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Nephrology Education Series

Calcium Phosphate Review

Andrew Bland, MD, FACP, FAAP UICOMP · UDPA · Butler COM 2025-01-01 23 min read

Calcium and Phosphate Homeostasis Disorders: A Comprehensive Clinical Review

Executive Summary

Calcium and phosphate homeostasis represents one of the most tightly regulated physiological systems, with disruptions leading to significant morbidity and mortality. This review synthesizes current evidence regarding the pathophysiology, diagnosis, and management of hypocalcemia, hypercalcemia, hypophosphatemia, and hyperphosphatemia, with particular emphasis on renal mechanisms and the vitamin D-parathyroid hormone axis. The complex interplay between these minerals, their regulatory hormones, and organ systems requires systematic evaluation and targeted therapeutic interventions based on underlying etiology.

Introduction

Calcium and phosphate metabolism involves intricate regulatory mechanisms primarily controlled by parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (calcitriol), and fibroblast growth factor 23 (FGF23). The kidneys serve as the primary regulatory organ for both minerals, with approximately 60% of filtered calcium and 85-90% of filtered phosphate undergoing tubular reabsorption under hormonal control (Blaine et al., 2015). Disorders of mineral metabolism affect multiple organ systems and require comprehensive understanding of underlying pathophysiology for optimal management.

Physiological Regulation of Calcium and Phosphate Homeostasis

Calcium Homeostasis

Normal serum calcium ranges from 8.5-10.5 mg/dL (2.12-2.62 mmol/L), with approximately 50% existing in the ionized form, 40% bound to albumin, and 10% complexed with anions. The maintenance of calcium homeostasis involves three primary organs: the intestines (absorption), bones (storage), and kidneys (excretion and reabsorption).

Parathyroid hormone, secreted by chief cells in response to decreased ionized calcium detected by calcium-sensing receptors (CaSR), represents the primary regulatory hormone. PTH increases serum calcium through three mechanisms: enhanced renal tubular reabsorption in the distal convoluted tubule and connecting tubule, increased bone resorption via osteoclast activation, and stimulation of renal 1α-hydroxylase to produce calcitriol, which enhances intestinal calcium absorption (Peacock, 2021).

The kidney filters approximately 10 grams of calcium daily, with 98-99% undergoing reabsorption. Passive paracellular transport in the proximal tubule accounts for 65-70% of reabsorption, while active transcellular transport in the distal convoluted tubule, regulated by PTH and calcitriol, accounts for 10-15% (Alexander et al., 2023).

Phosphate Homeostasis

Normal serum phosphate ranges from 2.5-4.5 mg/dL (0.81-1.45 mmol/L), with levels varying by age, gender, and time of day. Phosphate homeostasis involves intestinal absorption (primarily jejunum), bone storage (85% of total body phosphate), and renal excretion.

The kidney represents the primary regulatory organ for phosphate balance, with 85-90% of filtered phosphate reabsorbed primarily in the proximal tubule via sodium-phosphate cotransporters (NaPi-2a and NaPi-2c). FGF23, produced by osteocytes and osteoblasts, serves as the primary phosphaturic hormone, downregulating NaPi cotransporters and inhibiting 1α-hydroxylase activity (Vervloet, 2022).

PTH also promotes phosphaturia through NaPi cotransporter internalization and degradation. The complex relationship between PTH, FGF23, and calcitriol creates an integrated regulatory system where changes in one parameter affect the others. Calcitriol stimulates FGF23 production, which in turn suppresses calcitriol synthesis, creating a negative feedback loop (Christov & Jüppner, 2018).

Hypocalcemia

Definition and Clinical Presentation

Hypocalcemia, defined as serum calcium below 8.5 mg/dL or ionized calcium below 4.5 mg/dL, presents with neuromuscular irritability ranging from perioral paresthesias to tetany, seizures, and laryngospasm. Cardiovascular manifestations include QT prolongation, heart failure, and hypotension. Chronic hypocalcemia may cause basal ganglia calcification, cataracts, and dental abnormalities (Cooper & Gittoes, 2018).

Etiology and Pathophysiology

Parathyroid Hormone Deficiency or Resistance

Hypoparathyroidism, the most common cause of chronic hypocalcemia, results from surgical removal (75% of cases), autoimmune destruction, genetic mutations, or infiltrative diseases. Post-surgical hypoparathyroidism occurs in 20-30% of total thyroidectomies, with permanent hypoparathyroidism in 1-5% (Orloff et al., 2018).

Pseudohypoparathyroidism represents end-organ PTH resistance due to GNAS gene mutations, resulting in hypocalcemia despite elevated PTH levels. Albright hereditary osteodystrophy features include short stature, round face, brachydactyly, and subcutaneous ossifications (Mantovani et al., 2018).

Vitamin D Deficiency and Metabolic Disorders

Vitamin D deficiency, affecting over one billion people globally, causes hypocalcemia through reduced intestinal calcium absorption. Risk factors include limited sun exposure, malabsorption, dietary insufficiency, and obesity. Severe deficiency (25-hydroxyvitamin D below 10 ng/mL) significantly impairs calcium homeostasis (Holick, 2017).

Vitamin D-dependent rickets type 1 results from 1α-hydroxylase deficiency, while type 2 involves vitamin D receptor mutations. Both present with hypocalcemia, secondary hyperparathyroidism, and rickets or osteomalacia (Carpenter et al., 2017).

Renal Causes

Chronic kidney disease (CKD) causes hypocalcemia through multiple mechanisms: decreased calcitriol production due to loss of functioning nephron mass, hyperphosphatemia leading to calcium-phosphate precipitation, and skeletal resistance to PTH. The prevalence of hypocalcemia increases with CKD progression, affecting 20-30% of patients with stage 4-5 CKD (Kidney Disease: Improving Global Outcomes CKD-MBD Work Group, 2017).

Acute kidney injury may cause hypocalcemia through hyperphosphatemia, particularly in rhabdomyolysis or tumor lysis syndrome. Nephrotic syndrome causes hypocalcemia through urinary loss of vitamin D-binding protein and 25-hydroxyvitamin D (Goldstein et al., 2019).

Other Causes

Critical illness-related hypocalcemia affects 50-70% of ICU patients through multiple mechanisms including cytokine-mediated suppression of PTH secretion, vitamin D deficiency, and magnesium depletion. Hypomagnesemia, present in 10-15% of hospitalized patients, causes functional hypoparathyroidism and PTH resistance (Steele et al., 2013).

Medications causing hypocalcemia include bisphosphonates (particularly with intravenous formulations), denosumab, cinacalcet, and chemotherapy agents including cisplatin and 5-fluorouracil. Proton pump inhibitors may cause hypocalcemia through hypomagnesemia after prolonged use (Liamis et al., 2021).

Diagnostic Approach

Initial evaluation includes measurement of albumin-corrected or ionized calcium, phosphate, magnesium, PTH, 25-hydroxyvitamin D, and creatinine. The PTH level distinguishes hypoparathyroidism (low or inappropriately normal PTH) from secondary hyperparathyroidism (elevated PTH). Additional testing may include 1,25-dihydroxyvitamin D, 24-hour urine calcium, and genetic testing for suspected hereditary disorders (Mannstadt et al., 2017).

Treatment Strategies

Acute Management

Symptomatic hypocalcemia requires immediate intravenous calcium administration. Calcium gluconate 10% (1-2 ampules in 50-100 mL normal saline over 10-20 minutes) provides 90-180 mg elemental calcium. Continuous infusion (50-100 mg elemental calcium per hour) may be necessary for persistent hypocalcemia. Cardiac monitoring is essential, particularly in digitalized patients (Schafer & Shoback, 2016).

Concurrent magnesium replacement is crucial, as hypomagnesemia prevents effective calcium correction. Intravenous magnesium sulfate (2-4 grams over 20 minutes) followed by continuous infusion may be required for severe deficiency.

Chronic Management

Chronic hypocalcemia management depends on underlying etiology. Hypoparathyroidism requires calcium supplements (1-3 grams elemental calcium daily in divided doses) and active vitamin D (calcitriol 0.25-2 mcg daily or alfacalcidol 0.5-3 mcg daily). The goal is maintaining serum calcium in the low-normal range (8-8.5 mg/dL) to avoid hypercalciuria and nephrolithiasis (Bollerslev et al., 2015).

Recombinant human PTH(1-84) received FDA approval for hypoparathyroidism not adequately controlled with calcium and active vitamin D. The REPLACE trial demonstrated improved calcium control and reduced supplement requirements, though increased hypercalcemia risk necessitates careful monitoring (Mannstadt et al., 2019).

Vitamin D deficiency treatment involves cholecalciferol or ergocalciferol supplementation. The Endocrine Society recommends 50,000 IU weekly for 8 weeks for deficiency, followed by maintenance therapy of 1,500-2,000 IU daily. Higher doses may be necessary for malabsorption or obesity (Holick et al., 2011).

Hypercalcemia

Definition and Clinical Presentation

Hypercalcemia, defined as serum calcium exceeding 10.5 mg/dL or ionized calcium above 5.5 mg/dL, presents with symptoms correlating with severity and rate of rise. Mild hypercalcemia (10.5-12 mg/dL) often remains asymptomatic. Moderate to severe hypercalcemia causes neuropsychiatric symptoms (confusion, lethargy, coma), gastrointestinal symptoms (anorexia, nausea, constipation), renal manifestations (polyuria, nephrolithiasis), and cardiovascular effects (hypertension, shortened QT interval, arrhythmias) (Minisola et al., 2015).

Etiology and Pathophysiology

Primary Hyperparathyroidism

Primary hyperparathyroidism represents the most common cause of outpatient hypercalcemia, with an incidence of 66 per 100,000 person-years in women and 25 per 100,000 in men. Solitary adenomas account for 85% of cases, with multigland hyperplasia (15%) and parathyroid carcinoma (less than 1%) comprising the remainder. Genetic syndromes including MEN1, MEN2A, and hyperparathyroidism-jaw tumor syndrome account for 5-10% of cases (Bilezikian et al., 2018).

The diagnosis requires elevated or inappropriately normal PTH with hypercalcemia. Modern presentations often involve mild, asymptomatic hypercalcemia discovered incidentally. However, subtle manifestations including decreased bone density, cognitive impairment, and cardiovascular disease may be present (Walker & Silverberg, 2018).

Malignancy-Associated Hypercalcemia

Malignancy causes 90% of inpatient hypercalcemia cases through humoral hypercalcemia of malignancy (80%) via PTH-related peptide secretion, or local osteolytic hypercalcemia (20%) from bone metastases. Common malignancies include squamous cell carcinomas, breast cancer, multiple myeloma, and lymphomas. The prognosis remains poor, with median survival of 2-3 months (Mirrakhimov, 2015).

Renal Causes

Tertiary hyperparathyroidism develops in CKD patients with prolonged secondary hyperparathyroidism, where parathyroid glands develop autonomous function. This affects 2-5% of dialysis patients and 30-50% of kidney transplant recipients. Post-transplant hypercalcemia may also result from improved bone mineralization and resolution of hyperphosphatemia (Evenepoel et al., 2017).

Familial hypocalciuric hypercalcemia, caused by inactivating CaSR mutations, presents with mild hypercalcemia, inappropriately normal PTH, and low urinary calcium excretion (calcium-creatinine clearance ratio below 0.01). This benign condition requires no treatment but must be distinguished from primary hyperparathyroidism (Hannan et al., 2018).

Medication-Induced Hypercalcemia

Thiazide diuretics cause mild hypercalcemia in 8-10% of patients through enhanced distal tubular calcium reabsorption and may unmask primary hyperparathyroidism. Lithium affects CaSR function, causing hypercalcemia in 10-15% of patients and hyperparathyroidism in 4-5% after long-term use. Other medications include calcium supplements, vitamin A intoxication, and teriparatide (Makras et al., 2020).

Diagnostic Evaluation

Initial assessment includes intact PTH measurement, which distinguishes PTH-mediated (primary hyperparathyroidism, familial hypocalciuric hypercalcemia, lithium-induced) from non-PTH-mediated causes. Suppressed PTH prompts evaluation for malignancy (PTHrP, serum/urine protein electrophoresis), vitamin D excess (25-hydroxyvitamin D, 1,25-dihydroxyvitamin D), and other causes. The 24-hour urine calcium and calcium-creatinine clearance ratio help distinguish familial hypocalciuric hypercalcemia from primary hyperparathyroidism (Cusano et al., 2021).

Treatment Approaches

Acute Management

Severe hypercalcemia (above 14 mg/dL) or symptomatic hypercalcemia requires immediate treatment. Initial management involves aggressive intravenous hydration with normal saline (200-300 mL/hour adjusted for cardiovascular status) to enhance renal calcium excretion. Loop diuretics should be avoided unless volume overload develops, as they may worsen hypercalcemia through hemoconcentration (Rosner & Dalkin, 2012).

Bisphosphonates represent first-line therapy for severe hypercalcemia. Zoledronic acid (4 mg IV over 15 minutes) demonstrates superior efficacy compared to pamidronate (60-90 mg IV over 2-4 hours), with normocalcemia achieved in 88% versus 70% of patients. Effects manifest within 2-4 days and persist for 3-4 weeks. Renal function adjustment is necessary for zoledronic acid (Saunders et al., 2019).

Denosumab (120 mg subcutaneously) offers an alternative for bisphosphonate-refractory hypercalcemia or renal insufficiency. Response occurs within 2-4 days with duration of 3-4 weeks. However, rebound hypercalcemia may occur, and severe hypocalcemia risk exists in vitamin D deficiency (Thosani & Hu, 2016).

Calcitonin (4-8 IU/kg every 6-12 hours) provides rapid but transient calcium reduction within 4-6 hours, useful as bridge therapy while awaiting bisphosphonate effects. Tachyphylaxis develops within 48-72 hours due to receptor downregulation.

Chronic Management

Primary hyperparathyroidism management involves surgical parathyroidectomy for symptomatic patients or those meeting surgical criteria: age below 50, serum calcium 1 mg/dL above normal, creatinine clearance below 60 mL/min, T-score below -2.5 or fragility fracture, or 24-hour urine calcium above 400 mg. Minimally invasive parathyroidectomy guided by preoperative imaging and intraoperative PTH monitoring achieves cure rates exceeding 95% (Wilhelm et al., 2016).

Medical management for non-surgical candidates includes cinacalcet (30-90 mg daily), which reduces serum calcium but doesn’t improve bone density. Bisphosphonates improve bone density without affecting serum calcium. Combined therapy may be considered for patients with both hypercalcemia and osteoporosis (Khan et al., 2017).

Hyperphosphatemia

Definition and Clinical Consequences

Hyperphosphatemia, defined as serum phosphate exceeding 4.5 mg/dL in adults, causes acute symptoms through calcium-phosphate precipitation leading to hypocalcemia and soft tissue calcification. Chronic hyperphosphatemia, primarily in CKD, accelerates vascular calcification, increases cardiovascular mortality, and contributes to secondary hyperparathyroidism and renal osteodystrophy (Hruska et al., 2015).

Etiology and Pathophysiology

Renal Insufficiency

CKD represents the predominant cause of chronic hyperphosphatemia. Phosphate retention begins when GFR falls below 60 mL/min/1.73m², though compensatory mechanisms (increased FGF23 and PTH) initially maintain normal serum levels. Overt hyperphosphatemia develops with GFR below 30 mL/min/1.73m². Each 1 mg/dL increase in phosphate associates with 18-35% increased mortality risk in dialysis patients (Block et al., 2015).

Acute kidney injury causes hyperphosphatemia through sudden loss of excretory capacity, particularly severe in rhabdomyolysis and tumor lysis syndrome where massive cellular phosphate release occurs.

Increased Phosphate Load

Tumor lysis syndrome, occurring spontaneously or after chemotherapy in high-grade malignancies, releases massive intracellular phosphate. Risk factors include high tumor burden, elevated LDH, and pre-existing renal insufficiency. Prophylactic measures include hydration, allopurinol or rasburicase, and phosphate monitoring (Cairo et al., 2017).

Rhabdomyolysis releases muscle phosphate content, with levels correlating with creatine kinase elevation. Vitamin D intoxication increases intestinal phosphate absorption. Excessive phosphate administration through enemas, laxatives, or intravenous replacement may cause acute hyperphosphatemia, particularly with renal impairment.

Transcellular Shifts

Metabolic or respiratory acidosis shifts phosphate extracellularly. Insulin deficiency in diabetic ketoacidosis causes hyperphosphatemia despite total body depletion, with treatment revealing underlying deficiency.

Pseudohyperparathyroidism and Hormonal Disorders

Pseudohyperparathyroidism causes hyperphosphatemia through PTH resistance despite elevated hormone levels. Acromegaly and hyperthyroidism increase renal phosphate reabsorption through growth hormone and thyroid hormone effects on NaPi cotransporters (Lederer, 2019).

Diagnostic Approach

Evaluation includes assessment of renal function, calcium, PTH, and 25-hydroxyvitamin D. Fractional excretion of phosphate below 5% suggests increased reabsorption or decreased filtered load. Additional testing for suspected tumor lysis syndrome includes uric acid, LDH, and potassium. The calcium-phosphate product above 55-70 mg²/dL² indicates high precipitation risk (Leaf & Christov, 2019).

Management Strategies

Acute Management

Acute severe hyperphosphatemia with hypocalcemia requires calcium replacement and enhanced elimination. Intravenous normal saline and loop diuretics enhance phosphate excretion in preserved renal function. Hemodialysis effectively removes phosphate (30-50 mg/dL over 4 hours) for severe cases or renal failure. Continuous renal replacement therapy may be necessary for ongoing phosphate release in tumor lysis syndrome (Ronco et al., 2019).

Chronic Management in CKD

Dietary phosphate restriction (800-1000 mg daily) represents first-line therapy but proves challenging given phosphate prevalence in processed foods. Protein restriction must be balanced against malnutrition risk. Education regarding hidden phosphate sources and phosphate-to-protein ratios optimizes dietary management (Kalantar-Zadeh et al., 2020).

Phosphate binders taken with meals reduce intestinal absorption. Calcium-based binders (calcium carbonate, calcium acetate) effectively lower phosphate but increase calcium load and vascular calcification risk. Non-calcium binders include sevelamer (also lowers LDL cholesterol), lanthanum carbonate, and iron-based binders (sucroferric oxyhydroxide, ferric citrate). The KDIGO guidelines recommend avoiding calcium-based binders when serum calcium is elevated (Ruospo et al., 2018).

Novel therapeutic approaches target FGF23-Klotho axis. Tenapanor, a sodium-hydrogen exchanger 3 inhibitor, reduces paracellular phosphate absorption. Nicotinamide inhibits NaPi cotransporters but requires further study (Vervloet et al., 2019).

Hypophosphatemia

Definition and Clinical Manifestations

Hypophosphatemia, defined as serum phosphate below 2.5 mg/dL, becomes symptomatic below 1.5 mg/dL. Acute manifestations include respiratory muscle weakness, rhabdomyolysis, hemolytic anemia, leukocyte dysfunction, and cardiac dysfunction. Chronic hypophosphatemia causes osteomalacia, rickets, and proximal muscle weakness (Imel & Econs, 2019).

Etiology and Pathophysiology

Decreased Intestinal Absorption

Malnutrition, particularly in alcoholism, causes hypophosphatemia through poor intake and increased urinary losses. Malabsorption syndromes, chronic diarrhea, and phosphate binders reduce absorption. Vitamin D deficiency impairs intestinal phosphate absorption through reduced NaPi-2b expression (Goretti Penido & Alon, 2012).

Increased Renal Losses

Primary hyperparathyroidism increases phosphate excretion through PTH-mediated NaPi cotransporter downregulation. Post-parathyroidectomy and hungry bone syndrome cause severe hypophosphatemia through rapid bone uptake.

FGF23-mediated disorders include X-linked hypophosphatemia (PHEX mutations), autosomal dominant and recessive hypophosphatemic rickets (FGF23 and DMP1 mutations respectively), and tumor-induced osteomalacia. These conditions share increased FGF23, renal phosphate wasting, and inappropriately low calcitriol (Minisola et al., 2017).

Fanconi syndrome, whether inherited or acquired, causes proximal tubular dysfunction with phosphate wasting, glucosuria, aminoaciduria, and metabolic acidosis. Causes include multiple myeloma, medications (tenofovir, ifosfamide), and heavy metal toxicity.

Vitamin D-dependent and resistant rickets cause hypophosphatemia through different mechanisms. Type 1 involves deficient calcitriol production, while type 2 involves receptor resistance, both resulting in decreased intestinal absorption and secondary hyperparathyroidism (Carpenter et al., 2017).

Intracellular Shifts

Refeeding syndrome occurs with aggressive nutrition in malnourished patients, causing phosphate shift into cells for ATP synthesis. Risk factors include BMI below 16, weight loss exceeding 15%, minimal intake for 10 days, or low baseline phosphate. Insulin administration, respiratory alkalosis, and hungry bone syndrome cause similar shifts (Friedli et al., 2017).

Diagnostic Evaluation

Assessment includes measuring PTH, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and calculating fractional excretion of phosphate. Elevated fractional excretion (above 5%) indicates renal losses. FGF23 measurement helps diagnose FGF23-mediated disorders. Genetic testing may identify hereditary hypophosphatemic disorders (Fukumoto, 2021).

Treatment Approaches

Acute Management

Severe symptomatic hypophosphatemia requires intravenous replacement. Sodium or potassium phosphate (0.08-0.16 mmol/kg over 6 hours) can be administered, with close monitoring to avoid hypocalcemia and soft tissue calcification. Doses exceeding 0.24 mmol/kg over 6 hours risk hypocalcemia and should be avoided (Geerse et al., 2020).

Chronic Management

Oral phosphate supplementation (1-3 grams daily in divided doses) treats chronic hypophosphatemia. Gastrointestinal side effects limit tolerability. Concurrent calcitriol prevents secondary hyperparathyroidism from phosphate supplementation.

X-linked hypophosphatemia treatment traditionally involved phosphate supplements and calcitriol, though outcomes remained suboptimal. Burosumab, an anti-FGF23 monoclonal antibody, received FDA approval for X-linked hypophosphatemia. The Phase 3 trial demonstrated improved phosphate levels, rickets healing, and growth in children, with improved pain and physical function in adults (Insogna et al., 2018).

Tumor-induced osteomalacia requires tumor localization and resection. When tumors cannot be located or resected, phosphate supplementation and calcitriol provide symptom management. Burosumab shows promise for unresectable cases (Jan de Beur et al., 2021).

Integrated Management Considerations

Drug Interactions and Monitoring

Calcium and phosphate management requires careful attention to drug interactions. Calcium reduces absorption of bisphosphonates, fluoroquinolones, and levothyroxine, requiring separated administration. Thiazide diuretics enhance calcium reabsorption while loop diuretics increase excretion. Vitamin D increases both calcium and phosphate absorption, potentially exacerbating hyperphosphatemia in CKD (Vondracek & Hoang, 2019).

Monitoring frequency depends on disorder severity and treatment phase. Acute management requires every 4-6 hour monitoring initially. Chronic management typically involves monthly monitoring until stable, then every 3-6 months. CKD patients require more frequent monitoring given complex interactions between calcium, phosphate, PTH, and FGF23.

Special Populations

Pregnancy alters mineral metabolism through increased calcitriol production, enhanced intestinal absorption, and increased renal excretion. Hypocalcemia may worsen during pregnancy and lactation due to fetal/infant calcium demands. Primary hyperparathyroidism during pregnancy increases risk of preeclampsia, neonatal hypocalcemia, and fetal loss, often requiring parathyroidectomy in the second trimester (Appelman-Dijkstra & Ertl, 2021).

Elderly patients demonstrate decreased vitamin D synthesis, reduced intestinal absorption, and declining renal function, increasing susceptibility to disorders. Medication polypharmacy increases interaction risks. Cognitive impairment may affect medication compliance and dietary adherence.

Conclusion

Calcium and phosphate disorders represent complex clinical challenges requiring systematic evaluation and targeted management based on underlying pathophysiology. The intricate regulatory mechanisms involving PTH, vitamin D, FGF23, and the kidneys necessitate comprehensive understanding for optimal patient care. Recent therapeutic advances, including recombinant PTH for hypoparathyroidism and anti-FGF23 antibodies for hypophosphatemic disorders, offer improved outcomes for previously challenging conditions. Future research directions include developing more effective phosphate binders, understanding genetic determinants of mineral metabolism, and optimizing personalized treatment strategies based on individual patient characteristics and comorbidities.

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Educational Resources

  • [[calcium-phosphorus-student-handout|Student Handout: Calcium Phosphorus]] — PA/medical student educational guide