Gender and kidney diseases

1. Gender and kidney diseases Dr. Wagner László1 – Dr. Fekete Andrea2 1 Transzplantációs és Sebészeti Klinika 2 I. sz. Gyermekklinika

2. Korenchevsky and Ross London, 1940

3. Sex difference in … • Anatomy • Development • Physiology • Associated renal diseases • Renal disease progression, Co-morbidities • End-stage renal disease • Transplantation • Therapy

4. Anatomy Kidney weight: M>F Kidney/Body weight: M>F M (male) – F (female)

5. Difference in Anatomy www.medpedia

6. Urinary tract infections (UTI) • Most common bacterial infections • Epidemiology: 10% of women getting an infection yearly and 60% having an infection during their life (app. 50x greater in women than in men) • Symptoms: dysuria, pollakisuria, haematuria, pyuria • Diagnosis: clinical symptoms, urine analysis • Treatment: oral antibiotics, cranberry juice

7. Urine analysis Sediment

8. Urinary tract infections Pathogens:

9. E.coli P. aeuruginosa Therapy: Aminoglycosides Meropenem Flurocinolons Ciprofloxacin, Tazobactam

10. Acute pyelonephritis • Fewer than UTI, predisposing factors: obstructive uropathies, immunsuppressed states • Symptoms: dysuria, pollakisuria, haematuria, pyuria, fever, back pain, vomiting • Blood: • - leukocytosis • - increased CRP • Urinary sediment: • - squamosus cells • - erythrocyte casts • - leukocytes Fairley KF, Diseases of the kidney , 1988

11. Sex difference in … Anatomy Development Physiology Associated renal diseases Renal disease progression, Co-morbidities End-stage renal disease Transplantation Therapy

12. Normal Kidney Development • Nephrogenesis: until 26th weeks of pregnancy, • Prenatal Ultrasound - Presence and size of the kidneys, volume of amniotic fluid - Parenchymal thickness, echogenity, cysts, dilatation - Bladder: volume, wall-thickness, proximal urethra - Associated anomalies

13. Kidney pathologies diagnosable by ultrasound during 19-23 weeks Renal agenesis Cystic kidney disease ARPKD ADPKD multicystic kidney dyplasia Obstructive Uropathies Bladder extrophy Others

14. Vesicoureteral reflux (VUR) • Primary: Congenital defect of longitudinal muscle of the intravesical ureter • Secondary: Caused by raised vesicular pressures associated with obstruction (posterior urethra valve, PU stenosis) • Symptoms:none, UTI, pyelonephritis • Diagnosis: antenatal ultrasound, voiding cystourethrogram • Therapy:none, conservative or surgical depending on grade and symptoms

15. VUR incidence between gender Epidemiology: VUR is present in more than 10% of the population, In children without UTI 17.2-18.5% have VUR, whereas in those with UTI 70%. Antenatal VUR is more often in males, later age 85% predominantly in females

16. Severity of VUR Jang HC, 2011 Korean J Urol

17. Posterior urethra valves dilatated bladder valve • Etiology: an obstructing membrane in the posterior male urethra as a result of abnormal in utero development • Epidemiology: only in males, 1:5000, 20% of childhood ESRD • Symptoms:none, bilateral hydronephrosis, abnormal bladder, megaureters • Diagnosis: antenatal ultrasound, voiding cystourethrogram • Therapy:surgical (vesicostomy, valve ablation) www.humpath.com, imagingconsult. com

18. Kidney pathologies diagnosable by ultrasound during 19-23 weeks Renal agenesis Cystic kidney disease ARPKD ADPKD multicystic kidney dyplasia Obstructive Uropathies Bladder extrophy Others

19. Renal cystic disease Unknown inheritance - solitary cysts - multicystic, dysplastic kidneys - medullary sponge kidney - aquired cysts Inherited - autosomal dominant (ADPKD, MCKD, VHL, tub. scler.) - autosomal recessive (ARPKD, NPH, BBS, etc.)

20. Renal diseaseswith abnormal renal structure • unilateral renal agenesia • bilateral renal agenesia • renal aplasia • horseshoe kidney • renal cyts (in ~50% of autopsys) • cystic kidney disease

21. ARPKD solitary cysts ADPKD healthy X aquired cytsts multicystic dysplastic kidney medullary sponge kidney nephronophtisis hydronephrosis

22. Solitary Cysts • Developmental anomalities , mostly on the outer side of the kidney • Most oftenrenal cysts, 50% of the population after 50 years 1% in children • Symptoms:none, abdominal pain, pressure, unregular motion • Diagnosis: mostly by chance, classification (simple, complicated) classify by, ultrasound or CT, follow-up • Therapy:mostly nothing, complicated cysts should be ablated http://library.med.utah.edu

23. Multiystic, dysplastic kidneys • Epidemiology: 1:2400, bilateral 20-35% • Male:Female: unilateral (2.4:1), bilateral (1:2) • Symptoms:none, abdominal tumor,pain, vomiting, haematuria, hypertension10% malignancy • In 50-70% other developmental abnormalities (vitium, esophagusatr.)-Potter • Diagnosis:ultrasound(prenatal)!, MCU (VUR?); DMSA (function?) • Therapy:nephrectomy (obstruction- rec.infections, pain, malignancy) http://library.med.utah.edu; Frye TP et al,2010, Ped Nephr

24. Medullary sponge kidney • Pathomechanism:Cystic dilatation of the collecting tubules • Epidemiology: 1:200-500, Female: Male (2:1) • Symptoms:none, haematuria, infections, renal stones (60%), hemihypertrophy (25%) • Diagnosis: mostly by chance, ultrasound: not typical, iv. urography • Therapy:treatment of infections and kidney stones, rarely rec. Infections leading to chronic renal insufficiency

25. Aquired renal cysts • Patomechanism: more cysts in both kidneys, cysts are enlarged tubules filled with oxalate leading to obstruction • In patients who are on dialysis for long (3 years 40%, 10 years 90%) • More often in men (3-4x) • Symptoms:bleeding, kidney stones, renaladenomas/carcinomas (7-50x) • Diagnosis: UH, CT Therapy: Nephrectomy? Quelle: European Renal Association

26. Autosomal dominant polycystic kidney disease (ADPKD) • Pathogenesis: Cystic degeneration of the kidney by a mutation in polycystin1 and 2 • Epidemiology: • - Most common inherited disease that leads to death, • - Incidence: 1:200-1:1000same in both gender, but the progression to ESRD is quicker in men • Symptoms: • In 50% progressive chronic renal insufficiency • ADPKD is often associated with liver and pancres cysts

27. Sex difference in … Anatomy Development Physiology Renal disease progression, Co-morbidities End-stage renal disease Transplantation Therapy

28. Parameters representing renal function • Serum creatinine • Blood urea nitrogen • Electrolytes • Urinary protein (albumine) !unspecific

29. Estimated GFR • In routine: estimates of creatinine clearance based on the serum creatinine level is used to measure GFR Cocroft- Gault formula MDRD formula Schwartz formula

30. Changes in glomerular filtration rate with age ♂ ♀ Wesson LG., 1969., Physiology of the Human Kidney.

31. In rats: Proteinuria with age Remuzzi A. 1988, Kidney Int.

32. Mesangial extracellular matrix production Hemodynamic differences Baylis C. 1994, J Clin Invest.

33. Age and gender Age Age Gender, Sex hormones Hypertension, Diabetes etc. Age

34. Sex difference in … Anatomy Development Physiology Renal disease progression, Co-morbidities End-stage renal disease Transplantation Therapy

35. Gender and chronic kidney disease causing nephrotic syndrome Gender and chronic kidney disease causing nephrotic/nephritis syndrome Silbiger. 2003 Adv Ren Replace Ther; .Silbiger . 1995. Am J Kidney Dis.; Brenner B 2005, The Kidney

36. ESRD incidence and mortality

37. Gender and diabetic nephropathy Seliger SL 2001 Cur Op in Nephrol and Hypert

38. Sex difference in … Anatomy Development Physiology Renal disease progression, Co-morbidities End-stage renal disease Transplantation Therapy

39. Transplantation

40. Gender and Kidney Survival Zeier M et al. JASN 2002.

41. Gender and allograft rejection Meier-Krische et al.Transplantation. 2001.

42. Risk factors of Chronic Allgoraft Nephropathy • Alloantigen dependent: • Histoincompatibility • Number and intensity of acute rejection • Non-compliance • Alloantigen independent: • Ischemia/Reperfusion injury • Hypertension • Metabolic factors • Drug toxicity • Donor and recipient gender Sex and sex hormones Different treatment strategy Between genders Müller, Szabo et al Kidney Int 1999, Müller, Szabo et al Kidney Int 2002, Szabo, Erdely et al Kidney Int 2003, Fekete, Szabo et al J Physiol 2004, Szabo, Müller et al J Am Soc Nephrol 2002

43. Fisher344  Lewis Estradiol Vehicle treatment for 16 weeks Testosterone 10 day Cyclosporine therapy Female ovariectomized recipient Male donor kidney Female donor kidney

44. Proteinuria in Rats Female donor kidney Male donor kidney Müller et al. Kidney Int. 1999.

45. Gender and kidney transplantation Gender and CAN Renal structure Chronic kidney disease Immunosuppression Gender and renal ischemia/reperfusion injury

46. Ischemia/reperfusion injury Female and male Wistar rats 50 minutes clampig of the renal artery and vein Right nephrectomy Analysis of kidney function, histology and tubular parameters

47. Gender and ischemia/reperfusion injury Male Female Müller et al. Kidney Int. 2002.

48. Postischemic renal blood flow) * p<0.05 vs. male Müller et al. Kidney Int. 2002.

49. Gender and immunosuppression Tain YL et al. Am J Nephrol. 2006.

50. Gender and donor/recipient characteristics More man on waiting lists More female living donations Problems: Female immune system more „aggressive” Female grafts more antigenic Female kidneys more susceptible to Cyclosporine A Recipients metabolic demand is a key determinant Hormonal status of donor and recipient Oh CK at al. Clin Transplant. 2006. Jindal RM et al. Am J Nephrol. 2005.