Chapter 2 part 1

Back by popular demand…all two of you…the second chapter of The Clinical Physiology of Acid Base and Electrolyte Disorders.

Chapter Outline

- Renal Circulation and GFR

    - RBF is 20% of cardiac output

        - In terms of mL per 100 g organ weight it is 4x the liver and exercising muscle and 8x coronary blood flow!

        - After the glomeruli the efferent arteriole have two fates

            - Peritubular capillaries in the cortex

                - Peritubular capillaries are not necessarily associated with their parent glomeruli. Weird.

            - Vasa recta from juxtamedullary glomeruli in the medulla

Joel Says: This seems wrong. Solute balance can be maintained down to a very low GFR. The R^2 here would be very low. Prove me wrong.

    - States that GFR is an important determinant of solute and water excretion.

- Glomerular anatomy and function

    - Structure

        - Glomerulus is a tuft of capillaries

            - Enclosed in a capsule of epithelial cells, called Bowman’s capsule

            - The epithelial cells of Bowman’s capsule are continuous with the epithelial cells of the proximal tubule

Josh says: Look at the review in Nature Reviews Nephrology from Rachel Lennon’s group

Complexities of the glomerular basement membrane

        - Filtration barrier

            - Epithelial cell (podocyte)

                - Epithelial cells adhere to the basement membrane via foot processes and the foot processes have slit diaphragms 

            - Basement membrane

Melanie talks about conduits through the glomeruli. Here is a cool review:

Why until just now? Undiscovered uniqueness of the human glomerulus! by L. Gabriel Navar, Owen Richfield

Am J Physiol Renal Physiol. 2018 Nov 1; 315(5): F1345–F1346. Published online 2018 Aug 15. doi: 10.1152/ajprenal.00369.2018 PMCID: PMC6293291

                - Produced by both the endothelial cells and podocytes

                - Formed from type IV collagen

                    - Abnormalities of type 4 collagen cause Alport

                        - The gene coding for the alpha 5 chain is the culprit

                        - COL4A5

                    - Abnormal Alpha 3 and 4 chains can also cause hereditary nephritis

                - Has other substances

                    - Laminin

                    - Nidogen

                    - Heparin sulfate proteoglycans

                        - Provides the negative charge

            - Enthothelial cell (fenestrated)

        - Protein excretion

            - Glomerular function: allow filtration of small solutes (Na and urea) while preventing filtration of larger molecules

                - Insulin MW 5,200 is freely filtered (upper range of freely filtered)

                - Preventing loss of protein prevents

                    - Negative nitrogen balance

                    - Development of hypoalbuminemia

                    - Infection from loss of immunoglobulin

                - Size and charge selectivity of the GBM

                    - pores are between cords of type 4 collagen

                    - The epithelial cells and slit diaphragms matter

                        - Macromolecules that pass through GBM can accumulate underneath the epithelial layer

                        - Isolated GBM in invitro studies is much more permeable to than intact glomerulus

                        - There is increased protein filtration in areas where the epithelial cells have detached from the GBM

                        - Mutations in nephrin, localized to the slit diaphragm causes congenital nephrotic syndrome

                    - Charge selectivity is important

                        - Neutral and cationic particle are more likely to be filtered

                        - Albumin (negative charge) is filtered 5% as well as same size neutral dextrans

                        - In glomerular disease, while there is increased filtration of proteins there is decreased filtration of small solutes due to loss of glomerular surface area

JC says: Take a look at this research on the serving coefficient in glomerular disease. Some surprising results.

Glomerular dysfunction in nephrotic humans with minimal changes or focal glomerulosclerosis

                            - Why do people in remission have what appears to be spilling more high molecular radius particles than normal and why do patients with active MCD have lower clearance across all molecular diameters?

        - Other glomerular functions

Josh says: Take a look at this interesting paper by Butt et al

A molecular mechanism explaining albuminuria in kidney disease

            - Synthetic

                - Epithelial cells produce GBM

            - Phagocytic

                - Remove circulating macromolecules that pass through GBM and get trapped in subepithelial space

Josh says: The sFLT1 (soluble VEGF receptor) relationship to preeclampsia is just so cool. And here’s the paper:

Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia