Diabetes mellitus refer Davidson textbook of medicine

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Note: Davidson's Principles and Practice of Medicine is not currently in the library. The closest equivalent authoritative internal medicine reference available is Harrison's Principles of Internal Medicine, 22nd Edition (2025), which covers the same diabetes mellitus content in equal depth. The following is sourced from Harrison's.

Diabetes Mellitus

Harrison's Principles of Internal Medicine, 22nd Ed. (2025) - Chapters 415-417

Definition & Classification

Diabetes mellitus (DM) is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The ADA classifies DM into four main categories:

Class	Key Features
Type 1 DM	Immune-mediated or idiopathic destruction of pancreatic beta cells; absolute insulin deficiency
Type 2 DM	Insulin resistance + relative insulin deficiency; progressive beta cell failure
Other specific types	Monogenic (MODY), pancreatic disease, drug-induced (e.g., glucocorticoids, immune checkpoint inhibitors), genetic syndromes
Gestational DM (GDM)	Glucose intolerance first detected in 2nd or 3rd trimester of pregnancy

Diagnostic Criteria

Test	Normal	Prediabetes	Diabetes Mellitus
HbA1c	<5.6% (<41 mmol/mol)	5.7-6.4% (42-47 mmol/mol)	≥6.5% (≥48 mmol/mol)
Fasting Plasma Glucose (FPG)	<5.6 mmol/L (100 mg/dL)	5.6-6.9 mmol/L (100-125 mg/dL)	≥7.0 mmol/L (126 mg/dL)
2-h PG (75g OGTT)	<7.8 mmol/L (140 mg/dL)	7.8-11.0 mmol/L (140-199 mg/dL)	≥11.1 mmol/L (200 mg/dL)
Random PG + symptoms	-	-	≥11.1 mmol/L (200 mg/dL) with symptoms

Prediabetes states: Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT) - both carry significant risk of progression to DM and cardiovascular disease.

Type 1 Diabetes Mellitus

Pathophysiology

Autoimmune destruction of pancreatic beta cells; >90% destruction required before clinical DM appears
Autoantibodies (anti-insulin, anti-GAD, anti-islet cell, anti-IA-2) are markers of autoimmunity
HLA associations: DR3, DR4, DQ2, DQ8 alleles increase susceptibility; DR2 is protective
Environmental triggers: enteroviruses (Coxsackie B), early cow's milk exposure, vitamin D deficiency

Genetics

Concordance in identical twins: 50% (meaning both genetic and environmental factors play a role)
Lifetime risk in first-degree relative: ~6%; general population risk ~0.4%

Clinical Features

Onset often in childhood/adolescence but can occur at any age
Classic symptoms: polyuria, polydipsia, polyphagia, weight loss, fatigue
Prone to diabetic ketoacidosis (DKA) without insulin

LADA (Latent Autoimmune Diabetes in Adults)

Autoimmune DM presenting in adults, slower progression to insulin dependence
Positive for GAD antibodies

Type 2 Diabetes Mellitus

Pathophysiology (the "Ominous Octet")

Type 2 DM results from multiple interacting defects:

Impaired insulin secretion - progressive beta cell failure
Insulin resistance in skeletal muscle (reduced glucose uptake)
Excessive hepatic glucose production - unregulated gluconeogenesis
Abnormal fat metabolism - increased lipolysis, elevated free fatty acids
Impaired incretin effect - reduced GLP-1 action
Increased glucagon secretion - alpha cell dysfunction
Increased renal glucose reabsorption (SGLT-2 upregulation)
Systemic low-grade inflammation

In the early stages, the pancreas compensates by increasing insulin output (hyperinsulinemia), maintaining near-normal glucose. When beta cells can no longer compensate, IGT develops, then frank DM.

Genetics

Concordance in identical twins: 70-90% (strongly genetic)
If both parents have T2DM, risk approaches 70%
600 genetic loci identified by GWAS; most prominent is variant of TCF7L2 (transcription factor 7-like 2)

Risk Factors

Obesity (especially central/visceral - ≥80% of T2DM patients are obese)
Physical inactivity
Age >45 years
Family history, ethnicity (South Asian, African, Hispanic higher risk)
History of GDM or polycystic ovary syndrome (PCOS)
Prediabetes (IFG/IGT)

Gestational DM (GDM)

Affects ~16% of pregnancies worldwide (IDF 2021)
Most revert to normal postpartum, but 35-60% develop DM within 10-20 years
Children of GDM pregnancies have increased risk of metabolic syndrome and T2DM
ADA recommends lifelong screening every 3 years post-GDM

Management

General Principles

Individualized glycemic targets (typically HbA1c <7% for most adults)
Three pillars: lifestyle modification + pharmacotherapy + complication screening

1. Lifestyle Management

Diabetes Self-Management Education and Support (DSMES): patient-centered education covering CGM/BGM, insulin administration, hypoglycemia prevention, foot care, exercise management
Medical Nutrition Therapy (MNT): reduce carbohydrates, limit simple sugars and fructose, Mediterranean-style diet (rich in monounsaturated/polyunsaturated fatty acids), individualized caloric intake
Physical activity: aerobic + resistance exercise; 150 min/week moderate-intensity recommended

2. Pharmacotherapy

TABLE: Agents for Type 1 and Type 2 DM (Harrison's 22nd Ed., Chapter 416)

Class	Mechanism	Examples	HbA1c Reduction	Key Advantages	Key Disadvantages
Biguanides	↓ Hepatic glucose production, ↑ insulin sensitivity	Metformin	1-2%	Weight neutral, no hypoglycemia, modest CV benefit	Diarrhea, nausea, lactic acidosis, B12 deficiency
SGLT-2 inhibitors	↑ Renal glucose excretion	Canagliflozin, dapagliflozin, empagliflozin	0.5-1.0%	↓ CV events, ↓ heart failure, renal protection, weight loss	Genital mycotic infections, DKA risk, dehydration
DPP-4 inhibitors	Prolong GLP-1 action; ↑ insulin, ↓ glucagon	Sitagliptin, saxagliptin, linagliptin	0.5-0.8%	Well tolerated, no hypoglycemia	Angioedema/urticaria, pancreatitis (rare)
GLP-1 receptor agonists	Augment insulin secretion, ↓ glucagon, slow gastric emptying, ↓ appetite	Semaglutide, liraglutide, dulaglutide, exenatide	1.5-2.0%	↓ CV events, weight loss, renal protection	Nausea/vomiting, pancreatitis; avoid in MEN2/medullary thyroid CA
GLP-1/GIP dual agonist	Dual incretin agonism	Tirzepatide	>2%	Greatest weight loss among injectables	Similar to GLP-1 RAs
Sulfonylureas	↑ Insulin secretion (ATP-K+ channel)	Glipizide, glyburide, glimepiride	1.5-2.0%	Inexpensive, effective	Hypoglycemia, weight gain
Thiazolidinediones (TZDs)	↑ Insulin sensitivity (PPAR-γ agonist)	Pioglitazone, rosiglitazone	1.0-1.5%	Pioglitazone may ↓ CV events	Weight gain, fluid retention, fracture risk, bladder cancer
Alpha-glucosidase inhibitors	↓ Intestinal carbohydrate absorption	Acarbose, miglitol	0.5-0.8%	No hypoglycemia, weight neutral	GI side effects (flatulence, diarrhea)
Insulin	Replaces/supplements endogenous insulin	Various (see below)	Variable	Universally effective	Hypoglycemia, weight gain

Insulin Types

Type	Onset	Peak	Duration	Examples
Rapid-acting	5-15 min	1-2 h	3-5 h	Lispro, aspart, glulisine
Short-acting (regular)	30-60 min	2-4 h	6-8 h	Regular insulin
Intermediate-acting	1-2 h	4-8 h	12-18 h	NPH
Long-acting (basal)	2-4 h	Minimal peak	20-24 h	Glargine, detemir
Ultra-long-acting	-	Peakless	>42 h	Degludec

MDI (Multiple Daily Injection) regimen for Type 1 DM: Basal insulin (glargine or degludec) + preprandial rapid-acting insulin (lispro/aspart/glulisine), adjusted using insulin-to-carbohydrate ratio (~1 unit per 10-15 g carbohydrate) and correction factor (1500/total daily insulin dose).

Acute Complications

Diabetic Ketoacidosis (DKA)

Primarily Type 1 DM; rare in T2DM (SGLT-2 inhibitors can cause "euglycemic DKA")
Triad: Hyperglycemia + Ketosis + Metabolic acidosis (pH <7.3, HCO3- <18)
Precipitants: infection, missed insulin, trauma, surgery, MI, pregnancy

DKA Management Protocol:

IV fluids: 0.9% saline 2-3 L over first 1-3 h (10-20 mL/kg/h); switch to 0.45% saline, then 5-10% dextrose in 0.45% saline when glucose reaches 250 mg/dL (13.9 mmol/L)
Insulin: IV regular insulin 0.1 units/kg bolus, then 0.1 units/kg/h continuous infusion
Potassium replacement: Do NOT give insulin if K+ <3.3 mmol/L; replace to keep K+ 4-5 mmol/L
Monitor blood glucose every 1-2 h; electrolytes every 4 h
Goal: glucose 8.3-11.1 mmol/L, bicarbonate ≥18 mmol/L, normal pH
Transition to SC insulin when eating; overlap IV/SC by 2-4 h

Hyperosmolar Hyperglycemic State (HHS)

Primarily Type 2 DM; severe hyperglycemia (>600 mg/dL), hyperosmolality, minimal ketosis
Higher mortality than DKA; profound dehydration is the hallmark
Treatment: aggressive fluid resuscitation, cautious insulin, electrolyte replacement

Hypoglycemia

Most common acute complication of insulin or sulfonylurea therapy
Symptoms: sweating, tremor, palpitations (adrenergic); confusion, seizure (neuroglycopenic)
Rule of 15: 15 g fast-acting carbohydrates → recheck in 15 min

Chronic Complications

Microvascular Complications

(Directly caused by chronic hyperglycemia)

1. Diabetic Retinopathy

Leading cause of blindness in working-age adults
Stages: Nonproliferative (background) → Preproliferative → Proliferative retinopathy
Features: microaneurysms, hard exudates, cotton wool spots, neovascularization
Screening: annual dilated eye exam from diagnosis (T2DM) or 5 years after diagnosis (T1DM)
Treatment: laser photocoagulation, anti-VEGF injections (bevacizumab, ranibizumab)

2. Diabetic Nephropathy (Diabetic Kidney Disease)

Stages: Microalbuminuria (30-300 mg/day) → Macroalbuminuria (>300 mg/day) → Declining GFR → ESRD
Pathology: Kimmelstiel-Wilson nodules (nodular glomerulosclerosis)
Treatment: ACE inhibitors or ARBs (first-line for proteinuria), SGLT-2 inhibitors (proven renoprotective), blood pressure control (<130/80 mmHg)

3. Diabetic Neuropathy

Most common complication overall
Types:
- Distal symmetric polyneuropathy (DSPN): "stocking-glove" pattern; loss of vibration, pain, temperature; predisposes to foot ulcers
- Autonomic neuropathy: gastroparesis, orthostatic hypotension, resting tachycardia, erectile dysfunction, neurogenic bladder, gustatory sweating
- Mononeuropathy: 3rd cranial nerve palsy (pupil-sparing), carpal tunnel syndrome
- Diabetic amyotrophy (proximal motor neuropathy): proximal muscle weakness
Treatment: glycemic control (prevention), gabapentin, pregabalin, duloxetine, TCAs for pain

Macrovascular Complications

(Accelerated atherosclerosis)

Cardiovascular disease: 2-4x greater risk of ASCVD; leading cause of death in T2DM
Peripheral arterial disease (PAD): claudication, critical limb ischemia, gangrene
Cerebrovascular disease: increased stroke risk
Heart failure: both HFrEF and HFpEF; SGLT-2 inhibitors reduce hospitalization for heart failure

Cardiovascular risk reduction:

Statin therapy (all DM patients >40 years, or with CV risk factors)
Aspirin (secondary prevention)
Blood pressure control: target <130/80 mmHg; ACE inhibitors/ARBs preferred
SGLT-2 inhibitors and GLP-1 RAs have proven CV outcome benefits

Other Complications

Diabetic foot: Neuropathy + PAD + infection - leading cause of non-traumatic amputation
Infections: increased susceptibility (candidiasis, UTIs, mucormycosis, malignant otitis externa)
Cataracts & glaucoma: accelerated
Cheiroarthropathy: thickened skin, limited joint mobility
Non-alcoholic fatty liver disease (NAFLD)
Hearing loss
Cognitive impairment/dementia (increased risk)
Osteoporosis and fractures

Prevention

Type 1 DM: No proven prevention strategy currently
Type 2 DM:
- Diabetes Prevention Program (DPP): Intensive lifestyle modification (5-7% weight loss + 150 min/week exercise) reduced T2DM incidence by 58% in prediabetes patients
- Metformin reduced incidence by 31% in DPP
- GLP-1 RAs (semaglutide 2.4 mg/week) produced 14.8% weight loss and significantly reduced progression

Glycemic Targets & Monitoring

Parameter	Target (most adults)
HbA1c	<7% (less stringent <8% for elderly/comorbid)
Fasting glucose	4.4-7.2 mmol/L (80-130 mg/dL)
Postprandial glucose (2 h)	<10 mmol/L (<180 mg/dL)
Blood pressure	<130/80 mmHg
LDL cholesterol	<1.8 mmol/L (<70 mg/dL) with ASCVD; <2.6 mmol/L (<100 mg/dL) without

Continuous Glucose Monitoring (CGM) now preferred over finger-stick monitoring for most insulin-treated patients; reduces HbA1c and hypoglycemia
Evidence base (DCCT trial): Intensive glycemic control in T1DM reduced retinopathy by 76%, microalbuminuria by 39%, neuropathy by 60%
UKPDS: In T2DM, each 1% reduction in HbA1c reduced microvascular complications by 37%, MI by 14%

Harrison's Principles of Internal Medicine, 22nd Ed. (2025) - Chapters 415 (Classification/Pathophysiology), 416 (Diagnosis/Management), 417 (Complications). Note: Davidson's Principles and Practice of Medicine is not currently in the available library; this content is from Harrison's, which covers the same core material and aligns with Davidson's 24th edition content.

Renal replacement therapy refer harrison

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Renal Replacement Therapy (RRT)

Harrison's Principles of Internal Medicine, 22nd Ed. (2025) - Chapters 323-325

Overview & Indications

Renal replacement therapy encompasses three modalities:

Hemodialysis (HD) - in-center or home
Peritoneal Dialysis (PD) - CAPD or CCPD
Kidney Transplantation

Indications for Initiating RRT

Commonly accepted criteria:

Indication	Details
Uremic symptoms	Anorexia, nausea, vomiting, lassitude, pruritus not attributable to reversible causes
Malnutrition	Evidence of ongoing protein-calorie malnutrition
Hyperkalemia	Refractory to conservative measures
Volume overload	Persistent ECFV expansion despite diuretic therapy
Metabolic acidosis	Refractory to medical therapy
Bleeding diathesis	Uremic platelet dysfunction
Encephalopathy or pericarditis	Very late indications - now rare
GFR threshold	Creatinine clearance or eGFR <10 mL/min per 1.73 m²

Important: There is no absolute level of serum creatinine, BUN, cystatin C, or eGFR that mandates RRT. Clinical judgement is required. There is also no benefit to initiating dialysis preemptively at a GFR of 10-14 mL/min per 1.73 m² compared to waiting for symptomatic uremia.

Preparation for RRT

In-center HD remains the most common modality in the USA (>80% of ESKD patients)
Temporary dietary protein restriction may relieve early uremic symptoms but risks malnutrition
Multidisciplinary approach: nephrologist, diabetes educator, dietitian, social worker, nurse
Early referral to nephrology is recommended for:
- Advanced planning and creation of dialysis access
- Education about ESKD treatment options
- Management of CKD complications (hypertension, anemia, metabolic acidosis, secondary hyperparathyroidism)
Avoid PICC lines in CKD stage 3b or higher - use internal/external jugular tunneled catheters instead, to preserve arm veins for future AVF

1. Hemodialysis (HD)

Principle

Hemodialysis relies on solute diffusion across a semipermeable membrane down a concentration gradient (blood → dialysate). Solute clearance is also enhanced by ultrafiltration (convective clearance via solvent drag).

Rate of diffusion depends on: concentration gradient, membrane surface area, mass transfer coefficient
Smaller molecules cleared more efficiently: urea (60 Da) > creatinine (113 Da)
Diffusion clears small solutes; convection clears larger middle molecules

Components of the Hemodialysis System

1. The Dialyzer

Hollow-fiber dialyzers: bundles of capillary tubes - blood flows inside, dialysate flows outside
Modern membranes: biocompatible synthetic (polysulfone-based); replaced older cellulose membranes that activated the complement cascade
High-flux membranes (pore sizes 0.01-0.001 μm) allow clearance of larger uremic solutes (e.g., beta-2 microglobulin, cytokines)

2. Dialysate Composition

Electrolyte composition is adjusted to achieve desired electrolyte balance
Bicarbonate-based buffer replaces acetate (now largely obsolete due to hemodynamic instability)
Key adjustable parameters: sodium concentration (sodium modeling), potassium, calcium, bicarbonate

3. Blood Delivery System

Blood pump drives blood through the extracorporeal circuit at 300-500 mL/min
Anticoagulation (typically heparin) prevents clotting in the circuit

Adequacy of Hemodialysis

Measured by Kt/V (urea clearance × treatment time / volume of urea distribution)
Target: Kt/V ≥ 1.4 per treatment (for 3x/week HD)
Also measured as URR (urea reduction ratio) - target >65%
Standard schedule: 3 sessions/week, each 3-4 hours
More frequent HD (daily, nocturnal) improves outcomes but requires motivated patients

Vascular Access for Hemodialysis

Preferred in order:

Access Type	Description	Advantages	Disadvantages
Arteriovenous Fistula (AVF)	Native artery-vein anastomosis (e.g., radiocephalic, brachiocephalic)	Lowest infection & thrombosis rates; longest survival; "gold standard"	Requires 4-8 weeks maturation; ~30-60% fail to mature
AV Graft	Synthetic bridge (ePTFE) between artery and vein	Easier to create; shorter maturation (2-3 weeks; some allow early cannulation within days)	Higher thrombosis and infection rates than AVF
Tunneled Central Venous Catheter (CVC)	Dual-lumen catheter (14.5-16 French) in jugular/subclavian/femoral vein with subcutaneous tunnel	Immediate use; useful as bridge	Highest infection and thrombosis risk; central vein stenosis; associated with accelerated mortality

Catheter complications:

Catheter-related bacteremia: treat with catheter exchange ± disruption of fibrinous sheath
Thrombotic occlusion: thrombolytic instillation (e.g., alteplase)
Central vein stenosis: more common with catheter contact time >3 months; treated with balloon angioplasty ± stenting
Catheter-related sepsis unresponsive to antibiotics: remove catheter

AVF/Graft care:

Examine for thrill (palpable) and bruit (audible) at each visit
Enlarged needle insertion sites and aneurysms: assess overlying skin thickness carefully
High-output cardiac failure can develop due to shunting through large AVFs - may require ligation

Complications of Hemodialysis

Complication	Details	Management
Intradialytic hypotension (most common)	Excessive ultrafiltration, autonomic dysfunction, reduced cardiac reserve, antihypertensive overuse	Stop ultrafiltration; give 100-250 mL isotonic saline; sodium modeling; cool dialysate; avoid meals during HD; avoid UF rate >13 mL/kg/h; midodrine (limited evidence)
Muscle cramps	Excessively rapid volume removal below dry weight	Reduce UF; sodium/UF profiling
Dialyzer reactions	Type A: IgE-mediated (ethylene oxide), anaphylaxis within minutes. Type B: complement activation, chest/back pain after several minutes	Type A: stop dialysis, treat anaphylaxis; switch sterilization method. Type B: usually resolves with continued dialysis
Infection/sepsis	AVF/graft/catheter infections; increased susceptibility	Strict aseptic technique; antibiotic therapy; catheter removal if refractory
Cardiovascular disease	Leading cause of death in dialysis patients	Risk factor modification, fluid control
Anemia	Erythropoietin deficiency	ESAs + IV iron
Mineral/bone disease	Secondary hyperparathyroidism	Phosphate binders, active vitamin D, calcimimetics

2. Peritoneal Dialysis (PD)

Principle

1.5-3 L of dextrose-containing solution is infused into the peritoneal cavity via a Tenckhoff catheter
Dwell time: usually 2-4 hours
Clearance via: diffusion (metabolic waste → dialysate down concentration gradient) + ultrafiltration (osmotic gradient from dextrose drives water removal)
Rate of diffusion diminishes as equilibration between plasma and dialysate is approached
Absorption from peritoneal cavity occurs via peritoneal capillaries and lymphatics
Net solute transport varies by patient and is altered by peritonitis, drugs, position, exercise

Forms of Peritoneal Dialysis

1. CAPD (Continuous Ambulatory Peritoneal Dialysis)

Dialysate manually infused into the peritoneal cavity and drained 4-5 times per day
Continuous dialysis throughout the day and night (during dwell)
No machine required; fully portable

2. CCPD (Continuous Cyclic Peritoneal Dialysis)

Automated PD machine (cycler) performs exchanges at night (8-10 h overnight)
Peritoneal cavity may remain full during the day (long day dwell) or dry

3. Combination

CCPD overnight + one or more manual CAPD exchanges during the day for added clearance

PD Catheter

Placed fluoroscopically, peritoneoscopically, laparoscopically, or open surgically
Internal cuff: placed within the rectus sheath just lateral to the linea alba
External cuff: located 2-4 cm from skin exit site (ingrowth ensures secure positioning)
Complications: omental entrapment (may require laparoscopic omentopexy), fibrinous sheath formation (can be disrupted by guidewire manipulation)

Adequacy of PD

Also measured by Kt/V (urea)
Weekly Kt/V target ≥ 1.7 (PD is continuous; target expressed per week)
Also includes residual renal function (RRF) in the calculation - preservation of RRF is a PD advantage

Peritoneal Membrane Transport Types (PET - Peritoneal Equilibration Test)

Type	Characteristics	Preferred PD Regimen
High transporters	Rapid equilibration; good small solute clearance but fast glucose absorption → less UF	CCPD with short dwell times
Low transporters	Slow equilibration; good UF but less solute clearance	CAPD with long dwell times
Average transporters	Intermediate	Either modality

Complications of PD

Complication	Details
Peritonitis (most serious)	S. epidermidis (most common), S. aureus, gram-negatives, fungi; cloudy effluent, abdominal pain, fever; treated with intraperitoneal antibiotics
Exit site/tunnel infection	S. aureus most common; treat with oral antibiotics; refractory cases require catheter removal
Hernias	Increased intra-abdominal pressure; inguinal, umbilical, incisional
Hydrothorax	Dialysate migration through diaphragmatic defect; right-sided pleural effusion
Ultrafiltration failure	Long-term membrane damage; high transporter status; encapsulating peritoneal sclerosis (EPS)
Encapsulating peritoneal sclerosis (EPS)	Late complication from repeated peritonitis and long-term glucose exposure; high mortality
Protein loss	5-15 g/day protein lost in effluent; malnutrition risk
Hyperglycemia	Glucose absorption from dialysate; especially in diabetics

PD vs. HD - Comparison

Feature	HD	PD
Efficiency	High (intermittent)	Low but continuous
Cardiovascular stress	Intermittent large fluid/solute shifts	More gentle, gradual
Residual renal function	Declines faster	Better preserved
Technique	In-center (3x/week) or home	Home-based; independent
Vascular access	Required	Not needed
Infection risk	Catheter-related bacteremia	Peritonitis
Outcomes	Similar overall survival	Similar (PD may have advantage in first 1-2 years)
Patient autonomy	Less (in-center)	More

No large-scale RCT has confirmed superiority of either HD or PD; the choice is largely driven by patient preference, lifestyle, anatomy, and comorbidities.

3. Kidney Transplantation

Kidney transplantation is the treatment of choice for ESKD - it improves survival and quality of life compared to dialysis.

First successful transplant: Boston, 1954 (between identical twins)
220,000 patients living with a functioning kidney transplant in the USA today
Introduction of azathioprine + prednisone (1960s) enabled allografts between non-identical individuals
Calcineurin inhibitors (cyclosporine, 1980s; tacrolimus) dramatically improved graft survival

Donor Sources

Type	Details
Living related donor (LRD)	Best outcomes; preemptive transplant possible (avoids dialysis entirely)
Living unrelated donor (LURD)	Emotionally related; outcomes similar to LRD
Deceased donor (DD)	Standard criteria (SCD) vs. expanded criteria donors (ECD - older, hypertensive, diabetic)
DCD (Donation after circulatory death)	Increasing use; slightly higher delayed graft function

Immunosuppression

Induction therapy (peri-operative, to reduce acute rejection risk):

Depleting agents: Antithymocyte globulin (ATG - rabbit or horse) - polyclonal antibodies causing lymphocyte depletion; immune recovery takes months to years
Non-depleting agents: Basiliximab (anti-IL-2R / anti-CD25 monoclonal antibody)
Alemtuzumab: Anti-CD52, broadly depletes B cells, T cells, NK cells, macrophages

Maintenance immunosuppression (Table 33-3, Harrison's 22nd Ed.):

Agent	Mechanism	Key Side Effects
Glucocorticoids (prednisone/prednisolone)	Block transcription of IL-1, -2, -3, TNF-α, IFN-γ	Hypertension, glucose intolerance, dyslipidemia, osteoporosis
Cyclosporine (CsA)	Calcineurin inhibitor via cyclophilin → blocks IL-2 production; stimulates TGF-β	Nephrotoxicity, hypertension, dyslipidemia, hirsutism, gingival hyperplasia
Tacrolimus	Calcineurin inhibitor via FKBP-12 → blocks IL-2 production	Similar to CsA but no hirsutism/gingival hyperplasia; diabetes more likely
Azathioprine	Mercaptopurine prodrug; inhibits purine synthesis	Bone marrow suppression (WBC > RBC > platelets)
Mycophenolate mofetil (MMF)	Inhibits inosine monophosphate dehydrogenase → blocks purine synthesis	Diarrhea, abdominal cramps; dose-related liver/marrow suppression uncommon
Sirolimus/Everolimus	mTOR inhibitor (blocks p70 S6 kinase in IL-2 receptor pathway)	Hyperlipidemia, thrombocytopenia, impaired wound healing
Belatacept	Fusion protein; binds CD80/CD86, prevents CD28-T cell activation	Post-transplant lymphoproliferative disease (PTLD)

Standard triple therapy: Tacrolimus + MMF + low-dose prednisolone

Rejection

Type	Mechanism	Timing	Features	Treatment
Hyperacute	Pre-formed donor-specific antibodies (DSA)	Minutes to hours intraoperatively	Immediate graft thrombosis and failure	Prevention (crossmatch); no treatment; graft nephrectomy
Acute cellular rejection	T-cell mediated	Days to weeks	Rising creatinine, fever, graft tenderness	High-dose IV methylprednisolone (pulse steroids); ATG for steroid-resistant
Acute antibody-mediated rejection (AMR)	DSA-mediated complement activation	Days to months	Rising creatinine, C4d deposition on biopsy	IVIG, plasmapheresis, rituximab, eculizumab
Chronic rejection / CAD	Immune + non-immune factors	Months to years	Slow progressive graft dysfunction, proteinuria	Optimize immunosuppression; control BP, lipids

Outcomes

1-year graft survival: ~95% (living donor), ~90% (deceased donor)
5-year graft survival: ~80% (living donor), ~70% (deceased donor)
Life expectancy is substantially better with transplant than with dialysis
Preemptive transplantation (before starting dialysis) yields best outcomes

Post-Transplant Complications

Complication	Details
Infections	Major cause of morbidity/mortality; bacterial (early), viral (CMV, BK virus, EBV - within first year), fungal, PCP
Malignancy	3-5x increased risk; skin cancers (squamous > basal cell), PTLD (EBV-driven), Kaposi's sarcoma
Cardiovascular disease	Leading long-term cause of death in transplant recipients
Delayed graft function (DGF)	Temporary ATN requiring dialysis post-transplant; more common with DCD kidneys
Calcineurin inhibitor nephrotoxicity	Chronic: renal fibrosis, afferent arteriolar hyalinosis
New-onset diabetes after transplant (NODAT)	Especially with tacrolimus + steroids
BK virus nephropathy	Reactivation of BK polyomavirus; can cause graft loss; reduce immunosuppression

Continuous Renal Replacement Therapy (CRRT) - for Acute Kidney Injury (AKI)

Used in ICU settings for hemodynamically unstable patients with AKI who cannot tolerate intermittent HD.

Modality	Abbreviation	Principle
Continuous venovenous hemofiltration	CVVH	Convection only; replacement fluid used
Continuous venovenous hemodialysis	CVVHD	Diffusion only; dialysate used
Continuous venovenous hemodiafiltration	CVVHDF	Both convection + diffusion
Slow continuous ultrafiltration	SCUF	Fluid removal only; no solute clearance

Advantages of CRRT over intermittent HD in AKI:

Hemodynamically gentler (slower fluid removal)
Allows better fluid management in ICU (continuous nutrition, medications)
Better middle molecule clearance in sepsis

Conservative Management (Non-Dialytic Care)

For patients who choose not to pursue dialysis (elderly, high comorbidity burden):

Protein restriction (0.6-0.8 g/kg/day)
Management of CKD complications: anemia, acidosis, hyperkalemia, hyperphosphatemia
Symptom-focused palliative care
Survival of months with conservative management vs. dialysis varies widely - in elderly with significant comorbidities, benefit of dialysis over conservative management may be marginal

Harrison's Principles of Internal Medicine, 22nd Ed. (2025) - Chapter 323 (Dialysis), Chapter 324 (Interventional Nephrology/Access), Chapter 325 (Kidney Transplantation), Chapter 322 (CKD/Preparation for RRT)

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