Anne-Lise Kamper Nefrologisk afdeling P Rigshospitalet Hvilke biokemiske variable anvendes i daglig klinisk praksis til vurdering af nyrefunktionen? Dansk Selskab for Klinisk Biokemi 27.03.2007 Anne-Lise Kamper Nefrologisk afdeling P Rigshospitalet Tak for invitationen Egen baggrund Nyrefunktionsundersøgelser gennemgået af Ulrik Gerdes, jeg vil komme ind på lidt detaljer for at kunne diskutere metoderne til vurdering af nyrefunktionen. Fokus på GFR markør, fordi de andre forstyrrelser ved nedsat nyrefunktion følger GFR, bedste mål for den samlede nyrefunktion. Groft sagt, ses disse forstyrrelser ved GFR < 30, fx anæmi

Indhold Nyrernes funktioner Patofysiologi Relevans af nyrefunktions-bestemmelse Undersøgelse af nyrefunktion i klinikken Proteinuri Mikroalbuminuri Nyrefunktion og kardiovaskulær sygdom Undersøgelse af tubulusfunktion

Nyrernes funktioner udskillelse af affaldsstoffer udskillelse af fremmede stoffer tilbageholdelse af stoffer regulering af salt- og vandbalance regulering af syre- og basebalance produktion af hormoner og enzymer nedbrydning af nogle proteiner Nyrerne er hovedansvarlige for fjernelse af så godt som alle naturlige affaldsstoffer, dvs. metaboliske slutprodukter. Det drejer sig især om urinstof (dannet fra aminosyrer), kreatinin (dannet fra musklernes kreatin), samt visse organiske syrer, herunder urinsyre. Også H+ må regnes til gruppen af affaldsstoffer, idet ikke-flygtige syrer, især svovlsyre, saltsyre og fosforsyre udgør en væsentlig del af de metaboliske slutprodukter. Herudover eliminerer nyrerne en række stoffer, der er fremmede for organismen, fx lægemidler og miljøgifte. Regulering af vand og saltudskillelsen formår at regulere volumen og sammensætning af legemets væskefaser. Andre organsystemer er også involveret i denne opgave: det kardiovaskulære system, endokrine organer og CNS. Disse udøver deres virkning ved at modificere nyrernes salt og vandudskillelse. Nyrerne sørger for ved reguleret udskillelse at holde indholdet af flere uorganiske ioner indenfor snævre grænser. Dette vanseliggøres ved at tilførsel og ekstrarenale tab kan variere stærkt. Det drejer sig om Na+, K+, Cl-, Ca++, Mg++, PO3',4. For visse stoffer som fx glucose er nyrens opgave at holde dem tilbage, undgå udskillelse. Organismen tillader kun en meget beskeden variation i ekstracellulærfasens H+ konc. Kroppens buffersystemer: lungerne og nyrerne udgør tilsammen et integreret forsvarssystem overfor pH forstyrrelser. Prostaglandiner, renin, EPo, 1,25 dihydroxy-cholecalciferol (den aktive form af vit. D) syntetiseres ud fra det i leveren dannede 25-OH-D3.

Nyrerne Ca 1 mill nefroner Stor blodperfusion Ultrafiltrat: GFR = 125 ml/min (180 l/døgn) Autoregulation af RBF og GFR i området 80–180 mmHg

Basale transportprocesser Karlsen FM: Basal nyrefysiologi

Ændringer i plasmakoncentrationer ved kronisk nyreinsufficiens plasmaconcentration glomerulær filtration b. tubulær adaption c. komplet adaption Normal- område Karlsen FM: Basal nyrefysiologi

Nyrepatofysiologi svigt af ekskretorisk funktion  ophobning af stofskifteprodukter  uræmi svigt af regulatorisk funktion  acidose, overhydrering, hyperkaliæmi, hyperfosfatæmi, hypertension svigt af endokrin funktion  anæmi, calciumfosfatforstyrrelser svigt af filtrationsbarrieren  proteinuri ???  arteriopati

Nyresyge patienter

Hvorfor er bestemmelse af nyrefunktionen af betydning? Diagnostik af nyresygdom, primær eller sekundær Kontrol af kronisk nyresygdom Vurdering af intervention, fx medicin, nyretransplantation Dosering af lægemidler, fx digoxin, gentamycin Identifikation af risikopatienter, fx for rtg.kontrast Diagnostik af toksisk renal påvirkning, fx ved kemoterapi Risikofaktor for kardiovaskulær sygdom og komplicerede behandlingsforløb Morfin: ophobning af aktiv metabolit, ændret proteinbinding Aminoglykosid: nefrotoksisk Digoxin: dosisreduktion Metformin: laktatacidose

Nyrens ekskretoriske funktion Clearancerenal = udskilt mængde pr. tidsenhed/p-konc. Glomerulær filtrationshastighed (GFR): Inulinclearance 51Cr-EDTA clearance P-creatinin, P-karbamid Estimeret creatininclearance, nomogram Endogen creatininclearance, døgnurinopsamling S-Cystatin C Estimeret GFR vha p-creatinin eller p-cystatin C, beregning , Fractionel clearance: clearance i % af GFR, eks. FENa

Vurdering af nyrefunktionen i klinikken Hvad gør nefrologer? P-creatinin, p-karbamid, hgb, p-albumin, p-Na, p-K, p-Ca, p-fosfat, PTH, p-urat Creatininclearance, sjældent Cr-EDTA clearance Hvad skal vi vælge og hvornår?

Vurdering af ekskretorisk nyrefunktion Pt 1 Pt 2 Pt 3 Pt 4 Pt 5 Alder (år)/køn 70 k 53 m 83 k 47 k 32 m Vægt (kg) 65 83 55 40 105 GFR (ml/min) 14 12 16 36 130 Ccreat (ml/min)* 14 10 9 42 120 P-creat (μmol/l) 397 856 230 118 160 * Gennemsnit af 3 døgnurinopsamlinger Normalværdier: GFR 70 – 140 ml/min. p-creatinin 60-130 mol/l for mænd, 40-110 mol/l for kvinder OBS muskelmasse Enkelt bestemmelse af nyrefunktionen

Plasma-creatinin Problemer: P-creatinin (mg/dl) Problemer: Non-lineær relation mellem GFR og plasmacreatinin Afhængighed af muskelmassen Øges efter indtagelse af langtidskogt kød det lilla felt: nedsat inulinclearance, men normal p-creatinin Inulinclearance (ml/min per 1.73 m2)

Endogen creatininclearance Creatininclearance (ml/min per 1.73 m2) Problemer: Ekstrarenal creatininclearance Tubulær creatininsekretion Unøjagtig urinopsamling Lilla felt: nedsat GFR, men normal creatininclearance GFR (ml/min per 1.73 m2)

Estimeret GFR baseret på p-creatinin Nomogram Cockroft og Gaults beregning: C creat = (140 - alder x vægt / p-creat i μmol/l) x k, hvor k er 1,25 hos mænd og 1,03 hos kvinder MDRD beregningerne …og mange flere Cockroft og Gault var primært udviklet til estimering af creat.clear., er siden valideret overfor GFR (Nefron 1976) Børn: Schwartz, Counahan-Barratt The MDRD Study equation was derived from primarily white subjects who had nondiabetic kidney disease, with mean GFR of 40 mL/min per 1.73 m2. Subsequently, there has been extensive evaluation of the performance of the equation in other populations including African Americans, Europeans, and Asians with non-diabetic kidney disease, diabetic patients with and without kidney disease, patients with liver disease, kidney transplant recipients, and potential kidney donors [19,32-51]. The following illustrate some of these important observations: Lidt om MDRD studiet, pt. Antal, inklusionskriterier.

K/DOQI Clinical practice guidelines for CKD. V. Evaluation of laboratory measurements for clinical assessment of kidney disease. Guideline 4

Abbreviated MDRD formel Er ikke egnet til beregning ved sengekanten

Estimering af GFR: MDRD baseret - validering K/DOQI Clinical practice guidelines for CKD. V. Evaluation of laboratory measurements for clinical assessment of kidney disease. Guideline 4

Validering af metoder til estimering af GFR MDRD anbefales af amerikanske guidelines

Predictive performance of renal function equations for patients with chronic kidney disease and normal serum creatinine levels. JASN 2002; 13: 2140 P-creat < 1.5 mg/dl Vurderes suboptimale Mdrd mest precise, men høj biased Mest accurat cockroft Anbefaler endogene eller exogene filtrationsa makører Ritz N=109

Case: 79-årig kvinde indlagt med pneumoni Case: 79-årig kvinde indlagt med pneumoni. Immobil i flere år, kørestolsbruger/sengeliggende. Vægt 99 kg, højde 162 cm, p-alb 33 g/l Endogen Ccrea 42 ml/min Estimeret GFR: Nomogram: 84 ml/min Gockroft & Gault: 81 ml/min MDRD: 67 ml/min G&G 96ml/min overfladekorr. 65 ml/min MDRD overfladekorr 54 ml7min MDRD 7 hvor p-alb pg p-karb indgår

Kvinde 80 år, p-creat 80 mol/l Vægt 100 kg vs. 60 kg Nomogram creatininclearance. Vægt og alder opsøges på de to akser og forbindes. Skæringsounktet R afmærkes. En ret linje mellem denne afmærkning og den aktuelt bestemte s-kreatinin på den højre akse vil give et rimeligt estimat for endogen kreatininclearance på aksen til venstre Kvinde 80 år, p-creat 80 mol/l Vægt 100 kg vs. 60 kg Kampmann J et al. Acta Med Scand 1974

Estimeret GFR baseret på p-creatinin The MDRD study equation is reasonably accurate in non-hospitalized patients known to have CKD, regardless of diagnosis The MDRD study equation and Cockcroft-Gault equation appear to be somewhat less accurate in obese individuals The MDRD study equation and Cockcroft-Gault equation may not be similarly accurate in different age groups The MDRD and the Cockcroft-Gault equations are less accurate in populations with normal GFR Among recipients of renal allografts, there have been variable results related to the accuracy of the MDRD and other estimation equations Estimation equations may be less accurate in populations of different ethnicities and from outside of the United States The following illustrate some of these important observations In a large study based upon the Third National Health and Nutrition Examination Survey (NHANES III), the abbreviated MDRD formula and the Cockcroft-Gault equations provide similar values within a wide-range of patient ages, which were consistent with age-specific historic inulin clearance values [53]. However, the Cockcroft-Gault equation provided higher estimates at younger ages, and lower estimates at older ages (eg, greater than 70 years of age) than that obtained with the simplified MDRD study equation. As an example, in a retrospective study of healthy potential kidney donors, the MDRD formula underestimated the measured GFR (iothalamate clearance) by 9 to 29 percent [32]. This was illustrated in a prospective study of 95 consecutive kidney transplant recipients with stable function, the GFR as measured by (99m)Tc-DTPA clearance was compared with the Cockcroft-Gault and several MDRD equations [46]. Accuracy within 50 percent of measured GFR was 91, 83, and 56 percent for the six variable MDRD, abbreviated MDRD, and Cockcroft and Gault equations, respectively. Although the MDRD equation has limitations in transplant recipients, most experts use the abbreviated formula in this setting. Available data suggest that these equations overestimate GFR in Asian populations, possibly related to differences in body mass and diet

Akut nyreinsufficiens Stigning ved ophævet nyrefunktion, GFR= 0: P-creatinin 100-150 umol/døgn P-carbamid 10-15 mmol/l/døgn Dvs. parametrene kan ”snyde” i den tidlige sygdomsfase

Case – akut nyreinsufficiens 66-årig mand indl. akut 16.3.07 af egen læge pga. nydiagnosticeret svær nyreinsufficiens. 14.03.07 kl 8 p-creat 704 umol/l 16.03.07 kl 20 p-creat 1162 umol/l 17.03.07 p-creat 1353 umol/l Start af HD den 17.3. Anti GBM pos, Good Pasture Syndrom

Biokemisk bestemmelse af GFR Behov for bedre markører Screening Den akut syge patient Den akut nyresyge patient Vi klarer os rimeligt ved kronisk nyreinsufficiens

Forudsat konstant dannelse

Genet er kortlagt Antaget at have alle egenskaber for en ideel GFR markør: Uafhængig af muskelmasse,, køn, frit filtrerbar Proteinase inhibitor Publiceret talrige arbejder.

Nyredonorer 15 donorer Før, 5, 12, 26, 54 dage efter donornefrektomi S-Cys C 15 donorer Før, 5, 12, 26, 54 dage efter donornefrektomi GFR GFR faldt fra median 93 til 61 på 5.dag (p<0.001 S-Cys c steg fra 0,79 (0.04-1.04) til 0.98 mg/l på 5. dag (p<0.002) P-creat steg fra 77 til 116 umol/l (p<0.002). Efter 5. dag var der ingen signifikante ændringer Ref cys c 0,54-1,21 Erlandsen et al. P-creat

S-cystatin C - observerede ekstra-renale påvirkninger HIV infektion Melanom Behandling med steroid Ekstraenal clearance Thyroidea-funktion Alder, køn, vægt, højde, rygning, CRP A solid-phase ELISA for determining human serum cystatin C is described. In 50 normal samples, cystatin C concentration was 1247 mg/L, which was in agreement with previously reported levels. Serum levels of cystatin C and b2-microglobulin (b2-M) were investigated in a time-course study during the development of HIV infection. A persistent and uniform increase in the b2-M concentration (2762 mg/L) was found. In contrast to b2-M, on the basis of cystatin C levels, 2 distinct populations were found, one of which demonstrated an increased concentration (1620 mg/L). Interestingly a 2nd group (21% of patients) exhibited an initial significant decrease in cystatin C concentration with a mean value of 377 (range 55-850) mg/L, followed by an increase. The biphasic pattern of cystatin C serum, a major cysteine proteinase inhibitor, during the course of HIV infection suggests a possible role for these proteinases (or proteinase inhibitors) in the development of this syndrome. However, significantly higher cystatin C concentrations were found in asthmatic patients compared to controls which suggests its role in the pathogenesis of asthma. Methylprednisolone increased and cyclosporin A decreased serum cystatin C concentrations after 1 week of therapy. Additionally these results support the need for the evaluation of cystatin C as a marker of glomerular filtration rate determination in asthma. Cystatin C has been proposed as an endogenous marker for measuring glomerular filtration rate (GFR) and is regarded as being equivalent to or better than creatinine. However, there are no published data on the production rate (Cys(pr)) or on the non-renal clearance of cystatin C (CL(nr)) in humans, which are essential parameters for GFR calculation. GFR was determined by measuring the plasma clearance of iohexol. Cystatin C, creatinine, urea and albumin were determined on the same serum samples as iohexol; 381 patients with a GFR range of 12-151 ml/min/1.73 m2, and 70 patients on haemodialysis were evaluated. Renal clearance of cystatin C (CLr) equals GFR * S (the sieving coefficient). Plasma clearance (CL) = CLr + CLnr. The relationship between Cys(pr) and the elimination rate (CL * serum-cystatin C) can be expressed as Cys(pr) = (S * GFR+CLnr) * serum-cystatin C. Assuming that the unknown values of Cys(pr) and CLnr are independent of GFR, the equation can be solved from GFR (iohexol clearance) and serum cystatin C (s-Cys) patient data. For S=1, we found Cys(pr) = 0.124 +/- 0.023 mg/min/1.73 m2 and Cl(nr)=22.3 ml/min/1.73 m2. For S = 0.94, found in rats, the values will be Cys(pr) = 0.117 mg/min/1.73 m2 and Cl(nr) = 21 ml/min/1.73 m2 and S-Cys in 70 patients on chronic haemodialysis was found to be 5.74 +/- 1.15 mg/l, in agreement with a calculated value of 5.56 mg/l (s-Cys=124/22.3) for GFR=zero. The mean value of the calculated Cl(nr) for the 70 patients was 22.7 +/- 6.6 ml/min/1.73 m2, which confirms the calculated level and indicates its biological variation. We thus propose the following formula for calculating GFR using the values found for CLnr and Cys(pr) in this study: GFR=124/s - Cys - 22.3 ml/min/1.73 m2, where serum cystatin C concentration is given as mg/l. A review. Glucocorticoid medication in adult renal transplant patients is associated in a dose-dependent manner with increasing cystatin C, leading to systematic underestimation of glomerular filtration rate (GFR). This does not preclude the use of cystatin C in detecting impaired renal function in renal transplant patients with glucocorticoids, because cystatin C was found to be significantly more accurate in detecting impaired renal function in this patient group. Further, data indicate the need for specific reference intervals in patients on glucocorticoid therapy. Conclusion   Thyroid dysfunction has a major impact on CysC levels. Therefore, thyroid function has to be considered when CysC is used as a marker of kidney function. In contrast to creatinine concentrations, CysC levels are lower in the hypothyroid and higher in the hyperthyroid state as compared with the euthyroid state. Background   It is well known that serum creatinine may be used as a marker of renal function only if taking into account factors that influence creatinine production, such as age, gender, and weight. Serum cystatin C has been proposed as a potentially superior marker than serum creatinine, because serum cystatin C level is believed to be produced at a constant rate and not to be affected by such factors. However, there are limited data on factors that may influence serum cystatin C levels, and there are limited data comparing cystatin C-based estimates of renal function with creatinine-based estimates that adjust for such factors, especially in individuals with normal, or mildly reduced, renal function. Methods   This was a cross-sectional study of 8058 inhabitants of the city of Groningen, The Netherlands, 28 to 75 years of age. Serum cystatin C and serum creatinine levels were measured, and creatinine clearance was determined from the average of two separate 24-hour urine collections. We performed multivariate analyses to identify factors independently associated with serum cystatin C levels after adjusting for creatinine clearance. Then, partial Spearman correlations were obtained after adjusting for factors that may influence serum cystatin C and creatinine levels. We also compared the goodness-of-fit (R2) of different multivariate linear regression models including serum cystatin C level and serum creatinine level for the outcome of creatinine clearance. Results   Older age, male gender, greater weight, greater height, current cigarette smoking, and higher serum C-reactive protein (CRP) levels were independently associated with higher serum cystatin C levels after adjusting for creatinine clearance. After adjusting for age, weight, and gender, the partial Spearman correlations between creatinine and, respectively, serum cystatin C level and serum creatinine level were -0.29 (P < 0.001) and –0.42 (P < 0.001), respectively. The R2 values for serum cystatin C level and serum creatinine level adjusted for age, weight, and gender were 0.38 and 0.42, respectively. The addition of cigarette smoking and serum CRP levels did not improve the R2 value for the multivariate serum cystatin C-based model.   Serum cystatin C appears to be influenced by factors other than renal function alone. In addition, we found no evidence that multivariate serum cystatin C–based estimates of renal function are superior to multivariate serum creatinine-based estimates. Keywords: serum creatinine, serum cystatin C, creatinine clearance, renal function measurement, PREVEND

Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement Kidney International, Vol. 65 (2004), pp. 1416–1421

Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement Efter korrektion for creatininclearance

Kidney function and markers of inflammation in elderly persons without chronic kidney disease: The health, aging, and body composition study Inflammatory markers are elevated in persons with estimated glomerular filtration rates less than 60ml/min/1.73m2. As cystatin C may detect small changes in kidney function not detected by estimated glomerular filtration rate, we evaluated the association between cystatin C and serum markers of inflammation in older adults with estimated glomerular filtration rate X60. This is an analysis using measures from the Health, Aging, and Body Composition Study, a cohort of well-functioning adults aged 70–79 years. Cystatin C correlated with all five inflammatory biomarkers: C-reactive protein (r¼0.08), interleukin-6 (r¼0.19), tumor necrosis factor a (TNF-a) (r¼0.41), soluble TNF receptor 1 (STNF-R1) (r¼0.61), and soluble TNF receptor 2 (STNF-R2) (r¼0.54); Po0.0005 for all. In adjusted analyses, cystatin C concentrations appeared to have stronger associations with each biomarker compared with estimated glomerular filtration rate or serum creatinine. Participants with a cystatin CX1.0mg/l had significantly higher levels of all five biomarkers compared to those with a cystatin Co1.0 (mean differences ranging 16–29%, all Po0.05). Cystatin C has a linear association with inflammatory biomarkers in an ambulatory elderly cohort with estimated glomerular filtration rates X60; associations are particularly strong with TNF-a and the STNF-R. Kidney International (2007) 71, 239–244. doi:10.1038/sj.ki.5002042; Kidney International (2007) 71, 239–244.

N=460 ● raske (n=50) ○ nyresyge (n=204) X transplanterede n=206) STOR spredning Figure 1 | Relationship between (a) cystatin C or (b) serum creatinine and measured GFR (iothalamate clearance) in 460 patients on a logarithmic scale. The closed circles represent healthy persons (n¼50). The open circles represent patients with native kidney disease only (n¼204). The crosses represent patients with solid organ transplants (n¼206). The regression lines for all three patient groups (native kidney disease, transplant recipients, and healthy) are shown. For (a) cystatin C, the regression lines represent GFR prediction equations for patients with native kidney disease (equation (1)) and transplant recipients (equation (3)). Glomerular filtration rate (GFR) estimates from serum creatinine has not been generalizable across all populations. Cystatin C has been proposed as an alternative marker for estimating GFR. The objective of this study was to compare cystatin C with serum creatinine for estimating GFR among different clinical presentations. Cystatin C and serum creatinine levels were obtained from adult patients (n¼460) during an evaluation that included a GFR measurement by iothalamate clearance. Medical records were abstracted for clinical presentation (healthy, native chronic kidney disease or transplant recipient) at the time of GFR measurement. GFR was modeled using the following variables: cystatin C (or serum creatinine), age, gender, and clinical presentation. The relationship between cystatin C and GFR differed across clinical presentations. At the same cystatin C level, GFR was 19% higher in transplant recipients than in patients with native kidney disease (Po0.001). The association between cystatin C and GFR was stronger among native kidney disease patients than in healthy persons (Po0.001 for statistical interaction). Thus, a cystatin C equation was derived using only patients with native kidney disease (n¼204). The correlation with GFR (r2¼0.853) was slightly higher than a serum creatinine equation using the same sample (r2¼0.827), the Modification of Diet in Renal Disease equation (r2¼0.825) or the Cockcroft–Gault equation (r2¼0.796). Averaged estimates between cystatin C and serum creatinine equations further improved correlation (r2¼0.891). Cystatin C should not be interpreted as purely a marker of GFR. Other factors, possibly inflammation or immunosuppression therapy, affect cystatin C levels. While recognizing this limitation, cystatin C may improve GFR estimates in chronic kidney disease patients. Kidney International (2006) 69, 399–405. doi:10.1038/sj.ki.5000073 KEYWORDS: serum creatinine; serum cystatin C; glomerular filtration rate; Kidney International (2006) 69, 399–405.

Can Cystatin C Replace Creatinine to Estimate Glomerular Filtration Rate? A Literature Review American Journal of Nephrology 2007;27:197-205

Forskellige materialer, forskellige formler, ikke konsistente resultater, små materialer

Kronisk nyresvigt i Danmark Incidens: 63/mill i 1990  121/mill i 2005 Diabetisk nefropati: 161:666 (24%) i 2005 Alder: 61% > 60 år i 2004 Prævalens af kronisk dialyse: 1054 i 1991  2536 i 2005 Mortalitet ved kronisk dialyse: 14-21% Transplanterede: 1649 i 2004 The data in Denmark are: The incidence of tratment for ESRD in Denmark has increased from around 60 per mill inhabitants in 1990 to around 120 per mill in the last 5 years? Thus we had 666 new patients in 2005. The main reason for this increase is that treatment is offered to older patients and patients with comorbidity The most common cause of ESRD is diabetic nephropathy. Interestingly the incidence of end-stage diabetic nephropathy has been stable during recent years. The mean age is . 21% af den danske population er > 60 år. The dialysis population has increased from 1054 in 1991 to 2536 in 2005, the increase has been rather small in the last years The mortality in dialysis patients is very high: 14% in peritoneal dialysis and 21% in hemodialysis (these patients are generally older and more ). Mortalitet for transplanterede: 3,3% Dansk Nefrologisk Selskabs Landsregister

Kronisk nyresvigt i DK 2005 (n=666) % Herhjemme udgør de vaskulære sygdomme, herunder nefrosclerose, knapt 15%............

Sygdomsforløb ved progredierende kronisk nyreinsufficiens GFR Fald i GFR med konstant hastighed, som er individuel dialysegrænse år 0 5 10

Udviklingen i p-creatinin ved progredierende kronisk nefropati

Symptomer ved kronisk nefropati Klinik GFR p-creatinin Fund (ml/min) (v. 65 kg) ________________________________________________________________________________________ let 30-59 170 mol/l hypertension nyreinsufficiens sec. hyperparathyreoidisme moderat 15-29 350 - + anæmi, træthed nyreinsufficiens svær <15 700 - vand-saltretention nyreinsufficiens gastro-intestinal og hudsympt. nyresvigt <5 1500 - lungeødem, coma acidose, hyperkaliæmi mors Normalværdier: GFR 70 – 140 ml/min. p-creatinin 60-130 mol/l for mænd, 40-110 mol/l for kvinder

Tab af barrierefunktionen: proteinuri Mangel på plasmaproteiner Vand og salt-retention: ødemtendens Ofte normal nyrefunktion Man skelner egentlig mellem glomerulær, tubulær, og overflow proteinuri. De svære proteinurier som her er glomerulære.

Filtrationsbarrieren Består af: 1. Endothelceller 2. Basalmembran (porøs) 3. Processer fra podocytter Negativt ladede glykoproteiner findes på alle overflader Størrelse og ladning er afgørende for hvilke molekyler, der passerer

Hvorfor er bestemmelse af proteinuri og mikroalbuminuri af betydning? Diagnose ved nyresygdom Risiko for udvikling af diabetisk nefropati Kontrol af behandlingsforløb Prognose for nyresygdom Risiko for komplikationer til svær proteinuri Risiko for kardiovaskulær sygdom Mikroalbuminuri som begreb stammer fra diabetologien, betegner forstadiet til den diabetiske nyresygdom

Proteinuri og mikroalbuminuri Proteinuri: stix positiv = over 3-500 mg/d Klinisk betydende proteinuri: over 2 g/d Mikroalbuminuri: 30-300 mg/d eller øget albumin/kreatinin ratio i spoturin Hvordan skal det undersøges?

Proteinuri Golden standard: albumin, protein i døgnurin Optimal beregning: fraktionel protein clearance: U-prot konc x p-creat / p-prot x U-creat konc I praksis: Urin stix, hvis positiv: Døgnurinopsamling med kvantitativ bestemmelse eller Spoturin albumin/creatinin ratio, protein/creatinin ratio Problem med spoturin: konc varierer med hydrering, koncentrering af urin, dette elimineres ved ratio. Der er god korrelation mellem ratio og døgnurin. Begrænsninger: kan ikke diagnosticere ved afvigende creat udskillelse, muskuløs, kakeksi (uden betydning for forløb), kan ikkepåvise ortostatisk proteinuri Helst morgenurin som spoturin Børn: der anbefales protein/creat ratio (flere lavmolekylære proteiner, glomerulære sygdomme mere sjældne) Voksne : albumin/creatinin ratio, albumin er mere sensitiv markør for nyresygdom > 500 mg proteinuri er det overvejende albumin

Urin protein-creatinin ratio This graph illustrates the close relation between total daily urinary protein excretion and the total protein-to-creatinine ratio (mg/mg) determined on a random urine specimen. Data from Ginsberg, JM, Chang, BS, Matarese, RA, Garella, S. N Engl J Med 1983; 309:1543. N Engl J Med 1983; 309: 1543

Mikroalbuminuri Stix unøjagtig Albumin/creatinin ratio foretrækkes Protein/creatinin ratio anbefales hos børn Stix dårligt pga svingende konc

Circulation 2003

Renal arteriopati

Kronisk nyresygdom og hospitalisering Hyppighed af hospitalisering (per 100 personår) 150 100 50 Et af de få studier, som har undersøgt relationen mellem kronisk nyresygdom og risiko for hospitaliering. Design: longitudinel cohorte studie Endpoint: Relation af longitudinel GFR til død, cardiovasculær events og hospitalisering. Mehode: Den longitudinelle GFR blev bestemt hos 1,120,295 voksne (mean age 52 år, 55% kvinder), registreret i et californisk health care delivery system, som fik bestemt p-creat mellem 1996og 2000, og som ikke tidl var dialyseret eller Tx. Outcome data fra journaler. Cox proportional hazards model. Median follow-up 2.84 år. Resultater: risiko for død steg, når GFR faldt under 60. Adjusted hazard ratios for død var 1.2, for GFR45-60, 1.8, 3.2 og 5.9 for GFR<15. Der var en invers correlation mellem cardiovascular event og GFR, adjusted hazard ratios var 1.4, 2.0, 2.8 og 3.4. Adjusted risk for hospitalisering: Resulaterne viser den kliniske og public health betydning af nedsat nyrefunktion. Estimeret GFR (ml/min/1.73 m2) >60 45-59 30-44 15-29 <15 N Engl J Med 2004; 351: 1296

Kardiovaskulær risikovurdering 3 3

Cystatin C and the risk of death and cardiovascular events among elderly persons N Engl J Med 2005; 352: 2049

Undersøgelse af tubulusfunktion Proksimale tubuli: Udskillelse af lav-molekylære proteiner: RBP, beta-2-mikroglobulin Udskillelse af stoffer, der normalt reabsdorberes: glukose, aminosyrer Udskillelse af proksimale tubulære enzymer Lithiumclearance

Undersøgelse af tubulusfunktion Ascenderende ben af Henles slynge: Tamm-Horsfall-glykoprotein Distale tubuli: pH, p-bikarbonat, p-fosfat, p-Ca, p-K, p-Na, p-Cl Urin pH, u-glukose, u-fosfat Medulla, papiller: U-osmolalitet, tørsteprøve, vasopressin-test

Konklusion Bedre biokemiske markører til vurdering af GFR ville være ønskeligt Der er stor forskningsaktivitet på området Estimeret GFR og s-cystatin C har ikke fundet en endelig plads i klinikken Basis for arbejdsgruppe

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Ritz

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Estimeret GFR vha cystatin-C, kombineret cystatin C og p-creat