Nephrology - Tubular disorders (not including RTA or stones) David Metz Paediatric Nephrology
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1 Nephrology - Tubular disorders (not including RTA or stones) David Metz Paediatric Nephrology
2 Bowman s capsule containing glomerular filtrate ACTION Uptake++ Fine tune Ca Mg Na Proximal convoluted tubule Distal convoluted tubule Create concentrated interstitium Mg and Ca uptake Collecting duct Water balance K secretion H secretion Loop of Henle (ascending and descending limbs, thick and thin)
3 "Renal Diuretics" by Haisook at en.wikipedia - Own workoriginally from en.wikipedia; description page is/was here.. Licensed under Creative Commons Attribution-Share Alike via Wikimedia Commons - al_diuretics.gif#mediaviewer/file:renal_di uretics.gif "Renal Diuretics" by Haisook at en.wikipedia - Own work
4 Transport mechanisms Transcellular Passive or active transporters Uniporter, cotransporter/symporter, exhanger/antiporter Facilitated diffusion (passive) along electrochemical gradients ATPases active transporters Secondary active favorable (chemical or electrochemical) gradient of 1 solute drives another (against unfavorable)
5 Transport mechanisms Channels Ion selective or non-selective Regulated by number of functional channels, and whether open or closed When open can see high rate of ion passage Paracellular route (through tight junctions, with segment specific ion selectivity) Endocytic receptors Substrates (or substrates bound to carrier proteins) endocytosed
6 Review of normal processes Glomerular filtrate (in Bowman s capsule) undergoes extensive reabsorption and exchange before final urine 99% of volume reabsorbed >99% of Na and Cl 85-95% K 95% Ca, 97% Mg, 80-95% Pi Reabsorption largely driven by Na reabsorption
7 Percentage Na reabsorption 8% Site of thiazide action 65% 25% Site of frusemide action 1.5% 0.5% left
8 PCT
9 Proximal tubule Lion s share of reabsorption (60% of glomerular filtrate) Most reabsorption is coupled to Na reclamation (applies to many segments of nephron) (low intracellular Na maintained by basolateral NaKATPase and Na-HCO3- cotransporter) All major solutes reabsorbed to some degree in PCT
10
11 Fanconi syndrome Generalized PCT defect Key = glucosuria, aminoaciduria, tubular proteinuria, hypophosphatemia, prta Also can see Na and K losses Na losses = hyponatremia, hypotension, dehydration, and secondary hypokalemia (RAAS activation) FTT (hypok, acidosis, hypopi) Polyuria/polydipsia/dehydration Osmotic diuresis from urinary solute losses, CD concentrating defect 2 hypokalemia Treat = treat cause, replace what s being lost
12 Causes Fanconi syndrome Genetic Cystinosis, Lowe s, galactosemia, tyrosinemia, Wilson s, HFI Toxin heavy metals, aminoglycosides, ifosfamide, mercaptopurine, multiple myeloma
13 Dent s disease X-linked PT dysfunction with LWM proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, progressive renal failure Concentrating defect (thus polyuria) Hematuria (likely from hypercalciuria/nc/stones) Can have broader PT dysfunction (renal fanconi) Aminoaciduria, phosphaturia (and rickets), glycosuria, uricosuria, kaliuresis, proximal RTA Orphanet Dx: LWMP, hypercalciuria, and at least one of NC, stones, hematuria, hypophosphatemia, progressive renal failure
14 Dent s: genetics 60% = Xp11.22 CLC-5 channel inactivation (voltage gated chloride channel) CLC-5 facilitates maximal acidification of endosomes 15% = OCRL1 gene also mutated in Lowe Syndrome (which includes cataracts, mental developmental delay, renal tubular acidosis)
15
16 Mechanism of abnormalities Proteinuria Proteins endocytosed in PCT Impaired endosomal acidification = impaired processing of proteins, and decreased recycling of endosomal membrane Hypercalciuria Related to hyperabsorption Ca at gut level Hyperphosphaturia / increased 1,25 D? Due to increased PTH at distal PCT (not endocytosed earlier)
17 Treatment DENT s For hypercalciuria Low NaCl diet Thiazides For bone disease Oral PO4 Vitamin D (watch U.Ca) Replacement of Na/K/H20 in more general PT dysfunction Progression to ESKD between 3 rd and 5 th decade in 30-80%
18 LOH
19 Loop of Henle Differential permeability to water, Na, Urea Generates hyperosmolar interstitium (and hypoosmolar filtrate) Ability of ascending limbs ability to reabsorb NaCl in excess of water (TAL selectively reabsorbs 25-35% of filtered NaCl without water)
20 Loop of Henle Countercurrent mechanism in LOH creates hypertonic medullary interstitium In TAL of LOH, NaCl driven into interstitium without H20 concentrated Allows for H20 reabsorption in collecting duct via aquaporin channels (into high concentration interstitium)
21 Salt-losing tubulopathies Frusemide = Bartter syndrome Thiazide = Gitelman syndrome Other diureticopathies Spironalactone = pseudohypoaldosteronis m 1 Amiloride Liddle
22 Bartter s 1:1,000,000 AR; four genetic variants Direct or indirect compromise of Na-K-2Cl co-transporter in TAL of LOH Defect of luminal NKCC2 Defect of luminal ROMK Defect of basolateral Cl channel ClC-ka or kb (or Barttin subunit)
23 Seyberth H et al, Bartter- and Gitelman-like syndromes: salt losing tubulopathies with loop or DCT defects, April 2011
24 Creates intracellular low Na, electronegative
25 Drives this Creates intracellular low Na, electronegative
26 K is recycled
27 Creates lumen positivity (K + Cl)
28 Creates lumen Positivity (K + Cl) Drives this Hence in some phenotypes also get Mg and Ca loss in urine hypomagnesemia, hypercalciuria + nephrocalcinosis
29 LOH Ca & Mg Ca and Mg transport = passive paracellular process driven by positive lumen potential Mediated by tight junctional permselectivity proteins claudin 16 (CLDN16) and claudin 19 (CLDN19) Also - basolateral CaSR activation of which inhibits Na transport (inhibits NKCC and ROMK) Thus decreased TTPG driving Ca and Mg reabsorption
30 Brenner: Brenner and Rector's The Kidney; 8th Edition
31 Bartter syndrome Defective NaCl uptake in LOH massive salt losses Wash out medullary concentration gradient Large increase in NaCl delivery to distal nephron (severe volume contraction if no compenstory mechanism seen in severe AN Bartter s) Compensation by RAAS activity Hyperplasia of JG apparatus and PG secretion Increased Na reabsorption in exchange for K/H-Cl excretion (hence hypokalemia) Ca/Mg losses (and nephrocalcinosis) in some phenotypes
32 Findings Hypokalemia, hypochloremic metabolic alkalosis Polyuria and isothenuria Hypercalciuria, hypomagnesemia (in some) High levels of some urinary prostaglandins (Hyper PG syndrome) High PRA and aldosterone
33 2 phenotypes Classic Bartter insidious onset early life FTT / longitudinal retardation Impaired ability to concentrate / dilute urine Polyuria, polydipsia, salt craving Prone to hypernatremic dehydration Constipation Severe antenatal / hyper PGE syndrome Severe AN salt wasting - polyhydramnios (with high chloride) +/- premature delivery Life threatening volume depletion (NaCl loss and polyuria) for a number of weeks (may not be hypokalemic initially - ROMK) After which classical Bartter constellation becomes evident
34 Calcium-sensing Receptor Mutation Potent gain of function CaSR mutation ( L125P) leading to autosomal dominant hypocalcaemia. Case described of this associated with Bartter-like syndrome (Vargas-Poussou et al, JASN 2002). Thakker 1999 NEJM p1177
35 DCT
36 Gitelman (DCT thiazide) DCT - minor capacity of salt reabsorption (8% cf 25%) Crucial role in fine-tuning of urinary calcium and magnesium excretion In Gitelman, more chronic solute imbalances similar to the effects of chronic treatment with thiazides. Increased apical Ca reabsorption and Mg loss (not well defined)
37 Percentage Na reabsorption 8% Site of thiazide action, Gitelman syndrome 65% 25% Site of frusemide action, Bartter syndrome 1.5% 0.5% left
38 Gitelman syndrome Present childhood or adolescence Less severe; usually N growth; salt craving, nocturia and paraesthesia Muscle cramps and tetany common; dizziness, jt pains, nocturia Biochemical: Mild hypokalemia & alkalosis Low serum Mg, low urine Ca Elevated PRA, normal aldosterone
39 Gitelman cf Bartter Very low U Ca calcium (cf. often elevated in BS) S Mg low, U Mg elevated Renin and aldosterone usually normal
40
41 Transporter / Pharm based (shows confusion)* Loop disorders (polyhydramnios; most = NC) L1 = (Type 1 Bartter) - NKCC2 (TAL) - frusemide L2 = (Type 2 Bartter) - ROMK (TAL/CCD) - frusemide/amiloride Combined (polyhydramnios) L-DC1 - ClC-Ka+b - TAL/DCT - frusemide-thiazide L-DC2 - (Type 4 Bartter) - Barttin (TAL/DCT) - frusemide/thiazide Sensorineural HL (Barttin subunit also on K-secreting cells of stria vascularis of inner ear) *Seyberth H et al, Bartter- and Gitelman-like syndromes: salt losing tubulopathies with loop or DCT defects, April 2011
42 DCT DC2 - (Gitelman Sx, 16q13) NCCT (NaCl cotransporter) - thiazide DC2 - (Type 3 Bartter, cbs) - ClC-Kb (Cl channel; DCT/TAL) - thiazide/frusemide Though can have polyhydramnios Only 20% have nephrocalcinosis
43 Seyberth H et al, Bartter- and Gitelman-like syndromes: salt losing tubulopathies with loop or DCT defects, April 2011
44
45 MANAGEMENT OF BARTTER SYNDROME NaCl, KCl, and water supplementation (titrated to response). NSAID (reduce hyperprostaglandin effeect) Indomethacin COX2 (eg celecoxib) Nutrition and fluids- Tube Care during illness/ surgery MANAGEMENT OF GITELMAN SYNDROME Normal diet. KCl supplementation +/- Mg as necessary. Rarely, Spironolactone.
46 DCT
47 Distal convoluted tubule Water impermeable furthers process of Na reabsorption and dilution of tubular urine Thiazide-sensitive Na-Cl cotransporter (NCC) NCC activity regulated by: distal Na delivery, aldosterone, WNK1 and WNK4 WNK1 and WNK4 mutations that upregulate NCC activity cause pseudohypoaldosteronism type 2 (familial hyperkalemic hypertension Gordon s) Less distal Na to aldosterone sensitive channels, intravascular NaCl excess K NCC defect (or basolateral Cl channel) Gitelman s, prior slides
48 DCT major distal site Ca/Mg reabsorption Calcium Luminal Ca entry (Ca selective TRPV5 channel) Basolateral Ca efflux through Ca-ATPases and Na-Ca exchangers Ca reabsorption regulated by PTH, calcitriol, ph, dietary Na intake and urinary excretion, thiazides (enhance Ca reabsorption by uncertain mechanism)
49 DCT major distal site Ca/Mg reabsorption Magnesium Main site of active regulated transcellular Mg reabsorption (10-15% of filtered load vs 70% in TAL) Luminal TRPM6/TRPM7 cation channel; regulated by luminal ph (acidosis = increased excretion) Unknown basolateral pathway (? Na-Mg exchange) Magnesium disorders discussed later
50 Luminal Ca channel Thiazidesensitive NaCl channel Luminal Mg channel Christov 2010, Am J Kidney Dis
51 Principal cells of collecting tubule ENaC Provides energy for ENaC Creates ve TEP for ROMK K + Na + ROMK Aldosterone increases number of open ENaC and number of Na-K- ATPase pumps ANP closes ENaC K-sparing diuretics close Na channels (amiloride, triamterene, spironalactone (competes with aldosterone))
52 CD
53 Connecting segment + collecting duct Completion of NaCl reabsorption Secrete K and H as required Concentrate urine (by reabsorption of H20)
54 Na reabsorption Connecting segment and CCD Luminal ENaC (epithelial Na channels) Regulated by aldosterone, inhibited by ANP (atrial natriuretic peptide) Activating mutations in ENaC Liddle Syndrome (monogenic HT) Inactivating mutation ENaC / aldosterone receptor Pseudohypoaldosteronism type 1 (salt wasting, hypotensive, hyperkalemia) ENaC Na transport leads to lumen-negative TEP Drives paracellular Cl reabsorption, K secretion (principal cells eg ROMK channel), H secretion (intercalated cells)
55 Chloride reabsorption Also two Cl transporters in CCD (B intercalated cells) Luminal exchange of HCO3 for Cl, in setting HCO3 load
56 K secretion / uptake Principal cell ROMK, K secretion (cortical and medullary collecting duct) ROMK affected by dietary K load, aldosterone, degree of lumen-negative electrical potential from ENaC mediated reabsorption, WNK1/4 Also K secretion by Ca-activated K channels of intercalated cell luminal membrane K reabsorption by H-K-ATPase of intercalated cell luminal membrane
57 Principal cells of collecting tubule ENaC Provides energy for ENaC Creates ve TEP for ROMK ROMK Aldosterone increases number of open ENaC and number of Na-K- ATPase pumps ANP closes ENaC K-sparing diuretics close Na channels (amiloride, triamterene, spironalactone (competes with aldosterone))
58 Principal cells of collecting tubule ENaC Provides energy for ENaC Creates ve TEP for ROMK K + Na + ROMK Aldosterone increases number of open ENaC and number of Na-K- ATPase pumps ANP closes ENaC K-sparing diuretics close Na channels (amiloride, triamterene, spironalactone (competes with aldosterone))
59 Distal RTA H+ secretion Another lecture
60 Water reabsorption Principal cells of cortical and medullary collecting ducts, inner medullary collecting duct cells ADH(vasopressin)-dependant water permeability, activated by luminal insertion of AQP2 water channels (aquaporin 2) ADH binds to vasopressin receptor V2R increases camp fusion of subluminal AQP2-bearing vesicles with the luminal membrane Water is then reabsorbed into hyper-osmolar medullary interstitium (created by LOH)
61 Tubular lumen Concentrated interstitium (hyperosmolar) AQP2 V2R ADH
62 Tubular lumen Concentrated interstitium (hyperosmolar) AQP2 Activates ADH V2R
63 Tubular lumen AQP2 Concentrated interstitium (hyperosmolar) ADH V2R
64 Tubular lumen H2O can now diffuse out following concentration gradient AQP2 ADH V2R Concentrated interstitium (hyperosmolar)
65 Nephrogenic DI Congenital rare XLR neph DI loss-of-function V2R mutations 90% of cases AR DI loss-of-function AQP2 mutations Acquired / secondary CKD, Obstructive uropathy, renal dysplasia, chronic pyelonephritis High Ca, low K Drugs lithium, tetracyclines
66 Congenital NDI From birth; breastfeeding may delay presentation (low solute) Dehydration, seizures, constipation, fever. Enuresis, nocturia. Mild FTT (? LOA due to fluid volumes required) Cognitive impairment (late presentation) Dx polyuria, Na, U. osm <200 (N>800)
67 Diagnosis of Polyuria Cause Onset P Na Max. Uosm with dehydration Central DI Usu Sudden Usu >143 Uosm after ADH % Uosm after ADH <300 >300 >50 Partial central DI Usu Sudden Usu >143 <600 > Nephrogenic DI Usu gradual Usu >143 <300 < Primary polydipsia Usu Gradual Usu < <9 Normal >800 >800 <9 Josh Kausman
68 Other tubular issues Calcium (covered in Endo talk) Magnesium Phosphate Acid handling (covered in acid-base talk)
69 Magnesium reabsorption 5-10% 15-20% Luminal Mg channel 65-75% Passive, paracellular, Claudin 16 (tight junction protein) 3-5%
70 TAL Ca&Mg paracellular diffusion driven by positive lumen potential (from K / Cl mvmt) Basolateral CaSR activation of which inhibits Na transport (inhibits NKCC and ROMK) Thus decreased TTPG driving Ca and Mg reabsorption
71 Mg channel in DCT
72 Claudin, loop of Henle Gut absorption Calcium sensing receptor abnormality HypoMg with abn NaCl transport
73
74 Symptoms of low Mg (general) Weakness, anorexia, tetany, +ve Trousseau and Chvostek, hypokalemia (needing Mg Rx to correct), hypocalcemia Apathy, delerium, coma Hypocalcemia and hypoparathyroidism (in severe Mg depletion) ECG changes ventricular arrythmias particularly during AMI / bypass
75 Symptoms Hypomagnesemia w/ 2 hypocalcemia <6m age with tetany, muscle spasms, sz Older: Clouded sensorium, disturbed speech, choreoathetoid mvmts Infantile isolated renal Mg wasting (dominant) Chondrocalcinosis Hypomagnesemia with hypercalciuria and nephrocalcinosis Rec UTI, polyuria/polydipsia, isosthenuria, renal stones FTT, vomiting, abdo pain, tetanic episodes, sz Hearing impairment, chondrocalcinosis, rickets, partial drta Ocular abnormalities
76 Calcium homeostasis Renal tubular Ca reabsorption: PCT-65%, TALH-20%, DCT-10%, CD-1.5% Ca reciprocal relationship with: Phosphate ph Symptoms common with or Ca levels
77 MJA 2004 p354
78 Phosphate homeostasis Level decreases with age When PTH and PO4 intake normal in N kidney 85-90% filtered PO4 reabsorbed 10-15% fractional excretion PO4 Measure TRP, TmP/GFR Derangements rarely cause clinical symptoms Chronic hypophosphatemia rickets
79 Rickets Calcipenic or Phosphopenic Calcipenic Vit D or Ca deficiency including poor absorption (antacids, PHT/PB, CF, hepatic insuff) Defective 1a-hydroxylase activity (VDDR type 1, or pseudovitamin D deficiency; AR) Normal 25 D, low 1,25 D 1,25-OH2 Vit D resistance (receptor defect, VDDR type 2; AR) Normal 25 D, very high 1,25 D
80 Phosphopenic rickets Renal phosphate wasting in PCT: Isolated renal PO4 wasting X-linked hypophosphatemic rickets AD hypophosphatemic rickets Oncogenic osteomalacia (tumour induced) Hypophosphatemic rickets with hypercalciuria High calcitriol, high U Ca excretion (cf above) Renal Fanconi (PO4 wasting plus aa, glucose, HCO3, Ca)
81 Renal PO4 wasting Reabsorption primarily in PCT Na-Phosphate co-transporters NaPi-2a and NaPi-2c (on luminal membrane) Major regulators of NaPi-2a and -2c PTH, dietary PO4 intake, FGF-23 (phosphatonin) (and to a lesser extent calcitriol) High FGF-23 or PTH leads to reduced PO4 reabsorption in PCT increased PO4 wasting into urine
82 Alizadeh Naderi A, Nature Reviews Nephrology 2010
83 Clinical In eg. XLH (most common) Progressive growth failure and bony deformities beginning first year of life (if untreated) Rachitic changes bowed legs, short stature, other (genu varum/valgum, metaphyseal widening, rachitic rosary, frontal prominence.
84 Oral phosphate and calcitriol Treatment (XLH) Phosphate in 4-5 spaced doses Increase as needed to see improved growth velocity (do NOT need to normalize s PO4) Rate limiter diarrhoea major issue Calcitriol required as Endogenous 1,25 (OH) Vit D suppressed by FGF-23 Needed for Absorption of PO4 Prevent secondary hyperparathyroidism (stimulated by episodes of low ionized Ca, from Ca-Pi complexing)
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