INTEGRATED VIEW OF DISORDERS OF THE CA 2+ BALANCE: A CLINICAL PERSPECTIVE

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1 Nephrocalcinosis INTEGRATED VIEW OF DISORDERS OF THE CA 2+ BALANCE: A CLINICAL PERSPECTIVE John Sayer Senior Clinical Lecturer in Nephrology Generalised deposi8on of calcium in kidney parenchyma and tubules (may be molecular/microscopic/macroscopic) May cause AKI /CKD Renal medulla typically involved Caused by increase in urinary calcium, phosphate and/or oxalate May or may not be associated with nephrolithiaisis.nephrocalcinosis olen suggests a serious metabolic defect Histology von Kossa stain for calcium phosphate Risk factors hypercalcaemia, hyperphosphataemia, increased calcium, phosphate and /or oxalate in urine. Hypocitraturia Nephrocalcinosis Hypercalcaemia and hypercalciuria primary hyperparathyroidism Sarcoidosis Vitamin D therapy Milk Alkali syndrome Hypercalciuria (without hypercalcaemia) Distal renal tubular acidosis Medullary sponge kidney Inherited tubulopathies Hyperphosphaturia tumour lysis sydrome oral sodium phosphate bowel preps Inherited tubulopathies Hyperoxaluria Primary hyperoxaluria fat malabsorp8on Dent disease X linked disorder Hypercalciuria, nephrocalcinosis, kidney stones, renal failure and rickets (Wrong et al QJM 1994) CLCN5 ( Lloyd et al Nature 1996) and OCRL1 muta8ons (Dent- 2) (Hoopes et al 2005; Bockenhauer, 2012) CLCN5 encodes a chloride- proton an8porter (allows acidifica8on of endosomes), expressed in sub apical endosomes of proximal tubule, medullary TAL and type A intercalated cells of collec8ng duct. (Jentsch PNAS 1998, Nature2000) LMWP are freely filtered at glomerulus and adsorbed by proximal tubule via receptors (including megalin) and then endocytosed. Impaired endosomal acidifica8on leads to decreased recycling of endosomes and protein transloca8on. 1

2 Dent disease Proximal tubular func8on Glucose reabsorp8on Phosphate reabsorp8on LMWP reabsorp8on Amino acid reabsorp8on Dent disease Hypercalciuria in Dent disease Hyperabsor8on of calcium from GI tract + fas8ng hypercalciuria PTH (which is not endocystosed normally) acts on late proximal tubule to ac8vate PTH receptors leading to hyperphosphaturia and increase 1- alpha- hydroxyla8on of Vitamin D. J Clin Invest. 2005;115(8): Balance between loss of Vit D- bound to Vitamin D binding protein and PTH receptor ac8va8on Scheinman SJ. Hosp Pract 2000; 35:49 Dent disease Dent disease Clinical manifesta8ons Childhood polyuria, microscopic haematuria, asymptoma8c proteinuria, kidney stones. Symptoma8c disease confined to males. Low Molecular Weight proteinuria in males (and carrier females) Sub nephro+c protein excre+on 1-2g/day from early childhood (50% albumin) Other signs of proximal tubular dysfunc8on glycosuria, aminoaciduria and phosphaturia are variable. Hypercalciuria (un8l renal func8on declines) and nephrocalcinosis (in 75%) Renal stones in 50% VitaminD3 normal/elevated, serum calcium normal, PTH normal or low 66% of males develop CKD and progress to ESRD years of age 25% have rickets or osteomalacia. Urinary acidifica8on is usually normal. Diagnosis In a male Low- molecular- weight proteinuria (can test for beta- 2- microglobulin or re8nol- binding protein) (Anthony Nordon, Oxford (KI,2000) Hypercalciuria (4mg/kg body weight in 24h) Nephrocalcinoisis/nephrolithiasis/haematuria/hypophosphatemia/CKD Gene8c tes8ng CLCN5 and OCRL1 (similarity of phenotypes implicates OCRL in endocy8c pathways; OCRL interacts with clathrin and regulates vesicular transport) Differen8al diagnosis- other Fanconi disorders: cys8nosis, mul8ple myeloma, Chinese herbs, tubular toxins 2

3 Dent disease Treatment Akempt to reduce calcium excre8on Restrict dietary sodium intake Thiazide diure8c Case study 1 Stephen B Noted to be bow legged at 13 months of age Normal serum calcium, low serum phosphate, raised alkaline phosphatase Treated with average doses of Vitamin D (not Vitamin D resistant) Aged 3 years further inves8ga8ons revealed aminoaciduria (especially Lysine); urinary calcium 135mg/24 hr (NR upto 300); urinary phosphate 546 mg/24 hr Total vitamin D levels normal Family hx father raised alk. phosphatase, paternal uncle renal colic Renal impairment (CKD), USS nephrocalcinosis and renal biopsy showing tubular inters88al disease Case study 1 Stephen B 24 h urine calcium 6.2 mmol/24 h ( ) Urine calcium/crea8nine ra8on 0.79 (0-0.7) 24 h urine protein 4.98 g /24h Serum phosphates 0.9 mmol/l; 0.7 mmol/l; 0.96 mmol/l; 1.56 mmol/ l Urine phosphate 546 mg/24 h (NR upto 1000mg) Case study 1 Stephen B Review of imaging USS and CT renal bilateral renal calculi and nephrocalcinosis, bilateral renal cysts Is this Dent disease? 3

4 Is this Dent disease? Criteria LMW proteinuria; hypercalciuria; + one of nephrocalcinosis/stones/ hypophosphataemia/renal failure/aminoaciduria/rickets/n FH reviewed mother well, no symptoms Gene8c tests arranged. Is this Dent disease? Criteria LMW proteinuria; hypercalciuria; + one of nephrocalcinosis/stones/ hypophosphataemia/renal failure/aminoaciduria/rickets/n FH reviewed mother well, no symptoms Gene8c tests arranged. Muta8ons in CLCN5 detected Worried about renal failure in his son..what can you tell him? QuesJon #1 John Sayer Dent disease may cause the following: Thick ascending limb of loop of Henle A. Glycosuria B. Hypomagnesaemia C. Hypophosphaturia D. Medullary nephrocalcinosis E. Nephro8c range proteinuria 4

5 BarRer syndrome Autosomal recessive tubulopathy Hypokalemia, metabolic alkalosis, hypereninaemia, hyperplasia of juxtaglomerular apparatus (Barker Am J Med 1962), hyperaldosteronism (+/- hypomagnesaemia) Tubular defects mimic chronic loop diure8c inges8on BarRer syndrome Clinical manifesta8ons OLen presents in childhood and may be associated with Growth retarda8on, learning difficul8es Hypokalaemia Polyuria and polydipsia Normal/increased calcium excre8on Normal/decreased serum Mg May be polyhydramnios during pregnancy and prematurity Two pa8ents with neonatal Barker's syndrome described by Landau et al Am J Med Genet 1995; 59: Both pa8ents have the typical facial appearance with prominent forehead, triangular face, drooping mouth, and large eyes and pinnae. BarRer syndrome Renal prostaglandin E2 produc8on olen markedly elevated PGE2 s8mulates renin release from JGA cells NSAIDs can reverse this effect Presenta8ons of Barrter Antenatal polyhydramnios, premature birth, salt was8ng crises, hypercalciuria, impaired urinary concentra8on (NKCC2 and ROMK) Classic weakness and hypovolaemia in first years of life, less hypercalciuria (CLCNKB) Nephrocalcinosis in Barker syndrome Antenatal forms (NKCC2 & ROMK) nephrocalcinosis/calculi Classic Barker (CLCNKB) and BSND (Bartn) nephrocalcinosis /stones less prominent Type 5 Barker (CASR ac8va8ng muta8ons) leading to hypocalcaemia has normal/ raised urinary calcium but at risk of nephrocalcinosis with calcium/vitamin D replacement BarRer syndrome Gene8c subtypes Type I NKCC2/SLC12A1 Type II ROMK/KCNJ1 Type III CLCNKB (may also give Gitelman s phenotypes eg hypocalciuria) Type IV Bar8n and CLCKa/CLCKb associated with sensorineural deafness Type V CASR hypocalcaemia and mild Barker phenotype, alkalosis not seen Barker s mimics Aminoglycosides (eg gentamicin) ac8ng as calcimime8cs 5

6 BarRer syndrome Diagnosis Urine diure8c screen Urine chloride concentra8on (in BS is raised, >40mmol/l) Urine calcium excre8on Antenatal diagnosis (raised chloride in amnio8c fluid) BarRer syndrome Treatment NSAIDs and K- sparing diure8cs (spironolactone, amiloride) ACE inhibitors (low BP may limit use) K supplementa8on (+/- magnesium supplementa8on) Differen8al diagnosis Surrep88ous vomi8ng and surrep88ous diure8c use Case study 2 4 year old girl- presented with developmental delay and abnormal gait Below 3 rd cen8le for weight and height Parents reported polydipsia X- ray legs revealed rickets Serum biochemistry- hypocalcaemia (2.05 umol/l,, NR ), serum K , bicarbonate 30, Mg 0.68 mmol/l (NR ) Treated with Vitamin D supplements..developed hypercalciuria and evidence of nephrocalcinosis on renal USS. Treated with hydrochlorothiazide and potassium chloride. At 9 yrs of age renal func8on declined promp8ng renal biopsy Case study 2 Renal biopsy no glomerular lesions, mild inters88al infiltrate, occasional foci of calcifica8on Diagnosis?? Renin >50 nmol/l/h (NR )?Barker syndrome type 5 CASR gene screened, normal 6

7 Case study 2 Renal biopsy reviewed hyperplasia of juxtaglomerular apparatus QuesJon #2 John Sayer The following are characteris8cs of Barker Syndrome: A. Hyperkalaemia B. Hypomagnesuria C. Maternal oligohydramnios D. Metabolic acidosis E. Secondary hyperaldosteronism USS medullary nephrocalcinosis Barker genes sequenced compound het changes in KCNJ1 (ROMK1) Why hypocalcaemia? likely maternal and childhood vitamin D deficiency responded to Vitamin D treatment Thick ascending limb of loop of Henle Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis Autosomal recessive Hypercalciuria Presents in childhood or adolescence with symptoma8c hypocalcaemia. May be hypokalaemia Recurrent stones and nephrocalcinosis Progressive renal failure (with 2 decades), polyuria, polydipsia, haematuria, recurrent UTIs Muta8ons in CLDN16 encoding claudin- 16 (alias paracellin- 1) 8ght junc8on protein (Simon et al Science 1999) Muta8ons in CLDN19 encoding claudin- 19 (also have ocular involvement macular coloboma, nystagmus and myopia) (Konrad 2006 Am J Hum Genet) 7

8 Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis Treatment Thiazide diure8cs to reduce calcium excre8on Magnesium supplementa8on Vitamin D and calcium supplementa8on may be required Treat UTIs and stone episodes Case study 3 Large Qatari family Index case II:1 presented age 20 years of age with macroscopic haematuria Previous loin pain, renal stone disease and UTIs Biochemistry hypercalciuria (24 h Ca 9.83mol/day) hypomagesaemia (0.52 mmol/l) hypocalcaemia (2.11 mmol/l). PTH elevated pmol/l (NR 1.3-6) vitamin D low (39 nmol/l NR >75). Serum crea8nine 160umol/l (CKD 3). Case study 3 USS renal calcifica8on CT- nephrocalcinosis USS neck (?!) no parathyroid adenoma Other siblings reviewed Similar biochemisty II:11 presented age 17 months with UTI, USS kidney showed severe nephrocalcinosis Case study 3 Homozygous muta8on in CLDN16 gene Heterozygous carriers (father and sibs) may be hypercalciuric and exhibit renal stone forma8on Differen8al diagnosis autosomal dominant hypocalcaemia (ac8va8ng muta8ons in CASR) leads to hypocalcaemia with hypercalciuria. Hypomagnesaemia can be a feature, PTH is low- normal range 8

9 QuesJon #4 John Sayer Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis may cause the following: A. Childhood recurrent UTIs B. Central nervouw system calcifica8on C. Deafness D. Reduc8on in frac8onal excre8on of magnesium E. Unresponsiveness to thiazide diure8cs Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis may cause the following: A: Reduc8on in frac8onal excre8on of magnesium B: Childhood recurrent UTIs C: Central nervous system calcifica8on D: Deafness E: Unresponsiveness to thiazide diure8cs Distal convoluted tubule Gitelman syndrome Autosomal recessive Hypokalemia, metabolic alkalosis, hypomagnesaemia, hypocalciuria, normal BP (Thiazide diure8c treatment) Late childhood and adult presenta8on Symptoms (not benign) include Cramps, fa8gue, polyuria and nocturia Chondrocalcinosis Hypertension later in life 9

10 Gitelman syndrome (Trans Assoc Am Phys 1966) Muta8ons in SLC12A3 (NCCT) (Simon Nat Genet 1996) CLCNKB muta8ons can cause a Gitleman phenotype (expressed in TAL and DCT) (Simon Nat Genet 1997) Treatment of Gitelman syndrome Dietary foods that are high in salt, potassium and magnesium Potassium: SlowK and Kay- Cee- L Liquid are preferable to SandoK. Usually less symptoma8c if K >3. Magnesium: Magnesium lactate (MagTab SR), Magnesium glycerophosphate and Magnesium aspartate. Aim for Mg > 0.6 to minimise symptoms Angiotensin Conver8ng Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARB). EAST syndrome Rare autosomal recessive disorder Epilepsy, Ataxia, Sensorineural deafness and a Gitelman like Tubulopathy (hypokalaemia, hypochloraemia, metabolic alkalosis with hypomagnesaemia and hypocalciuria) (Bockenhauer NEJM 2009) Neuro manifesta8ons are severe (and primary rather than secondary to electrolyte disturbance) Muta8ons in KCNJ10 loss of electrical driving force for ion transport in DCT Hamilton K L, and Devor D C Am J Physiol Renal Physiol 2012;302:F1069-F1081 QuesJon #3 John Sayer All of the following are characteris8c of Gitelman Syndrome exept: A. Hypocalciuria B. Hypomagnesemia C. Hypotension D. Nephrocalcinosis E. Resembles treatment with thiazide diure8cs Gordon s syndrome Alias Pseudohypoladosteronism type 2/ familial hyperkalaemic hypertension (Gordon Aust Ann Med 1970; Gordon J Hypertenison 1988) Mirror image of Gitelman syndrome Hypertension/hyperkalaemia/metabolic acidosis/low- normal renin and aldosterone/hypercalciuria Caused by muta8ons in WNK kinases (WNK1 and WNK4) causing increased chloride reabsorp8on in distal nephron (increased expression of Na- Cl cotransporter in DCT) and K reten8on in CD (Wilson, 2001 Science) Normally WNK4 inhibits NCC and ROMK, mutated WNK4 increases NCC Muta8ons in WNK1 reduce inhibi8on of WNK4 Autosomal dominant Colic /stone forma8on may be presen8ng feature Treatment low dose thiazide diure8c and dietary salt restric8on 10

11 Case study 4 11 yr old male episodes of dizziness and muscle weakness Rou8ne bloods showed K 6.4 mmol/l Serum chloride 115 mmol/l (98-108) Serum bicarbonate 18 mmol/l (22-26) Systolic BP >95 th percen8le for age Renin 32 (5-47 uu/ml) Aldosterone 11 (3-28 ng/dl) Case study 4 Diagnosis Gordon syndrome Familial pakern of hyperkalaemia (mother, maternal grandmother) Muta8ons confirmed in WNK4 Treated with hydrochlorothiazide normalisa8on of all lab findings K 4.4, Cl 103, Bic 25 QuesJon #5 John Sayer All of the following are characteris8c of Gordon s Syndrome exept: A. Hypercalciuria B. Hyperkalaemia C. Hypotension D. Low frac8onal excre8on of sodium E. Responds to thiazide diure8cs Thank you for your arenjon 11

12 Claudin-14 Mouse fed high Ca diet upregulated Claudin-14 in TALH. (Gong, EMBO J 2012) Claudin 14 functions as a barrier for paracellular cation permeation:co-expression of claudin-14 with claudin-16 inhibits permeability of claudin-16 (Gong, EMBO J 2012) Claudin-14 blocks claudin-16 channel and phenocopies FHHNC Calcium Transport in the TALH Process of Calcium reabsorption in TALH is tightly regulated by CASR Loupy et al JCI 2012 & Dimke et al Am J Physiol 2013 CASR regulates Ca 2+ resorption through changes in paracellular permeabilities Claudin-1 6 & 19 _ CaSR Calcium Transport in the TALH Calcium Transport in the TALH CaSR Senses normal serum calcium CaSR Senses high serum calcium mir-9 & mi-r374 mir-9 & mir-374 down regulated 3 UTR Claudin-14 mrna 3 UTR Claudin-14 mrna mrna decay Claudin-16 mediated calcium reabsorption mrna decay Claudin-14 protein Reduced Claudin-16 mediated calcium reabsorption 12

13 Dent disease may cause the following: A: Medullary nephrocalcinosis B: hypomagnesaemia C: Hypophosphaturia D: Glycosuria E: Nephro8c range proteinuria The following are characteris1cs of Bar3er Syndrome A: Secondary hyperaldosteronism B: Metabolic acidosis C: Hyperkalaemia D: Maternal oligohydramnios E: Hypomagnesuria All of the following are characteris1c of Gitelman Syndrome except A: Nephrocalcinosis B: Resembles treatment with thiazide diurebcs C: Hypocalciuria D: Hypotension E: Hypomagnesemia Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis may cause the following: A: Reduc8on in frac8onal excre8on of magnesium B: Childhood recurrent UTIs C: Central nervous system calcifica8on D: Deafness E: Unresponsiveness to thiazide diure8cs 13

14 All of the following are characteris1c of Gordon s Syndrome except A: Hypercalciuria B: Responds to thiazide diurebcs C: Hyperkalaemia D: Hypotension E: Low fracbonal excrebon of sodium Note I haven t talked about CASR in collec8ng duct I haven t talked about hypocalciuric syndrome (enamel renal syndrome) FAM20A. Defect likely to be in inters88um rather than urine Integrated view of disorders of the Ca 2+ balance: Molecularly guided tour along the nephron René J.M. Bindels Department of Physiology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands. The kidney plays a crucial role in the maintenance of the body calcium balance. Ca 2+ is an essen8al ion in all organisms and par8cipates in a large variety of structural and func8onal processes. Of all Ca 2+ filtered by the glomerulus, the majority (99%) is reabsorbed. Reabsorp8on of Ca 2+ largely takes place through paracellular transport in the proximal part of the nephron (~70%) and the thick ascending limb (~25%). The final amount of Ca 2+ excre8on via the urine is determined in the distal part of the nephron, through a 8ghtly regulated process of ac8ve Ca 2+ reabsorp8on. Transcellular Ca 2+ transport is specifically located in the second part of the distal convoluted tubule and connec8ng tubule, also known as the distal convolu8on. This ac8ve transcellular transport is hallmarked by the apical transient receptor poten8al vanilloid 5 (TRPV5) epithelial Ca 2+ channel, regulated by an array of events, and mediated by hormones, including 1,25- dihydroxyvitamin D 3, parathyroid hormone, and estrogen. Once in the renal cell, Ca 2+ is buffered by the Ca 2+ - binding protein calbindin- D 28K and the complex diffuses intracellularly towards the basolateral side. Finally, Ca 2+ is extruded towards the blood compartment by the ATP- dependent Ca 2+ - ATPase and the Na + - Ca 2+ exchanger type 1. Novel molecular mechanisms have been iden8fied, such as the direct regulatory effects of klotho and 8ssue kallikrein on the abundance of TRPV5 at the apical membrane. The newly discovered mechanisms could provide poten8al pharmacological targets in the therapy of renal Ca 2+ was8ng. In the presenta8on a guided molecular tour along the nephron will be made detailing the contribu8on of the individual segments to the overall renal Ca 2+ handling. Integrated view of disorders of the Ca 2+ balance: a clinical perspec+ve John A Sayer Ins8tute of Gene8c Medicine Newcastle University, Newcastle upon Tyne, United Kingdom Renal calcium handling disorders manifest clinically in a wide spectrum of phenotypes. The specific phenotypes depend on the exact nephron segments that are affected. New insights into renal physiology and disease mechanisms have been gained by studying the clinical and molecular phenotypes of pa8ents with inherited tubulopathies which exhibit hypercalciuria or hypocalciuria. Gene8c disorders of calcium handling within the proximal tubule, thick ascending limb of the loop of Henle, distal convoluted tubule and collec8ng duct will be discussed in terms of their clinical presenta8on, biochemical profile and molecular gene8c defects. These will include Dent s disease, Barker s syndrome, Familial hypomagnesemia with hypercalciuria and nephrocalcinosis, Gitelman s syndrome and Gordon s syndrome. An integrated knowledge of clinical presenta8ons of these condi8ons alongside drugs and acquired condi8ons that may mimic them will allow beker recogni8on, understanding and treatment of these condi8ons. 14