1. Acute Kidney Injury (AKI)

▼1.1 Definition & KDIGO Staging

AKI is defined by KDIGO 2012 as any of: rise in SCr ≥0.3 mg/dL within 48h; rise in SCr ≥1.5× baseline within 7 days; or urine output <0.5 mL/kg/h for ≥6h.

KDIGO Stage	Serum Creatinine Criteria	Urine Output Criteria	Action
Stage 1	×1.5–1.9 baseline OR ↑≥0.3 mg/dL	<0.5 mL/kg/h for 6–12h	Identify cause, optimize volume, nephrotoxin avoidance
Stage 2	×2.0–2.9 baseline	<0.5 mL/kg/h for ≥12h	Nephrology consult, consider RRT planning
Stage 3	×3.0 baseline OR SCr ≥4.0 mg/dL OR initiation of RRT	<0.3 mL/kg/h for ≥24h OR anuria ≥12h	RRT strongly considered; ICU level care

⚡ High-Yield: AKI Staging Pearls

Use the criterion that gives the highest stage (SCr or UO — whichever is worse)
Baseline SCr: use lowest value in past 3 months; if unknown, estimate from CKD-EPI assuming eGFR 75
Staging is prognostic: Stage 3 AKI has 30-day mortality ~30–50% in ICU; progression to CKD 5-fold increased risk
AKIN criteria (2007) and RIFLE criteria (2004) preceded KDIGO; KDIGO integrates both

▶1.2 Prerenal AKI

Prerenal AKI is the most common cause of AKI (~55–60%), resulting from decreased effective arterial blood volume (EABV) leading to reduced renal perfusion without intrinsic tubular damage.

Causes of Decreased EABV

True volume depletion: GI losses, hemorrhage, burns, third-spacing, excessive diuresis
Low cardiac output: Heart failure, cardiogenic shock, massive PE, cardiac tamponade
Vasodilation: Sepsis, anaphylaxis, cirrhosis, hepatorenal physiology
Afferent arteriolar constriction: NSAIDs (block PGE2 vasodilation), calcineurin inhibitors, radiocontrast
Efferent arteriolar dilation: ACE inhibitors/ARBs (↓ AngII → ↓ efferent tone → ↓ GFR, especially in bilateral RAS or AKI superimposed on CKD)

Parameter	Prerenal	Intrinsic (ATN)	Postrenal
FENa	<1%	>2%	Variable (often >1%)
FEUrea	<35%	>35%	Variable
Urine osmolality	>500 mOsm/kg	<350 mOsm/kg	Variable
Urine Na	<20 mEq/L	>40 mEq/L	Variable
BUN:Cr ratio	>20:1	10–15:1	Variable
Urine sediment	Bland (hyaline casts)	Muddy brown granular casts	RBCs, WBCs if obstruction complicated
Response to fluids	Rapid improvement	No response	Improves after relief

🔑 Clinical Pearl — FENa Exceptions: FENa <1% does NOT always mean prerenal. Low FENa is also seen in: contrast nephropathy (early), hemoglobin/myoglobin nephropathy (rhabdomyolysis), early AIN, acute GN, acute bilateral urinary obstruction. In these settings, use FEUrea (<35% = prerenal physiology) — more reliable when diuretics are given, as diuretics increase urinary Na excretion spuriously raising FENa.

FENa = (U_Na × P_Cr) / (P_Na × U_Cr) × 100

▶1.3 Intrinsic AKI — ATN, AIN, GN

Acute Tubular Necrosis (ATN)

Most common cause of intrinsic AKI. Results from ischemic or nephrotoxic injury to proximal tubular cells. Characterized by muddy brown granular casts and tubular epithelial cell casts on urine microscopy.

Ischemic ATN: Prolonged prerenal → tubular ischemia. High-risk: sepsis, major surgery, cardiogenic shock
Nephrotoxic ATN — Exogenous: Aminoglycosides (proximal tubule), cisplatin, radiocontrast, amphotericin B, NSAIDs, ethylene glycol
Nephrotoxic ATN — Endogenous: Myoglobin (rhabdomyolysis), hemoglobin (hemolysis), uric acid (TLS), myeloma light chains (cast nephropathy)

Acute Interstitial Nephritis (AIN)

Immune-mediated inflammation of the renal interstitium. Classic triad (fever, rash, eosinophilia) present in only 10–15% of drug-induced AIN. Most AIN is diagnosed on biopsy.

Cause	Common Agents	Key Features
Drug-induced (most common, ~70%)	PPIs (#1 cause), NSAIDs, beta-lactams, sulfonamides, vancomycin + pip-tazo, fluoroquinolones, allopurinol, diuretics	Onset weeks after exposure; eosinophiluria (low sensitivity ~30%); WBC casts
Infection-associated	Streptococcus, Legionella, EBV, CMV, hantavirus	Concurrent systemic infection; improve with treatment of infection
Immune-mediated	Sjögren syndrome, SLE, sarcoidosis, IgG4-related disease	Extrarenal features; plasma cell infiltrate in IgG4-RD
TINU syndrome	Tubulointerstitial nephritis and uveitis	Young patients; anterior uveitis + AIN; HLA-DQA1*01 association

🔑 PPI-Induced AIN: PPIs are now the leading drug cause of AIN. The latency period is typically 3–12 months (unlike beta-lactams which cause AIN within days–weeks). PPI-AIN is granulomatous on biopsy in up to 30% of cases. Consider PPI as a cause of unexplained AKI even without the classic triad. Stopping the PPI often leads to partial recovery; steroids (prednisone 1 mg/kg/day) may improve recovery if initiated early (<3 weeks of onset).

Rapidly Progressive GN (RPGN)

Nephritic syndrome progressing to renal failure over days–weeks. Characterized by crescents on biopsy (>50% of glomeruli). Three immunopathologic types:

Type	IF Pattern	Diseases	Serologies
Type I — Anti-GBM	Linear IgG	Goodpasture syndrome, anti-GBM GN	Anti-GBM Ab
Type II — Immune complex	Granular ("lumpy-bumpy")	IgA nephropathy, lupus nephritis, post-strep GN, MPGN	Low complement, ANA, ANCA negative
Type III — Pauci-immune (ANCA)	Negative/"pauci"	GPA (c-ANCA/PR3), MPA (p-ANCA/MPO), EGPA	ANCA positive

▶1.4 Diagnostic Workup & Urine Microscopy

Urine Finding	Interpretation	Clinical Context
Muddy brown granular casts	Tubular injury (ATN)	Post-ischemic, nephrotoxic AKI
RBC casts	Glomerulonephritis	Nephritic syndrome; dysmorphic RBCs suggest GN
WBC casts	AIN or pyelonephritis	Drug AIN, infection; eosinophiluria in drug AIN
Waxy/broad casts	CKD (chronic tubular atrophy)	Suggests long-standing disease
Granular casts (non-muddy)	Non-specific; can be seen in many conditions	Concentrated urine, vigorous exercise
Oval fat bodies / "Maltese cross"	Heavy proteinuria / nephrotic syndrome	Lipid casts seen under polarized light
Uric acid crystals	Tumor lysis, gout nephropathy	Yellow-brown rhomboid/rosette shapes
Calcium oxalate crystals	Ethylene glycol toxicity or hyperoxaluria	Envelope-shaped (dihydrate) or dumbbell (monohydrate)

Additional Workup by Suspected Etiology

All AKI: UA with microscopy, BMP, CBC, renal US (assess for obstruction, kidney size)
If GN suspected: ANA, anti-dsDNA, C3/C4, ANCA (PR3+MPO), anti-GBM, SPEP, cryoglobulins, HBV/HCV, ASO titer, blood cultures
If myeloma suspected: SPEP/UPEP, serum free light chains, skeletal survey
If rhabdomyolysis: CK, urine myoglobin (dipstick positive for blood with no RBCs), LDH
Renal biopsy: Indicated when cause unclear, AKI unexplained, suspected GN/AIN/vasculitis needing treatment, or AKI requiring urgent therapy

▶1.5 Management & RRT Indications

General Principles

Remove precipitating cause; optimize hemodynamics
Avoid nephrotoxins: NSAIDs, aminoglycosides, contrast (if avoidable), ACEi/ARBs in setting of volume depletion
Volume resuscitation: Balanced crystalloids (Lactated Ringer's or PlasmaLyte) preferred over 0.9% NaCl in most AKI — SMART trial and SALT-ED trial showed lower MAKE30 outcomes with balanced crystalloids vs NS
Avoid hypervolemia: associated with worse outcomes in AKI; target euvolemia
Drug dosing: adjust for reduced GFR; review all medications

RRT Indications — "AEIOU"

⚡ High-Yield: AEIOU Indications for Emergent Dialysis

A — Acidosis: pH <7.1 refractory to medical management
E — Electrolytes: Hyperkalemia refractory to medical therapy (K >6.5 with ECG changes, or >7.0)
I — Intoxications: Dialyzable toxins: methanol, ethylene glycol, lithium, salicylates, valproic acid, theophylline, metformin
O — Overload: Volume overload refractory to diuretics (pulmonary edema)
U — Uremia: Uremic encephalopathy, pericarditis, bleeding diathesis (platelet dysfunction)

STARRT-AKI trial (NEJM 2020): No benefit of accelerated (early) vs standard RRT initiation in critically ill AKI. Decision to initiate RRT should be based on clinical indications, not a specific creatinine or BUN threshold alone.

RRT Modalities in AKI

Modality	Mechanism	Best For	Considerations
IHD (intermittent HD)	Diffusion + convection	Hemodynamically stable; rapid toxin removal	Hemodynamic instability risk; requires vascular access
CRRT (CVVH/CVVHD/CVVHDF)	Slow continuous convection/diffusion	Hemodynamic instability; brain injury; fluid removal	Requires anticoagulation; circuit clotting; intensive nursing
PIRRT / SLED	Hybrid: slow-efficiency HD 6–12h	Bridge between IHD and CRRT; ICU patients	Less anticoagulation needed; hemodynamically gentler than IHD
Peritoneal dialysis	Diffusion across peritoneum	Pediatric AKI; resource-limited settings; no vascular access	Inadequate for catabolic AKI; peritonitis risk

▶1.6 Contrast-Induced Nephropathy & Hepatorenal Syndrome

Contrast-Induced Nephropathy (CIN) / Post-Contrast AKI (PC-AKI)

Rise in SCr ≥0.3 mg/dL or ≥1.5× within 48–72h of iodinated contrast, without alternative explanation. Incidence much lower than historically reported (~1–2% in general population, up to 5–30% in high-risk patients).

Risk factors: Pre-existing CKD (eGFR <30 highest risk), diabetes, volume depletion, HF, concurrent nephrotoxins, high-osmolality contrast, large contrast volume

Prevention Strategies

IV hydration: 0.9% NaCl or sodium bicarbonate 1–1.5 mL/kg/h for 3–12h pre- and 6–12h post-contrast — most important intervention
Use lowest volume of low/iso-osmolal contrast
Hold nephrotoxins (NSAIDs, vancomycin, aminoglycosides) perioperatively
Hold metformin 48h post-contrast in eGFR <30 (risk of lactic acidosis)
N-acetylcysteine (NAC): ACT trial — NAC does NOT reduce CIN vs placebo. Not recommended
Statins: pre-procedural statin loading may reduce PC-AKI in some RCTs (data not definitive)

Hepatorenal Syndrome (HRS)

Functional AKI in cirrhosis/portal hypertension due to severe renal vasoconstriction (↓ renal blood flow) from systemic vasodilation, RAAS activation, and impaired cardiac output — without intrinsic renal disease.

Feature	HRS-AKI (formerly HRS-1)	HRS-CKD (formerly HRS-2)
Onset	Rapid (<2 weeks); precipitated by SBP, GI bleed, large volume paracentesis	Gradual, chronic
Prognosis	Poor; median survival <2 weeks without treatment	Intermediate
GFR trajectory	Rapidly declining	Slowly progressive
Treatment	Terlipressin + albumin (preferred); norepinephrine + albumin	Midodrine + octreotide + albumin (bridge to transplant)

CONFIRM trial (NEJM 2021): Terlipressin + albumin significantly improved HRS-AKI reversal vs placebo (32% vs 17%, p<0.001). FDA approved 2022. Main risk: respiratory failure (careful patient selection required).

Diagnosis requires exclusion of: ATN (no muddy casts, no improvement with fluids alone), structural kidney disease (no proteinuria >500 mg/day, no hematuria, normal US), nephrotoxins, volume depletion not responding appropriately.

▶1.7 Practice Questions

Q1. A 72-year-old man on lisinopril and furosemide develops AKI (SCr 3.2, baseline 1.1) after 3 days of vomiting. Urine Na 12 mEq/L, urine Cr 180 mg/dL, serum Na 138, serum Cr 3.2. UA shows hyaline casts only. What is the FENa and most appropriate next step?

Answer: FENa = (12 × 3.2) / (138 × 180) × 100 = 38.4/24,840 × 100 = 0.15% → Prerenal AKI

Next step: Isotonic fluid resuscitation (LR or NS); hold ACEi and diuretic until recovered. FEUrea may be more helpful here since the patient is on furosemide. The low FENa (<1%), high BUN:Cr ratio, concentrated urine, bland sediment, and clinical context all confirm prerenal etiology. Expect prompt creatinine improvement within 24–48h of volume repletion.

Q2. A 55-year-old woman started omeprazole 6 months ago. She presents with SCr 3.8 (baseline 0.9), mild fever, sterile pyuria, and eosinophiluria. UA shows WBC casts. Which biopsy finding and treatment are most appropriate?

Answer: PPI-induced Acute Interstitial Nephritis. Biopsy: interstitial lymphocytic (and eosinophilic) infiltrate; tubulitis; no glomerular involvement; may show granulomas (30%). Treatment: discontinue PPI immediately; consider prednisone 1 mg/kg/day × 4–6 weeks if no improvement within 1–2 weeks of drug cessation (evidence limited but widely practiced). Complete recovery occurs in ~50%; residual CKD in others if treatment delayed.

Q3. A 68-year-old with NASH cirrhosis (MELD 26) develops AKI. SCr rises from 1.0 to 2.8 over 72h following SBP treatment. After 2 days of albumin 1g/kg IV, SCr remains 2.8. Urine Na is 8 mEq/L, UA is bland, urine protein trace. What is the diagnosis and treatment?

Answer: Hepatorenal Syndrome-AKI (HRS-AKI). Criteria met: AKI in cirrhosis; no response to 2 days of volume expansion; no alternative cause; bland sediment; low urine Na. Treatment: Terlipressin 1 mg IV q4–6h (or 2 mg IV q12h) + albumin 20–40 g/day. If terlipressin unavailable: norepinephrine 0.5–3 mg/h IV + albumin. Definitive treatment is liver transplantation. Reversal of HRS-AKI significantly improves post-transplant renal outcomes.

📚 Key References — AKI

[G] KDIGO AKI Guideline 2012. Kidney Int Suppl 2012;2:1–138. Defining and staging AKI.
[T] SMART (2018): Self et al. Balanced crystalloids vs saline in critically ill adults. NEJM 2018;378:829–839.
[T] STARRT-AKI (2020): STARRT-AKI Investigators. Timing of RRT in AKI. NEJM 2020;383:240–251.
[T] CONFIRM (2021): Wong et al. Terlipressin + albumin for HRS-AKI. NEJM 2021;384:818–828.

2. Chronic Kidney Disease (CKD)

▼2.1 Definition, GFR Categories & Albuminuria

CKD = abnormalities of kidney structure or function present for >3 months, with health implications. Defined by either: eGFR <60 mL/min/1.73m² (G3a–G5), OR markers of kidney damage (albuminuria ≥30 mg/g, abnormal urinary sediment, electrolyte disorders, structural abnormality, history of transplant) regardless of eGFR.

GFR Category	eGFR (mL/min/1.73m²)	Description	Albuminuria Categories
G1	≥90	Normal or high (damage present)	A1: <30 mg/g (normal–mildly ↑)
G2	60–89	Mildly decreased	A2: 30–300 mg/g (moderately ↑)
G3a	45–59	Mildly-moderately decreased	A3: >300 mg/g (severely ↑)
G3b	30–44	Moderately-severely decreased	Risk ↑ as albuminuria category ↑
G4	15–29	Severely decreased
G5	<15	Kidney failure (dialysis or Tx)

🔑 Risk Stratification: CKD staging combines GFR category + albuminuria category into a heat map (green→yellow→orange→red). The highest risk category is G5+A3. Both independently predict CKD progression, cardiovascular events, and mortality. A urine ACR should be checked in every CKD patient at every visit.

▶2.2 CKD-MBD (Mineral & Bone Disease)

CKD-MBD: systemic disorder of mineral metabolism (Ca, PO4, PTH, FGF-23, Vitamin D) → vascular calcification, renal osteodystrophy, fractures, and cardiovascular disease.

Pathophysiology Sequence (begins at eGFR ~60)

↓ GFR → ↓ PO4 excretion → ↑ FGF-23 (phosphaturic, suppresses 1-αhydroxylase)
↑ FGF-23 → ↓ calcitriol (1,25-OH₂D) → ↓ GI Ca absorption → hypocalcemia
↓ calcitriol + hypocalcemia → ↑ PTH (secondary hyperparathyroidism)
PTH → bone resorption → osteitis fibrosa cystica; vascular calcification

Treatment Targets (KDIGO 2017)

Phosphate: Target toward normal range (3.5–5.5 mg/dL in non-dialysis CKD)
PTH: G5D (dialysis): maintain iPTH 2–9× upper limit of normal (~150–600 pg/mL)
Calcium: Avoid hypercalcemia; do not use calcium supplements routinely

Phosphate Binder	Mechanism	Advantages	Disadvantages
Sevelamer carbonate	Non-Ca, non-Al polymer; binds PO4 in gut	No Ca loading; may reduce LDL; no Al toxicity	GI side effects; expensive; large pill burden
Calcium carbonate / Calcium acetate	Ca binds PO4 in gut	Inexpensive; also treats hypocalcemia	Risk of hypercalcemia and vascular calcification
Lanthanum carbonate	Rare earth metal; very high PO4 affinity	Small pill burden; effective	Bone deposition unclear long-term
Sucroferric oxyhydroxide	Iron-based binder	Low pill burden (1–2 tabs/meal)	GI side effects; discolors stool black

Secondary Hyperparathyroidism Treatment

Calcitriol (1,25-OH₂D): suppresses PTH, but raises Ca and PO4 — use cautiously
Paricalcitol / Doxercalciferol: Vitamin D analogs — less effect on Ca/PO4 than calcitriol
Cinacalcet (calcimimetic): binds calcium-sensing receptor → ↑ sensitivity to Ca → ↓ PTH release; does NOT raise Ca/PO4; preferred when Ca already elevated. EVOLVE trial: cinacalcet did not reduce CV events vs placebo in HD patients (though post-hoc age-adjusted analysis suggested benefit).
Etelcalcetide (IV calcimimetic): given IV at end of HD; more potent than cinacalcet; treats severe HPT
Parathyroidectomy: for severe refractory HPT (PTH >1000 pg/mL with Ca/PO4 elevation unresponsive to medical therapy)

▶2.3 Anemia of CKD

Normochromic normocytic anemia due primarily to ↓ EPO production by peritubular interstitial cells. Additional factors: iron deficiency, chronic inflammation (↑ hepcidin → ↓ iron release), shortened RBC survival, blood loss from HD access.

Evaluation

CBC, reticulocyte count, iron studies (serum iron, TIBC, transferrin saturation, ferritin)
Absolute iron deficiency: serum ferritin <100 ng/mL OR transferrin saturation <20%
Functional iron deficiency: adequate stores but unable to mobilize (↑ hepcidin): ferritin 100–500 + TSAT <20%

Treatment

Iron repletion first: IV iron preferred in HD patients (ferric gluconate, iron sucrose, ferumoxytol, LMW iron dextran). Target ferritin 200–500 ng/mL, TSAT 20–30%
PIVOTAL trial (NEJM 2019): High-dose proactive IV iron vs low-dose reactive in HD → fewer ESA requirements, fewer transfusions, no safety signal; lower mortality trend
Erythropoiesis-stimulating agents (ESAs): Epoetin alfa, darbepoetin alfa. Target Hgb 10–11.5 g/dL (NOT normalize Hgb to >13).
TREAT trial (NEJM 2009): Darbepoetin targeting Hgb 13 g/dL → 2× risk of stroke vs placebo with no CV benefit; established upper Hgb target
Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHI): Daprodustat, roxadustat — oral ESA alternative; FDA-approved (roxadustat 2023). Caution: VTE, CV events

🔑 ESA Hyporesponsiveness: Most common cause = iron deficiency (functional or absolute). Other causes: infection/inflammation (↑ hepcidin), Al toxicity, hyperparathyroidism, hemoglobinopathy, pure red cell aplasia (anti-EPO antibodies — rare but serious; switch ESA formulation, consider immunosuppression). Always correct iron before increasing ESA dose.

▶2.4 SGLT2 Inhibitors & Novel Therapies in CKD

SGLT2 Inhibitors — Landmark Trials

Trial	Drug	Population	Key Result
CREDENCE (2019)	Canagliflozin	T2DM + CKD (eGFR 30–90, ACR >300)	43% ↓ ESKD/renal death; stopped early for efficacy
DAPA-CKD (2020)	Dapagliflozin	CKD eGFR 25–75, ACR 200–5000 (with OR without T2DM)	39% ↓ composite kidney outcome; benefit in non-diabetic CKD (IgA, FSGS)
EMPA-KIDNEY (2023)	Empagliflozin	CKD eGFR 20–45 (low ACR) or eGFR 45–90 (ACR ≥200)	28% ↓ kidney disease progression or CV death; broadest eGFR range

⚡ SGLT2i Mechanisms in CKD (beyond glucose lowering)

Tubuloglomerular feedback: SGLT2i → ↓ Na/glucose reabsorption in PCT → more Na to macula densa → afferent arteriolar constriction → ↓ intraglomerular pressure → renoprotection
↓ Proteinuria, ↓ tubular oxygen demand, anti-inflammatory, anti-fibrotic effects
Benefit seen independent of glucose-lowering effects — confirmed in non-diabetics (DAPA-CKD, EMPA-KIDNEY)
Initial eGFR "dip" (3–5%) on SGLT2i is expected and does not require dose reduction — reflects hemodynamic effect
Current recommendation: add SGLT2i to all CKD patients with ACR ≥200 regardless of diabetes status (KDIGO 2022)

Finerenone (Nonsteroidal MRA)

Finerenone — nonsteroidal, selective mineralocorticoid receptor antagonist. Reduces fibrosis, inflammation, and aldosterone-mediated kidney/CV damage.

FIDELIO-DKD (NEJM 2020): T2DM + CKD on max RAS blockade; 18% ↓ kidney outcomes (ESKD/40% eGFR decline/renal death); 14% ↓ CV events
FIGARO-DKD (NEJM 2021): Similar population, milder CKD; primarily CV benefit (13% ↓ MACE)
Combined FIDELITY analysis: robust kidney AND CV benefit across spectrum
Key advantage over spironolactone: Less hyperkalemia (selectivity), no gynecomastia/sexual dysfunction
Contraindicated if K >5.0 or eGFR <25

▶2.5 Practice Questions

Q1. A 60-year-old with T2DM and CKD G3b A3 (eGFR 38, ACR 680 mg/g) is on lisinopril 40 mg. HbA1c 7.1%. BP 132/78. K+ 4.2, iPTH 92 pg/mL, PO4 4.2 mg/dL. Which additional medication has the strongest evidence to slow CKD progression?

Answer: Dapagliflozin (SGLT2 inhibitor). DAPA-CKD and EMPA-KIDNEY trials demonstrated robust renoprotective benefit in diabetic and non-diabetic CKD with albuminuria >200 mg/g. Finerenone is also an excellent answer (FIDELIO-DKD), adding anti-fibrotic and CV benefit. Current KDIGO 2022 guidelines recommend SGLT2i for all CKD with eGFR 20–45 or ACR ≥200, and finerenone for T2DM + CKD. Both should be considered. The K+ of 4.2 is acceptable for finerenone. PO4 and PTH are not yet at treatment thresholds.

Q2. A dialysis patient has iPTH 820 pg/mL, Ca 9.6 mg/dL, PO4 6.8 mg/dL. Which therapy is most appropriate for the secondary hyperparathyroidism?

Answer: Cinacalcet (or etelcalcetide). The elevated PTH with normal-to-low calcium argues against calcitriol (which would raise calcium further). Cinacalcet works by sensitizing the CaSR → ↓ PTH without raising Ca or PO4. First, aggressively treat hyperphosphatemia with non-calcium phosphate binders (sevelamer). Parathyroidectomy reserved for PTH >1000 pg/mL refractory to medical therapy with hypercalcemia or severe hyperphosphatemia. EVOLVE trial showed no significant CV mortality benefit from cinacalcet in an intention-to-treat analysis, though it effectively lowers PTH.

📚 Key References — CKD

[G] KDIGO CKD Guideline 2022. Kidney Int Suppl 2013;3:1–150 (updated 2022).
[T] DAPA-CKD (2020): Heerspink et al. Dapagliflozin in patients with CKD. NEJM 2020;383:1436–1446.
[T] EMPA-KIDNEY (2023): The EMPA-KIDNEY Collaborative Group. NEJM 2023;388:117–127.
[T] FIDELIO-DKD (2020): Bakris et al. Finerenone in CKD and type 2 diabetes. NEJM 2020;383:2219–2229.
[T] PIVOTAL (2019): Macdougall et al. IV iron in HD patients. NEJM 2019;380:447–458.

3. Glomerular Diseases

▼3.1 Nephrotic vs Nephritic Syndrome

Feature	Nephrotic Syndrome	Nephritic Syndrome
Proteinuria	>3.5 g/day (massive)	Mild–moderate (typically <3.5 g/day)
Hematuria	Absent or minimal	Present (RBC casts, dysmorphic RBCs)
Edema	Massive (periorbital, anasarca)	Mild–moderate
Hypertension	Variable	Common (salt/water retention)
GFR	Usually preserved initially	Often reduced (↑ Cr)
Complement	Usually normal (except MPGN)	Low (post-strep, MPGN, lupus)
Albumin	Low (<3 g/dL)	Normal or mildly low
Lipids	Hyperlipidemia, lipiduria	Normal
Key diseases	MCD, FSGS, MN, diabetic nephropathy, amyloidosis	IgA nephropathy, post-strep GN, ANCA vasculitis, lupus nephritis, anti-GBM

🔑 Overlap Syndromes: Membranoproliferative GN (MPGN) and lupus nephritis class III/IV/V can present with features of BOTH nephrotic and nephritic syndrome simultaneously ("nephrotic-nephritic overlap"). IgA nephropathy occasionally presents with nephrotic-range proteinuria particularly in FSGS-variant.

▶3.2 Primary Glomerulopathies — MCD, FSGS, MN, IgA

Disease	LM	IF	EM	Treatment
Minimal Change Disease (MCD)	Normal glomeruli	Negative	Diffuse podocyte foot process effacement	Prednisone 1 mg/kg/day; 90% remission in children. Cyclophosphamide, tacrolimus for relapses
FSGS	Focal (some) segmental (part) sclerosis + hyalinosis	IgM, C3 in sclerotic areas (non-specific)	Foot process effacement (diffuse in primary)	Prednisone; CNI (tacrolimus) for steroid-resistant. Sparsentan (FDA 2023). Treat secondary cause first
Membranous Nephropathy	GBM thickening; "spikes" on silver stain	Granular IgG + C3 along GBM	Subepithelial deposits	Anti-PLA2R+ primary MN: rituximab (MENTOR trial preferred over CNI). KDIGO 2021: wait-and-see initially; treat if worsening
IgA Nephropathy	Mesangial hypercellularity; MEST-C score	IgA dominant mesangial deposits	Mesangial electron-dense deposits	RAS blockade; fish oil; steroids if high-risk. Sparsentan (PROTECT trial); Iptacopan; SGLT2i

Membranous Nephropathy — Key Points

Anti-PLA2R antibodies: positive in 70–80% of primary MN; levels correlate with disease activity; useful for monitoring and predicting relapse
Secondary MN causes: SLE (class V), HBV, solid tumor malignancy (especially in older patients — screen with CT chest/abdomen/pelvis + PSA/CEA), drugs (gold, D-penicillamine, NSAIDs)
MENTOR trial (NEJM 2019): Rituximab superior to cyclosporine for achieving and maintaining complete/partial remission in anti-PLA2R+ primary MN
Rituximab: 375 mg/m² × 4 doses weekly (lymphoma regimen) OR 1g × 2 doses 2 weeks apart; monitor B-cell depletion and anti-PLA2R levels

IgA Nephropathy — MEST-C Score (Oxford Classification)

M — Mesangial hypercellularity (>4 cells/mesangial area): M0 vs M1
E — Endocapillary proliferation: E0 vs E1
S — Segmental glomerulosclerosis: S0 vs S1
T — Tubular atrophy/interstitial fibrosis: T0 (<25%), T1 (25–50%), T2 (>50%)
C — Crescents: C0 (none), C1 (≤25%), C2 (>25%)

Poor prognosis: proteinuria >1 g/day, hypertension, impaired GFR at presentation, T2 or C2 on biopsy.

🔑 Sparsentan (Filspari™, FDA 2023): Dual endothelin receptor + angiotensin receptor blocker. First non-immunosuppressive agent FDA-approved for IgA nephropathy (PROTECT trial: 40% greater proteinuria reduction vs irbesartan). Also approved for FSGS. Monitoring: liver function tests, teratogenic.

▶3.3 Lupus Nephritis & ANCA Vasculitis

Lupus Nephritis — ISN/RPS Classification

Class	Histology	Clinical	Treatment
Class I	Minimal mesangial	Normal UA, normal Cr	No specific renal therapy
Class II	Mesangial proliferative	Mild proteinuria/hematuria	Hydroxychloroquine; low-dose steroids if needed
Class III	Focal proliferative (<50% glomeruli)	Active sediment, proteinuria, variable Cr	High-dose steroids + MMF or cyclophosphamide
Class IV	Diffuse proliferative (≥50% glomeruli) — most severe	Nephritic syndrome, ↑ Cr, low C3/C4	High-dose steroids + MMF (preferred) or EURO cyclophosphamide
Class V	Membranous (± proliferative features)	Nephrotic syndrome; can coexist with III or IV	Steroids + MMF; rituximab for resistant
Class VI	Advanced sclerosing (>90% sclerotic)	End-stage; minimal active inflammation	Prepare for RRT; no benefit from IS

⚡ Lupus Nephritis Induction — Key Points

MMF vs Cyclophosphamide: ALMS trial — MMF non-inferior to IV cyclophosphamide for induction; better tolerated (less nausea, alopecia, infection). MMF preferred in non-severe LN and in women of childbearing age.
AURORA trial (2021): Voclosporin (novel CNI) added to MMF/steroids → significantly higher complete renal response at 52 weeks vs standard therapy (40.8% vs 22.5%)
BLISS-LN trial (2020): Belimumab (anti-BLyS) added to standard therapy → primary efficacy renal response 43% vs 32%; primary endpoint met. Now standard of care for moderate-severe LN.
Maintenance: MMF 1.5–2 g/day preferred over azathioprine (MAINTAIN Nephritis trial)
All LN patients: hydroxychloroquine 5 mg/kg/day (renal protection, prevents flares, improves CV outcomes)

ANCA-Associated Vasculitis (AAV) — Renal Involvement

Feature	GPA (Granulomatosis with Polyangiitis)	MPA (Microscopic Polyangiitis)	EGPA (Eosinophilic)
ANCA type	c-ANCA / PR3-ANCA (80–90%)	p-ANCA / MPO-ANCA (60–70%)	p-ANCA/MPO (50%); many ANCA negative
Respiratory	Upper (sinusitis, saddle-nose) + lower (nodules, cavities)	Pulmonary capillaritis (hemoptysis)	Asthma, eosinophilia, nasal polyps
Kidney	Pauci-immune crescentic GN (RPGN)	Pauci-immune crescentic GN	Less common renal involvement
Biopsy	Granulomas (necrotizing) + crescents	Crescents (no granulomas)	Eosinophilic infiltration + crescents

Treatment (AAV): Induction: rituximab (375 mg/m² × 4) + high-dose steroids — RAVE/RITUXVAS trials: rituximab non-inferior to cyclophosphamide; preferred in relapsing disease, PR3-ANCA. Severe (dialysis-dependent or pulmonary hemorrhage): consider plasmapheresis (PEXIVAS trial showed no benefit on renal outcomes, but may be used in life-threatening pulmonary hemorrhage). Maintenance: rituximab q6mo for 2 years preferred over azathioprine (MAINRITSAN trial).

▶3.4 Practice Questions

Q1. A 35-year-old man presents with 8 g/day proteinuria. Biopsy: thickened GBM with "spikes" on silver stain; IF shows granular IgG+C3 along GBM; EM shows subepithelial deposits. Anti-PLA2R antibody titer is 1:320. What is the diagnosis and initial management?

Diagnosis: Primary Membranous Nephropathy (anti-PLA2R positive).
Management: KDIGO 2021 recommends initial watch-and-wait for 6 months with RAS blockade (ACEi/ARB), dietary sodium restriction, statins. Initiate immunosuppression if: worsening proteinuria, eGFR decline >30%, or persistent severe proteinuria despite conservative therapy. First-line IS: Rituximab (per MENTOR trial, superior to cyclosporine for sustained remission). Monitor anti-PLA2R titer as biomarker of treatment response — antibody clearance precedes proteinuria reduction by months.

Q2. A 29-year-old woman with SLE presents with hematuria, proteinuria 4.2 g/day, SCr 2.1 (baseline 0.8), C3 58 (low), C4 6 (low), anti-dsDNA 1:640. Biopsy shows diffuse proliferative GN with wire-loop lesions and full-house immunofluorescence. What class is this and what is the preferred induction regimen?

Diagnosis: Lupus Nephritis Class IV (diffuse proliferative). Wire-loop lesions = massive subendothelial immune complex deposits; full-house IF = IgG, IgA, IgM, C1q, C3 — pathognomonic for lupus nephritis.
Induction: High-dose glucocorticoids (pulse methylprednisolone 500–1000 mg/day × 3 days, then prednisone 0.5–1 mg/kg/day) + MMF 1.5–3 g/day. Add voclosporin 23.7 mg BID (AURORA trial) or belimumab (BLISS-LN trial) for enhanced efficacy. Start hydroxychloroquine if not already on it. Monitor: SCr, UA, C3/C4, anti-dsDNA, spot urine PCR q3 months.

4. Electrolyte Disorders

▼4.1 Hyponatremia

Hyponatremia (Na <135 mEq/L) is the most common electrolyte disorder. Approach: First confirm true hyponatremia (rule out pseudohyponatremia/hyperglycemia), then assess volume status, then urine Osm and urine Na.

Step-by-Step Approach

Plasma osmolality: Low (<275) = hypotonic hyponatremia (true). Normal or high = pseudohyponatremia (proteins, lipids) or hyperglycemia (correct Na: add 1.6 mEq/L per 100 mg/dL glucose above 100)
Volume status: Hypovolemic / Euvolemic / Hypervolemic
Urine osmolality: <100 = primary polydipsia or reset osmostat; >100 = ADH excess
Urine Na: <20 = renal Na conservation (hypovolemia, low effective circulating volume); >20 = SIADH, CSW, renal salt wasting, Addison's

Volume Status	Urine Na <20	Urine Na >20
Hypovolemic	GI/skin losses, hemorrhage, third-spacing	Diuretics, salt-wasting nephropathy, cerebral salt wasting, Addison's disease
Euvolemic	Primary polydipsia (U-Osm <100), hypothyroidism	SIADH (most common); glucocorticoid deficiency; drugs
Hypervolemic	CHF, cirrhosis, nephrotic syndrome (↓EABV → ↑ADH)	Advanced AKI/CKD

SIADH Diagnostic Criteria (Bartter-Schwartz)

Plasma Osm <275; Urine Osm >100 (usually >300); Urine Na >40; Euvolemic; Normal adrenal/thyroid function; No diuretics
Causes: CNS (stroke, tumor, meningitis), Pulmonary (pneumonia, TB, COPD, mechanical ventilation), Drugs (SSRIs, carbamazepine, cyclophosphamide, vincristine, desmopressin, NSAIDs, PPIs), Malignancy (small cell lung cancer — most common ectopic)

Treatment of Hyponatremia

⚡ Correction Rate — Critical

Symptomatic (seizure, coma): Raise Na by 4–6 mEq/L in first 1–2 hours with 3% NaCl bolus 150 mL over 20 min (repeat ×2–3 prn)
Maximum correction: ≤8–10 mEq/L per 24h to prevent Osmotic Demyelination Syndrome (ODS)
High ODS risk (correct even more slowly, max 8 mEq/L/24h): alcoholism, malnutrition, liver disease, K <3, Na <120 with chronic duration
If overcorrected: give D5W + DDAVP (desmopressin) to re-lower Na

Hypovolemic: Isotonic NS + treat underlying cause (stop diuretics)
SIADH: Fluid restriction 800–1000 mL/day (first-line); salt tabs; loop diuretics + oral salt; vaptans (tolvaptan) for severe/refractory SIADH but ONLY if monitored (risk overcorrection)
Hypervolemic (CHF/cirrhosis): Treat underlying disease; fluid restriction; vaptans less used due to hepatotoxicity (cirrhosis)

▶4.2 Potassium Disorders

Hyperkalemia — Emergency Protocol

Intervention	Mechanism	Onset	Duration	Note
IV Calcium gluconate 1–2 g (10%) over 10 min	Membrane stabilization (NOT lower K)	Immediate (1–3 min)	30–60 min	Repeat if ECG unchanged after 5 min; first priority if ECG changes present
Insulin 10 units IV + Dextrose 50g	Intracellular shift (Na/K ATPase)	15–30 min	4–6h	Lower K by 0.5–1.5 mEq/L; monitor glucose q1h
Albuterol 10–20 mg nebulized	β2 agonist → intracellular shift	15–30 min	2–4h	Additive to insulin; lowers K by 0.5–1 mEq/L
Sodium bicarbonate (only if severe acidosis)	Intracellular shift	30–60 min	Hours	Minimal effect in non-acidemic patients; not recommended alone
Furosemide	Urinary K excretion	1–2h	Ongoing	Requires residual renal function; most effective removal
Patiromer / SZC (sodium zirconium cyclosilicate)	GI K binder/exchange	2–7h (patiromer); 1h (SZC)	Ongoing	SZC faster onset; preferred for outpatient maintenance; do NOT use as emergent therapy
Dialysis	Removes K directly	Minutes (if on HD)	During session	Most rapid definitive removal; use in emergent refractory hyperkalemia

ECG Changes in Hyperkalemia (progressive with ↑ K)

Peaked/tall T waves (first sign, often K 5.5–6.5)
Prolonged PR interval, flat P waves (K 6.5–7.0)
Widened QRS, sine-wave pattern (K >7.0)
Ventricular fibrillation / asystole (K >8–9)

🔑 Pseudohyperkalemia: Hemolysis (most common), extreme leukocytosis (>100,000 WBC), thrombocytosis (>1,000,000 platelets) — all release intracellular K in vitro. Suspect when K elevated without symptoms or ECG changes; confirm with plasma K (heparinized tube, not serum).

▶4.3 Calcium, Magnesium & Phosphate

Hypocalcemia

Correct for albumin: Corrected Ca = measured Ca + 0.8 × (4 − albumin). Or use ionized Ca directly.
Causes: Hypoparathyroidism (post-surgical #1), hypomagnesemia, vitamin D deficiency, CKD (↓ calcitriol), pancreatitis (Ca soap formation), hungry bone syndrome, hypoalbuminemia (pseudo)
Symptoms: Tetany (Chvostek's sign — facial nerve tap; Trousseau's sign — carpal spasm with BP cuff), perioral numbness, QT prolongation, seizures
Treatment: Symptomatic/severe: IV calcium gluconate (1–2 g over 10–20 min, then infusion). Mild: PO calcium carbonate/citrate + vitamin D. If hypomagnesemia: replace Mg first.

Hypomagnesemia — Critical Points

Mg <1.8 mg/dL. Often overlooked. Causes refractory hypokalemia (Mg needed for ROMK function → K retention) and refractory hypocalcemia (↓ PTH release, PTH resistance)
Causes: GI losses (diarrhea, malabsorption), alcoholism (most common outpatient), PPIs (>1 year use), loop diuretics, aminoglycosides, amphotericin B, cisplatin
Gitelman syndrome: autosomal recessive; SLC12A3 mutation (NCC cotransporter); hypokalemia, hypomagnesemia, metabolic alkalosis, hypocalciuria
Treatment: IV Mg sulfate for severe/symptomatic; oral Mg oxide/glycinate for mild (limited by diarrhea)

▶4.4 Practice Questions

Q1. A 60-year-old with small cell lung cancer is found to have Na 115 mEq/L. She has mild confusion. Urine Osm 520, Urine Na 68, plasma Osm 245. She appears euvolemic. What is the diagnosis, and how would you correct her sodium if she has a seizure?

Diagnosis: SIADH (ectopic ADH from SCLC). Criteria: hyponatremia with low plasma Osm, inappropriately concentrated urine (Osm >100), urine Na >40, euvolemia, no diuretics.
If seizure: Bolus 3% NaCl 150 mL IV over 20 minutes. Repeat up to 2–3× until seizure stops. Target: raise Na by 4–6 mEq/L acutely. Do NOT exceed 8–10 mEq/L correction in 24h to prevent osmotic demyelination syndrome (ODS). Once Na ≥120 and symptoms resolved, switch to fluid restriction. This patient has chronic hyponatremia (SCLC — likely gradual) so is at HIGH risk for ODS; correct conservatively.

Q2. A 75-year-old on lisinopril and spironolactone is admitted with K+ 7.4 mEq/L. ECG shows wide QRS with sine wave pattern. Place the following interventions in correct order: (A) IV calcium gluconate, (B) IV insulin + D50, (C) Dialysis, (D) Albuterol nebulizer, (E) Kayexalate.

Correct order: A → B → D → C → (E last, poorest evidence)
1. A (Calcium gluconate): Membrane stabilization — immediately protects heart. FIRST priority when ECG changes present.
2. B (Insulin + dextrose): Shift K into cells — acts within 15–30 min.
3. D (Albuterol): Additional intracellular shift, additive to insulin.
4. C (Dialysis): Definitive removal — if refractory or oliguric/anuric. SZC/Patiromer are preferred outpatient binders but onset too slow for emergency. Kayexalate (sodium polystyrene sulfonate) has poor evidence and risk of intestinal necrosis — avoid in post-op or ileus patients. Stop spironolactone and lisinopril.

5. Acid-Base Disorders

▼5.1 Systematic Approach to Acid-Base

pH: <7.35 = acidemia; >7.45 = alkalemia
Primary disorder: pCO₂ ↑ → respiratory acidosis; pCO₂ ↓ → respiratory alkalosis; HCO₃ ↓ → metabolic acidosis; HCO₃ ↑ → metabolic alkalosis
Compensation: (Is it appropriate?)
Anion gap: AG = Na − (Cl + HCO₃). Normal = 8–12 (albumin-uncorrected). If hypoalbuminemia: add 2.5 for every 1 g/dL below 4 g/dL (corrected AG)
Delta-delta (Δ/Δ): If HAGMA present: (AG − 12) / (24 − HCO₃). <1 = additional NAGMA; 1–2 = pure HAGMA; >2 = additional metabolic alkalosis

Disorder	Primary Change	Expected Compensation
Metabolic Acidosis	↓ HCO₃	pCO₂ = 1.5×HCO₃ + 8 ± 2 (Winter's formula)
Metabolic Alkalosis	↑ HCO₃	pCO₂ = 0.7×HCO₃ + 21 ± 2
Respiratory Acidosis (acute)	↑ pCO₂	HCO₃ ↑ by 1 per 10 mmHg ↑ pCO₂
Respiratory Acidosis (chronic)	↑ pCO₂	HCO₃ ↑ by 3.5 per 10 mmHg ↑ pCO₂
Respiratory Alkalosis (acute)	↓ pCO₂	HCO₃ ↓ by 2 per 10 mmHg ↓ pCO₂
Respiratory Alkalosis (chronic)	↓ pCO₂	HCO₃ ↓ by 5 per 10 mmHg ↓ pCO₂

▶5.2 High Anion Gap Metabolic Acidosis (HAGMA)

GOLDMARK Mnemonic

Letter	Cause	Distinguishing Features
Glycolaldehyde / Glycols	Ethylene glycol (anti-freeze), propylene glycol	↑ Osmolar gap; calcium oxalate crystals in urine; ethylene glycol → oxalic acid; neurologic symptoms; give fomepizole + HD
Oxoproline	5-Oxoprolinemia (pyroglutamic aciduria)	Chronic acetaminophen use + malnutrition; glutathione depletion; rare
L-lactate	Type A (hypoperfusion): sepsis, shock, ischemia; Type B: metformin, seizures, malignancy, thiamine deficiency	Lactate >2 mmol/L; most common HAGMA in ICU; serum lactate level
D-lactate	Short bowel syndrome; bacterial overgrowth	Normal serum lactate (D-lactate not measured by standard assay); neurologic symptoms post high-carb meal
Methanol	Methanol (wood alcohol)	↑ Osmolar gap; visual changes (optic nerve toxicity); metabolized to formaldehyde/formic acid; give fomepizole + HD
Aspirin (salicylates)	ASA overdose	Mixed HAGMA + respiratory alkalosis (primary resp alk); tinnitus, hyperthermia; urine salicylate level
Renal failure	CKD/ESRD uremia	Accumulation of sulfates, phosphates, urates; modest AG elevation (rarely >25)
Ketoacidosis	DKA (insulin deficiency), alcoholic KA, starvation KA	↑ β-hydroxybutyrate (DKA/AKA); urine/serum ketones; glucose typically ↑ in DKA (can be low in AKA)

🔑 Osmolar Gap: = Measured Osm − Calculated Osm. Calculated Osm = 2Na + (glucose/18) + (BUN/2.8). Normal <10. Elevated (>20) suggests unmeasured osmoles (ethanol, methanol, ethylene glycol, isopropanol, mannitol). Ethanol itself raises Osm without causing HAGMA — use to distinguish ethanol from toxic alcohols.

▶5.3 Non-Anion Gap Metabolic Acidosis & RTA

Feature	Type 1 (Distal) RTA	Type 2 (Proximal) RTA	Type 4 RTA
Defect	Cannot secrete H⁺ in collecting duct (H⁺-ATPase failure)	Cannot reabsorb HCO₃ in PCT (<85% reabsorbed)	Aldosterone deficiency/resistance → ↓ K and H excretion
Urine pH	>5.5 always (cannot acidify)	>5.5 when HCO₃ > threshold; <5.5 when depleted	<5.5 (can acidify)
Serum K	Hypokalemia	Hypokalemia (variable)	Hyperkalemia
HCO₃ level	Very low (<10 often)	Moderate (14–20)	Mild–moderate (15–22)
Urine AG	Positive (+) — impaired NH₄ excretion	Negative (−) when acidotic (NH₄ high)	Positive (+) — ↓ NH₄ excretion
Stones/nephrocalcinosis	Yes — Ca phosphate stones, nephrocalcinosis	Hypophosphatemia/Fanconi	No
Causes	Sjögren's (#1 autoimmune), amphotericin B, toluene, lithium, hypercalciuria, genetic	Fanconi syndrome, myeloma, carbonic anhydrase inhibitors (acetazolamide), tenofovir, Wilson's disease	DM + CKD (#1), ACEi/ARBs/NSAIDs, heparin, calcineurin inhibitors, Addison's disease
Treatment	Alkali supplementation (sodium bicarbonate or citrate) + K replacement	Bicarbonate + K + treat underlying cause; high doses needed (large ongoing HCO₃ loss)	Treat underlying; fludrocortisone for hypoaldosteronism; furosemide if hypervolemic

⚡ Urine Anion Gap (UAG)

UAG = Urine Na + Urine K − Urine Cl. Estimates urinary NH₄⁺ (NH₄Cl is unmeasured, paired with Cl).
Negative UAG (Cl > Na+K): NH₄⁺ excretion HIGH → appropriate renal response to acidosis → extrarenal cause (diarrhea, GI HCO₃ loss)
Positive UAG (Na+K > Cl): NH₄⁺ excretion LOW → renal tubular acidosis or advanced CKD

▶5.4 Practice Questions

Q1. ABG: pH 7.24, pCO₂ 28 mmHg, HCO₃ 12 mEq/L. Na 140, Cl 102. Glucose 90. BUN 14. What is the primary disorder, is compensation appropriate, and what is the anion gap?

Primary disorder: Metabolic acidosis (↓pH, ↓HCO₃).
AG: 140 − (102 + 12) = 26 (high AG metabolic acidosis). Correct for albumin if low.
Compensation check (Winter's): Expected pCO₂ = 1.5(12) + 8 ± 2 = 26 ± 2. Measured pCO₂ = 28 → appropriate compensation. No additional respiratory disorder.
Delta-Delta: (26−12)/(24−12) = 14/12 = 1.17 → within 1–2 = pure HAGMA. Next: check lactate, ketones, renal function, osmolar gap (GOLDMARK).

Q2. A 34-year-old with Sjögren's syndrome has Na 140, K 2.8, Cl 112, HCO₃ 16, pH 7.32, pCO₂ 32. Urine pH 6.8, UAG +22. Which type of RTA and what is the appropriate treatment?

Type 1 (Distal) RTA. Key findings: NAGMA (AG = 140−112−16 = 12), hypokalemia, urine pH >5.5 despite acidemia (cannot acidify urine), positive UAG (low NH₄ excretion), Sjögren's syndrome (most common autoimmune cause). Risk of nephrocalcinosis and calcium phosphate stones (alkaline urine + hypercalciuria).
Treatment: Potassium citrate (both alkalinizes and replaces K) or sodium bicarbonate + separate K supplementation. Dose: HCO₃ 1–2 mEq/kg/day. Monitor for nephrolithiasis with renal ultrasound.

6. Dialysis

▼6.1 Hemodialysis — Principles & Prescription

HD removes solutes and fluid via diffusion (concentration gradient across semipermeable membrane) and convection (solvent drag during ultrafiltration). Standard prescription: 3×/week, 3–5h sessions, blood flow 400–500 mL/min, dialysate flow 500–800 mL/min.

Dialysis Adequacy

Kt/V: K = dialyzer clearance; t = time; V = distribution volume of urea. Target spKt/V ≥1.4 per session (single-pool); Kt/V <1.2 = inadequate
URR (Urea Reduction Ratio): Target ≥65%. (pre-BUN − post-BUN) / pre-BUN
HEMO trial (NEJM 2002): High-flux (Kt/V 1.71) vs standard (1.32) dialysis → no difference in mortality; high-flux membrane may benefit patients on HD >3.7 years and with CVD (subgroup analysis)

Vascular Access (preferred order: AVF > AVG > CVC)

Access Type	Pros	Cons	Maturation
AVF (Arteriovenous Fistula)	Lowest infection/thrombosis rate; longest patency; best survival	Requires surgical creation and maturation time; may fail to mature (~40%)	6–12 weeks
AVG (AV Graft)	Higher success of maturation; quicker to use	Higher thrombosis + infection rates; shorter patency than AVF	2–4 weeks
CVC (Tunneled catheter)	Immediate use; no maturation needed	Highest CRBSI rate; central vein stenosis; worst survival outcomes	Immediate

🔑 Steal Syndrome: Ischemia distal to AV access (hand/arm) due to blood diversion from high-flow fistula. Presents with pain, paresthesias, coolness, pallor, weakness. Grade III–IV requires surgical intervention (DRIL procedure — Distal Revascularization-Interval Ligation; or banding to reduce flow). Avoid subclavian vein catheterization in patients likely to need future AV access (risks central vein stenosis → ipsilateral arm edema/fistula failure).

▶6.2 Peritoneal Dialysis

PD uses the peritoneal membrane as a semipermeable membrane; dialysate instilled into peritoneal cavity, equilibrates via diffusion and osmosis, then drained. Glucose provides osmotic gradient for UF.

PD Adequacy

Target weekly Kt/V (peritoneal + renal) ≥1.7; weekly creatinine clearance ≥50 L/1.73m²
Residual renal function (RRF) is better preserved with PD than HD — major advantage, especially early on

PD Peritonitis — Most Common Complication

Diagnosis: 2 of 3 criteria: (1) symptoms (abdominal pain, cloudy effluent); (2) effluent WBC >100/mm³ with >50% PMNs; (3) positive effluent culture or Gram stain.

Organism	Frequency	Treatment
Gram-positive (Staph epidermidis, Staph aureus, Strep)	60–70%	IP cefazolin or vancomycin (if MRSA risk/resistant)
Gram-negative (E. coli, Klebsiella, Pseudomonas)	20–30%	IP ceftazidime or aminoglycoside; Pseudomonas: IP ceftazidime + PO fluoroquinolone × 21 days; consider catheter removal
Fungal (Candida)	<5%	Catheter removal immediately + antifungal × 4–6 weeks; very high mortality if untreated
Culture-negative	10–20%	Empiric gram-positive coverage; reconsider diagnosis

Indications to remove PD catheter: Fungal peritonitis, refractory peritonitis (not responding at 5 days), relapsing peritonitis, tunnel/exit-site infection with peritonitis.

HD vs PD Comparison

Feature	Hemodialysis	Peritoneal Dialysis
Frequency	3×/week in-center	Daily (CAPD) or nightly automated (APD)
Small solute clearance	Higher	Lower (but continuous)
Middle molecule clearance	Better with high-flux/hemodiafiltration	Better with PD (larger pores)
Residual renal function preservation	Poorer	Better
Vascular access	Required (fistula/graft/catheter)	Not needed (peritoneal catheter instead)
Hemodynamic stability	Intradialytic hypotension common	Continuous UF → more stable BP
Infection	CRBSI; bacteremia	Peritonitis; exit-site infection
Best candidates	Poor peritoneal anatomy, prior abdominal surgery, high catabolic state, large body size	Residual renal function, CHF, preference for home therapy, remote location, needle phobia

▶6.3 Practice Questions

Q1. A HD patient with a tunneled catheter develops chills, fever, and rigors during a session. Blood cultures grow MRSA. What are the next steps in management?

Catheter-related bloodstream infection (CRBSI) with MRSA:
1. Start IV vancomycin (dosed per HD protocol, typically 20–25 mg/kg with levels targeted to 15–20 mcg/mL pre-HD).
2. Remove catheter — MRSA bacteremia is an absolute indication for catheter removal (cannot be salvaged). Place temporary non-tunneled catheter at new site if needed.
3. Duration: 6 weeks of antibiotics if complicated (endocarditis, septic emboli, osteomyelitis); minimum 2–3 weeks if uncomplicated (cultures clear within 72h, no metastatic infection). TEE to rule out endocarditis (high yield in Staph aureus bacteremia).
4. Bridge to permanent AV fistula creation once bacteremia cleared.

7. Renal Transplantation

▼7.1 Immunosuppression Protocols

Standard Triple Therapy (Maintenance)

Calcineurin inhibitor (CNI): Tacrolimus (preferred over cyclosporine — less rejection, more nephrotoxicity/DM) or cyclosporine
Antimetabolite: Mycophenolate mofetil (MMF) or mycophenolic acid; azathioprine (less potent)
Corticosteroids: Prednisone (taper; many centers attempt steroid withdrawal at 3–12 months)

Induction Therapy

Agent	Mechanism	Indication
Basiliximab (anti-IL-2Rα)	Blocks IL-2 receptor on T cells; non-depleting	Standard risk transplants; well-tolerated
Anti-thymocyte globulin (ATG)	T-cell depleting; polyclonal rabbit antibody	High-risk (sensitized, delayed graft function expected, marginal donor, repeat transplant)
Belatacept	CTLA4-Ig; blocks CD28-B7 co-stimulation → T-cell anergy	Alternative to CNI in patients with CNI intolerance; slower rejection treatment in acute phase

▶7.2 Rejection — T-cell vs Antibody-Mediated

Feature	T-cell Mediated Rejection (TCMR)	Antibody-Mediated Rejection (ABMR)
Banff criteria	Tubulitis (t), interstitial inflammation (i); IF/TA, arteritis	Microvascular inflammation (g+ptc≥2), C4d positivity, donor-specific antibodies (DSA)
C4d staining	Negative	Often Positive (peritubular capillaries)
DSA	Absent	Present (class I or II HLA antibodies)
Timing	Days to months post-transplant	Early (<3 months, acute), or late (months–years, chronic)
Treatment	Pulse steroids (methylprednisolone 500mg IV × 3); ATG for steroid-resistant	IVIG + plasmapheresis; rituximab; eculizumab (for complement-mediated)

Chronic Allograft Nephropathy / IF-TA

Interstitial fibrosis and tubular atrophy (IF-TA) on biopsy — final common pathway for many insults: chronic rejection, CNI toxicity, recurrent disease, infection. Progressive decline in eGFR ± proteinuria years post-transplant. Optimize CNI levels; treat modifiable causes; consider belatacept conversion.

▶7.3 Infectious Complications & BK Virus

Timeline of Post-Transplant Infections

0–1 month: Donor/recipient-derived (bacteremia, wound infection, UTI); surgical complications
1–6 months: Opportunistic infections peak — CMV, PCP (Pneumocystis), BK virus, aspergillus, toxoplasma, Listeria
>6 months: Community-acquired infections; late viral reactivation (CMV, EBV → PTLD); skin cancers

BK Virus Nephropathy (BKVN)

BK polyomavirus reactivation due to over-immunosuppression; infects tubular epithelial cells
Decoy cells (viropathic tubular cells) in urine → BK viruria → BK viremia → nephropathy
Screening: Monthly plasma BK PCR for first 2 years; urine cytology for decoy cells
Thresholds for action: BK viremia >10,000 copies/mL (presumptive BKVN); biopsy confirms (SV40 immunostain)
Treatment: Reduce immunosuppression (first reduce MMF; then reduce tacrolimus target). No proven antiviral. Leflunomide, cidofovir, IVIG — limited evidence. Recovery of renal function variable.

CMV Management

Highest risk: donor seropositive (D+) / recipient seronegative (R−)
Prophylaxis: Valganciclovir 900 mg/day for 3–6 months (D+/R− → 6 months)
Treatment of CMV disease: IV ganciclovir 5 mg/kg q12h; switch to oral valganciclovir when stable; treat until CMV PCR undetectable × 2
Ganciclovir-resistant CMV: UL97 mutation (reduced phosphorylation) or UL54 mutation; use foscarnet or cidofovir

▶7.4 Practice Questions

Q1. A kidney transplant recipient (D+/R−) is on tacrolimus, MMF, prednisone. At 3 months, creatinine rises from 1.2 to 2.0. Biopsy: interstitial inflammation, tubulitis (t2, i2), no microvascular inflammation, C4d negative, DSA negative. What is the diagnosis and treatment?

Diagnosis: Acute T-cell Mediated Rejection (TCMR), Banff grade IA (tubulitis t2, interstitial inflammation i2, C4d negative, DSA negative).
Treatment: Pulse methylprednisolone 500 mg IV daily × 3 days. Monitor creatinine closely. If no improvement after 3–5 days of steroid pulses → ATG (thymoglobulin) for steroid-resistant TCMR. Optimize tacrolimus trough (target 8–12 ng/mL in first year). Also check for and treat BK viremia, CMV, drug levels.

8. Tubulointerstitial & Cystic Diseases

▼8.1 ADPKD

Autosomal dominant polycystic kidney disease: most common hereditary kidney disease. Mutations in PKD1 (85%; chromosome 16; more severe) or PKD2 (15%; chromosome 4; later ESRD). Prevalence 1:400–1:1000. Bilateral cysts progressively enlarge → ESRD typically in 50s–60s (PKD1) or 70s (PKD2).

Extrarenal Manifestations

Intracranial aneurysms (ICA): 5–10%; screen MRA if family history of ICA/SAH or high-risk occupation. Rupture risk increases with aneurysm size >7mm
Hepatic cysts: Most common extrarenal manifestation (70–80%); rarely cause liver failure
Mitral valve prolapse: 25%; usually asymptomatic
Diverticulosis, hernias

Treatment

BP control: HALT-PKD trial (NEJM 2014): rigorous BP control (target 95/60–110/75 mmHg) with ACEi → ↓ TKV growth and CV events vs standard control. ACEi preferred (also reduces proteinuria).
Tolvaptan (V2 receptor antagonist → ↓ cAMP → ↓ cyst growth): TEMPO 3:4 trial (NEJM 2012): tolvaptan slowed TKV growth by 49% and slowed eGFR decline vs placebo over 3 years. FDA approved 2018 for ADPKD with rapidly progressing disease. Main risk: hepatotoxicity — monthly LFTs required; contraindicated in liver disease. Aquaretic side effects (polyuria, nocturia, thirst) are expected.
Rapidly progressive disease criteria: eGFR decline >5 mL/min/year; TKV Mayo imaging class 1C/1D/1E; PKD1 mutation; age <55 with TKV >750 mL

▶8.2 Nephrolithiasis

Stone Type	Frequency	X-ray	Cause	Treatment/Prevention
Calcium oxalate	70–80%	Radiopaque	Hypercalciuria, hyperoxaluria, hypocitraturia, low urine volume	High fluid intake; thiazide diuretics (↓ Ca excretion); potassium citrate (↑ citrate, alkalinizes)
Calcium phosphate	5–10%	Radiopaque	High urine pH, distal RTA, hyperparathyroidism	Acidify urine; treat RTA; PHPT surgery
Struvite (Mg-NH₄-PO₄)	10–15%	Radiopaque (staghorn)	Urease-producing bacteria (Proteus, Klebsiella, Pseudomonas)	Antibiotics; urological intervention; acetohydroxamic acid
Uric acid	5–10%	Radiolucent	Low urine pH (gout, metabolic syndrome, DM), hyperuricosuria	Alkalinize urine (potassium citrate, NaHCO₃) to pH 6.5–7; allopurinol; hydration
Cystine	<1%	Slightly opaque (ground-glass)	Cystinuria (autosomal recessive SLC3A1/SLC7A9); hexagonal crystals	High fluid intake (>4L/day); alkalinize urine >7.5; D-penicillamine or tiopronin (cystine-binding agents)

🔑 24-Hour Urine Evaluation: Collect for recurrent stone formers or single stone in high-risk patients. Measure: urine volume (target >2.5L/day), calcium, oxalate, uric acid, citrate, sodium, creatinine, pH. Hypercalciuria: >250 mg/day (women) or >300 mg/day (men). Hypocitraturia: <320 mg/day (most common metabolic abnormality in recurrent stone formers).

▶8.3 Practice Questions

Q1. A 35-year-old with ADPKD (PKD1, eGFR 52, declining 6 mL/min/year, TKV 2100 mL on MRI) asks about tolvaptan. What criteria are met for treatment, and what monitoring is required?

Criteria met: Rapidly progressive ADPKD defined by eGFR decline >5 mL/min/year AND Mayo imaging class (TKV 2100 mL at age 35 → class 1E — very high). PKD1 mutation further supports aggressive course.
Tolvaptan: FDA-approved for adults at risk of rapidly progressive ADPKD. Dose: 45/15 mg split dose AM/PM → titrate to 90/30 mg. Monitoring required: LFTs monthly × 18 months, then q3–6 months (hepatotoxicity risk — DILI reported; contraindicated in liver disease). Educate on aquaretic effects (polyuria 7–11 L/day, nocturia, thirst) — patient must have access to water at all times. Stop if ALT >3× ULN or symptoms of liver injury.

9. Renovascular & Vascular Diseases

▼9.1 Renal Artery Stenosis

Feature	Atherosclerotic RAS	Fibromuscular Dysplasia (FMD)
Demographics	Older (>55), male, smoker, PAD, DM	Young–middle-aged women (15–50)
Location	Ostial/proximal (plaque)	Mid-distal renal artery ("string of beads")
Imaging	CT/MR angiography shows atherosclerotic plaque	"String of beads" (medial fibroplasia) on MRA/CTA
Clues	Flash pulmonary edema, bilateral; SCr ↑ with ACEi; asymmetric kidney size; severe resistant HTN	Renovascular HTN in young woman; sometimes headache (FMD involves carotids too)
Treatment	Medical therapy (ACEi/ARB, statins, antiplatelet). CORAL trial (NEJM 2014): stenting did NOT reduce CV events vs medical therapy alone. Revascularization for refractory HTN, flash pulmonary edema, rapidly declining eGFR.	Percutaneous transluminal angioplasty (PTA) without stenting; cure/improve HTN in 60–90%

▶9.2 Thrombotic Microangiopathies (TMA)

TMA: microangiopathic hemolytic anemia (MAHA) + thrombocytopenia + end-organ damage (kidney, brain). Pentad of TTP: MAHA, thrombocytopenia, fever, neurological symptoms, renal failure (all 5 in <5% of cases).

Feature	TTP	HUS (typical/STEC)	Atypical HUS (aHUS)
Mechanism	ADAMTS13 deficiency (hereditary or auto-Ab) → ultra-large VWF multimers → platelet aggregation	Shiga toxin (STEC O157:H7) → endothelial injury → TMA	Complement alternative pathway dysregulation (CFH, CFI, C3, CFB mutations or anti-CFH antibodies)
Predominant organ	Brain (neurological symptoms dominant)	Kidney (severe AKI, bloody diarrhea prodrome)	Kidney (severe AKI); recurrence after renal Tx without treatment
ADAMTS13	<10% activity (diagnostic)	Normal (>10%)	Normal (>10%)
Treatment	Plasma exchange (PLEX) + steroids; rituximab for refractory/relapsing; caplacizumab (anti-VWF nanobody) reduces organ damage and recurrence	Supportive; NO antibiotics (↑ Shiga toxin release); dialysis if needed; eculizumab for severe	Eculizumab (anti-C5 complement inhibitor) — dramatically improves outcomes; meningococcal prophylaxis required; ravulizumab (longer-acting) preferred

🔑 ADAMTS13 <10% = TTP — Start PLEX Immediately: Do not delay plasma exchange waiting for ADAMTS13 result in suspected TTP. Mortality without treatment: 90%. With PLEX: <20%. If ADAMTS13 result comes back >10%, reconsider diagnosis (aHUS, STEC-HUS, malignant HTN, HELLP, drug-induced TMA). Caplacizumab (Cablivi): anti-VWF nanobody, rapidly stops VWF-platelet interaction; reduces exacerbations, TTP-related death, and major thromboembolic events — use alongside PLEX+steroids.

▶9.3 Practice Questions

Q1. A 28-year-old woman presents with Hgb 7.2, platelets 22,000, SCr 4.8, confusion, and fever. Peripheral smear: schistocytes ++. ADAMTS13 activity: 4%. What is the diagnosis and immediate management?

Diagnosis: Thrombotic Thrombocytopenic Purpura (TTP) — ADAMTS13 <10% is diagnostic.
Immediate management:
1. Plasma exchange (PLEX) — start immediately, 1–1.5 plasma volumes daily. Continue until platelet count >150,000 for 2 consecutive days, then taper.
2. High-dose steroids: Methylprednisolone 1 mg/kg/day or dexamethasone 40 mg/day × 4 days.
3. Caplacizumab 11 mg IV on day 1, then 11 mg SC daily — reduces organ ischemia and time to remission.
4. Rituximab 375 mg/m² weekly × 4 — for anti-ADAMTS13 antibody (acquired TTP); reduces relapse rate.
Do NOT transfuse platelets (unless life-threatening bleeding — risks thrombosis). Do NOT give FFP alone (insufficient — use plasma exchange). Avoid aspirin/anticoagulation acutely.

10. Kidney in Systemic Diseases

▼10.1 Diabetic Kidney Disease (DKD)

DKD: most common cause of ESKD in the developed world (30–40% of dialysis patients). Defined by albuminuria >30 mg/g and/or eGFR <60 in a patient with DM in the absence of other kidney disease. Classic progression: normoalbuminuria → microalbuminuria (30–300) → macroalbuminuria (>300) → GFR decline → ESKD.

Pathology

Early: glomerular hyperfiltration (↑ GFR initially), GBM thickening, mesangial expansion
Late: nodular glomerulosclerosis (Kimmelstiel-Wilson nodules — pathognomonic for DKD on biopsy), diffuse glomerulosclerosis, hyalinosis, interstitial fibrosis

Treatment Algorithm

Glycemic control: HbA1c target 7–7.5% (ACCORD: intensive control → ↓ albuminuria but no eGFR benefit; UKPDS: early glycemic control reduces microvascular complications)
BP control: Target <130/80 mmHg; ACEi/ARB first-line if albuminuria
RAAS blockade: ACEi or ARB for macroalbuminuria; dual blockade (ACEi+ARB) NOT recommended (ONTARGET/VA NEPHRON-D: increased adverse events without benefit)
SGLT2i: Add for all DKD with eGFR ≥20 + ACR ≥200 (CREDENCE, DAPA-CKD, EMPA-KIDNEY)
Finerenone: Add for T2DM + DKD on max RAS blockade (FIDELIO/FIGARO)
GLP-1 RA: Semaglutide, liraglutide — CV benefit; FLOW trial (semaglutide): 24% ↓ kidney outcomes in T2DM+CKD; now recommended for CKD+T2DM

⚡ FLOW Trial (NEJM 2024) — Semaglutide in DKD

Semaglutide 1 mg SQ weekly vs placebo in T2DM + CKD (eGFR 50–75 + ACR 300–5000 OR eGFR 25–50 + ACR ≥100): 24% ↓ primary kidney outcome (≥50% eGFR decline, ESKD, renal/CV death). First GLP-1 RA trial to show dedicated renal endpoint benefit. Mechanism: anti-inflammatory, anti-fibrotic, ↓ BP, ↓ proteinuria, beyond weight/glucose effects.

▶10.2 Amyloidosis & Multiple Myeloma

Feature	AL Amyloidosis	AA Amyloidosis
Precursor protein	Immunoglobulin light chain (monoclonal plasma cell)	Serum amyloid A (chronic inflammation)
Underlying disease	Multiple myeloma, MGUS, Waldenström's	RA, IBD, familial Mediterranean fever, chronic infection
Presentation	Nephrotic syndrome, cardiomyopathy (restrictive), autonomic neuropathy, macroglossia, periorbital ecchymosis	Nephrotic syndrome; hepatosplenomegaly
Biopsy	Congo red staining → apple-green birefringence; EM: 8–12 nm fibrils	Same Congo red; stains with anti-AA antibody
Treatment	Daratumumab-based regimens (anti-CD38); autologous SCT for eligible patients	Treat underlying disease; colchicine for FMF (↓ SAA)

Multiple Myeloma & Kidney

Cast nephropathy ("myeloma kidney"): Most common; free light chains (Bence Jones proteins) → combine with Tamm-Horsfall protein → tubular casts → obstruction + inflammation → AKI. Treatment: chemotherapy (bortezomib-based) + hydration; thalidomide in renal failure
Light chain deposition disease (LCDD): Non-amyloid deposits (kappa LC usually); Congo red negative; IF shows linear monoclonal LC deposits along GBM and TBM
Fanconi syndrome: LC toxicity to proximal tubule → aminoaciduria, glycosuria, phosphaturia, bicarbonaturia

▶10.3 Kidney in Pregnancy

Normal pregnancy: GFR ↑ 40–60% by end of 1st trimester (hyperfiltration); serum Cr decreases (normal in pregnancy: <0.8 mg/dL); mild hydronephrosis (right > left); urine PCR up to 300 mg/day may be normal.

Condition	Timing	Key Features	Management
Preeclampsia	>20 weeks	HTN + proteinuria (>300 mg/day); severe: BP ≥160/110, PLT <100K, LFTs ↑ 2×, SCr ≥1.1, visual/CNS symptoms	Delivery is curative. Antihypertensives (labetalol, nifedipine, hydralazine IV for severe). Magnesium for seizure prophylaxis in severe features. Aspirin 81 mg from 12 weeks (prevention in high-risk)
HELLP syndrome	>20 weeks (most postpartum)	Hemolysis + Elevated LFTs + Low Platelets; may occur without hypertension	Delivery; steroids (controversial); platelet transfusion if <20,000 or bleeding
Acute fatty liver of pregnancy (AFLP)	3rd trimester	Liver failure, DIC, hypoglycemia, encephalopathy; 50% have AKI	Immediate delivery; ICU support; distinguish from HELLP (AFLP has prolonged PT, hypoglycemia)
Postpartum HUS	Postpartum	TMA (MAHA, thrombocytopenia, AKI); often complement-mediated (aHUS)	Eculizumab; rule out ADAMTS13 deficiency (TTP)

🔑 Medication Safety in Pregnancy: ACEi/ARBs are absolutely CONTRAINDICATED in pregnancy (category X/D — teratogenic, oligohydramnios, renal agenesis, skeletal defects). Switch to labetalol, methyldopa, or nifedipine before conception or immediately if discovered pregnant. NSAIDs: avoid in 3rd trimester (premature ductus closure, oligohydramnios). Statins: discontinue during pregnancy.

▶10.4 Practice Questions

Q1. A 70-year-old presents with nephrotic syndrome, cardiomyopathy (elevated troponin, diastolic dysfunction), macroglossia, and periorbital bruising. SPEP: small monoclonal spike. Urine immunofixation: free lambda light chains. Which test is most likely to confirm the diagnosis?

Diagnosis: AL Amyloidosis (lambda light chain type).
Most confirmatory test: Abdominal fat pad biopsy (least invasive, 70–80% sensitivity) or bone marrow biopsy — both with Congo red staining showing apple-green birefringence under polarized light. Kidney biopsy has highest sensitivity (>95%) but more invasive. Cardiac biopsy if needed. Also check: serum free light chain ratio, cardiac biomarkers (BNP, troponin T — NT-proBNP >332 or troponin T ≥0.035 indicates high-risk cardiac stage III disease). Treatment: daratumumab-bortezomib-dexamethasone (Dara-VCD) ± autologous SCT if eligible.

11. Fluid & Volume Management

▼11.1 IV Fluid Selection & Physiology

Fluid	Na (mEq/L)	Cl (mEq/L)	K	Buffer	Tonicity	Use
0.9% NaCl ("Normal Saline")	154	154	0	None	Isotonic	Hypernatremia correction (caution), metabolic alkalosis, hypochloremia; NOT ideal for large-volume resuscitation
Lactated Ringer's (LR)	130	109	4	Lactate 28	Slightly hypotonic	Volume resuscitation (preferred — balanced); surgery; trauma; avoid in hyperkalemia
PlasmaLyte 148	140	98	5	Acetate+Gluconate	Isotonic (balanced)	Most physiologic; preferred ICU resuscitation; least impact on acid-base
D5W (5% dextrose)	0	0	0	None	Hypotonic (free water)	Free water replacement (hypernatremia); NOT for resuscitation; raises glucose
0.45% NaCl ("Half-Normal")	77	77	0	None	Hypotonic	Maintenance fluids; DKA (after initial resuscitation)
3% NaCl (Hypertonic)	513	513	0	None	Hypertonic	Symptomatic hyponatremia; cerebral edema; careful rate control

⚡ NS vs Balanced Crystalloids — Key Trials

SMART (2018) + SALT-ED (2018): Balanced crystalloids (LR or PlasmaLyte) vs NS in critically ill and non-ICU patients → balanced crystalloids: lower MAKE30 (major adverse kidney events) — driven by ↓ need for RRT and ↓ 30-day mortality
NS causes hyperchloremic non-anion gap metabolic acidosis (↑ Cl → ↓ HCO₃ to maintain electroneutrality) and may ↑ renal vasoconstriction
Specific situations to still use NS: hypochloremic metabolic alkalosis (vomiting), traumatic brain injury (iso-osmolar needed), hyponatremia (use 3% NS for symptomatic)

▶11.2 Diuretics & Diuretic Resistance

Diuretic	Site of Action	Electrolyte Effects	Clinical Use
Furosemide (loop)	TAL — inhibits NKCC2	↓K, ↓Mg, ↓Ca, ↓Na, metabolic alkalosis	Edema, AHF, HTN, hypercalcemia
Hydrochlorothiazide / Chlorthalidone (thiazide)	DCT — inhibits NCC	↓K, ↓Na, ↑Ca (hypercalcemia), ↑uric acid, metabolic alkalosis	HTN, calcium stone prevention, nephrogenic DI, CHF (mild)
Spironolactone / Eplerenone (MRA)	CD — aldosterone receptor antagonist	↑K (hyperkalemia), metabolic acidosis, ↓Na	Heart failure (RALES trial), ascites, hyperaldosteronism, post-MI (EPHESUS)
Amiloride / Triamterene (K-sparing)	CD — ENaC blocker	↑K, mild metabolic acidosis	Hypokalemia prevention; Liddle syndrome; lithium-induced NDI (amiloride)
Acetazolamide	PCT — carbonic anhydrase inhibitor	↓HCO₃ (metabolic acidosis), ↓K	Metabolic alkalosis, altitude sickness, glaucoma

Diuretic Resistance Strategies

Increase loop diuretic dose (dose-response shifts in CKD/CHF — higher doses needed)
Switch to IV (better bioavailability; furosemide PO bioavailability 10–100%, highly variable)
Add thiazide diuretic (metolazone or HCTZ) — sequential nephron blockade; blocks DCT compensation. High risk of electrolyte shifts — monitor K, Mg closely
Continuous infusion vs bolus (DOSE trial: no significant difference in all endpoints — either is acceptable)
Add tolvaptan (V2 blocker) for dilutional hyponatremia + congestion in CHF
Ultrafiltration if refractory (CARRESS-HF trial: ultrafiltration not superior to diuretic therapy, more AKI)

▶11.3 Practice Questions

Q1. A patient presents with pH 7.55, HCO₃ 38, pCO₂ 48, K 3.1, Cl 88. She has been vomiting for 5 days. What is the acid-base disorder and ideal IV fluid?

Disorder: Hypochloremic hypokalemic metabolic alkalosis with appropriate respiratory compensation. Vomiting → loss of HCl → ↓ Cl, ↑ HCO₃, ↓ K (aldosterone stimulated by volume depletion).
Treatment: 0.9% Normal Saline + KCl. Chloride repletion is essential — this is chloride-responsive metabolic alkalosis (urine Cl <20 mEq/L). NS provides Cl to allow renal HCO₃ excretion. KCl corrects hypokalemia (also helps HCO₃ excretion). Do NOT use balanced crystalloids (LR, PlasmaLyte) which contain no/little Cl buffer — would worsen alkalosis. Volume repletion stops aldosterone-driven K loss.

12. Nephrology Emergencies

▼12.1 Rhabdomyolysis, TLS & RPGN

Rhabdomyolysis

Skeletal muscle breakdown → release of myoglobin, K, PO4, LDH, CK into circulation. AKI in 30–40% of cases. Risk: CK >5000 U/L (AKI likely if >15,000–20,000).

Urine: dipstick positive for blood with NO RBCs on microscopy (myoglobinuria)
Electrolytes: hyperkalemia, hyperphosphatemia, hypocalcemia (early), hypercalcemia (recovery phase)
Treatment: aggressive IV fluid resuscitation (goal UO 200–300 mL/h); isotonic saline first-line; sodium bicarbonate to alkalinize urine (myoglobin less nephrotoxic at pH >6.5) — controversial but widely used; avoid nephrotoxins; treat hyperkalemia; dialysis if refractory AKI/hyperkalemia

Tumor Lysis Syndrome (TLS)

Massive release of intracellular contents after rapid cell death (chemotherapy, spontaneous in high-burden lymphoma). Laboratory TLS: 2 of: ↑ uric acid (>8 mg/dL), ↑ K (>6 mEq/L), ↑ PO4 (>4.5 mg/dL), ↓ Ca (<7 mg/dL). Clinical TLS = laboratory TLS + AKI/arrhythmia/seizure/death.

Treatment: aggressive IV hydration (2–3 L/m²/day); allopurinol (xanthine oxidase inhibitor — prevention) or rasburicase (urate oxidase — rapidly converts uric acid to allantoin; treatment of choice for high-risk or established hyperuricemia; contraindicated in G6PD deficiency → hemolysis). Phosphate binders for hyperphosphatemia. Dialysis for refractory hyperkalemia/hyperphosphatemia/AKI.

Rapidly Progressive GN (RPGN) Emergency

Crescentic GN — nephritic syndrome with loss of >50% GFR within weeks. Biopsy urgently.

Type I (anti-GBM ± Goodpasture): Pulse steroids + cyclophosphamide + plasmapheresis (removes circulating anti-GBM antibodies — especially if pulmonary hemorrhage or creatinine <7 and not yet on dialysis)
Type III (ANCA — GPA/MPA): Pulse steroids + rituximab (or cyclophosphamide); plasmapheresis for severe cases/dialysis-dependent (PEXIVAS: no benefit on composite outcome, but used for pulmonary hemorrhage)
Type II (immune complex): Treat underlying disease (lupus → high-dose steroids + MMF/CYC; IgA → steroids; post-strep → supportive)

▶12.2 Practice Questions

Q1. A 22-year-old athlete collapses during a marathon. CK 85,000, SCr 4.2, K 6.1, dipstick shows 3+ blood with no RBCs on microscopy. What is the diagnosis and fluid management target?

Diagnosis: Exertional Rhabdomyolysis with AKI.
Heme-positive urine without RBCs = myoglobinuria. CK >5000 is diagnostic; >15,000–20,000 predicts AKI.
Management:
1. Aggressive IV fluid resuscitation: start NS or LR at 500–1000 mL/h initially, targeting urine output 200–300 mL/h (3 mL/kg/h). Adjust rate once UO goal met.
2. Monitor: K, PO4, Ca, BMP, CK q4–6h; urine output hourly; fluid balance.
3. Treat hyperkalemia (K 6.1 without ECG changes: insulin + glucose ± albuterol; hold K-raising meds).
4. Sodium bicarbonate (1–2 ampules in 1L D5W) may be added to maintain urine pH >6.5 — reduces myoglobin precipitation. Avoid if HCO₃ already >30 or severe hypocalcemia.
5. Avoid NSAIDs, contrast, nephrotoxins. Dialysis if refractory AKI or hyperkalemia.

Q2. A 65-year-old with new diagnosis of diffuse large B-cell lymphoma starts R-CHOP. 48 hours later: uric acid 12.8, K 6.4, PO4 5.9, Ca 6.8, SCr 3.1. What is the diagnosis and preferred uric acid-lowering treatment?

Diagnosis: Tumor Lysis Syndrome (TLS) — meets laboratory criteria (uric acid, K, PO4, Ca all abnormal) and clinical criteria (AKI).
Treatment of hyperuricemia: Rasburicase 0.2 mg/kg IV (single dose often sufficient) — recombinant urate oxidase that converts uric acid to allantoin (100× more soluble); rapidly lowers uric acid within hours. Superior to allopurinol for established TLS with AKI. Contraindicated in G6PD deficiency (rasburicase generates H₂O₂ → hemolysis). Check G6PD before giving, or use allopurinol if unknown/deficient.
Also: IV hydration 200–300 mL/h (unless fluid overloaded), phosphate binders, treat hyperkalemia, consider urgent dialysis for severe electrolyte/fluid/AKI combination.

📚 Key References — Emergencies & Across Topics

[G] KDIGO Glomerulonephritis Guideline 2021. Kidney Int Suppl 2021;100(4S):1–276.
[T] PEXIVAS (2020): Walsh et al. Plasma exchange in ANCA-associated vasculitis. NEJM 2020;382:622–631.
[T] FLOW (2024): Perkovic et al. Semaglutide in T2DM + CKD. NEJM 2024;391:1837–1847.
[T] PROTECT (2023): Heerspink et al. Sparsentan in IgA nephropathy. NEJM 2023;388:2036–2046.
[T] TEMPO 3:4 (2012): Torres et al. Tolvaptan in ADPKD. NEJM 2012;367:2407–2418.
[T] AURORA 1 (2021): Rovin et al. Voclosporin for lupus nephritis. NEJM 2021;385:2070–2082.
[T] BLISS-LN (2020): Furie et al. Belimumab for lupus nephritis. NEJM 2020;383:1117–1128.

1. Acute Kidney Injury (AKI)

Causes of Decreased EABV

Acute Tubular Necrosis (ATN)

Acute Interstitial Nephritis (AIN)

Rapidly Progressive GN (RPGN)

Additional Workup by Suspected Etiology

General Principles

RRT Indications — "AEIOU"

RRT Modalities in AKI

Contrast-Induced Nephropathy (CIN) / Post-Contrast AKI (PC-AKI)

Prevention Strategies

Hepatorenal Syndrome (HRS)

📚 Key References — AKI

2. Chronic Kidney Disease (CKD)

Pathophysiology Sequence (begins at eGFR ~60)

Treatment Targets (KDIGO 2017)

Secondary Hyperparathyroidism Treatment

Evaluation

Treatment

SGLT2 Inhibitors — Landmark Trials

Finerenone (Nonsteroidal MRA)

📚 Key References — CKD

3. Glomerular Diseases

Membranous Nephropathy — Key Points

IgA Nephropathy — MEST-C Score (Oxford Classification)

Lupus Nephritis — ISN/RPS Classification

ANCA-Associated Vasculitis (AAV) — Renal Involvement

4. Electrolyte Disorders

Step-by-Step Approach

SIADH Diagnostic Criteria (Bartter-Schwartz)

Treatment of Hyponatremia

Hyperkalemia — Emergency Protocol

ECG Changes in Hyperkalemia (progressive with ↑ K)

Hypocalcemia

Hypomagnesemia — Critical Points

5. Acid-Base Disorders

GOLDMARK Mnemonic

6. Dialysis

Dialysis Adequacy

Vascular Access (preferred order: AVF > AVG > CVC)

PD Adequacy

PD Peritonitis — Most Common Complication

HD vs PD Comparison

7. Renal Transplantation

Standard Triple Therapy (Maintenance)

Induction Therapy

Chronic Allograft Nephropathy / IF-TA

Timeline of Post-Transplant Infections

BK Virus Nephropathy (BKVN)

CMV Management

8. Tubulointerstitial & Cystic Diseases

Extrarenal Manifestations

Treatment

9. Renovascular & Vascular Diseases

10. Kidney in Systemic Diseases

Pathology

Treatment Algorithm

Multiple Myeloma & Kidney

11. Fluid & Volume Management

Diuretic Resistance Strategies

12. Nephrology Emergencies

Rhabdomyolysis

Tumor Lysis Syndrome (TLS)

Rapidly Progressive GN (RPGN) Emergency

📚 Key References — Emergencies & Across Topics

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