Diabetes Mellitus

1. Normal Glucose Physiology (Baseline)

2. Classification

3. Pathophysiology

Type 1 DM

• Stage 1: Two or more autoantibodies present; normoglycemia
• Stage 2: Autoimmunity + dysglycemia
• Stage 3: Frank hyperglycemia meeting diagnostic criteria

Type 2 DM

1. Insulin resistance - peripheral tissues (muscle, fat, liver) respond poorly to insulin. Increased insulin demand is compensated for years by beta-cell hypersecretion.
2. Beta-cell failure - over time, beta cells become dysfunctional. First-phase insulin release is selectively impaired. Eventually, fasting hyperglycemia develops.

4. Diagnosis

• Rosen's Emergency Medicine, p. 2535

5. Clinical Features

6. Long-Term Complications

• Advanced glycation end-products (AGEs) - form from glucose reacting with proteins; bind to RAGE receptors; trigger cytokine release (TGF-beta, VEGF), ROS generation, and procoagulant states
• Protein kinase C activation - promotes VEGF-driven neovascularization (retinopathy) and TGF-beta-driven fibrosis (nephropathy)
• Polyol pathway - aldose reductase converts excess glucose to sorbitol, depleting NADPH; damages nerves and lens
• Robbins & Kumar Basic Pathology, p. 749

Microvascular Complications

• Diabetic retinopathy - proliferative scarring of the retina; leading cause of adult-onset blindness
• Diabetic nephropathy - glomerulosclerosis; leads to chronic kidney disease; associated with ~15-year reduction in life expectancy
• Diabetic neuropathy - distal symmetric polyneuropathy (burning/numbness in feet); autonomic neuropathy (gastroparesis, orthostatic hypotension, bladder dysfunction)

Macrovascular Complications

• Accelerated atherosclerosis of coronary, cerebral, and peripheral arteries
• 2-4x increased risk of MI and stroke
• Peripheral arterial disease - can progress to gangrene and amputation

7. Management

Type 1 DM

Type 2 DM

1. Lifestyle modifications - caloric restriction, physical activity, weight loss (first-line for all patients)
2. Metformin - suppresses hepatic glucose output; first-line drug; weight-neutral
3. Sulfonylureas - stimulate pancreatic insulin release
4. Thiazolidinediones (TZDs) - increase peripheral insulin sensitivity (PPAR-gamma agonists)
5. GLP-1 receptor agonists (e.g., semaglutide, liraglutide) - enhance glucose-dependent insulin secretion + cause significant weight loss; also have cardiovascular benefits
6. GIP/GLP-1 dual agonists (e.g., tirzepatide) - even greater reductions in weight and blood glucose
7. SGLT2 inhibitors (e.g., empagliflozin) - block renal glucose reabsorption; have cardiorenal protective effects
8. DPP-4 inhibitors - prolong endogenous incretin activity; modest glucose-lowering
9. Insulin - required in later stages when beta-cell function is severely depleted

Monitoring & Targets

• Annual eye exams (retinopathy screening)
• Annual foot examination - assess pedal pulses, sensation (monofilament, vibration), reflexes
• Annual urine albumin-to-creatinine ratio (nephropathy)
• HbA1c target typically < 7% for most adults
• Blood pressure and lipid control are equally important - Harrison's, p. 3247

8. Special Situations

• Classification difficulty: Adults with new-onset type 1 DM are often misdiagnosed as type 2. Young age (<35), non-obese BMI, DKA, or personal/family history of autoimmunity should prompt testing for islet cell autoantibodies.
• Gestational DM: Screened at 24-28 weeks; resolves postpartum in most cases but increases lifetime risk of type 2 DM.
• Monogenic diabetes (MODY): Rare; consider in childhood/early adulthood onset with autosomal inheritance pattern and no autoimmune markers.

Recent Evidence Note

Hydroureteronephrosis

1. Anatomy of Obstruction - Where It Occurs

2. Causes

Congenital (Intrinsic)

• UPJ obstruction - most common congenital ureteral abnormality; more common in boys (5:2 ratio) and on the left side; caused by abnormal smooth muscle investment, ureteral kinking, or aberrant lower pole renal artery compression
• UVJ obstruction (megaureter) - aperistaltic or narrowed segment at the ureterovesical junction
• Ureterocele - cystic dilation of the distal ureter within the bladder, often associated with ureteral duplication; nearly always causes significant hydroureteronephrosis
• Posterior urethral valves - male infants; obstructs below the bladder, causes bilateral hydroureteronephrosis
• Smith & Tanagho's General Urology; Campbell-Walsh-Wein Urology

Acquired - Intrinsic

Acquired - Extrinsic Compression

• Malignancy - approximately 70% of tumors causing ureteral obstruction are genitourinary (cervical cancer most common, then bladder and prostate); breast, GI carcinoma, and lymphoma make up most of the rest - Comprehensive Clinical Nephrology 7e
• Retroperitoneal fibrosis - mediates bilateral ureteral encasement
• Pregnancy - two mechanisms: (1) mechanical compression of the ureters at the pelvic brim by the gravid uterus (right side > left due to dextrorotation), and (2) progesterone-mediated smooth muscle relaxation; begins at ~20 weeks gestation - NKF Primer on Kidney Diseases
• Lymphocele / pelvic hematoma - post-surgery or transplant
• Enlarged pelvic lymph nodes

3. Pathophysiology

1. Continued glomerular filtration despite the obstruction causes progressive dilation of the renal pelvis, calyces, and ureter proximal to the blockage
2. Rising intrapelvic pressure is transmitted back through the collecting ducts, compressing the renal vasculature - this causes arterial insufficiency and venous stasis
3. Tubular dysfunction first - the papillae, most vulnerable to pressure, are damaged earliest; the primary functional loss is tubular concentrating ability (tubular function is impaired before GFR falls)
4. Interstitial inflammation and fibrosis follows, mediated by:
   • TGF-β1 - key profibrotic cytokine
   • Angiotensin II (upregulated rapidly post-obstruction) - causes vasoconstriction, stimulates TGF-β1 and TNF-α, drives interstitial fibrosis; ACE inhibitors/ARBs can partially attenuate this
   • IL-18 - triggers tubular epithelial-to-mesenchymal transition (EMT) and fibroblast proliferation
   • Thromboxane A2 (TXA2) and prostaglandins - alter renal hemodynamics
5. GFR falls later as pressure-mediated ischemia propagates and fibrosis replaces functional nephrons
6. Sudden complete obstruction causes early GFR compromise before significant dilation develops; with partial/intermittent obstruction, massive dilation can develop with relatively preserved function initially

• Campbell-Walsh-Wein Urology; Brenner & Rector's The Kidney

4. Morphology (Gross and Microscopic)

• With subtotal or intermittent obstruction, the kidney may reach lengths of 20 cm
• The organ becomes largely a thin-walled, fluid-filled sac - the greatly distended pelvicalyceal system
• Renal parenchyma is compressed and atrophied; papillae are obliterated; pyramids are flattened
• The ureter proximal to the obstruction is dilated and tortuous (hydroureter)

• Early: tubular dilation and atrophy
• Late: loss of glomeruli, replacement of renal parenchyma by fibrous tissue
• Superimposed pyelonephritis is common
• Robbins & Kumar Basic Pathology, p. 528

5. Clinical Features

• Robbins; Comprehensive Clinical Nephrology 7e

6. Diagnosis

• Ultrasound - first-line imaging; sensitive for identifying hydronephrosis (dilated renal pelvis and calyces) and hydroureter; used in antenatal screening and emergency settings. Mild dilation may be physiological (e.g., early pregnancy)
• CT urography (non-contrast) - gold standard for ureteric calculi; identifies level and cause of obstruction
• MRI urography - useful in pregnancy (avoids radiation)
• Diuretic renography (MAG3 scan) - quantifies differential renal function and drainage kinetics; distinguishes obstructed from non-obstructed dilation
• Antegrade pyelography (percutaneous) - best for defining the exact level of obstruction, especially when retrograde approach fails; can be combined with percutaneous nephrostomy (PCN)
• Retrograde ureteropyelography - endoscopic; detailed assessment of the ureteral lumen

7. Management

Acute/Urgent Relief

• Bladder outlet obstruction - urethral or suprapubic catheter
• Upper tract obstruction - retrograde double-J (DJ) ureteral stent placement is preferred; percutaneous nephrostomy (PCN) is the fallback if retrograde approach fails or if the patient is septic (PCN avoids endoscopic manipulation that could worsen bacteremia)
• In bilateral obstruction, draining the kidney with better-preserved parenchyma on CT/ultrasound is sufficient initially
• DJ stents and PCN tubes need replacement every 3-6 months; complications include migration, obstruction, infection, and lower urinary tract symptoms (urgency, frequency in ~70% of patients with stents)
• Comprehensive Clinical Nephrology 7e

Definitive Treatment (by cause)

Post-Obstructive Diuresis

• Retained solutes (osmotic diuresis)
• Downregulation of tubular transporters (NKCC2 reduction, decreased aquaporin-2 phosphorylation)
• Early phase is partly prostaglandin (COX-2) mediated; late phase is tubular transporter-dependent
• Patients require careful fluid and electrolyte monitoring to avoid dehydration and electrolyte imbalance
• Brenner & Rector's The Kidney; Campbell-Walsh-Wein

8. Special Situations

• Physiological hydroureteronephrosis of pregnancy: right side predominates; mild and normally resolves postpartum; pathological obstruction (e.g., stone) should be excluded if pain or fever is present
• Post-renal transplant obstruction: most common in the early post-operative period; causes include poor ureteral implantation, blood clots, ischemic stricture, lymphocele compression, or BPH in the recipient. Ultrasound shows hydronephrosis; managed with DJ stenting or PCN
• Antenatally detected hydronephrosis: most common indication for fetal urinary tract investigation; many cases resolve spontaneously; those that persist require postnatal workup with ultrasound and voiding cystourethrogram (VCUG) to exclude vesicoureteral reflux