---

Question A - Mr John (CKD Case)

Q1. Common Causes of CKD [2 marks]

• Diabetes mellitus (most common cause worldwide, ~44% of ESRD cases)
• Hypertension / Nephrosclerosis
• Obesity
• Amyloidosis

• Atherosclerosis
• Hypertensive nephrosclerosis

• Glomerulonephritis (IgA nephropathy, FSGS, membranous nephropathy)
• Lupus nephritis
• Polyarteritis nodosa

• Chronic pyelonephritis
• Tuberculosis

• Nephrotoxins: analgesics (NSAIDs), heavy metals, contrast agents

• Renal calculi, prostatic hypertrophy, urethral constriction

• Polycystic kidney disease (ADPKD - most common hereditary cause)
• Renal hypoplasia

---

Q2. How Does Prolonged NSAID Use Cause Kidney Damage? [3 marks]

• Under normal conditions, renal prostaglandins (PGE2, PGI2) maintain afferent arteriolar dilation and preserve GFR, especially when the renin-angiotensin system is activated (heart failure, dehydration, existing CKD).
• NSAIDs inhibit COX-1 and COX-2, blocking prostaglandin synthesis → afferent arteriolar vasoconstriction → reduced renal blood flow and GFR → acute kidney injury.

• Particularly risky in patients with depleted intravascular volume (e.g., existing CKD, hypertension, elderly).
• Meta-analysis: pooled OR for AKI with NSAID use = 1.73; in patients with pre-existing CKD the OR rises to 1.63.

• Reduced medullary blood flow (due to COX-2 inhibition) causes apoptosis of medullary interstitial cells → papillary necrosis.

• Idiosyncratic hypersensitivity reaction to NSAIDs causing massive proteinuria and AIN. Accounts for ~15% of all AKI. Associated with fever, rash, eosinophilia.

• Long-term regular analgesic use (NSAIDs, acetaminophen, aspirin combination) leads to chronic tubulointerstitial damage → progressive CKD. Risk of chronic renal failure is 2.5x higher in regular users vs. non-users.

• NSAIDs blunt the effects of antihypertensives (ACE inhibitors, diuretics, beta-blockers), worsening hypertensive nephropathy. They increase sodium retention and peripheral vascular resistance.

---

Q3. Why Is Proteinuria a Significant Finding in CKD? [3 marks]

• The glomerular filtration barrier (podocytes, basement membrane, endothelium) normally prevents protein passage. Proteinuria indicates disruption of this barrier, pointing to glomerular disease (e.g., glomerulonephritis, diabetic nephropathy).

• Proteinuria causes direct tubular toxicity: filtered proteins (albumin, transferrin, complement) are reabsorbed by proximal tubular cells and trigger inflammatory cytokine release, causing tubulointerstitial fibrosis and progressive nephron loss.
• Higher proteinuria = faster decline in GFR, regardless of the underlying cause.

• Proteinuria is an independent risk factor for cardiovascular disease and mortality - a systemic marker of vascular endothelial injury.

• Heavy proteinuria (>3.5 g/day) causes hypoalbuminaemia → reduced oncotic pressure → oedema (explains Mr John's leg and facial swelling).
• Also leads to hyperlipidaemia, hypercoagulability, and infection susceptibility.

• Reduction of proteinuria with RAAS blockers (ACE inhibitors/ARBs) slows CKD progression; proteinuria level guides treatment intensity.

---

Q4. Dietary Modifications for Mr John (CKD) [2 marks]

---

---

Question B - Mrs Aayesha (Type 2 DM Case)

Q1. Significance of HbA1c in DM Management; Reasons for Falsely Low and High Values [3 marks]

• Diagnosis: HbA1c ≥6.5% (48 mmol/mol) is diagnostic of diabetes (since 2010). Does not require fasting.
• Monitoring: Tracks long-term glycaemic control. Target: <7% (53 mmol/mol) for most T2DM patients (ADA).
• Complication prediction: Directly correlates with risk of microvascular complications - retinopathy, nephropathy, neuropathy (DCCT trial evidence).
• Mrs Aayesha's HbA1c = 9.2% (extremely poorly controlled, very high risk of complications).

• Haemolytic anaemia (shortened RBC lifespan - less time for glycation)
• Haemoglobin variants: HbS (sickle cell), HbC, HbE (may not be detected by some assays)
• Recent blood transfusion (dilutes glycated haemoglobin with donor RBCs)
• Iron-deficiency anaemia treatment (iron infusion/transfusion)
• Pregnancy (increased RBC turnover in 3rd trimester)
• Chronic blood loss

• Iron-deficiency anaemia (decreased RBC turnover - RBCs stay longer in circulation, more time for glycation)
• Vitamin B12/folate deficiency (increased RBC survival)
• Splenectomy (prolonged RBC lifespan)
• Uraemia/CKD (carbamylated haemoglobin can interfere with some assays)
• Labile pre-HbA1c (Schiff base intermediate): rapid acute hyperglycaemia; accounts for 8-30% of total HbA1 in diabetics - produces misleadingly high results if not removed before analysis.
• Alcoholism (acetaldehyde reacts with haemoglobin)

---

Q2. Acute and Chronic Complications of Poorly Controlled DM [5 marks]

Acute Complications:

• Primarily Type 1 DM but can occur in T2DM under stress
• Insulin deficiency → unrestrained lipolysis → ketone body accumulation → metabolic acidosis
• Features: Kussmaul breathing, vomiting, fruity breath, altered consciousness
• Diagnosis: glucose >250 mg/dL, ketones positive, pH <7.3, bicarbonate <18 mEq/L

• More common in Type 2 DM (as in Mrs Aayesha)
• Extreme hyperglycaemia (glucose >600 mg/dL), severe dehydration, high osmolality without ketoacidosis
• Can cause coma, high mortality

• Commonest acute complication in treated diabetics
• Symptoms: sweating, tremor, confusion, seizures, loss of consciousness
• Can cause cardiac arrhythmias, brain damage if prolonged

• Poorly controlled DM impairs neutrophil function and complement → susceptibility to bacterial, fungal infections (UTIs, skin infections, mucormycosis, TB)

Chronic Complications:

• Diabetic foot (neuropathy + vasculopathy + infection)
• Cataracts and glaucoma (osmotic lens swelling from sorbitol accumulation)
• Infections (chronic immune impairment)

---

Q3. Lifestyle Modification Plan for Mrs Aayesha [2 marks]

• Target 5-7% weight reduction (Mrs Aayesha's BMI = 32 - obese)
• Low glycaemic index carbohydrates; limit refined sugars and processed foods
• Restrict saturated fats; increase fibre (vegetables, legumes, whole grains)
• Reduce sodium to <2 g/day (she has hypertension BP 140/90)
• Caloric deficit of 500-750 kcal/day to promote weight loss
• Small, frequent meals to avoid postprandial glucose spikes

• ≥150 minutes/week of moderate-intensity aerobic exercise (brisk walking, swimming)
• Resistance training 2-3 times/week
• Avoid prolonged sitting; break sedentary time every 30 minutes
• Exercise improves insulin sensitivity, lowers HbA1c by ~0.5-1%

• 5-7% weight loss reduces T2DM progression by 58% (Diabetes Prevention Program)
• Aim for BMI <25 as long-term goal

• Regular self-monitoring of blood glucose
• HbA1c check every 3 months until target reached, then every 6 months
• Regular eye exams, foot exams, BP monitoring (target BP <130/80 in DM)

• Diabetes self-management education
• Stress management (cortisol raises blood glucose)

---

---

Question C - Young Female with SLE

Immunopathogenesis of SLE [2 marks]

• Normally, apoptotic cells are rapidly cleared. In SLE, impaired phagocytosis (especially by macrophages) leads to accumulation of apoptotic debris.
• Nuclear antigens (DNA, histones, ribonucleoproteins) are exposed on the surface of blebs from dying cells.

• Dendritic cells activated by the apoptotic debris present nuclear antigens to T helper cells.
• Autoreactive B cells escape tolerance mechanisms and receive T-cell help.
• Autoreactive CD4+ T cells drive B-cell differentiation into plasma cells that produce anti-nuclear antibodies (ANA), including anti-dsDNA, anti-Smith, anti-Ro, anti-La, anti-histone antibodies.

• Autoantibodies form immune complexes with their target nuclear antigens (e.g., anti-dsDNA + dsDNA).
• Immune complexes deposit in small vessels of kidneys (causing lupus nephritis), skin, joints, and brain.
• This activates complement (C1q, C3, C4) → consumption of complement (low C3, low C4 are diagnostic markers) → recruitment of neutrophils and macrophages → inflammation and tissue injury.
• Complement-mediated cell lysis also explains bicytopenia (anaemia + thrombocytopenia) seen in this patient.

• Immune complexes containing nucleic acids stimulate Toll-like receptors (TLR7, TLR9) on plasmacytoid dendritic cells → massive production of type I interferons (IFN-alpha) → further activation of autoreactive T and B cells → self-perpetuating cycle of autoimmunity.

---

Diagnostic Criteria for SLE [4 marks]

1. Entry criterion: ANA titer ≥1:80 (this patient is ANA positive - criterion met)
2. Additive weighted criteria (≥10 points needed for classification):

---

Management of SLE [4 marks]

• Sun protection (UV triggers flares) - sunscreen SPF 50+, protective clothing
• Vaccinations (avoid live vaccines if on immunosuppression)
• Smoking cessation, cardiovascular risk reduction
• Bone protection (calcium, vitamin D) if on steroids

• Regular CBC, urine dipstick (detect nephritis early), complement levels (C3/C4), anti-dsDNA titres
• Ophthalmology: annual eye screening for HCQ-related retinopathy
• Bone density (DEXA scan) if on long-term steroids

• Bicytopenia (as in this patient): IV methylprednisolone + MMF or cyclophosphamide if severe
• Lupus nephritis: MMF (preferred induction) or cyclophosphamide; hydroxychloroquine always continued
• Pregnancy in SLE: high-risk; continue HCQ, avoid MMF and cyclophosphamide in first trimester

---

• Guyton and Hall Textbook of Medical Physiology, Table 32.4
• Firestein & Kelley's Textbook of Rheumatology: NSAID renal effects
• Tietz Textbook of Laboratory Medicine, 7th ed.: HbA1c clinical utility
• Goldman-Cecil Medicine, International Edition, Table 245: SLE classification criteria and management