13/09/2014. Body magnesium homeostasis. Hereditary Magnesium Deficiency - clinical perspecave. bone and sof Assues, intracellular compartments

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1 Body magnesium homeostasis Hereditary Magnesium Deficiency - clinical perspecave Dr. Karl P. Schlingmann Pediatric Nephrology University Hospital Münster Germany 12 mmol diet intesane stool 8 mmol extracellular fluid kidney bone and sof Assues, intracellular compartments urine 4 mmol QuesAon 1 Body magnesium homeostasis 12 mmol DistribuAon of magnesium in the human body Which of the following answers is correct? 1. only a minor poraon of body magnesium is present in bone diet intesane 25-33% S- Mg mmol/L 60% ionized 34% protein- bound 6% complexed Serum RBC 0.3% 0.5% RBC- Mg ~ mM Bone, Muscle, sof Assues 53% 27% 19% 2. intracellular magnesium is about 10 4 Ames lower than extracellular magnesium stool kidney 3. less than 1% of body magnesium is present in blood plasma 8 mmol FE 3-5% 4. the majority of plasma magnesium is complexed to phosphate, citrate or sulfate urine 4 mmol 1

2 Magnesium deficiency Magnesium deficiency - > which parameter is appropriate to indicate body magnesium deficiency??? - > serum magnesium - > intracellular magnesium - > urine magnesium excreaon (in relaaon to serum magnesium) - > urine magnesium excreaon during intravenous magnesium infusion (magnesium loading test) hereditary disorders" diabetes mellitus coronary heart disease asthma" S-Mg" Prevalence (S- Mg, as a funcaon of cut- off level used) - > Lasserre et al (Switzerland); n=1375, S- Mg <0.75mmol/l = 4.3% <50y, = 8.4% >50y - > Ehrlich 1997 (Germany); n=3894, S- Mg <0.76mmol/l = 4.15%, S- Mg <0.7mmol/l = 0.98% Gesamt-Mg" - > Syedmoradi et al (Iran); n=1558, S- Mg <0.75mmol/l = 4.6% - > Schimatschek et al (Germany); n=16.000, S- Mg <0.76mmol/l = 14.5% Magnesium deficiency EAology: - > insufficient intake with diet - > increased demand (stress, physical acavity, sport, pregnancy - > gastrointesanal disease (celiac disease, short gut, malabsorpaon syndromes) - > kidney disease - > diabetes mellitus CisplaAn Gentamycin Amphotericin B Foscarnet Drug- induced magnesium deficiency Cyclosporin A Tacrolimus Theophyllin Bisphosphonates - > alcohol abuse - > drugs Pentamidine Hydrochlorothiazide Furosemide - > hereditary disorders LaxaAves Proton pump inhibitors (PPI) 2

3 Clinical symptoms of magnesium deficiency Clinical symptoms of magnesium deficiency symptoms of moderate magnesium deficiency: lethargy, muscle weakness, dizziness, nausea, abdominal pain, vomiang symptoms of prolonged/severe magnesium deficiency: days: reduced urinary Mg excreaon weeks: nausea, vomiang, lethargy Months/years: paresthesia, muscle weakness seizures, cardiac arrythmia signs of increased neuromuscular excitability, tremor, carpopedal spasms, Muscle cramps (especially of calf muscles), tetany, scerebral seizures neuropsychiatric symptoms: distracaon, irritability, confusion, psychosis, depression, parkinsonism cardiac symptoms: QT- prolongaaon, premature contracaons, ventricular tachycardia, torsades- de- pointes associated/secondary electrolyte disturbances: renal Kpotassium and phosphate wasang, hypoparathyroidism, PTH- end organ resistance Increased risk for the development of metabolic syndrome exacerbaaon of asthma bronchiale and other atopic diseases? Hereditary Hypomagnesemia Case 1 3

4 Yousra and Mehdi A., born 1992 and 1995 Yousra and Mehdi A., born 1992 and > healthy parents of Moroccan descent, parental consanguinity (1st degree cousins), no family history of renal disease - > unevenoul pregnancy, birth at term - > at 2 and 4 years of age hospital admission for recurrent febrile urinary tract infecaons (E.coli) - > no vesicoureteric reflux in VCU - > Laboratory EvaluaAon: S- Calcium 2.23/2.40mmol/l, S- Mg 0.48/0.53mmol/l (S- Na, S- K, S- Cl, S- Po4 normal) S- CreaAnine 1.2/1.8mg/dl (~ <0.5mg/dl for age) PTH 136/418pg/ml (15-65) ph 7.37/7.24, HCO3 21.3/12.7mmol/l, SBE - 2.7/ > renal ultrasonography: bilateral nephrocalcinosis Yousra and Mehdi A., born 1992 and 1995 QuesAon 2 - > Laboratory EvaluaAon - Urine: hematuria, proteinuria (100mg/dL) Ca- excreaon = 0.21/0.28mmol/kg/day (<0.1) Ca/crea = 1.6/2.8mol/mol (age dependent, <0.9 to <1.5 ) FE- Mg = 11.8%/9.0% (3-5%, <1% during hypomagnesemia) citrate/crea = 0.09/0.02mol/mol (>0.25) - > body length ~ 3rd- 10th percenale What is the most likely diagnosis? 1. hypophosphatemic rickets with hypercalciuria (HHRH) 2. hypomagnesemia with secondary hypocalcemia (HSH) 3. familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) 4. autosomal- dominant hypocalcemia (ADH) - > no skeletal abnormaliaes 4

5 Yousra and Mehdi A., born 1992 and > FHHNC = Familial Hypomagnesemia with hypercalciuria and nephrocalcinosis - > MutaAonal Analysis: CLDN16 - His141Asp, homozygous H141D Yousra and Mehdi A., born 1992 and > Treatment: Mg- supplementaaon (Mg- Glutamate/- Citrate 0.5mmol/kg/day) Na- Bicarbonate (Buffering of metabolic acidosis) hydrochlorothiazide (1.5mg/kg/day, decrease of calcium excreaons) citrate (200mg/kg/day) (treatment of metabolic complicaaons of renal insufficiency) Ss! Claudin- 16 protein Yousra and Mehdi A., born 1992 and 1995 FHHNC - Familial Hypomagnesemia with hypercalciuria and nephrocalcinosis - > follow- up: Mehdi: - > ESRD 01/2000, hemodialysis - > renal transplant 10/2000, graf failure 01/ > 2nd renal transplant 10/ > BK nephropathy, chronic rejecaon, S- Crea ~3mg/dl Yousra: - > ESRD 05/2008, hemodialysis - > renal transplant (LRD) 02/ > recurrent UTI, actual S- Crea 2.4mg/dl Hypomagnesemia / Hypercalciuria / 30/30 100% Nephrocalcinosis Polyuria / Polydipsia 28/31 90% Incomplete drta 17/20 85% Hypocitraturia 12/15 80% Urinary tract infecaons 22/32 70% Nephrolithiasis 10/31 32% Chronic Renal Failure (CRF) 28/30 93% Hyperparathyroidism Eye involvement 8/31 26% 5

6 Development of chronic renal insufficiency / progression to end stage renal disease Calcium and magnesium reabsorpaon in the thick ascending limb (TAL) mtal mtal ROMK CaSR GFR ml/min/ 1.73m NKCC2 ClC age Tight Junctions FHHNC - Familial Hypomagnesemia with hypercalciuria and nephrocalcinosis Claudin- expression along the tubule CT PCT DCT CCD ctal Paracellin- 1/Claudin- 16 Claudin- 19 PST mtal OMCD Fs Ss STOP Fs 67 % of mutated alleles Ss Ss Marburg New Haven Fs FrameshiF Ss Splice- site Leu151Phe in 48% of mutated alleles Claudin 1 Claudin 2 Claudin 3 Claudin 4 Claudin 5 Claudin 7 Claudin 8 Claudin10 Claudin11 Claudin14 Claudin15 Claudin16 dtl atl IMCD Ca 2+ Cldn-10 Cldn-16 Cldn-3 Scaffolding Proteins Cldn-11 6

7 Pathophysiology of FHHNC FuncAonal characterisaaon of FHHNC mutaaons Wildtype function funcaon ParAal loss of funcaon Complete loss of funcaon Haisch et al, AJKD 2011 Claudin-16 function Konrad et al. JASN 2008 age at onset progression to end stage renal disease in FHHNC years 6 * 8 * * deltagfr (ml/min/1,73m CLCL PLPL CLPL 0 CLCL PLPL CLPL ANOVA, P < 0,025 ANOVA, P < 0,005 7

8 progression to end stage renal disease in FHHNC progression to end stage renal disease in FHHNC GFR PLPL CLPL CLCL GFR Partial Loss Complete Loss age age Genotype- Phenotype: Start of Dialysis End Stage Renal Disease 5y 10y 15y 20y 0% 3% 20% 25% (n=46) Case 2 7% 18% 54% 70% (n=23) (p < 0,05 at 15 yrs) Konrad et al. JASN

9 Tuana Z., born 2009 Tuana Z., born > healthy parents of Turkish descent, no known parental consanguinity, no family history of renal disease - > unevenoul pregnancy, birth at term - > at 11 weeks episode with muscle saffness and deviaaon of eyes - > admission to local hospital with emergency doctor - > admission status: stable vital signs, one short episode of focal seizure with spontaneous recovery, no neurological deficits, no signs of infecaon, temperature 37.2 C. laboratory evaluaaon: unremarkable infecaous parameters, normal values for glucose, total protein, liver enzymes, LDH, uric acid. Na 141mmol/l, K 4.1mmol/l, Ca 1.7mmol/l, Mg 0.18mmol/l. blood gases: ph 7.37, HCO3 18.5, BE 4.9, lactate 3.4mmol/l. endocrinology: PTH 3pg/ml. urine analysis: Ca/Crea 0.08mg/mg, FE- Mg 0.2%, (FE- Na 0.8%, FE- K 14%). renal ultrasonography without pathological findings. Tuana Z., born 2009 Tuana Z., born 2009 iniaal therapy: intravenous supplementaaon of magnesium and calcium laboratory evaluaaon afer intravenous therapy: Ca 2.4mmol/l, PTH 21pg/ml, Mg 0.84mmol/l. long term treatment with oral magnesium (~2mmol/kg/d) (RDA 0.25mmol/kg/d = 6mg/kg/d, adults ~300mg/d) - > summary of clinical and biochemical data: - > severe hypomagnesemia (<0.2mmol/l) - > hypocalcemia - > hypoparathyroidism - > urine excreaon of divalent caaons? laboratory evaluaaon under oral therapy: Ca 2.5mmol/l, PTH 36pg/ml, Mg 0.59mmol/l. urine electrolytes under oral subsatuaon: Ca/Crea 0.18mg/mg, FE- Mg 6.3%. 9

10 Tuana Z., born > Magnesium Loading Test Renal magnesium excreaon in relaaon to serum (UF) magnesium 100µmol/kg KG iv y=0.06x QuesAon 3 Hypomagnesemia with secondary hypocalcemia (HSH) What kind of disturbance in renal magnesium transport do you suspect? Prevalence: rare bei Manifestation Inheritance: autosomal recessive renal magnesium conservaaon is undisturbed 2. defecave magnesium reabsorpaon in the proximal tubule 3. defecave magnesium reabsorpaon in the loop of Henle Age at manifestaaon: 3 weeks to 10 months Symptoms at generalized seizures, manifestaaon: musclespasms, tetany Mg ++ Serum [mmol L -1 ] defecave magnesium reabsorpaon in the distal convolute Laboratory findings: extreme hypomagnesemia ( mmol/l), hypocalcemia, hyperphosphatemia, hypoparathyroidism 10

11 Hypomagnesemia with secondary hypocalcemia (HSH) Hypomagnesemia with secondary hypocalcemia (HSH) Prevalence: rare Inheritance: autosomal recessive 2.6 bei Manifestation Prevalence: rare Inheritance: autosomal recessive 80 bei Manifestation Age at manifestaaon: 3 weeks to 10 months Symptoms at generalized seizures, manifestaaon: musclespasms, tetany Ca ++ Serum [mmol L -1 ] Age at manifestaaon: 3 weeks to 10 months Symptoms at generalized seizures, manifestaaon: musclespasms, tetany PTH [pg/ml] Laboratory findings: extreme hypomagnesemia ( mmol/l), hypocalcemia, hyperphosphatemia, hypoparathyroidism Laboratory findings: extreme hypomagnesemia ( mmol/l), hypocalcemia, hyperphosphatemia, hypoparathyroidism Therapy: Mg ++ [mmol kg -1 d -1 ] Hypomagnesemia with secondary hypocalcemia (HSH) high dose magnesium supplementaaon iniaal/ acute therapy: usually iv subsatuaon maintenance therapy (livelong): oral magnesium supplementaaon main side effect: diarrhea QuesAon 4 Oral magnesium supplementaaon Which magnesium compound is thought to possess the highest bioavailability? 1. magnesium carbonate 2. magnesium oxide 3. magnesium sulfate 4. magnesium aspartate 0.5 RDA 11

12 Oral magnesium supplementaaon Hypomagnesemia with secondary hypocalcemia (HSH) Bioavailability of different magnesium salts (Ranade, Somberg Am J Ther 2001) A Serum and Ca 2+ during follow- up at under manifestaeon subsetueon 0.7 Goals of therapy: Mg ++ Serum [mmol L - 1 ] B Ca ++ Serum [mmol L - 1 ] at least subnormal serum normocalcemia, normal PTH normal physical and intellectual development 1.4 HSH pathophysiology QuesAon 5 kidney intesane oral magnesium supplementaaon in HSH 1. has no beneficial effect on serum Mg levels 2. increases intesanal Mg- uptake via the paracellular route y=0.06x acavates the transcellular pathway in the intesane 4. inhibits the calcium- sensing- receptor (CaSR) in kidney 12

13 intesanal magnesium absorpaon intesanal magnesium absorpaon kineacs kineacs K + ATPase Na +? Na + absorpaon total paracellular transcellular K + ATPase Na +? Na + absorpaon paracellular - uptake uptake intesane decreasing Serum- Mg during infancy serum (mmol/l) physiologic Range kidney TRPM6 age in months 13

14 Distal Convolute (DCT) Mitochondrial Hypomagnesemia = MTTI mutaaon => hypomagnesemia, hypertension, hypercholesterolemia Distal Convolute (DCT) SeSAME syndrome = KCNJ10 mutaaons => epilepsy, ataxia, deafness, Tubulopathy (Gitelman like) Gitelman Syndrome (GS) TRPM6 TRPM6 = SLC12A3 (NCCT) mutaaons => renal salt wasang, alkalosis, hypokalemia and hypomagnesemia Isolated dominant Hypomagnesemia (IDH) = FXYD2 mutaaons => hypomagnesemia, hypocalciuria, seizures at school age Isolated dominant Hypomagnesemia (IDH) = KCNA1 (Kv1.1) mutaaons Renal Cysts an Diabetes Syndrome (RCAD) => muscle cramps, tetany, myokymia hypomagnesemia, normocalciuria = HNF1ß mutaaons => glomerulocysac kidney disease plus MODY5 Hypo- Mg with secondary Hypo- Ca (HSH) = TRPM6 mutaaons => combined intesanal and renal Mg- AbsorpAon Defect Hypo- Mg with secondary Hypo- Ca (HSH) = TRPM6 mutaaons => combined intesanal and renal Mg- AbsorpAon Defect Hypomagnesemia with CNS involvement Isolated recessive Hypomagnesemia (IRH) = EGF mutaaons => hypomagnesemia, normocalciuria, seizures, mental retardaaon = CNNM2 mutaaons => hypomagnesemia, normocalciuria, seizures, mental retardaaon Diagnostic work-up of hereditary hypomagnesemia / NC >4mg/kg/d or >0.5mol/mol Crea hypocalcemia? hypomagnesemia? PTH ADH PTH FHHNC calcium excreaon? Hypocalciuria = <0.1mol/mol Crea hypomagnesemia/ salt wasang/ hypokalemia/ alkalosis? GS SeSAME hypo- magnesemia? IDH MTTI n hypo- magnesemia? TRPM6 EGF HNF1b KCNA1 Conclusions - > hereditary disorders of magnesium homeostasis comprise a heterogenous group of diseases affecang renal magnesium conservaaon in TAL or DCT - > geneac defects in TAL mediated magnesium transport lead to combined Ca and Mg wasang - > the CLDN16/CLDN19 genotype has a criacal influence on the clinical course - > paaents with a defect in DCT- mediated magnesium reabsorpaon might exhibit hypocalciuria as an addiaonal finding mtal DCT 14