{
  "id": "kidney",
  "title": "Kidney",
  "lang": "en",
  "source_lang": "en",
  "summary": "The kidney is a paired organ that filters blood, removes metabolic waste, produces urine, regulates fluid, electrolyte, and acid–base balance, and secretes hormones affecting blood pressure and red blood cell production.",
  "category": "health",
  "subcategory": "anatomy-physiology",
  "type": "concept",
  "aliases": [
    "renal organ",
    "ren"
  ],
  "generated_at": "2026-10-08",
  "model": "pro/claude-haiku-5-5",
  "url": "https://aiwiki.page/en/kidney/",
  "translations": {
    "zh-Hans": {
      "url": "https://aiwiki.page/zh/kidney/",
      "json": "https://aiwiki.page/zh/kidney.json"
    }
  },
  "sections": [
    {
      "heading": "",
      "text": "The kidney is a paired organ, one on each side of the spine, that filters the blood, removes metabolic waste, and produces urine. Through this work it helps keep the body's fluid volume, electrolyte composition, and acid–base balance within narrow limits, a role that is central to homeostasis. Kidneys also secrete hormones that influence blood pressure, red blood cell production, and calcium metabolism, so their failure affects nearly every organ system. Because nearly all of the body's blood passes through them many times a day, their physiology connects to the cardiovascular system, metabolism of glucose, and the immune system.\n\nThis entry covers the kidney from anatomy to disease and medicine. It begins with the gross structure and the nephron, the functional unit that performs filtration, reabsorption, and secretion. It then examines how each segment handles water, ions, and acid, how the kidney's hormonal functions work, and how waste and drugs are cleared. Developmental biology, the cell types of the kidney, and the historical discovery of its functions follow. The second half turns to kidney disease: acute injury, chronic kidney disease and its staging, specific glomerular, cystic, and stone disorders, the global epidemiology, diagnosis, and kidney replacement therapy. The entry closes with comparative anatomy across vertebrates and the open problems in regeneration and bioengineering."
    },
    {
      "heading": "Gross anatomy and blood supply",
      "text": "Position and external form\n\nThe kidneys are paired retroperitoneal organs on the posterior abdominal wall, on either side of the vertebral column, usually between the twelfth thoracic and third lumbar vertebral levels. The liver displaces the right kidney downward, so the right kidney normally sits slightly lower than the left. In adults each kidney is about 10–12 cm long, 5–7 cm wide and 3–5 cm thick, and weighs roughly 120–170 g. Each is enclosed by a fibrous capsule, perirenal fat and renal fascia, and the adrenal gland rests on its upper pole. The medial border is concave and contains the renal hilum, through which the renal artery and nerves enter and the renal vein, ureter and lymphatic vessels leave. Inside the hilum, the renal pelvis lies behind the vessels. From anterior to posterior the usual order is the renal vein, then the artery, then the pelvis. The renal artery arises from the abdominal aorta a little below the superior mesenteric artery, and the left renal vein passes between the aorta and that artery to reach the inferior vena cava.\n\nInternal structure\n\nOn a longitudinal section, the kidney has an outer cortex, a darker inner medulla and a central sinus that holds the pelvis, calyces, vessels and fat. The medulla is organized into eight to eighteen cone-shaped renal pyramids. Their bases face the cortex, and their tips, the papillae, project into the calyces. Cortical tissue extends between the pyramids as renal columns. Each papilla drains into a minor calyx. Several minor calyces merge into two or three major calyces, which join the renal pelvis. The pelvis narrows into the ureter at the hilum, and urine is propelled along the ureter to the bladder by peristaltic waves. The cortex houses the renal corpuscles and most of the tubular segments, while the medulla contains the loops of Henle and collecting ducts. This layout underlies the urine-concentrating mechanism described in other sections.\n\nRenal circulation\n\nThe kidneys receive roughly a fifth to a quarter of resting cardiac output, about 1.0–1.2 L/min in an adult at rest. This flow is far larger than the organ's own metabolic needs. Its main purpose is to deliver plasma for filtration. Renal plasma flow is about 600 mL/min, and roughly a fifth of that plasma is filtered into the tubules. The renal artery divides into segmental arteries, which give rise to interlobar arteries running upward through the renal columns between the pyramids. At the corticomedullary junction, the interlobar arteries curve into arcuate arteries that arch over the bases of the pyramids. Interlobular arteries branch from the arcuate arteries and travel outward through the cortex, giving off afferent arterioles that each supply one glomerulus. Efferent arterioles leave each glomerulus and form a second capillary network. In the cortex this is the peritubular capillary bed. Juxtamedullary nephrons also send long vasa recta into the medulla. Venous return follows the same pattern in reverse, from interlobular to arcuate and interlobar veins, and then to the renal vein. The cortex is well oxygenated, whereas the medulla receives comparatively little oxygen relative to its demand, which makes it vulnerable to ischaemic injury.\n\nInnervation and lymphatic drainage\n\nRenal nerves are predominantly sympathetic. They arrive through the renal plexus, which receives fibres from the lower thoracic and upper lumbar sympathetic chain, largely at T10–L1. These fibres control arteriolar tone, which in turn shapes renal blood flow and glomerular filtration. They also stimulate renin release from juxtaglomerular cells and enhance tubular sodium reabsorption, linking the nerves to systemic blood pressure control through hormonal pathways. Parasympathetic supply is sparse, and the kidney receives little direct vagal input. Afferent sensory fibres travel with the sympathetic nerves back to the same spinal segments, which explains why renal pain, such as that caused by a stone lodged in the ureter, is felt in the flank and referred toward the groin. Lymphatic vessels follow the blood vessels from the cortex and medulla toward the hilum. They drain mainly into lumbar (lateral aortic) nodes around the aorta and inferior vena cava. Together, the autonomic and lymphatic connections tie the kidney's filtration and blood flow to the wider physiological network of the body."
    },
    {
      "heading": "The nephron: structure and classes",
      "text": "The nephron is the functional unit of the kidney. Each nephron begins with the renal corpuscle, a tuft of capillaries called the glomerulus enclosed by the cup-shaped Bowman's capsule, where blood plasma is first filtered. The filtrate then passes into the renal tubule, which is divided into the proximal tubule, the loop of Henle (with descending and ascending limbs), the distal tubule, and finally the collecting duct, where several nephrons drain. Most of the reabsorption and secretion that shapes the final urine happens along this tubule, and the segments differ in their transport functions (described in later sections).\n\nNumber and development\n\nEach human kidney contains roughly one million nephrons, although the range across individuals is very wide. Autopsy and imaging studies report averages of about 900,000 to 1 million per kidney, with individual kidneys ranging from about 200,000 to more than 2.5 million. In a study of young adults in the United States, the figure was about 1.2 to 1.4 million per kidney. Nephron endowment is set during fetal life. Nephrogenesis is completed around 34 to 36 weeks of gestation, and no new nephrons form after that point. Because of this, the total is essentially fixed at birth. Loss of nephrons with age, hypertension, or kidney disease reduces the number over time, but it is not replaced. When one kidney is removed, the remaining kidney grows mainly by enlargement of its existing nephrons rather than by producing new ones. Low nephron endowment, often linked to low birth weight or preterm birth, is an area of active study because of its association with later hypertension and kidney disease.\n\nCortical and juxtamedullary nephrons\n\nNephrons fall into two main classes according to the position of their glomeruli and the length of their loops of Henle. Cortical nephrons make up about 85 percent of the total. Their glomeruli lie in the outer cortex, and their short loops of Henle penetrate only a short distance into the outer medulla. Juxtamedullary nephrons, about 15 percent of the total, have glomeruli close to the junction between cortex and medulla. Their long loops of Henle extend deep into the inner medulla, often down to the tip of the renal papilla. Because the relative numbers of the two types and the length of their loops together determine how well the kidney can concentrate urine, juxtamedullary nephrons are the main contributors to the medullary osmotic gradient. The concentrating mechanism itself is treated in a later section.\n\nBlood supply of the tubule\n\nBlood reaches the glomerulus through the afferent arteriole and leaves through the efferent arteriole. The glomerular capillaries are a high-pressure bed whose purpose is filtration. The efferent arteriole then breaks up into a second capillary network, the peritubular capillaries, which are low-pressure and surround the proximal and distal tubules. In cortical nephrons, this network lies around the convoluted segments. In juxtamedullary nephrons, a specialized set of long capillaries called the vasa recta descends alongside the loop of Henle into the medulla and returns back up. The peritubular capillaries take up water and solutes that the tubule has reabsorbed, returning them to the circulation. The vasa recta behaves as a countercurrent exchanger. Its slow, looping flow lets it supply the medulla with oxygen and nutrients while removing reabsorbed water without washing away the solute gradient that the loop of Henle builds. Cortical nephrons have a much smaller vasa recta, reflecting their shorter loops."
    },
    {
      "heading": "Glomerular filtration",
      "text": "Glomerular filtration is the first step of urine formation. Plasma is pushed out of the glomerular capillaries into Bowman's space, and the resulting fluid, the filtrate, is then modified along the glomerular tubule. Only a fraction of the renal plasma flow is filtered: the filtration fraction is typically about 20%.\n\nThe three-layer filtration barrier\n\nFiltration is governed by a barrier with three layers. The innermost is the fenestrated endothelium of the capillaries, whose pores are roughly 70–100 nm across. This layer is a coarse sieve that keeps blood cells in the circulation. Beneath it lies the glomerular basement membrane, a matrix of collagen IV and heparan sulphate proteoglycans. Its negative fixed charge repels anionic plasma proteins such as albumin, so the barrier is selective for charge as well as size. The outermost layer is formed by podocytes, whose interdigitating foot processes are bridged by slit diaphragms. These gaps are about 20–30 nm wide and contain transmembrane proteins, chiefly nephrin and podocin. Mutations that disrupt nephrin or podocin cause proteinuria and renal failure, which shows how central this last layer is. Taken together, the barrier retains cells and most large proteins, and it passes water and small solutes freely. Proteins up to roughly 70 kDa can enter the filtrate, though in practice the filter is far more selective than size alone would suggest.\n\nStarling forces\n\nUltrafiltration follows the same Starling principles that govern exchange at other capillary beds. Hydrostatic pressure in the glomerular capillaries, about 55 mmHg, pushes fluid outward. Opposing it are the hydrostatic pressure in Bowman's space (about 15 mmHg) and the colloid osmotic pressure of plasma proteins (about 30 mmHg). The net filtration pressure is therefore roughly 10 mmHg. The rate of filtration can be written as:\n\n\\[\\text{GFR} = K_f \\times \\left[(P_{GC} - P_{BS}) - (\\pi_{GC} - \\pi_{BS})\\right]\\]\n\nHere \\(P_{GC}\\) and \\(P_{BS}\\) are the hydrostatic pressures in the glomerular capillary and Bowman's space, \\(\\pi_{GC}\\) and \\(\\pi_{BS}\\) are the corresponding oncotic pressures, and \\(K_f\\) is the filtration coefficient, which combines the hydraulic permeability of the barrier with its surface area. Mesangial cells between capillary loops regulate that surface area. As water leaves the capillary, plasma protein concentration and oncotic pressure rise along its length, which progressively limits further filtration. Because almost no protein enters Bowman's space, the filtrate is essentially plasma without its large proteins, though it retains the water, electrolytes, glucose, and small molecules of plasma.\n\nGlomerular filtration rate and its regulation\n\nThe glomerular filtration rate (GFR) is the sum of the filtration rates of all functioning nephrons. Values are normally expressed per 1.73 m² of body surface area, and in young adults they are about 120 mL/min/1.73 m², declining with age. The total filtered volume is therefore around 180 L per day. Measurement and estimation are discussed elsewhere, but GFR is conventionally reported as a body-size-normalised figure so that individuals can be compared.\n\nGFR depends on the pressures and flows set by the two arterioles. Constriction of the afferent arteriole lowers glomerular capillary pressure and therefore GFR. Constriction of the efferent arteriole, which is promoted by angiotensin II, raises capillary pressure and can preserve GFR when afferent flow falls, although it also increases the protein concentration of the blood leaving the glomerulus. Autoregulation keeps GFR relatively stable over a wide range of systemic pressures, approximately a mean arterial pressure of 80 to 180 mmHg. The myogenic response of the afferent arteriole, which contracts when stretched, and tubuloglomerular feedback are the two intrinsic mechanisms responsible.\n\nTubuloglomerular feedback\n\nTubuloglomerular feedback adjusts GFR to the amount of solute reaching the distal nephron. The macula densa, a plaque of specialised cells in the distal tubule near the glomerulus, senses the NaCl concentration of the tubular fluid through the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2) on its luminal membrane. When NaCl delivery rises, the macula densa signals the afferent arteriole to constrict, which lowers single-nephron GFR. When delivery falls, the arteriole dilates and GFR rises. The signalling molecules involved include adenosine, ATP, and nitric oxide. Because the mechanism is driven by NKCC2, loop diuretics that block this transporter do not raise GFR through this pathway even though they increase NaCl concentration at the macula densa. The same cells also influence renin release. Tubuloglomerular feedback thus keeps the load delivered to the distal tubule within a narrow range, and its sensitivity is greater when extracellular fluid volume is reduced."
    },
    {
      "heading": "Tubular reabsorption and secretion by segment",
      "text": "Proximal tubule\n\nThe proximal tubule performs most of the bulk reabsorption. Its basolateral Na⁺/K⁺-ATPase keeps intracellular sodium low, so sodium entering across the apical membrane carries other solutes along with it. The Na+/K+-ATPase in the basolateral membrane keeps intracellular sodium below the level in the filtrate, and glucose enters the cell with Na+ at a 1:1 ratio through the SGLT. Glucose is recovered almost completely here. SGLT2 sits in the early S1/S2 segments and works as a low-affinity, high-capacity pathway, whereas SGLT1 in the distal S3 part is a high-affinity, low-capacity pathway. SGLT2 is believed responsible for 80–90% of renal glucose reabsorption, and SGLT1 for the rest. Glucose then leaves the cell through a basolateral transporter, GLUT2.\n\nSodium also enters through the apical Na⁺/H⁺ exchanger NHE3, which colocalises with SGLT2 and drives much of the proximal sodium uptake. Inhibiting NHE3 promotes bicarbonate excretion, which is why bicarbonate handling is tied to this segment. Water follows the solutes passively, so the fluid leaving the proximal tubule stays close to plasma osmolality. This coupling has a clinical consequence: SGLT2 inhibitors block sodium reabsorption, and with it uric acid reabsorption, which increases uric acid excretion and lowers serum uric acid by about 0.8–1.0 mg/dl.\n\nThick ascending limb\n\nThe thick ascending limb recovers a large share of the filtered salt. It reabsorbs 25–30% of the NaCl filtered by the glomeruli, using the apical Na⁺-K⁺-2Cl⁻ cotransporter NKCC2. The segment has no water channels, so it removes salt while leaving water in the tubule, which dilutes the fluid and helps build the medullary osmotic gradient discussed elsewhere. The thick ascending limb is impermeable to water, allowing it to pump Na+ ions, without water, into the interstitium.\n\nNKCC2 also has a signalling role in the macula densa. In the specialized cells of the macula densa, NKCC2 senses luminal chloride concentration and initiates the signal for tubuloglomerular feedback.\n\nLoop diuretics such as furosemide, bumetanide and torsemide act here. They work by competing for the chloride binding site of NKCC2. These drugs are not specific and also potently inhibit NKCC1. Because most sodium has already been removed upstream, their effect is limited. Since the proximal tubule is the main site of sodium reabsorption, blocking all NKCC2 channels can only raise sodium excretion to a limited degree, which gives loop diuretics a ceiling effect. Blocking NKCC2 at the macula densa also reduces sodium entry into macula densa cells, which stimulates renin release, leading to fluid retention and increased glomerular filtration. In nephrotic syndrome, salt and water retention often resist loop diuretics, through mechanisms that are still uncertain.\n\nDistal convoluted tubule\n\nThe distal convoluted tubule (DCT) lies immediately after the cortical thick ascending limb and is defined by the thiazide-sensitive sodium–chloride cotransporter, NCC. In euvolemic conditions, the DCTs receive around 8–10% of the filtered sodium and reabsorb 5–7%. The main pathway for transcellular sodium reabsorption is the electroneutral NCC, present at the luminal membrane in all DCT cells. The segment is divided functionally: magnesium is reabsorbed mainly in DCT1 and calcium in DCT2 and the connecting tubule. Its energy supply is substantial, since the DCT is the most mitochondria-rich segment of the nephron, and these mitochondria provide ATP for reabsorbing 5–10% of the filtered sodium load.\n\nThiazide diuretics block NCC. Thiazide diuretics inhibit the sodium-chloride cotransporter in the early DCT, reducing sodium reabsorption, which increases sodium and water excretion and is useful in treating hypertension. NCC activity is regulated by WNK kinases through the SPAK and OSR1 kinases. Inactivating mutations of the NCC gene cause Gitelman syndrome, whereas overactive WNK signalling produces Gordon syndrome, with high blood pressure and high potassium. A loss-of-function mutation in the gene that codes for NCC causes Gitelman syndrome.\n\nConnecting tubule and collecting duct\n\nThe connecting tubule and collecting duct contain principal cells and intercalated cells. Principal cells handle sodium and potassium. Sodium uptake by these cells is mediated mainly by the thiazide-sensitive NCC and amiloride-sensitive sodium channels, in the mid-distal segments. The collecting duct is also the site where vasopressin analogues, mineralocorticoids and amiloride act.\n\nIntercalated cells control acid–base balance. Type A intercalated cells secrete H⁺ and reabsorb HCO₃⁻ through a vacuolar H⁺-ATPase in the apical membrane, while type B cells operate in the opposite direction, which is why they matter in alkalosis.\n\nTubular secretion of organic ions, potassium and protons\n\nSecretion moves solutes from peritubular blood into the lumen, mostly in the proximal tubule. Organic anions are taken up across the basolateral membrane by organic anion transporters (OAT1 and OAT3) and exported into the lumen by apical multidrug-resistance proteins such as MRP2 and MRP4. Organic cations are taken up mainly by OCT2 and released by apical MATE transporters and P-glycoprotein. The same apical and basolateral transporters are shared by many drugs, which is the basis of many drug–drug interactions.\n\nPotassium is secreted mainly by principal cells in the late distal tubule and collecting duct, through apical potassium channels driven by the basolateral Na⁺/K⁺-ATPase. Secretion rises with aldosterone and with higher tubular flow. Hydrogen ions are secreted by the proximal tubule's NHE3 and by the intercalated cells' H⁺-ATPases, linking secretion directly to bicarbonate handling and plasma pH."
    },
    {
      "heading": "Urine concentration and water balance",
      "text": "Countercurrent multiplication and the medullary gradient\n\nUrine concentration depends on an osmotic gradient that rises from about 300 mOsm/kg at the corticomedullary junction to roughly 1,200 mOsm/kg at the papillary tip in humans. The gradient is built by a countercurrent multiplier in the loop of Henle. The thick ascending limb actively pumps sodium, potassium, and chloride out of the lumen through the NKCC2 cotransporter, but it is impermeable to water. Its fluid therefore becomes dilute as it rises, while the surrounding interstitium becomes more hyperosmotic. The descending limb is the reverse: it is highly permeable to water (through aquaporin-1) but poorly permeable to salt, so fluid flowing down equilibrates with the increasingly concentrated interstitium and gives up water. Because this exchange repeats along the length of the medulla, many small transport steps add up to a large axial difference. Long juxtamedullary nephrons extend deepest into the medulla and contribute most to the gradient.\n\nThe vasa recta, the medullary capillaries, act as countercurrent exchangers. Their descending limbs take up salt and urea while losing water, and their ascending limbs return water and carry solute away. This arrangement removes the water and solute that would otherwise dissipate the gradient, but the vasa recta do not generate the gradient themselves.\n\nVasopressin and aquaporin water channels\n\nWater permeability of the collecting duct is set by antidiuretic hormone (arginine vasopressin), which is released from the posterior pituitary in response to rising plasma osmolality and to falls in blood volume or pressure. Vasopressin binds V2 receptors on the basolateral membrane of principal cells. The resulting cyclic AMP and protein kinase A signalling phosphorylates aquaporin-2 (AQP2), a water channel stored in intracellular vesicles, and promotes its insertion into the apical membrane. Water then leaves the cell across basolateral aquaporin-3 and aquaporin-4 channels and follows the osmotic gradient into the interstitium. Chronic vasopressin exposure also increases AQP2 gene expression. In the absence of the hormone, AQP2 is largely retained inside the cell and the duct remains relatively impermeable to water, so dilute urine is excreted. Osmotic movement of water through membranes by osmosis is the physical basis of this control.\n\nUrea recycling\n\nUrea accounts for a large share of the medullary solute load, often cited at around half of the osmolality at maximal antidiuresis. Urea is freely filtered at the glomerulus, and a substantial portion is reabsorbed in the proximal tubule. In the inner medullary collecting duct, vasopressin increases urea permeability through UT-A1 and UT-A3 transporters, allowing urea to move into the medullary interstitium. Urea then diffuses into the thin limbs of the loop of Henle, which carry it back toward the collecting duct, so the solute circulates between tubule and interstitium instead of being lost. Urea transporters in the vasa recta, including UT-B, limit its washout. Because urea is a product of amino-acid catabolism, its production rises with dietary protein, and high-protein intake increases the solute load the kidney must handle.\n\nDilute and concentrated urine and their limits\n\nHuman urine can range from about 50 mOsm/kg at maximal dilution to about 1,200 mOsm/kg at maximal concentration. Concentrating ability is limited by the medullary gradient and by the obligatory solute excretion each day. A typical daily solute load of roughly 600 mOsm must be excreted, so at maximal concentration the minimum urine volume is about 0.5 L per day. Reduced medullary gradients, as in advanced age, chronic kidney disease, or high solute loads, lower the maximum concentration and force greater urine volume.\n\nDiabetes insipidus\n\nDiabetes insipidus is named for polyuria and thirst, not for glucose; it is distinct from diabetes-mellitus. Its hallmark is the excretion of large volumes of dilute urine, often exceeding 3 L per day, with compensatory polydipsia. Central diabetes insipidus results from deficient vasopressin secretion caused by pituitary or hypothalamic damage, tumours, surgery, trauma, or inherited defects, and it generally responds to synthetic desmopressin. Nephrogenic diabetes insipidus results from a kidney that does not respond to vasopressin, most often through mutations in the V2 receptor gene or in AQP2, or through drugs such as lithium, and it may also be provoked by hypercalcaemia or hypokalaemia. Diagnosis rests on measuring urine and plasma osmolality, often during a supervised water deprivation test, and on the response to desmopressin, which distinguishes the central and nephrogenic forms."
    },
    {
      "heading": "Electrolyte and acid–base regulation",
      "text": "The kidney sets the amount of each electrolyte that leaves the body in urine, so it is central to homeostasis of the electrolyte and ion content of the extracellular fluid. Most of the filtered load of sodium, chloride, potassium, calcium, magnesium, and phosphate is reabsorbed along the nephron, and the final urine composition is decided mainly in the distal nephron under hormonal control. Each ion is handled by a different combination of segments and transporters, and the hormones that set them are largely separate: aldosterone for sodium and potassium, parathyroid hormone (PTH) and active vitamin D for calcium and phosphate, and FGF23 as a modulator of the phosphate axis.\n\nSodium is reabsorbed along nearly the whole tubule, and chloride follows it passively or through coupled transporters. The sodium–chloride cotransporter of the distal convoluted tubule is the target of thiazide diuretics, and the epithelial sodium channel (ENaC) of the late distal tubule and collecting duct is the main site of regulated sodium retention. Aldosterone, acting through the mineralocorticoid receptor, increases ENaC activity and the basolateral Na⁺/K⁺-ATPase, so that sodium is reclaimed in exchange for potassium and hydrogen ions. Because sodium reabsorption in this segment makes the lumen electrically negative, potassium is pushed out into the urine as well.\n\nPotassium is handled in two phases. The proximal tubule reabsorbs roughly two-thirds of the filtered potassium and the loop of Henle reabsorbs a further fifth, so the amount reaching the distal nephron is modest. Under normal conditions most potassium excretion is then regulated by the aldosterone-sensitive distal nephron, where the apical ROMK channel allows potassium secretion, and the amount excreted can range from very little to more than the filtered load depending on dietary intake. Potassium intake, plasma potassium, aldosterone, and distal sodium and flow rate all feed into this control, and aldosterone can stimulate potassium secretion even when sodium is not retained, a pattern known as the aldosterone paradox. Potassium disorders arise when this system fails. As glomerular filtration falls, fewer nephrons remain to deliver sodium and fluid to the distal segments, and the reduced secretory capacity, together with drugs that block the renin–angiotensin–aldosterone system or the mineralocorticoid receptor, makes hyperkalaemia more likely. Hypokalaemia can instead follow excessive loss of potassium in urine from diuretics or from high aldosterone states.\n\nCalcium and phosphate are controlled by a hormonal network. Most filtered calcium is reabsorbed in the proximal tubule and thick ascending limb, and PTH increases calcium reabsorption in the distal convoluted tubule through the TRPV5 channel while also stimulating the kidney's activation of vitamin D. Phosphate reabsorption is governed by the sodium-phosphate cotransporters NaPi-IIa and NaPi-IIc in the proximal tubule. Both PTH and FGF23, a hormone secreted mainly by bone, reduce their surface expression, and FGF23 acts with its co-receptor α-Klotho. FGF23 also suppresses the renal production of calcitriol, so its effects on phosphate and calcium are interlinked with those of PTH. Magnesium is mostly reabsorbed in the thick ascending limb through paracellular pathways that depend on claudin-16 and claudin-19, and the distal convoluted tubule fine-tunes magnesium excretion through the TRPM6 channel.\n\nAcid–base regulation depends on two linked processes: reabsorption of filtered bicarbonate and excretion of hydrogen ions. The proximal tubule reabsorbs about 80% of filtered bicarbonate, mainly through the apical Na⁺/H⁺ exchanger NHE3 and the basolateral electrogenic transporter NBCe1-A, and the thick ascending limb and distal nephron reabsorb most of the rest, so that the final urine is almost free of bicarbonate. Hydrogen ions secreted into the lumen are buffered in two ways. They bind filtered bicarbonate, which returns it to the blood, and they combine with urinary buffers such as phosphate, the so-called titratable acid, which is usually about 20 to 40 mmol per day. Most of the secreted hydrogen ions are bound to ammonia, which is made in proximal tubule cells from glutamine. Ammonia formation accounts for roughly half to two-thirds of net acid excretion, and it also generates new bicarbonate, which is returned to the blood. The collecting duct, through intercalated cells, determines the final urine pH. For this reason ammonium excretion is the main compensatory response to metabolic acidosis, whereas bicarbonate reabsorption adjusts most readily to respiratory disturbances. When the body is alkalotic, the kidney reabsorbs less bicarbonate and excretes the excess, and in metabolic acidosis, as in diabetic ketoacidosis, the kidney increases ammonium production and hydrogen ion excretion. These processes are not always fully effective; in advanced kidney disease, reduced ammonia production and the loss of tubular mass lead to a tendency toward metabolic acidosis.\n\nThe kidney's acid–base and potassium functions are closely connected, since hydrogen and potassium exchange in the collecting duct and intracellular potassium levels influence bicarbonate handling. Changes in plasma potassium can therefore shift acid–base status, and acidosis can in turn raise plasma potassium. Taken together, these regulatory mechanisms keep the pH of the blood within a narrow range, and their failure is one of the earliest and most consequential features of declining kidney function."
    },
    {
      "heading": "Endocrine functions of the kidney",
      "text": "Renin and the renin–angiotensin–aldosterone system\n\nThe kidney is the main source of renin, the enzyme that starts the hormonal cascade regulating arterial pressure and extracellular volume. Renin is made and stored by juxtaglomerular (JG) cells, which sit in the walls of the afferent arterioles just before they enter the glomeruli. A fall in afferent arteriole pressure triggers renin release from JG cells, whereas increased pressure suppresses it. Sympathetic input acts on β1-adrenoceptors on these cells and also promotes release. The second signal comes from the macula densa, a plaque of tubular cells in the distal nephron. The macula densa tracks sodium chloride concentration in tubular fluid and prompts JG cells to release renin when that concentration falls. In this pathway, macula densa cells release prostaglandin E2, which stimulates JG cells to secrete renin (when macula densa cells detect low NaCl, they synthesize and secrete prostaglandin E2, which induces the release of renin).\n\nRenin cleaves angiotensinogen, a protein made in the liver, to angiotensin I, which is then converted to angiotensin II by angiotensin-converting enzyme. Angiotensin II constricts arterioles and stimulates the zona glomerulosa of the adrenal cortex to secrete aldosterone. Aldosterone acts mainly on the distal tubule, increasing sodium reabsorption in exchange for potassium. The combined effect is systemic and intrarenal vasoconstriction plus sodium and water retention, which restores blood volume and pressure. Because the system is so sensitive to renal perfusion, it is also one of the main targets of hypertension treatment.\n\nErythropoietin\n\nErythropoietin (EPO) is a hormone that drives red blood cell formation. In adults, most of it is made by interstitial fibroblasts in the kidney, now often called renal EPO-producing cells. Under hypoxaemic conditions, cortical fibroblasts primarily produce erythropoietin. Production is governed by oxygen supply rather than by a simple feedback loop from the marrow. The EPO gene is switched on by hypoxia-inducible factor 2α (HIF-2α), which is normally destroyed in well-oxygenated cells but stabilized when oxygen falls. Under normal oxygen conditions the α subunits of HIFs are degraded through hydroxylation of specific proline residues, whereas hypoxia blocks this hydroxylation and stabilizes them. The hormone then acts on erythroid progenitors in the bone marrow, supporting red cell production and thus hemoglobin levels. In chronic kidney disease, these cells transform into scar-forming myofibroblasts and lose EPO-producing capacity, which is one reason for renal anemia. In CKD, pericytes transdifferentiate to myofibroblasts, and subsequently the ability of EPO production decreases, leading to renal anemia.\n\nActivation of vitamin D\n\nVitamin D is biologically inert when first formed. It is hydroxylated in the liver to 25-hydroxyvitamin D, and the kidney then performs the second, decisive step. The enzyme 25-hydroxyvitamin D3 1α-hydroxylase (CYP27B1) is located mainly in the proximal tubule, where it converts 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D, or calcitriol. The major site of 1-α hydroxylase activity is the proximal tubule of the kidney. Because this step is the main control point for calcitriol production, its regulation largely determines how much active hormone circulates. The major inducer of 1-alpha-hydroxylase is parathyroid hormone; it is also induced by low blood levels of phosphate. Calcitriol in turn is inactivated by 24-hydroxylation, a pathway that is regulated in the opposite direction.\n\nCalcitriol acts on the intestine, where it increases calcium absorption, and on bone, where it supports mineralization. Active vitamin D compounds directly increase intestinal and renal Ca2+ reabsorption through up-regulation of Ca2+ transport proteins. Failure of this step produces disease: mutations in CYP27B1 cause vitamin D–dependent rickets type 1, with low calcium and poorly mineralized bone. Renal failure also impairs calcitriol synthesis early in the course of CKD, which is one reason mineral disorders are common in that setting.\n\nRenal gluconeogenesis\n\nThe kidney, mainly its cortex and proximal tubule, can produce glucose from gluconeogenic precursors such as lactate, glutamine, and glycerol, and release it into the blood. This function becomes important during fasting. Estimates of the renal share of systemic glucose output vary across studies and conditions, but the kidney's contribution rises as the fast lengthens, when it supplies a substantial portion of circulating glucose, complementing the liver. Glucagon, adrenaline, and cortisol stimulate renal gluconeogenesis, while insulin suppresses it. Acidosis also increases it, because glutamine metabolism that yields ammonium for acid excretion is linked to glucose production; this connects renal glucose output to acid–base balance. Renal gluconeogenesis therefore complements the liver in maintaining glucose supply to the brain and other tissues during metabolic stress."
    },
    {
      "heading": "Clearance of nitrogenous waste and drugs",
      "text": "Nitrogenous wastes\n\nMost of the nitrogen that the body must discard originates in amino acid catabolism. In mammals the liver converts toxic ammonia into urea, and the urea diffuses into the bloodstream, travels to the kidneys, and is filtered and excreted in the urine. Urea is the dominant nitrogenous solute in urine; by one estimate it makes up approximately 90% of the nitrogen-containing components of urine. Because urea is also reabsorbed in the tubules, its urinary excretion is not a simple function of filtration, which is one reason it is a poor marker of kidney function compared with creatinine.\n\nCreatinine is a different kind of waste. It arises from creatine in skeletal muscle, so its production depends on muscle mass rather than diet or protein intake in the same way urea does. It is produced at a relatively constant rate, is not metabolised, and is freely filtered by the glomerulus. Uric acid, the end product of purine catabolism in humans, is handled differently: it is filtered, extensively reabsorbed and secreted in the proximal tubule. OAT4, OAT10, and URAT1 in the apical membrane contribute to proximal tubular urate absorption, which is why serum urate depends so strongly on tubular transport rather than filtration alone.\n\nRenal clearance\n\nRenal clearance is a quantitative way to describe how efficiently the kidney removes a substance from plasma. The renal clearance of a drug is the volume of plasma that is cleared of that drug by the kidneys per unit time. Clearance is calculated as the product of urinary concentration and urine flow divided by plasma concentration, \\(C = \\frac{U \\cdot V}{P}\\).\n\nComparing a substance's clearance with the glomerular filtration rate (GFR) reveals what the tubules do to it. A substance that is filtered and neither secreted nor reabsorbed has a clearance equal to GFR. The renal clearance of inulin is therefore equal to the glomerular filtration rate of 125 mL/min. Clearance greater than this indicates net tubular secretion, and clearance lower indicates net reabsorption. The reference compound for the opposite extreme is para-aminohippurate: it is freely filtered, fully secreted and not reabsorbed.\n\nCreatinine occupies an intermediate position, and this matters clinically. The proximal tubules secrete approximately 15% of urinary creatinine in patients with a normal GFR. Sources differ on the exact figure; one review reports that this secretory component accounts for ~10% of the urinary creatinine excretion in healthy individuals. As kidney function declines, the secreted fraction rises, so creatinine-based clearance progressively overestimates GFR. Cimetidine can be used to block this secretion in research settings, because cimetidine inhibits creatinine secretion, such that CrCl equals GFR, provided there are no difficulties with bladder emptying.\n\nRenal handling of drugs and toxins\n\nDrugs leave the body through the kidney by the same three processes. Glomerular filtration is a low-efficiency route whose rate depends on GFR and on the unbound fraction of drug in plasma. Active tubular secretion is mediated by transporters. The OCT2 transporter is predominantly expressed on the basolateral membrane of tubular epithelial cells and is responsible for the renal uptake of water-soluble cationic compounds such as metformin and cisplatin. Organic anions are handled mainly by OAT1 and OAT3, and OAT1 and OAT3 are involved in the renal clearance of methotrexate, a chemotherapeutic agent used to treat autoimmune diseases. Uptake across the basolateral membrane is followed by efflux into the lumen by apical transporters such as MATE1 and MATE2-K, so the process is vectorial.\n\nBecause several drugs share the same transporters, co-administration can change renal clearance. Inhibition of these carriers can reduce how fast a drug is secreted. Probenecid, an inhibitor for organic anion transport system, inhibited the renal clearance of penicillin, consequently increased the efficacy of penicillin, a classic example from the 1960s and 1970s. A more recent example involves cimetidine and metformin, where the perpetrator drug reduced CL_R by 28/45% in the reported studies, with a corresponding rise in metformin exposure.\n\nDose selection for renally cleared drugs\n\nFor drugs whose elimination depends largely on the kidney, the dose or dosing interval is adjusted as GFR falls, because glomerular filtration of drugs is a low-efficiency process and therefore depends on the glomerular filtration rate and the unbound fraction of drug in blood. Many beta-lactam antibiotics are cleared partly by OAT3, which is why benzylpenicillin and cefotaxime appear among the drugs whose elimination depends on this transporter. Aminoglycosides and vancomycin are other examples in which renal function governs both exposure and the risk of kidney injury, and clinicians commonly adjust their dosing using estimated GFR or creatinine clearance and monitor drug concentrations. Metformin is withheld when GFR is low, because its clearance is reduced and lactic acidosis becomes more likely. These practices rely on creatinine-based estimates, which have limits: as GFR falls the proportion of creatinine secreted by renal tubules increases, so plasma creatinine will overestimate GFR when GFR is low. Dosing decisions therefore draw on both estimated GFR and an awareness of how these measurements behave in severe impairment."
    },
    {
      "heading": "Cell types and the juxtaglomerular apparatus",
      "text": "Resident cells of the glomerulus\n\nThe glomerulus is made up of three cell types, the endothelial cells, the podocytes and the mesangial cells, and a fourth type, parietal epithelial cells, lines Bowman's capsule. The three core types depend on one another for normal function. Podocytes are highly specialized, terminally differentiated cells that serve a crucial role in glomerular filtration function. They extend foot processes around the capillaries, and the foot processes are cellular extensions of podocytes that wrap around the outer surface of glomerular capillaries, forming interdigitations with foot processes of adjacent podocytes and creating filtration slits called the slit diaphragm. Because podocytes have permanent cell cycle exit, they cannot be replaced by division, and podocyte damage leads to proteinuria.\n\nGlomerular endothelial cells sit on the blood side of the filtration barrier, and their fenestrated lining is separated from the podocytes by the glomerular basement membrane. Mesangial cells occupy the centre of the tuft. They make up about 30–40% of the glomerular cell population and lie between the capillary loops embedded in the mesangial matrix. They anchor the glomerular capillaries to the vascular stalk to provide structural support, and by contracting they indirectly participate in filtration by reducing the glomerular surface area; they are also thought to take part in matrix turnover and innate immune responses. Parietal epithelial cells are heterogeneous: PECs at the urinary pole maintain features of proximal tubular cells and PECs at the vascular pole maintain features of podocytes, and they serve as podocyte progenitors.\n\nTubular epithelial cells\n\nTubular epithelial cells are adapted to the transport work of their segment. Proximal tubule cells carry a dense brush border of microvilli that enlarges the luminal surface for reabsorption, and they contain large numbers of mitochondria. These organelles generate the ATP that powers basolateral Na⁺/K⁺-ATPase, which drives sodium-coupled uptake of glucose, amino acids and phosphate. Thick ascending limb cells are similarly rich in mitochondria but have few microvilli, and their energy supply fuels the sodium–potassium–chloride cotransport described elsewhere in this article. Thin limb cells are flat and largely passive, whereas principal and intercalated cells of the collecting duct differ in their transporters and handle sodium, potassium and acid–base balance in opposite ways.\n\nThe juxtaglomerular apparatus\n\nThe juxtaglomerular apparatus is a sensor located where the distal nephron touches its own glomerulus. The juxtaglomerular apparatus comprises afferent and efferent arterioles, complemented by granular, renin-secreting cells, the macula densa, a specialized group of distal tubular cells and lacis cells. It is an anatomic structure which links the distal end of the thick ascending limb at the macula densa with the glomerular vascular pole. The macula densa is a plaque of tightly packed cells in the final part of the thick ascending limb, and the basal lamina is absent between macula densa and juxtaglomerular cells to allow direct contact between these cells.\n\nThe macula densa acts as the sensor. It responds to low sodium chloride concentration in the tubular fluid by signalling to the adjacent granular cells. Macula densa cells stimulate juxtaglomerular cells to release renin when they detect a drop in chloride concentration in tubular fluid. Granular cells are modified smooth muscle cells in the wall of the afferent arteriole, and some of the smooth muscle cells of the afferent arteriole in the region just before the glomerulus have a somewhat different phenotype and are granulated as they contain vesicles within which is the hormone renin. Their renin release is also modulated by nerves: renin secretion is also stimulated by sympathetic nervous stimulation, mainly through β1 adrenoreceptor activation. Other inputs include high sympathetic nerve activity, low systemic and afferent-arteriole pressure, and increased PGE2.\n\nThe third component, extraglomerular mesangial (lacis) cells, forms a pyramid between the two arterioles, with its base on the macula densa and apex continuous with the glomerular mesangium. The apparatus is central to local regulation of renin secretion and glomerular vascular tone via the tubuloglomerular feedback mechanism, which links tubular flow to glomerular filtration. The renin that granular cells release feeds into the renin–angiotensin–aldosterone system, which is covered in the endocrine section.\n\nInterstitial cells and fibroblasts\n\nRenal interstitial fibroblasts are not part of the filtration apparatus, but they produce much of the body's erythropoietin. A large majority of circulating EPO is produced by a population of interstitial fibroblastlike cells in the renal cortex and outer medulla. These renal Epo-producing (REP) cells produce erythropoietin in a hypoxia-inducible manner, so their output rises when tissue oxygen falls. Injury changes them. In tissue damage, alterations observed in the interstitial fibroblast-like cells included an increased number and complexity of cellular processes, enhanced expression of contractile elements, particularly of the intermediate filament desmin, and many of these cells convert into myofibroblasts that deposit matrix. In CKD, renal fibrosis and scarring are mediated by myofibroblasts, a subset of mesenchymal cells that produce collagen. The loss of erythropoietin output in chronic kidney disease is therefore linked to the same transformation that drives scarring. Some of this change is reversible: by eliminating the inflammatory signals, myofibroblast-transformed REPs restart producing Epo, regaining their physiologic phenotypes.\n\nInterstitial cells also contribute to renin supply. Although kidney juxtaglomerular cells are known to continuously produce renin, renal interstitial cells can express renin too, and under anaemic conditions and in injured kidneys the interstitium becomes an additional source of this enzyme."
    },
    {
      "heading": "Embryonic development of the kidney",
      "text": "Three successive kidney forms\n\nVertebrate kidneys arise from the intermediate mesoderm in three overlapping stages: the pronephros, the mesonephros and the metanephros. In mice, the Wolffian duct grows caudally and induces each form in turn, with the metanephros appearing at the level of the middle hindlimb. The first two forms are transient. In humans, most pronephric and mesonephric tubules regress by about week eight, while the metanephros becomes the permanent kidney in mammals, reptiles and birds. Its collecting system begins to form around weeks four to five of gestation, and the nephrons start producing urine around week ten. The metanephric kidney is initially pelvic and then ascends the posterior abdominal wall as the lumbosacral region of the body grows and the trunk straightens.\n\nReciprocal induction and branching\n\nMetanephric development begins when the ureteric bud, an outgrowth of the nephric (Wolffian) duct, invades the metanephric mesenchyme, also called the metanephrogenic blastema. The two tissues act on each other in both directions. Signals from the mesenchyme drive the bud to branch repeatedly, and the branches form the collecting ducts, the calyces and the renal pelvis, while the unbranched stalk becomes the ureter. In turn, the bud tips induce the surrounding cap mesenchyme to condense and undergo a mesenchymal-to-epithelial transition, producing renal vesicles that mature into nephrons. Because each branch tip recruits nephron progenitors, the amount of branching largely determines how many nephrons form, which is why defects in branching are thought to predispose to later chronic kidney disease.\n\nGDNF, secreted by the mesenchyme, acts through the RET receptor on the bud and is the principal driver of branching; downstream MAPK and PI3K–AKT pathways modulate it. Other signals, including FGF, BMP, Wnt, Shh, Notch and VEGF, are arranged in feedback loops. These loops keep the relative proportions of mesenchymal, epithelial and vascular tissue in balance, so that cells committing to one pathway suppress alternatives.\n\nTiming and nephron endowment\n\nNephrogenesis ends before birth in humans, so the adult nephron complement is fixed in utero and does not regenerate. Estimates of the end point vary: one review places completion at about 32 to 36 weeks of gestation, and another states that roughly 90% of human fetal nephrons form between 26 and 36 weeks. In preterm infants, nephron formation can continue for a short period after birth. Preterm kidneys show accelerated maturation, with a narrower nephrogenic zone, fewer renal vesicles and abnormal glomeruli.\n\nLow birth weight, whether from intrauterine growth restriction (IUGR) or preterm birth, is associated with a reduced nephron number. Autopsy studies have found fewer nephrons in stillborn infants with IUGR than in appropriately grown controls. Individuals with low nephron numbers often show compensatory enlargement of their glomeruli. Epidemiological data link low birth weight, IUGR and preterm birth with a higher risk of hypertension and chronic kidney disease in adulthood; a Norwegian study of more than two million people found that these factors add cumulative risk for end-stage kidney disease later in life. Experimental evidence, however, suggests that reduced nephron number is not necessarily a direct cause of hypertension. Maternal obesity, diabetes and preeclampsia are among the gestational stresses also associated with these outcomes. Because little can currently be done to increase nephron number after birth, attention focuses on prenatal care and postnatal nutrition.\n\nGenes and signalling pathways\n\nEarly patterning of the kidney field depends on transcription factors such as Hox paralogues, LIM1, OSR1, PAX2 and PAX8, and EYA1. Later, WT1, SIX2, SALL1 and HNF1B define the competence of the mesenchyme to respond to bud signals. The major signalling systems include the GDNF–RET axis, Wnt, FGF, Hedgehog, retinoic acid and BMP. BMP4 restricts where the bud can form, while BMP7 supports the survival of nephron progenitors. Correct insertion of the ureter into the bladder also requires RET, BMP4 and the SLIT–ROBO axis.\n\nDisruptions of these pathways cause congenital anomalies of the kidney and urinary tract (CAKUT), which include renal agenesis, dysplasia, duplex collecting systems, obstructive uropathies and vesicoureteral reflux. CAKUT is a major cause of kidney failure in childhood. Single-gene defects account for roughly 10 to 20% of cases, and copy-number and other genomic variants may explain up to a third, with more than 50 genes implicated so far. Genotype–phenotype correlation is often weak, and environmental factors such as maternal diabetes and fetal hypoxia can modify the presentation. Human kidney organoids and gene-editing tools are now being used to test candidate pathways experimentally."
    },
    {
      "heading": "Historical discovery of kidney function",
      "text": "Before the seventeenth century, the kidney's role was poorly understood, and explanations of urine formation were largely speculative. Malpighi's microscopic work changed that. In 1666 Marcello Malpighi used the new microscope to describe the glomeruli and proposed that urine forms by filtration between the blood and the renal tubules. Andreas Vesalius had earlier illustrated kidney anatomy, but his drawings did not address function.\n\nIn the nineteenth century the question was whether the glomerulus filters plasma or secretes water. In 1842 William Bowman published a detailed description of the Malpighian bodies, showing how the capsule of the glomerulus continues into the proximal tubule and how the glomerular capillaries are arranged. Bowman, however, argued that the glomerulus secreted water and that the tubules secreted other solutes. In the same year, Carl Ludwig reached the opposite conclusion: that the glomerulus performs a high-volume, pressure-driven ultrafiltration, and that the tubules reabsorb most of the filtrate. Rudolf Heidenhain's 1874 findings swung opinion back toward Bowman's view, and Arthur Cushny's 1917 book judged the evidence insufficient to settle the matter. The controversy was resolved in the 1920s, when micropuncture, a technique for sampling fluid from individual tubule segments, allowed physiologists to measure what each part of the nephron actually did.\n\nTwentieth-century work built the quantitative framework for renal physiology. Ernest Starling's colloid-osmotic theory explained how hydrostatic and oncotic pressures govern fluid movement across capillary walls, a principle later applied to glomerular filtration. Renal clearance, the rate at which the kidney removes a substance from plasma, became the standard way to compare filtration, secretion and reabsorption for individual solutes. Tubular transport was mapped segment by segment in the same period.\n\nThe renin–angiotensin system has a comparably long history. In 1898 Robert Tigerstedt and Per Bergman at the Karolinska Institute reported that extracts of rabbit kidney raised blood pressure when injected into other rabbits, and they named the active substance renin. Their observation then lay largely dormant for about four decades. In 1934 Harry Goldblatt produced experimental hypertension in dogs by clamping a renal artery, which revived interest in the kidney as a source of pressor activity. Around 1936, two independent groups, one in Buenos Aires and one at Eli Lilly in Indianapolis, showed that the kidney releases a pressor agent. By 1939 the groups had established that renin is an enzyme acting on a plasma substrate to produce a peptide vasoconstrictor, which Page and Helmer named angiotensin II in 1940.\n\nThe last part of this history concerns the replacement of failed kidney function. Working in occupied Kampen during the Second World War, Willem Kolff built a rotating-drum dialysis machine, and in the 1940s he and colleagues began treating patients with it. Kidney transplantation followed in the 1950s. On 23 December 1954, Richard Herrick received a kidney from his identical twin at Peter Bent Brigham Hospital in Boston, a procedure carried out by Joseph Murray and John Merrill. Because the donor and recipient were genetically identical, rejection was not an obstacle, and Murray later shared the 1990 Nobel Prize for this work. Peter Medawar's subsequent studies of transplant immunity and the development of immunosuppressive drugs made transplantation feasible between unrelated individuals, and cadaveric donation also began in the 1950s. Together, dialysis and transplantation made kidney failure a treatable condition, which established nephrology as a distinct clinical specialty."
    },
    {
      "heading": "Acute kidney injury",
      "text": "Definition and diagnostic criteria\n\nAcute kidney injury (AKI) is a rapid decline in kidney function over hours to days. The 2004 RIFLE criteria combined creatinine-based and urine-output thresholds. The recent KDIGO definition is a combination of AKIN and RIFLE. It defined AKI by a ≥ 0.3 mg/dl increase in creatinine within 48 hours, or a ≥50% above baseline within 7 days. Under the KDIGO framework, a diagnosis can rest on a creatinine rise of at least 0.3 mg/dL within two days, a creatinine level that has reached 1.5 times baseline within the past week, or urine flow below 0.5 mL/kg per hour sustained for six hours (three alternative criteria).\n\nCreatinine is a lagging signal. Serum creatinine tends to climb only after about half of kidney function has been lost, which is why urine output is also monitored. The KDIGO oliguria threshold is 0.5 mL/kg per hour, and one study found that urine output could flag AKI about 11 hours before creatinine changed.\n\nPrerenal, intrinsic and postrenal causes\n\nInjury is classified by the anatomical site of the defect. Prerenal AKI is the most common form and often progresses to intrinsic injury if it is not corrected promptly. Typical triggers include volume loss, sepsis, heart failure, cirrhosis, and drugs such as ACE inhibitors and NSAIDs (prerenal causes). When perfusion is restored quickly, prerenal azotemia reverses rapidly within 24 hours because the integrity of the kidney parenchyma has remained intact. Severe or prolonged hypoperfusion, however, can injure tubular epithelial cells and lead to structural intrinsic AKI. NSAIDs add a separate route, since inhibiting prostaglandin synthesis results in afferent arteriole vasoconstriction.\n\nIntrinsic AKI involves the tubules, glomeruli, microvasculature, or interstitium of the kidneys. Recognised causes include glomerulonephritis, lupus nephritis, acute tubular necrosis, certain antibiotics, chemotherapeutic agents, and contrast dye. In tubular injury, damaged epithelial cells lose their tight junctions, so filtrate leaks back into the interstitium, while dying cells slough off into the tubules, forming obstructing casts, further decreasing GFR and leading to oliguria.\n\nPostrenal AKI results from obstruction of urine outflow. The most common causes are renal or ureteral calculi, tumors, blood clots, or any urethral obstruction. Once the blockage is relieved, rapid relief of urinary obstruction in postrenal failure results in a prompt decrease of vasoconstriction. The categories often overlap, especially in hospitalised children (multifactorial etiologies).\n\nClinical course\n\nThe course is often described in four phases: an onset phase, an oliguric phase in which tubular damage reduces urine output, a diuretic phase in which urine output rises while tubular repair remains incomplete, and a recovery phase in which tubular swelling resolves (onset, oliguric, diuretic and recovery phases). Not every patient is oliguric; for AKI caused by many nephrotoxicants, polyuria, not oliguria, is often the primary effect that occurs. During recovery, urine volume climbs steadily, and heavy losses of water and solutes can occur, so fluid and electrolyte replacement needs close attention. The prognosis depends on the presence or absence of urine output, the quantity of urine output, the duration of anuria, and the underlying cause and severity of kidney injury. Early return of renal blood flow is especially favourable: early renal blood flow normalization predicts a better prognosis for recovery of kidney function. In hospitalised patients, AKI is also tied to substantial in-hospital morbidity and death (in-hospital morbidity and mortality).\n\nLong-term consequences\n\nFor many years, recovery of creatinine was assumed to mean a benign outcome. Since 2008, multiple observational studies have shown a strong reproducible association between acute kidney injury, including mild cases, and the subsequent development of chronic kidney disease. Among long-term survivors, approximately 12.5% may be dialysis dependent and 19-31% may have chronic kidney disease. Survivors also face higher long-term mortality than patients without AKI (compared with critically or non-critically ill patients without acute kidney injury).\n\nRisk appears to scale with severity and duration, yet it is not confined to severe episodes. The risks of CKD incidence or progression, as well as kidney failure, were higher among individuals with more severe AKI stages or longer AKI durations, and even individuals with the lowest AKI stage or a short duration remained at higher risk. Patients whose creatinine has returned to baseline still show elevated risk, and each episode of recurrence is associated with an increased risk for progression to advanced CKD. Pre-existing conditions modify the picture: the magnitude of risk seems highly dependent on the presence of comorbid conditions, including cardiovascular disease, hypertension, diabetes mellitus, preexisting CKD, and renal recovery. Not all studies agree on size of effect. In the CRIC cohort, after adjustment for prior eGFR and proteinuria, the association between mild to moderate AKI and worsening subsequent kidney function in patients with CKD was small. Overall, AKI is increasingly regarded as a risk factor for the onset and acceleration of chronic kidney disease, and survivors with incomplete recovery need structured follow-up."
    },
    {
      "heading": "Chronic kidney disease and its staging",
      "text": "KDIGO's 2024 guideline defines CKD as abnormalities of kidney structure or function that last a minimum of 3 months and have implications for health. The time requirement is what separates CKD from acute kidney injury. A single low creatinine or a one-off positive urine test does not establish the diagnosis; the abnormality has to persist.\n\nStaging: the CGA system\n\nSince the 2012 KDIGO guideline, clinicians have described CKD using three coordinates. CKD is classified based on Cause, Glomerular filtration rate (GFR) category (G1–G5), and Albuminuria category (A1–A3), abbreviated as CGA. The cause is identified first, then the level of filtration and the degree of urinary protein loss.\n\nThe G categories are based on estimated GFR in mL/min/1.73 m². G1 is 90 or above, G2 is 60–89 (mildly decreased), G3a is 45–59, G3b is 30–44, G4 is 15–29, and G5 is below 15, which corresponds to kidney failure. In the absence of evidence of kidney damage, neither G1 nor G2 fulfils the criteria for CKD. A normal or high GFR therefore does not by itself indicate disease; markers of damage are needed.\n\nAlbuminuria is usually measured as the urine albumin-to-creatinine ratio, and the A categories are assigned from persistent values. The categories are defined using UACR and must be present for at least 3 months: A1 is below 30 mg/g, A2 is 30–300, and A3 is above 300. Albuminuria is often the earliest sign of glomerular damage, and a greater amount of albuminuria, or a higher persistent albuminuria category, can indicate a greater progression or risk of CKD.\n\nCombined risk\n\nKDIGO combines the G and A categories into a grid of colour-coded risk levels. Green indicates low risk (if no other markers of kidney disease, no CKD), yellow moderately increased risk, orange high risk, and red very high risk. Research has shown that higher specific stages or categories, characterized by level of GFR and albuminuria independently, portend greater relative risk for adverse outcomes, including progression, cardiovascular disease, all-cause and cardiovascular mortality, kidney failure, and acute kidney injury.\n\nCauses and mechanisms\n\nThe major causes of CKD are diabetes and hypertension; nearly half of all CKD cases arise from diabetes with or without hypertension. Other causes include glomerulonephritis, lupus, polycystic kidney disease, long-term analgesic use, renal artery atherosclerosis, urinary tract obstruction, and sickle cell disease.\n\nIn diabetes, sustained hyperglycaemia raises the pressure and flow within individual glomeruli, promotes thickening of the glomerular basement membrane and expansion of the mesangium, and causes loss of podocytes. Tubular cells are also injured by glycated proteins and oxidative stress, and fibrosis gradually replaces functioning tissue. In hypertension, elevated systemic pressure is transmitted to the glomerular capillaries, and arteriolar damage (hyalinosis and sclerosis) reduces the kidney's ability to buffer that pressure. Both conditions lead to glomerulosclerosis, tubulointerstitial fibrosis, and progressive nephron loss, after which the surviving nephrons hyperfilter and eventually fail as well.\n\nProgression, kidney failure and uraemia\n\nAlbuminuria, or proteinuria more broadly, accelerates decline. Filtered proteins are toxic to tubular cells, and they promote inflammation and fibrosis in the interstitium, so a patient with heavy proteinuria tends to lose GFR faster than one with the same GFR and little protein in the urine. Kidney failure is generally identified by a GFR below 15 mL/min/1.73 m² or by the need for dialysis or transplantation; Stage 5 was defined as GFR below 15 or kidney failure treated by dialysis or transplantation in the earlier KDOQI framework.\n\nAs excretion fails, nitrogenous waste and other solutes accumulate, a state known as uraemia. Its manifestations include anaemia from reduced erythropoietin production, disordered phosphate and calcium handling with bone disease, hyperkalaemia, metabolic acidosis, fluid overload that worsens hypertension and heart failure, pericarditis, neuropathy, pruritus, and altered mental state.\n\nBurden\n\nThe scale of CKD has grown considerably. In the Global Burden of Disease (GBD) 2023 analysis, 788 million (95% uncertainty interval 743–843) people aged 20 years and older were estimated to have CKD, up from 378 million (354–407) in 1990. In 2023, CKD was the ninth leading cause of death globally, accounting for 1·48 million (1·30–1·65) deaths. Earlier GBD releases reported different totals; a GBD 2021 analysis, for example, gave an estimated 674 million individuals affected in 2021. These differences reflect model versions, case definitions and data sources, so cross-study comparisons should be made with care."
    },
    {
      "heading": "Specific kidney disorders",
      "text": "Glomerular diseases\n\nGlomerular diseases share a common outline: the filtration barrier is damaged, so blood or protein leaks into the urine, and the glomerular filtration rate (GFR) often falls. Glomerulonephritis is the broad term for inflammation of the glomeruli. Its typical acute form, the nephritic syndrome, combines haematuria (sometimes with red-cell casts), hypertension and reduced GFR. Nephrotic syndrome is defined by heavy proteinuria, low serum albumin, oedema and high blood lipids. It usually reflects injury to the podocytes, as in minimal change disease, focal segmental glomerulosclerosis and membranous nephropathy. In membranous nephropathy, subepithelial immune deposits are typically formed when antibodies target podocyte antigens, a mechanism shared with other autoimmune diseases. Lupus nephritis, anti-glomerular basement membrane disease and ANCA-associated crescentic glomerulonephritis each involve a different immune trigger, such as circulating immune complexes, antibodies against basement-membrane collagen, or neutrophil-activating autoantibodies.\n\nIgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Its defining feature is IgA, mainly the IgA1 subclass, deposited in the mesangium. The leading explanation is a multi-hit model. In the first hit, IgA1 in the circulation carries hinge-region O-glycans that lack galactose, creating galactose-deficient IgA1 (Gd-IgA1), which acts as an autoantigen. In the second hit, the body makes IgG or IgA autoantibodies against these abnormal glycans. In the third hit, the two form immune complexes that lodge in the mesangium and activate complement, largely through the alternative and lectin pathways. In the fourth hit, the mesangial cells proliferate, the extracellular matrix expands and proinflammatory cytokines are released. The first hit has a heritable component, and genome-wide studies have linked IgAN to loci affecting glycosylation enzymes such as C1GALT1 and its chaperone C1GALT1C1. Serum Gd-IgA1 is elevated in about three-quarters of patients by one lectin-based assay, which makes it a candidate biomarker. Diagnosis still depends on a renal biopsy showing IgA deposits. A substantial minority of patients progress to kidney failure, and corticosteroids and other immunosuppressants can slow this progression. Closely related IgA deposition occurs in IgA vasculitis (Henoch–Schönlein purpura) nephritis, which is common in children with systemic vasculitis.\n\nPolycystic kidney disease\n\nAutosomal dominant polycystic kidney disease (ADPKD) is the most frequent inherited kidney disorder, with an estimated incidence of about 1 in 400 to 1,000. Multiple fluid-filled cysts progressively enlarge the kidneys and can also arise in the liver, pancreas and seminal vesicles. Most cases are caused by heterozygous pathogenic variants in PKD1, located on chromosome 16p13.3 and accounting for roughly 80–85% of cases, or in PKD2 on chromosome 4q21, which accounts for most of the remainder. The two genes encode polycystin-1 and polycystin-2. These proteins are found in primary cilia, where they are thought to act as mechanosensors that help maintain normal tubular structure. ADPKD follows a two-hit model: a germline variant is present in every cell, and a somatic event inactivates the second allele in an individual tubular cell, allowing focal proliferation and cyst formation. Each child of an affected parent has a 50% risk of inheriting the variant. Genotype strongly influences outcome. Truncating PKD1 variants are associated with kidney failure in the fifth or sixth decade, whereas PKD2 variants usually cause a later and milder course. Rarer genes, including GANAB, DNAJB11, ALG5, ALG9 and IFT140, account for a small share of families, and co-inheritance of variants in both main genes (bilineal or digenic inheritance) is linked to earlier and more severe disease. The recessive form, autosomal recessive polycystic kidney disease, is caused by variants in PKHD1 and usually presents in childhood. Management of ADPKD centres on blood pressure control, and the vasopressin V2 receptor antagonist tolvaptan is approved to slow cyst growth in patients at high risk of rapid decline.\n\nKidney stones\n\nKidney stones (nephrolithiasis) are solid crystalline masses that form in the urinary tract when urine becomes supersaturated with stone-forming salts. Most stones contain calcium. Calcium oxalate is the most common type, making up roughly 35–70% of stones in one common classification, followed by calcium phosphate (about 5–20%) and mixed calcium oxalate–phosphate stones (about 10–30%). Uric acid, struvite (associated with urease-producing urinary infections) and cystine stones (caused by the inherited disorder cystinuria) account for most of the rest. Published estimates of the calcium share vary, partly because of how stones are classified. Supersaturation of calcium and oxalate is the driving force for calcium oxalate crystallization, and urinary citrate normally inhibits this process by binding calcium. Hypercalciuria and hyperoxaluria are the main metabolic risk factors. Other contributors include low urine volume, hypocitraturia, and high urinary uric acid. Diet is important. Animal protein and salt raise urinary acid and calcium excretion, whereas high-oxalate foods raise oxalate load. Dietary calcium is protective when taken with meals, because it binds oxalate in the gut, so restricting calcium can increase stone risk. Obesity, chronic diarrhoeal bowel disease, bariatric surgery and family history also increase risk. Acute treatment focuses on pain control and stone passage, while recurrence prevention depends on fluid intake and correction of the metabolic abnormality, and more complex stones may require procedures such as shock-wave lithotripsy or ureteroscopy.\n\nRenal cell carcinoma and other tumours\n\nRenal cell carcinoma (RCC) is the most common cancer arising in the adult kidney. Clear-cell carcinoma is the dominant subtype, and papillary and chromophobe forms account for most of the remainder. Smoking, obesity and hypertension are established risk factors, and inherited von Hippel–Lindau syndrome, caused by mutations in the VHL gene, predisposes to clear-cell tumours through activation of hypoxia-inducible pathways. Many tumours are found incidentally on imaging. For localized disease, the main treatment is surgical removal, with partial nephrectomy preferred for small tumours when technically feasible and radical nephrectomy used for larger ones; carefully selected small masses may be monitored rather than treated immediately. Advanced disease is managed with targeted agents that block vascular endothelial growth factor signalling or mTOR, and with immune checkpoint inhibitors, often in combination. Other renal tumours include urothelial carcinoma of the renal pelvis, which is managed more like bladder cancer, Wilms tumour (nephroblastoma), the most common childhood kidney cancer, and the benign oncocytoma."
    },
    {
      "heading": "Global epidemiology and public health",
      "text": "Estimates of CKD burden vary with the dataset, the case definition and the modelling method. The most recent comprehensive analysis, the Global Burden of Disease (GBD) 2023 study, covers 204 countries and territories and puts the adult population with CKD at 788 million (95% uncertainty interval 743–843) people aged 20 years and older in 2023, against 378 million in 1990. Much of that growth is demographic. Raw prevalence rose by about 18.9% between 1990 and 2023, a change reflecting the ageing of the world's population, while the age-standardised prevalence rose only about 3.5%, to 14.2% of adults. Earlier GBD work told a different story: the 2021 round reported 674 million affected individuals and a slight decline in age-standardised prevalence since 1990. Secondary sources therefore quote a range of figures, from \"more than 800 million\" in KDIGO's 2025 conference report to about 850 million in WHO-related materials.\n\nMortality estimates follow a similar pattern of upward movement. In 2023 CKD was the ninth leading cause of death worldwide, accounting for 1.48 million (1.30–1.65) deaths, and the 12th leading cause of DALYs. Advocacy groups describe a steady climb in the rankings: one source notes that CKD rose from the 17th leading cause of death in 1990 to the 10th in 2020, and to the 9th in 2024. Projections are more pessimistic still. Modelling suggests CKD will become the fifth leading cause of death by 2040, and one review expects it to become the fifth-highest cause of years of life lost. Part of the concern is that many deaths occur at relatively young ages, so the years lost per death are high. Annual death totals also differ across sources, since they depend on whether kidney disease is counted as the underlying cause or as a contributing cause. Cardiovascular disease is a major link: KDIGO's 2025 conference report notes that CKD is a major driver for CVD.\n\nBurden is unevenly distributed. In GBD 2023, the region with the highest age-standardised prevalence was north Africa and the Middle East (18.0%), and more than one-third of people with CKD lived in China (152 million) and India (138 million). The GBD 2021 analysis found that high-income North America's prevalence remained stable yet showed high mortality, while East Asia's prevalence fell by 11.7%, and regions with low socio-demographic indices, including parts of sub-Saharan Africa and South Asia, bore the greatest burdens. Access to care is the sharpest inequity. Over two million people receive dialysis or a transplant, but more than 80% of these people reside in high-income countries. The transplant and dialysis costs are also high: in high-income countries, kidney replacement therapy can consume up to 3% of health care budgets. Many deaths are therefore linked to the lack of access to treatment rather than to the disease alone.\n\nThe principal modifiable risk factors are metabolic. Diabetes and hypertension are the leading causes of CKD in the GBD analysis, and metabolic risk factors accounted for most DALYs and deaths from CKD. In China, the hypertension-attributed share became the leading cause of death much earlier in time (since 2004). Other drivers include obesity, smoking, diet and inactivity. Commentators also point to smoking, unhealthy diets, physical inactivity, and alcohol, along with rising temperatures as an environmental factor. Because these risks overlap with diabetes, hypertension and cardiovascular-disease, screening programmes often target people with those conditions.\n\nPublic health responses have gained momentum. In 2025 the WHO adopted its first resolution dedicated to kidney disease at the 78th World Health Assembly. It is a notable shift, because an earlier WHO action plan on noncommunicable diseases had focused on cardiovascular diseases, cancer, chronic respiratory diseases, and diabetes, but not kidney disease. The resolution is organised around four key areas, including awareness and the integration of case-finding into primary care. Earlier, KDIGO had argued that CKD can be detected using simple laboratory tests, and that treatment can prevent or delay complications. Its 2024 clinical practice guideline is now the principal reference for evaluation and management. Key questions remain open, including how to reach underserved populations and how to finance screening and treatment in low-resource settings."
    },
    {
      "heading": "Diagnosis and monitoring",
      "text": "Urinalysis and albuminuria\n\nUrinalysis is usually the first laboratory step. Dipstick strips rely on a pH-indicator dye that changes colour in the presence of protein. The dye responds more strongly to albumin than to other urinary proteins, so the strip is most sensitive to albuminuria. Strips are fast and inexpensive, but their semi-quantitative readings agree only moderately with laboratory measurements. In one diagnostic study of 970 subjects, disagreement with KDIGO albuminuria categories ranged from 27% for one strip brand to 73% for another. KDIGO guidance accepts a 1+ strip result as a substitute for quantitative testing only where laboratory testing is unavailable. Microscopy of the urine sediment looks for red blood cells, white cells, and casts. These findings point toward glomerular or tubulointerstitial disease and often prompt further investigation.\n\nQuantitative testing usually uses a spot urine albumin-to-creatinine ratio (ACR). Normalising to creatinine corrects for urine concentration, so a random sample gives nearly the same information as a 24-hour collection. KDIGO grades albuminuria as A1 (below 30 mg/g, or 3 mg/mmol), A2 (30–300 mg/g), and A3 (above 300 mg/g). Protein-to-creatinine ratios are used when total protein, rather than albumin alone, needs measuring, as in some glomerular diseases. Exercise, fever, infection, menstruation, and marked hyperglycaemia can transiently raise urinary albumin, so an unexpected elevated result is normally repeated before it is interpreted.\n\nEstimated GFR\n\nBecause direct measurement of glomerular filtration rate requires infusion of a marker and timed collections, clinicians use estimating equations. The 2021 CKD-EPI creatinine equation removed the race coefficient used in earlier versions. For adults it estimates GFR from serum creatinine, age, and sex:\n\n\\[\\text{eGFR} = 142 \\times \\min\\left(\\frac{S_{cr}}{\\kappa},1\\right)^{\\alpha} \\times \\max\\left(\\frac{S_{cr}}{\\kappa},1\\right)^{-1.200} \\times 0.9938^{\\text{Age}} \\times 1.012 \\quad [\\text{if female}]\\]\n\nHere \\(S_{cr}\\) is standardised serum creatinine in mg/dL, κ is 0.7 for females and 0.9 for males, and α is −0.219 for females and −0.144 for males.\n\nCystatin C is an alternative filtration marker. It is produced at a relatively steady rate, is less affected by muscle mass and diet than creatinine, and is largely cleared by the kidney, though kidney microlesions can alter it early. The 2021 combined creatinine–cystatin C equation was the most accurate against measured GFR in the validation study and showed smaller differences across populations. The choice of equation matters clinically: in one cohort of 435 patients, about 10% were placed in different KDIGO GFR categories depending on which equation was used. Creatinine-based estimates are unreliable in people with unusual muscle mass, such as amputees or those with severe malnutrition, in pregnancy, and in acute kidney injury, where creatinine has not reached a steady state. Some drugs also alter tubular creatinine secretion and can shift the value without changing true filtration.\n\nImaging and renal biopsy\n\nUltrasound is the usual first imaging study. It is radiation-free and shows kidney size, cortical thickness, echogenicity, cysts, masses, and hydronephrosis, which indicates urinary obstruction. Computed tomography is used for stones, masses, and obstruction, but iodinated contrast agents carry a risk of kidney injury, which must be weighed when kidney function is already reduced. MRI characterises renal masses and vessels without iodinated contrast; gadolinium-based agents are used with caution at low GFR.\n\nRenal biopsy, usually performed percutaneously under ultrasound or CT guidance, remains the definitive method for identifying the pattern of glomerular disease, such as the immune deposits seen in glomerulonephritis or lupus nephritis, and for assessing rejection in a transplanted kidney. Light microscopy, immunofluorescence, and electron microscopy are typically combined on the same specimen. Before the procedure, clinicians check blood pressure and coagulation, because bleeding is the main complication.\n\nBiomarkers under development\n\nSerum creatinine and blood urea nitrogen are slow and nonspecific indicators of acute injury, and this lag motivates the search for earlier markers. Candidates include urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), interleukin-18, liver-type fatty acid-binding protein, and cystatin C. KIM-1 is a transmembrane glycoprotein that is essentially absent from healthy kidneys, is upregulated in proximal tubular cells during injury, and is shed into urine. In a systematic review, urinary KIM-1 showed a pooled sensitivity of about 74% and specificity of about 84% for acute kidney injury, which is useful but not sufficient alone. Several injury markers, including KIM-1 and NGAL, have been qualified by the US FDA and the European Medicines Agency as safety biomarkers in preclinical drug development, although their routine clinical use in patients remains limited. Current research favours combined panels over single markers, and reference intervals must account for age and sex, particularly in children."
    },
    {
      "heading": "Kidney replacement therapy",
      "text": "Kidney replacement therapy (KRT) takes over the filtration, fluid, electrolyte and excretory work of the kidney when native function has fallen to a level that cannot sustain life. It has three forms: haemodialysis, peritoneal dialysis, and transplantation. Each carries different access requirements, burdens and risks.\n\nHaemodialysis\n\nIn haemodialysis, blood leaves the body through an arterial line, passes through a dialyser containing thousands of hollow semipermeable fibres, and returns through a venous line. Waste solutes move across the membrane by diffusion, and excess water is removed by ultrafiltration driven by a pressure gradient. The dialysate bath is adjusted to correct potassium, bicarbonate and calcium abnormalities, and anticoagulation is usually given to keep the circuit from clotting. Guidelines recommend that the vascular access deliver at least about 300 mL/min through the dialyser. Most people on hemodialysis have the procedure three times a week. Home and nocturnal schedules, which involve longer and more frequent sessions, are also used in some settings.\n\nVascular access is one of the most important practical issues. A surgeon connects one of the patient's arteries to a vein, usually under the skin of the upper arm or forearm. The resulting arteriovenous (AV) fistula is generally the preferred long-term option. It takes 6–8 weeks to heal and, where possible, should be created at least 2–3 months before dialysis starts. As blood flows through it, the vein grows and its walls become thicker and stronger. When suitable veins are lacking, a synthetic graft can bridge artery and vein; grafts can often be used sooner than fistulas but may require additional maintenance over time. Central venous catheters, placed in the neck, chest or groin, allow immediate treatment but are a bridge rather than a destination, because they provide a slower rate of blood flow and have a higher risk of infection and blood clots.\n\nPeritoneal dialysis\n\nPeritoneal dialysis uses the patient's own peritoneal membrane as the exchange surface. A catheter placed in the abdomen allows dialysate to be infused into the peritoneal cavity, to dwell there, and to be drained. Dextrose in the solution creates the osmotic pressure that drives water removal. In continuous ambulatory peritoneal dialysis (CAPD), the patient performs manual exchanges: a patient performs CAPD manually about four times a day. Each drain and fill procedure usually takes about 1 hour. Automated systems use a cycler: the machine automatically infuses, dwells, and drains dialysate, often overnight, which spares the patient daytime exchanges. Peritoneal dialysis avoids needles and the need for a vascular access, but the catheter route carries infection risk in the form of peritonitis, and it depends on a clean home environment and on the continued function of the peritoneal membrane.\n\nTransplantation\n\nTransplantation generally gives better long-term survival and quality of life than dialysis. Grafts can come from living donors, or from people who have died after brain death or after circulatory death. Living-donor kidneys usually function immediately: immediately upon transplantation, 97% of live donor kidneys are fully functional, versus 50-60% of deceased donor kidneys. A deceased donor kidney might take several days or weeks to function normally. Survival also differs: in one review, 5-year survival is approximately 80 percent and 65 percent in live-donor and deceased-donor transplantation, respectively.\n\nDonor–recipient matching addresses the immune barrier. The donor organ acts as an alloantigen, and prior sensitization, HLA mismatch, ABO incompatibility, and delayed graft function are among the recognised risk factors for rejection. Rejection may be T-cell mediated or antibody-mediated, and chronic rejection is still the primary cause of kidney allograft loss. Incompatible living donation can be made possible by removing recipient antibodies before surgery. Recipients therefore take immunosuppressive drugs, which can be divided into induction and maintenance drugs. Induction agents are given around the time of surgery, when rejection risk is highest, while maintenance regimens, typically combining a calcineurin inhibitor, an antiproliferative agent and sometimes corticosteroids, continue indefinitely. This lifelong suppression raises the risk of infection and malignancy.\n\nAllocation, waiting lists and ethics\n\nDeceased-donor kidneys are allocated through national or regional systems. In the United States, the Organ Procurement and Transplantation Network, operated under contract by UNOS, uses a point-based allocation system that weighs waiting time, HLA match, antibody sensitisation, age and geography. Waiting times can be very long: the wait for a deceased donor kidney in New York averages five to seven years. Living donation, including paired exchanges that link incompatible donor–recipient pairs, offers an alternative route. Consent frameworks differ, from explicit opt-in systems to presumed consent in some European countries.\n\nAllocation raises contested questions: how to balance waiting time against medical urgency, whether to prioritise likely graft success, how to treat older or high-risk candidates, and how to avoid racial bias in eligibility criteria. Organ sale is prohibited in most countries, and donation after circulatory death raises its own ethical debates.\n\nGlobal disparities and cost\n\nAccess to KRT varies sharply. Many people who need dialysis or transplantation in low- and middle-income countries never receive it, and where treatment exists it often depends on out-of-pocket payment. Dialysis is expensive to sustain over decades, and in many health systems it consumes a large share of kidney-related spending. Transplantation usually costs more at the outset but is generally less expensive over the long term, which is one reason transplant access is a central policy goal. Expanding home-based dialysis and building transplant capacity are among the strategies discussed by international kidney organisations."
    },
    {
      "heading": "Comparative anatomy and evolution",
      "text": "Kidney designs across vertebrate groups\n\nAcross 230 bird species in 25 orders, salt glands, large kidneys and life in saline habitats appear to have evolved independently more than once. Vertebrate kidney design shows the same kind of variation in its building blocks. A zebrafish embryo's pronephros begins with just two nephrons, which later serve as a scaffold for a mesonephros of several hundred nephrons. Across the vertebrates, structural complexity rises toward the metanephros of mammals, which contains up to a million nephrons.\n\nIn adult fishes and amphibians, the working kidney is the mesonephros, and postembryonic nephrogenesis is well documented in the mesonephric kidneys of these groups. Mammals follow a different pattern: new nephron formation stops around birth and does not occur in adults. In amniotes, the earlier forms are dismantled during development and the final metanephric kidney replaces them. Among jawless cyclostomes, the pronephros itself constitutes the mature kidney.\n\nLoop of Henle, reptiles and birds\n\nThe loop of Henle is the structure most closely linked to urine concentration, and reference sources do not fully agree on where it occurs. Britannica describes it as a long U-shaped portion of the tubule in the nephrons of reptiles, birds and mammals. A classic account by Knut Schmidt-Nielsen, however, states that reptiles have no loops in their kidneys, so there is no countercurrent multiplier system. A 2020 review of renal evolution describes the loop as a later innovation that coupled reabsorption to the glomeruli to restrict the loss of useful solutes.\n\nBirds present a mixed picture. Avian kidneys have a reptilian-type nephron without loops in the cortex and a mammalian-type nephron with long or intermediate loops in the medulla, and only a small share of nephrons (15–25%) carry a loop. Estimates vary; another review gives 70%–90% of nephrons without a loop. Even so, birds can excrete urine about twice as concentrated as plasma, though their looped nephrons are less developed than those of mammals.\n\nMammals stand apart in this respect. Mammals are the only vertebrate class in which the kidney is always the main organ of osmoregulation. The loop's principal role is the recovery of water and sodium chloride from urine, which yields urine far more concentrated than blood. Species from arid habitats show this most clearly: many desert species have highly efficient loops of Henle, and the kangaroo rat is often cited as an extreme example.\n\nSalt glands and marine adaptation\n\nAnimals that drink seawater face a salt problem that kidneys alone may not solve. Marine birds possess salt-secreting nasal glands that produce hypertonic sodium chloride solutions when they take in seawater. The secreted fluid is several times as concentrated as the most concentrated urine birds can produce. In an integrated system with the kidneys, marine and estuarine birds cannot survive without these glands. Salt glands are not limited to seabirds; functional salt glands have been documented in several terrestrial orders.\n\nComparisons among closely related ducks show how the two organs share the work. Barrow's goldeneye, the most marine species, has the highest rates of kidney filtration, tubular reabsorption and salt-gland secretion, and only it can secrete all the infused salt through its glands; the most freshwater species, the mallard, has lower rates for all three processes. Marine teleost fishes meet the same challenge at the gills, where excess salt is pumped out by a mechanism that is essentially the reverse of the one used by freshwater fish.\n\nOrigins of the nephron and early excretory systems\n\nExcretory structures appear in many invertebrates, but they are not kidneys in the vertebrate sense. Nephridia in some invertebrates are analogous to kidneys, yet they are not kidneys. Within vertebrates, the kidney is usually traced to fishes, where renal glomeruli and tubules evolved independently and later merged into a single functional unit. The earliest vertebrates, which descended from marine chordates, probably lived in fresh or slightly saline water. Some authors therefore argue that kidney features were refined in freshwater before marine fishes acquired them.\n\nHomer W. Smith, whose book From Fish to Philosopher framed much of twentieth-century renal evolution, proposed that the loss of valuable solutes such as sodium, potassium, glucose, and amino acids with the filtrate posed a problem for emerging life forms. In his view, kidneys developed a loop of Henle and linked it to the glomeruli to limit these losses. Smith's reconstruction was speculative, but it links filtration and reabsorption as a single evolutionary response to water and solute balance.\n\nComparative evidence and human water balance\n\nComparative physiology has informed the understanding of how mammals conserve water, including humans. The countercurrent arrangement of the loop, the collecting duct and the vasa recta explains how a medullary solute gradient is built, and desert mammals show the outer limit of that system. Humans share the mammalian pattern of kidney-centred osmoregulation, although their urine-concentrating capacity is more modest than that of the kangaroo rat. Birds and reptiles, which have different nephron arrangements, illustrate how alternative routes, such as salt glands and cloacal handling, can compensate when the kidney is limited."
    },
    {
      "heading": "Open problems and future directions",
      "text": "Whether the adult kidney can regenerate in a meaningful way is still unresolved. Mammalian kidneys do not generate new nephrons after birth, so nephrons lost to injury are not replaced. After acute tubular injury, surviving epithelial cells mainly repair the damage by spreading, dividing, and re-covering denuded tubules. When repair fails, the usual result is scarring (fibrosis) rather than restored architecture. Several groups have described progenitor-like cells in adult tubules and glomerular niches as possible therapeutic sources, but their identity, their in vivo contribution, and their ability to form functional nephrons remain contested. Current work therefore focuses on protecting surviving nephrons, on directing repair signalling, and on isolating or expanding progenitor-like cells. No regenerative therapy of this kind is clinically established.\n\nKidney organoids offer a laboratory route to the same goals. Different laboratories have been able to partially reproduce kidney organogenesis in a dish using human pluripotent stem cells, producing so-called kidney organoids. These structures contain self-organized nephron-like structures composed of early podocyte cell clusters connected to tubular structures expressing markers of proximal tubules, loops of Henle and distal tubules. Their main use so far is disease modelling. Introducing mutations linked to polycystic kidney disease or glomerulonephritis into healthy cells produced cyst formation in the first case and altered cell-to-cell interactions in the second, which could lead to leaky filters. Another group modelled a congenital nephrotic syndrome, identified defects in the slit diaphragm, and corrected the causative mutation. Because cells can be taken from a patient, reprogrammed, and differentiated, patient-specific renal disease features can be modeled in vitro. Organoids are also used for toxicity testing, for example by tracking injury markers after cisplatin exposure.\n\nThe limits are considerable. Current organoids resemble immature tissue, show limited vascularization, and do not have a functional glomerular filtration barrier. Their composition is also variable, and they lack an integrated urinary outflow system. Research on bioengineering approaches, such as microfluidic chips and bioprinting, aims to improve maturation and scalability.\n\nXenotransplantation of gene-edited pig kidneys has moved from animal and brain-dead donor studies into formal trials. The FDA approved the first clinical trials for kidney xenotransplantation in the U.S. in February 2025. Three programmes are running: one uses a kidney with ten gene edits, another pairs a single-edit kidney with thymus tissue, and a third uses a kidney with 69 edits. In a 2026 report in The Lancet, a 66-year-old recipient went 271 days without dialysis on a pig graft before receiving a human kidney, and the authors noted microvascular injury to the porcine kidney, which bears on immunosuppression, donor engineering, and monitoring. Early hyperacute rejection has been largely overcome through gene editing of donor animals, but the occurrence of accelerated rejection could pose significant limitations to the success of the procedure. Experts hope for approval within a decade. The ethical questions include the risk of transmitting animal viruses to recipients, animal welfare, informed consent, and whether xenografts should compete with human organs for allocation.\n\nImplantable or wearable artificial kidneys aim to replace dialysis machines. A bioartificial kidney pairs synthetic filtration membranes with living renal cells intended to reproduce reabsorptive, metabolic, and endocrine functions. Purely mechanical filters rely on passive physical filtration and cannot replicate the metabolic and endocrine functions of native kidneys. The best-known effort, The Kidney Project led by Shuvo Roy and William Fissell, has tested small prototypes in healthy pigs, and its filtration membranes are patterned from silicon using techniques borrowed from electronics manufacturing. Some designs are meant to run on the patient's own blood pressure, which removes the need for electrical pumps. The main obstacles are the supply of cells, immune isolation of transplanted cells, and long-term durability, including clotting and the survival of cells under high blood shear."
    }
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      "url": "https://britannica.com/science/loop-of-Henle"
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    {
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    {
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    {
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    {
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  ],
  "license": "https://creativecommons.org/licenses/by/4.0/"
}