1. Renal Pathophysiology 3 Diseases that Affect the Kidney and Urinary Tract Acute and Chronic Renal Failure Nancy Long Sieber, Ph.D.December 5, 2011

2. Plumbing Problems Kidney Stones – Calcium – Cystine – Struvite – Uric Acid Crystals - Gout Vesicoureteral Reflux

3. Kidney Stones

4. Struvite Bladder Stones from a Dog

5. Gout Crystals of uric acid form in the blood and precipitate in joints, causing severe pain. They can also deposit in the renal tubules, creating uric acid kidney stones. Uric acid is a product of purine metabolism, and is normally excreted in the urine. – Generated during normal cell turnover – Purines are also part of normal diet (they are a component of nucleic acids) Kidneys are responsible for about 2/3 of uric acid excretion, the liver does the rest.

6. What Causes Gout? High plasma uric acid levels can result from eating foods high in purine, such as, lobsters, champagne, foie gras. “Rich man’s gout”. Also, excess alcohol consumption can be a cause of gout. “Poor man’s gout”. Acidosis causes crystals to precipitate Can develop secondarily to renal failure, metabolic syndrome or leukemia.

8. Acute Renal Failure Defined by increases in serum creatinine (generated by normal muscle breakdown) and urea (from protein metabolism), reflecting decreased GFR Creatinine is used as an indicator of GFR Urea is passively reabsorbed in the renal tubules. More urea in the blood indicates less urea is being filtered. Normal Values: – plasma creatinine: 1 mg/dl – plasma urea (BUN): 8-25 mg/dl

9. Causes of Acute Renal Failure Pre-renal – kidneys ok, but blood flow/supply is reduced, resulting in decreased GFR. Intrarenal – usually result of acute tubular necrosis Post-renal – results from obstruction of urinary tract (eg: kidney stone).

10. Risk Factors for Chronic Kidney Disease Hypertension Diabetes Autoimmune diseases Glomerulonephritis – inflammation of the glomerulus leading to blood & protein loss – can be primary disease or secondary to other problems Low birthweight Exposure to certain drugs, Genetic factors eg: polycystic kidney disease Socioeconomic risk factors include: – Older age – African American, Native American or Hispanic ethnicity, – Low income/education.

11. Stages of Kidney Disease StageDescription GFR mL/min/1.73m 2 1 Slight kidney damage with normal or increased filtration More than 90 2 Mild decrease in kidney function 60-89 3 Moderate decrease in kidney function 30-59 4 Severe decrease in kidney function 15-29 5Kidney failureLess than 15 (or dialysis)

12. The Development of Chronic Renal Failure (also known as “established chronic renal disease”) Results from irreversible, progressive injury to the kidney. Characterized by increased plasma creatinine and urea, indicating decreased GFR, as well as loss of hormonal functions of the kidney.

13. Polycystic Kidney Disease http://phil.cdc.gov/PHIL_Images/02071999/00002/20G0027_lores.jpg

14. Autoimmune Disease Example: Lupus (SLE) Cause of SLE is unknown, genetic and immune factors involved. Autoantibodies against many cellular components, including DNA, and other molecules in the nucleus and cytoplasm of cells are produced Characterized by “flares” followed by periods of remission. 90% of cases are in women of childbearing age.

15. Renal Damage from Lupus In the renal system, damage results largely from deposition of antigen-antibody immune complexes in the glomeruli. This leads to the appearance of protein in the urine, and can cause acute (and eventually chronic) renal failure.

16. Antigen-Antibody Complex http://www.cartage.org.lb/en/themes/sciences/lifescience/generalbiology/ Physiology/LymphaticSystem/Antibodymediated/antigenAB.gif

17. Deposition in Tissues Leads to Inflammation http://www.bact.wisc.edu/Microtextbook/images/book_4/chapter_15/15-30.gif

18. Diabetic Nephropathy Diabetics have abnormal thickening of the mesangial matrix, the material that surrounds and supports the glomerular capillaries. Diabetics also tend to have atherosclerosis. When it affects the renal artery, it can decrease renal blood flow, further lowering the GFR.

19. Normal Protein Handling by Kidney http://www.unckidneycenter.org/patients/images/protein.jpg

20. Proteinuria Glomerular proteinuria – altered size and change function of glomerular barrier Tubular proteinuria – altered reaborption Overload proteinuria – excessive filtered load

21. Nephrotic syndrome protein in urine greater than 3g/day decreased protein concentrations in the plasma edema excess lipids in the plasma Characteristic of SLE and diabetic nephropathy.

22. Edema in Nephrotic Syndrome

23. Consequences of Kidney Failure: Problems with Na+ and Water Balance Na+ handling – can lead to hypo- or hypernatremia – If GFR is low, and salt intake is high, the kidney’s cannot excrete enough salt and salt is retained. – But, if the salt intake is very low, the diminished capacity of the tubule to reabsorb sodium can lead to excessive sodium loss and hyponatremia. Water handling: – The ability of the kidney to generate the osmolar gradient that allows for excretion of concentrated or dilute urine is compromised. – Problems of osmolarity (hypo or hypernatremia) occur if the patients drink too much or too little water. Consequences: – Hypertension – Edema

24. Other Consequences of Renal Failure Uric Acid retention – may result in gout or arthritis, also causes itchiness and rash. Potassium Handling – Potassium excretion increases with GFR. Big reductions in GFR result in inability to excrete K+, and increased plasma potassium results. – This can result in cardiac arrthymias. Acid Base Status – Normal metabolism results in the formation of acid, which is normally excreted in the urine. – When the GFR gets low enough, acids cannot be excreted and plasma pH drops (i.e. the concentration of H+ ions increases). Buildup of Drugs and Toxins – The kidney is a major site of excretion of many drugs. – Patients with reduced kidney function have a reduced ability to excrete these and they may build up in the blood.

25. Still Other Consequences of Renal Failure: Calcium metabolism – Failure to activate vitamin D decreases calcium absorption in the gut – Causes breakdown of bone – Also, failure to excrete phosphate leads to formation of calcium phosphate salts in soft tissues, which further lowers plasma calcium levels. Hormonal abnormalities – The kidneys help clear the body of insulin, so patient with renal failure often have hyperinsulinemia. – Sex steroid levels are low, often causing amenorrhea in women and impotence in men. Anemia – The kidney is the site of production of erythropoetin, a hormone necessary to the formation of red blood cells. Neurologic effects – Build up of toxins can cause seizures, and other neurologic problems Gastrointestinal consequences – Nausea and vomiting resulting from electrolyte disturbances.

26. Dietary changes necessary for people with chronic renal disease or failure : People with renal failure produce very little urine. Therefore they must restrict their consumption of fluids. People who are not on dialysis often need to eat a diet that is very low in protein, to avoid producing too much urea. The calories that normally come from protein in the diet are replaced with extra carbohydrates (if the patient is not diabetic) and fats. Once a patient goes on dialysis they actually need more protein than normal. Sodium, potassium, calcium and phosphate levels in the plasma need to be monitored, and dietary changes are often needed (commonly a low sodium, and low dairy diet).

27. Treatment of Chronic Renal Failure: Dialysis Hemodialysis – must go to a clinic about 3 times per week for about 4 hours Peritoneal Dialysis – more frequent, but can be done at home. Generally better outcomes. Also: Transplantation

28. http://www.renalpatients.co.uk/images/kidney.jpg

29. Hemodialysis http://www.ebme.co.uk/arts/neph/image3.gif

30. Peritoneal Dialysis