or chronic
dysfunction in one organ may induce acute or chronic dysfunction in the other.

  • Progressive left ventricular failure: decreased cardiac output, reduced
    systemic perfusion, decreased renal function. Mitral regurgitation here is a
    consequence, not a cause.
  • Progressive right ventricular failure: back pressure causes kidney interstitial
    oedema.
  • The failing heart activates RAAS, the sympathetic nervous system and AVP,
    producing vasoconstriction, salt and water retention and expansion of
    intravascular volume; by Starling’s law this gives peripheral oedema, and high
    cardiac afterload, dilated cardiomyopathy and raised left atrial pressure give
    pulmonary oedema.

Non-osmotic (baroreceptor-driven) AVP release. The cardioregulatory centre
receives glossopharyngeal and vagal afferents from high-pressure baroreceptors in
the heart and connects via the sympathetic trunk, ganglia and nerves to
peripheral vasoconstriction; AVP and angiotensin II act on the kidney and drive
aldosterone release. The kidney’s response, decreased solute-free water
excretion and decreased sodium excretion, is what produces the hyponatraemia.

Sequence leading to salt and water retention. Heart failure (low cardiac
output states) and sepsis (high cardiac output, vasodilated states) both converge
on a threatened or low blood pressure, which unloads the high-pressure
baroreceptors, giving three parallel arms:

  1. Increased AVP, increasing distal nephron sodium reabsorption.
  2. Increased sympathetic output, decreasing renal blood flow and GFR and
    increasing proximal tubular reabsorption of sodium and water.
  3. Increased renin-angiotensin, increasing aldosterone and so distal nephron
    sodium reabsorption.

All three converge on increased extracellular volume and oedema and increased
venous and intracardiac pressures. Increased atrial receptor discharge and
increased natriuretic peptide act as negative feedback on AVP, sympathetic
output and renin-angiotensin, and the raised venous/intracardiac pressures both
feed back to inhibit further activation and feed forward to worsen the fall in
renal blood flow and GFR.

Dual haemodynamic pathways for acute cardiorenal syndrome.

  • Arterial underfilling: decreased cardiac output, decreased effective
    circulating volume, decreased renal blood flow and plasma flow, activation of
    RAAS and SNS, inflammatory pathways, then decreased GFR with sodium and water
    retention, increased oedema and preload and increased afterload, feeding back
    to the heart.
  • Venous congestion: venous congestion and venous hypertension with raised
    intra-abdominal pressure, decreased arteriovenous perfusion gradient, kidney
    interstitial oedema, activation of RAAS and SNS and inflammatory pathways, into
    the same central box, linking heart and kidney bidirectionally.

Fluid overload maintains AKI. Extrinsic pressure from intra-abdominal
hypertension, increased venous pressure and increased renal vascular resistance
raise interstitial pressure and cause renal oedema (local inflammation, venous
congestion, tubular leakage), which raises tubular pressure, reduces the
glomerular ultrafiltration gradient and increases renal vascular resistance
further: a self-reinforcing cycle.

Treating the cardio-renal case. The options put were 2 L of normal saline to
raise blood pressure, withholding an ACE inhibitor because of AKI, frusemide
treating the pulmonary oedema without affecting survival, dialysis to correct the
AKI, and ACE inhibitor worsening the blood pressure. Immediate management is
oxygen, morphine and frusemide.

Why ACEI or ARB despite a low blood pressure. Recalling that
, an ACEI or ARB decreases afterload, improves cardiac output
which in turn improves blood pressure, improves renal perfusion, and promotes
natriuresis. On the Frank-Starling curves, the failing heart’s shallow,
low-plateau curve is shifted up toward the normal curve by ACEI or ARB at the
congested (high preload) end.

Identifying the cause of AKI in acute heart failure. After decongestion, if
creatinine rises or AKI appears, do a clinical assessment for fever, infection
(urine, chest, skin, other) and hypotension. If present, address the infection.
If not, distinguish no decongestion (clinically reassess and look for other
causes of AKI) from adequate decongestion (continue). Signs of adequate
decongestion are increased urine output, weight loss and reduced breathlessness.

Renal autoregulation and blood pressure

On the graph of intraglomerular pressure against mean arterial pressure, the
normal curve plateaus early. Chronic hypertension with normal renal function
shifts the plateau to the right (higher pressures). Chronic hypertension with
chronic renal disease is steep with no autoregulatory plateau at all. Any form
of cardiovascular instability cuts across the autoregulatory range. In the
annotated patient, admission BP 110/70 against a pre-admission BP of 160/90
means that a chronically hypertensive kidney, whose autoregulatory range has
shifted right, becomes vulnerable to AKI when the blood pressure falls back
toward “normal” levels.

Diabetic kidney disease and cardiovascular risk

Case: 48 year old woman with T2DM for 10 years, smoker, claudication at 200
m, BP 156/96, creatinine 160 µmol/L, eGFR 31 mL/min, HbA1c 64 mmol/mol,
cholesterol 6.1 mmol/L, HDL 0.9 mmol/L. The class estimated her 5 year
cardiovascular risk from options of 6%, 20%, 28%, 32% and 59%.

The New Zealand CVD and ESRD risk calculator for people with type 2 diabetes was
run twice on essentially the same patient.

  • European ethnicity, previously smoked, 8 years duration: 5 year CVD risk 19.9%,
    5 year MI risk 6.9%, 5 year ESRD risk 21.2%.
  • Maori wahine, currently smoking, 10 years duration: 5 year CVD risk 28.3%, 5
    year MI risk 10.7%, 5 year ESRD risk 51.7%.

Shared inputs in both runs: age 48, female, systolic BP 156 mmHg, HbA1c 64
mmol/mol, no previous CVD, total cholesterol 6.1 mmol/L, HDL 0.9 mmol/L, urine
ACR 126 mg/mmol, serum creatinine 160 µmol/L, on BP-lowering medication. The
point is the size of the shift in calculated risk, especially ESRD risk, from
ethnicity and current smoking status.

Drug questions posed. Which drug or drugs have the greatest impact on CV risk
reduction, from insulin, sulphonylureas (glipizide), metformin alone, metformin
plus vildagliptin, metformin plus empagliflozin, or dulaglutide (a GLP-1
agonist). Which drugs do not produce hypoglycaemia, from insulin, metformin,
sulphonylureas (glipizide), empagliflozin (SGLT2 inhibitor), or the combinations
2 and 4, or 1 and 3. Which drug usually requires no dose modification in chronic
kidney disease, from insulin, metformin, glipizide and empagliflozin.

Risks and properties of SGLT2 inhibitors (the class was asked which statement
is false): benefit in non-diabetic kidney disease; increased risk of euglycaemic
ketoacidosis if the individual is unwell and not eating; demonstrated benefit in
both HFpEF and HFrEF; an eGFR reduction of up to 25% acceptable on commencing the
drug; and the statement that they need to be stopped if eGFR falls below 20
mL/min.

Foundations of treatment for CKD with T2D.

  • Cessation of tobacco smoking
  • Healthy diet with a low glycaemic index and restricted sodium
  • Maintenance of a healthy weight
  • Optimising physical behaviours
  • Glycaemic control, individualised (HbA1c target 6.5-8.0%)
  • Lowering blood pressure to at least less than 130/80 mmHg (individualised
    targets from under 130/80 to under 140/90)
  • Management of dyslipidaemia centred on statins, with ezetimibe, fibrates and
    PCSK9 inhibitors also listed; ESC guidelines suggest fibrates alongside
    lifestyle modification in statin-intolerant people with low HDL and high
    triglycerides

Pillars of therapy. Metabolic dysregulation, haemodynamic perturbations and
inflammation form an interlinked cycle driving cardiorenal disease, and each drug
class enters at a different point.

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

Combination therapy and CKD progression (hazard ratios with 95% CI, all
favouring therapy over conventional care, improving as classes are combined):

  • SGLT2i 0.63 (0.53-0.77)
  • GLP-1 RA 0.86 (0.72-1.02)
  • ns-MRA 0.77 (0.67-0.88)
  • GLP-1 RA + ns-MRA 0.66 (0.53-0.83)
  • SGLT2i + GLP-1 RA 0.54 (0.42-0.70)
  • SGLT2i + ns-MRA 0.49 (0.38-0.61)
  • SGLT2i + ns-MRA + GLP-1 RA 0.42 (0.31-0.56)

Module summary

  • Understand renal physiology and pathophysiology.
  • Link changes in renal physiology to clinical presentations, particularly
    important in acute kidney injury.
  • Drugs work by correcting pathophysiology: ACE inhibitors, ARBs, diuretics,
    SGLT2 inhibitors.
  • The kidneys are the key regulator of blood pressure and hypertension.
  • They play an important role in drug clearance.
  • Clinical integration of the patient in front of you.

“To be a good doctor one has to be a good physiologist.” W Hall. And, from Sir
William Osler, “medicine is a science of uncertainty and an art of probability.”

Self-test

  1. Describe the classic presentation of renal colic given in the lecture,
    including the associated urinary finding.
  2. List the renal stone types with their approximate frequencies, and name the
    one associated with infection and the one that is radiolucent.
  3. Explain, in one sentence, the mechanism of stone formation as the lecture
    states it.
  4. State the size thresholds that determine management of a ureteric stone.
  5. Distinguish the imaging recommended for a first suspected or complicated
    kidney stone from that recommended for recurrent uncomplicated stones, and
    define what makes a stone “complicated”.
  6. Contrast the metabolic evaluation offered to a first-time stone former with
    that offered to a recurrent or high-risk stone former.
  7. Explain why bowel disease is asked about in the stone history.
  8. List the dietary targets for a patient with calcium-based stones (urine
    output, sodium, calcium, protein, fruit and vegetables).
  9. Predict what dietary advice differs between calcium oxalate and calcium
    phosphate stones.
  10. List the community-acquired urinary pathogens with their frequencies where
    given.
  11. Describe first-line antibiotic options and duration for uncomplicated UTI.
  12. Explain why alkalinising the urine is a problem if the patient is on
    nitrofurantoin.
  13. State the frequency thresholds that define recurrent UTI and so justify
    prophylaxis, and give the NNT to prevent any recurrence in one year.
  14. Describe the evidence given for topical oestrogens and for cranberry juice
    in preventing recurrent UTI.
  15. A 72 year old woman on candesartan with stable CKD (eGFR 45) is treated with
    trimethoprim for an E. coli UTI, and her eGFR falls to 37. List the
    explanations the lecture asks you to consider.
  16. Explain why recurrent Proteus mirabilis UTI should prompt imaging, and state
    what the images in the lecture showed.
  17. Describe the age-stratified investigation of haematuria.
  18. List the risk factors that raise suspicion of significant urological disease
    in a patient with haematuria.
  19. State the thresholds for nephrology referral during primary care monitoring
    of haematuria for a nephrological cause.
  20. Describe how a patient with non-visible haematuria is monitored for a
    urological cause, and what would prompt referral back to urology.
  21. Define synpharyngitic haematuria as presented in Case 2, and state the
    teaching rule about haematuria with proteinuria and a negative culture.
  22. Describe the four-hit hypothesis for primary IgA nephropathy.
  23. List the four presenting patterns of IgA nephropathy and the approximate age
    at which each peaks.
  24. Describe the glomerular changes seen in IgA nephropathy compared with a
    healthy glomerulus.
  25. Explain how the relative contributions to nephron loss change over the
    natural history of IgA nephropathy, and where the two therapeutic strategies
    act on that timeline.
  26. Explain what plasma sodium actually reflects, and the first clinical
    assessment required in hyponatraemia.
  27. Describe the control of AVP release and its effect on water handling,
    including the normal plasma osmolality range.
  28. Both hyponatraemia cases had urine osmolality 700-800 mosm/kg with plasma
    osmolality 260 mosm/kg. Explain what drove excess AVP in each case.
  29. State the treatment principle for SIADH given in the lecture, and list the
    other causes named.
  30. Define cardio-renal syndrome and distinguish the renal consequence of
    progressive left ventricular failure from that of right ventricular failure.
  31. Describe the three parallel arms by which unloading of high-pressure
    baroreceptors produces salt and water retention, and name the inhibitory
    inputs.
  32. Distinguish the arterial underfilling pathway from the venous congestion
    pathway in acute cardiorenal syndrome.
  33. Explain how fluid overload and interstitial oedema maintain an established
    AKI.
  34. Justify using an ACE inhibitor or ARB in a heart failure patient with a low
    blood pressure and a rising creatinine.
  35. List the immediate management of acute pulmonary oedema given in the lecture.
  36. Describe the assessment pathway when creatinine rises during decongestion of
    acute heart failure, and the signs of adequate decongestion.
  37. Explain why a chronically hypertensive patient can develop AKI at a blood
    pressure that would be normal for someone else.
  38. Compare the calculated 5 year CVD and ESRD risks for the European
    previously-smoking version of the diabetes case with the Maori
    currently-smoking version.
  39. List the foundational (non-pillar) treatments for a patient with CKD and type
    2 diabetes, including the blood pressure and HbA1c targets.
  40. Describe the four therapy pillars for cardiorenal disease, the drug class of
    each and its principal actions.
  41. Using the hazard ratios given, explain what happens to CKD progression as
    drug classes are combined.
  42. Integrative: a patient has diabetic kidney disease and heart failure and is
    started on an SGLT2 inhibitor and an ACE inhibitor. Using the pillar diagram
    and the ACEI/ARB rationale, explain the haemodynamic effect each has on the
    glomerulus, and state what eGFR change is acceptable on starting the SGLT2
    inhibitor.

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