Uremia & CKD Pathophysiology

Overview: definition, causes and progression

Definition. Chronic kidney disease (CKD) is a GFR below 60 mL/min/1.73 m², or evidence of kidney damage such as albuminuria of at least 30 mg/g creatinine, persisting for more than 3 months. Staging combines GFR category (G1–G5) with albuminuria category; kidney failure (G5) is a GFR below 15. Diabetic nephropathy is the leading cause, followed by hypertensive nephrosclerosis, glomerulonephritis and autosomal dominant polycystic kidney disease.

Hyperfiltration. Whatever the initial injury, surviving nephrons compensate by raising their single-nephron GFR: the afferent arteriole dilates and angiotensin II constricts the efferent arteriole. The resulting glomerular capillary hypertension injures podocytes, producing proteinuria and secondary (adaptive) FSGS. Filtered protein reabsorbed by proximal tubular cells triggers inflammation, interstitial fibrosis and tubular atrophy, and each lost nephron adds load to the rest. This cycle explains why CKD keeps progressing after the original insult has resolved and why proteinuria is both a marker and a driver of decline.

Slowing progression. Therapy aims to lower intraglomerular pressure. ACE inhibitors and ARBs dilate the efferent arteriole. SGLT2 inhibitors (empagliflozin, dapagliflozin) block proximal Na⁺-glucose reabsorption, increasing NaCl delivery to the macula densa and restoring tubuloglomerular feedback, which constricts the afferent arteriole. Both reduce proteinuria and slow GFR loss; SGLT2 inhibitors can cause genital mycotic infections, volume depletion and euglycemic DKA. Blood pressure and glucose control complete the strategy.

A modest early creatinine rise (up to about 30%) after starting an ACE inhibitor, ARB or SGLT2 inhibitor reflects the intended drop in glomerular pressure and is not a reason to stop; watch potassium with RAAS blockade.

Fluid, electrolyte and metabolic consequences

Metabolic acidosis. With fewer nephrons the kidney makes too little ammonium to excrete the daily acid load. Acidosis begins with a normal anion gap and becomes high–anion-gap in advanced disease as sulfate, phosphate and urate accumulate. Chronic acidosis dissolves bone buffer, wastes muscle and speeds CKD progression; oral sodium bicarbonate corrects it.

Hyperkalemia. Remaining nephrons increase K⁺ secretion, but hyperkalemia appears as GFR falls, especially with ACE inhibitors, ARBs, potassium-sparing drugs, acidosis or high intake. Potassium binders allow RAAS blockade to continue: patiromer releases Ca²⁺ in exchange for K⁺ in the colon (and binds Mg²⁺, causing hypomagnesemia), whereas sodium zirconium cyclosilicate exchanges Na⁺ and H⁺ for K⁺ and can cause edema from its sodium load.

Salt and water retention. Reduced filtration limits Na⁺ and water excretion, producing edema, volume-dependent hypertension, left ventricular hypertrophy, pulmonary edema and heart failure. Salt restriction and loop diuretics are the mainstays; overload that resists them requires dialysis.

Dyslipidemia and growth. Reduced lipoprotein lipase activity raises triglycerides and lowers HDL; with hypertension, inflammation and vascular calcification, this makes cardiovascular disease the leading cause of death in CKD. Children with CKD grow poorly because of acidosis, malnutrition, renal osteodystrophy and resistance to growth hormone.

Uremia and the need for dialysis

Uremic syndrome. Retained nitrogenous wastes and other toxins cause anorexia, nausea, vomiting and a metallic taste; fibrinous pericarditis with a friction rub; encephalopathy with asterixis progressing to confusion, seizures and coma; peripheral neuropathy; pruritus; and, in extreme cases, uremic frost, a dusting of urea crystals on the skin.

Uremic bleeding. Uremic toxins impair platelet adhesion and aggregation, largely by disturbing the vWF–glycoprotein Ib interaction. Mucosal and procedural bleeding occurs with a prolonged bleeding time but a normal platelet count, PT and PTT. Desmopressin acts quickly by releasing vWF and factor VIII from endothelium; transfused platelets soon become dysfunctional in uremic plasma. Dialysis, correcting anemia (more red cells push platelets toward the vessel wall) and conjugated estrogens also help.

Urgent dialysis indications.

• Metabolic acidosis or hyperkalemia refractory to medical therapy
• Dialyzable intoxications such as methanol, ethylene glycol, lithium or salicylates
• Volume overload unresponsive to diuretics
• Uremic complications: pericarditis, encephalopathy, bleeding

Anemia and CKD–mineral bone disorder

Anemia. Erythropoietin is made by hypoxia-sensing peritubular interstitial fibroblasts of the renal cortex. As fibrosis destroys them, a normocytic, normochromic anemia with low reticulocytes develops, worsened by iron deficiency, hepcidin-mediated iron sequestration and shortened red cell survival. Iron is repleted first (often intravenously), then an erythropoiesis-stimulating agent (ESA) keeps hemoglobin around 10–11.5 g/dL. Targeting a normal hemoglobin (13 g/dL or more) increased stroke, thrombosis and cardiovascular events, and ESAs raise blood pressure. Poor response should prompt a search for iron deficiency, inflammation or severe hyperparathyroidism.

Renal osteodystrophy. Failing kidneys retain phosphate (so dietary phosphate is restricted and binders are taken with meals), which stimulates FGF23; FGF23 and lost renal mass both suppress 1α-hydroxylase, so calcitriol falls. Less calcitriol means less intestinal calcium absorption and hypocalcemia, which together with hyperphosphatemia drives secondary hyperparathyroidism. High PTH causes high-turnover bone disease (osteitis fibrosa cystica: bone pain, subperiosteal resorption, fractures), and phosphate excess promotes vascular calcification. After years the glands may secrete autonomously (tertiary hyperparathyroidism with hypercalcemia, often persisting after transplant); oversuppression of PTH can instead cause low-turnover adynamic bone disease.

Aluminum-based phosphate binders are avoided in CKD: aluminum accumulates and causes encephalopathy (dialysis dementia), osteomalacia and microcytic anemia.

Complications of dialysis

β₂-microglobulin amyloidosis. β₂-microglobulin, the light chain of MHC class I molecules, is normally filtered and catabolized by the kidney and is poorly removed by conventional dialysis. After years of dialysis it deposits as amyloid in synovium, tendons and bone, causing carpal tunnel syndrome, destructive arthropathy and bone cysts.

Acquired cystic kidney disease. The native kidneys of patients on long-term dialysis develop multiple cysts regardless of the original disease and carry an increased risk of renal cell carcinoma.

Dialysis disequilibrium syndrome. In the first sessions, especially with a very high BUN, rapid urea removal lowers plasma osmolality faster than brain osmolality; water moves into the brain, producing cerebral edema with headache, nausea, restlessness, confusion and sometimes seizures. Short, gentle initial sessions prevent it.