This document summarizes recent advances in renal pharmacology presented by Dr. Kalpana Tiwari. It begins by classifying kidney disease as either acute or chronic, then describes stages and treatments for acute kidney injury including optimization of hemodynamics, elimination of nephrotoxins, and initiation of renal replacement therapy if needed. Chronic kidney disease is defined and stages outlined. New pharmacological treatments discussed include ferric citrate, ferric carboxymaltose, belatacept, tolvaptan, etelcalcetide, and ravulizumab-cwvz. The mechanisms of action and side effects of these drugs are summarized.

1. Recent advances in Renal Pharmacology
Presenter:
Dr. Kalpana Tiwari

2. Kidney disease classified on duration
 Acute
 Chronic

3. Acute kidney injury
• Define by inability to maintain acid-base, fluid and electrolyte balance to
excrete nitrogenous wastes
• Serum creatinine > 0.3 mg/dL within 48 hours
• Urine production < 400–500 mL/day or < 20 mL/h

4.  Stage 1- 1.0 - 1.5 fold increase in serum creatinine or urinary output <
0.5 mL/kg/h over 6–12 hours
 Stage2- 2.0 - 2.9 fold increase in serum creatinine or decline in urinary
output < 0.5 mL/kg/h over 12 hours or longer
 Stage 3- 3-fold increase in serum creatinine, or greater than or equal
to> 4 mg/dL urinary output < 0.3 mL/kg/h for 24 hours or for 12
Stage of AKI

8. differential diagnosis of acute kidney injury.

9. Treatment

10. General Treatment
1. Optimization of systemic and renal hemodynamics through
volume resuscitation
2. Elimination of nephrotoxic agents (e.g., ACE inhibitors, ARBs,
NSAIDs, aminoglycosides) if possible
3. Initiation of renal replacement therapy

11. Pre-Renal AKI
Prevention and treatment of prerenal azotemia requires optimization of
renal perfusion
Severe acute blood loss should be treated with packed red blood cells
Treatment for pre-renal AKI-
• Fluids
• Vasopressin
• Fenoldopam

12. FLUIDS
• KDIGO advocates use of isotonic crystalloids rather than
colloids (albumin or starches)
• Colloids may be chosen to avoid excessive fluid administration
requiring large volume resuscitation, or in specific patient
subsets

13. Vasopressors
• Vasoactive agents improve kidney perfusion in volume
resuscitated patients with vasomotor shock
• Dopamine associated with a greater number of adverse events
than Norepinephrine

14. Fenoldopam
• Fenoldopam mesylate: pure dopamine type-1 receptor agonist
• For critically ill patients with impaired renal function, a
continuous infusion of fenoldopam 0.1mg/kg/min improves
renal function when compared to low dose dopamine

15. Cirrhosis and Hepatorenal Syndrome
• Albumin may prevent AKI in those treated with antibiotics for SBP
• Bridge therapies [in combination with IV Inf albumin (25–50 mg/d)]
include:
• Terlipressin (a vasopressin analog)
• Combination therapy with octreotide (a somatostatin analog) and
Midodrine (an α 1-adrenergic agonist)
• Norepinephrine

16. Treatment of Intrinsic AKI
• KDIGO recommend not using diuretics to prevent AKI
• KDIGO suggest not using diuretics to treat AKI, except in the management
of volume overload
• Indicated only for management of fluid balance, hyperkalemia, and
hypercalcemia.

17. Glomerulonephritis or Vasculitis
• May respond to immunosuppressive agents and/or plasmapheresis
• Allergic interstitial nephritis due to medications requires discontinuation
of the offending agent.
• Glucocorticoids have been used, but not tested in randomized trials.
• AKI due to scleroderma (scleroderma renal crisis) should be treated with
ACE inhibitors

18. Post-renal AKI Treatment
• Prompt relief of urinary tract obstruction
• Relief is usually followed by an appropriate diuresis and may
require continued administration of IVF & electrolytes for a
period of time

19. Indications for Dialysis
• A – Acidosis
• E – Electrolyte disturb, usually hyperkalemia
• I – Intoxications (lithium, ethylene glycol, etc)
• O – Overload (volume overload)
• U – Uremia (symptoms, signs )

20. CHRONIC KIDNEY DISEASE
• It is kidney damage (structurally or functionally) for ≥ 3 months with or without decrease
glomerular filtration rate (GFR)
OR
• GFR < 60ml/min for ≥ 3 months with or without kidney damage
OR
• Persistent microalbuminuria/Persistent proteinuria/Persistent hematuria
OR
Structural abnormalities of the kidneys (polycystic kidney disease, reflux nephropathy)
proven by ultrasound

21. General symptoms for CKD:
 Fatigue, anorexia, nausea, and a metallic taste in mouth
 Neurologic symptoms such as irritability, memory impairment, insomnia, restless
legs, paresthesia and twitching
 Generalized pruritus (without rash) decreased libido and menstrual irregularities
 Pericarditis, a rare complication of CKD

22. Stages of CKD

23. Management
• Dietary Management
• 1. Protein restriction
• 2. Salt and water restriction
• 3. Potassium restriction
• 4. Phosphorus restriction

24. DIAGNOSIS OF CKD
• Decrease GFR for ≥ 3 months
Urinalysis:
• Dipstick proteinuria, if positive, do daily or 24hrs proteinuria test
 If proteinuria is ≤1g/24hrs, then consider urinary syndrome
 If proteinuria is 1 to 3g/24hrs, nephritic syndrome/ tubulointerstitial
 If proteinuria is ≥3.5g/24hrs, consider nephrotic syndrome
• RBCs, RBC casts, suggests glomerulonephritis
• Pyuria or/and WBC casts are suggestive of interstitial nephritis/pyelonephritis
• GFR evaluation; usually decreased

25. Non-pharmacological treatment
• Admit patient especially in stage of exacerbation
• Diet: Restrict dietary protein to< 40 g/day, Restrict Na+, K+, PO4- intake,
avoid potassium containing foods e.g. banana
• Water and electrolyte balance:
• i. Daily fluid intake = previous day’s urine output + 600 ml (for insensible
losses)
• ii. Strict fluid input and output chart
• General health advice e.g. smoking cessation, Avoid nephrotoxins e.g.
NSAIDs , Herbal medication

26. Pharmacological treatment
Diuretics: Furosemide, oral /IV, 40-120 mg daily
Treatment of anemia Injection erythropoietin 50-100units IV/SC 3times weekly
Treatment is initiated-
i. ACEIs- Lisinopril, oral, 5-40 mg daily Or Ramipril, oral, 2.5-10 mg daily
ii. ARBs- Losartan, oral, 25-100 mg daily or Valsatan, oral, 80-160 mg daily
hyperkalaemia/metabolic acidosis
• 10% Calcium gluconate, IV, 10-20 ml over 2-5 minutes Plus Sodium
Bicarbonate, IV, 8.4% 50mEq, over 5 minutes Plus • Regular Insulin, IV, 10
units in 50-100 ml Glucose 50%

27. Pharmacological treatment con’t…
• Treatment of hyperphosphatemia: i. Phosphate binders (calcium acetate/
calcium carbonate 2 capsules (1334mg ) orally with food)
• Treatment of hypocalcaemia:
i. Calcium citrate 1g/day
ii. Vitamin D supplement; 2 tablets (800 IU) once daily
• Treatment of bleeding: Desmopressin 0.3 mcg/kg IV over 15-30mins

28. Recent Advances in Pharmacotherapy
Chronic Kidney Disease
• Ferric citrate
• Ferric carboxymaltose injection
• Belatacept
• Tolvaptan
• Etelcalcetide
• Ravulizumab-cwvz

29. Ferric citrate
• It lowers phosphate levels without raising calcium or aluminum levels
Side Effects
• Adverse effects :diarrhea discolored feces constipation nausea vomiting
• Mechanism of Action
• Ferric iron binds dietary phosphate in GI tract and precipitates as ferric phosphate.
compound is insoluble and excreted in stool.
• By binding phosphate in GI tract and decreasing absorption,
• ferric citrate lowers the phosphate concentration in the serum.

30. Ferric carboxymaltose injection
 Non-dialysis dependent chronic kidney disease
Side Effects:
Nausea, hypertension, flushing, hypophosphatemia, dizziness
Mechanism of Action:
Ferric carboxymaltose injection is a colloidal iron hydroxide in complex
with carboxymaltose, a carbohydrate polymer that releases iron

31. Belatacept
• Selective T-cell (lymphocyte)
• Dosing for Initial Phase:
Day 1 (day of transplantation, prior to implantation) and Day 5 (approximately 96 hours after Day 1
dose): 10 mg per kg
End of Week 2 and Week 4 after transplantation: 10 mg per kg
End of Week 8 and Week 12 after transplantation: 10 mg per kg
• Dosing for Maintenance Phase:
End of Week 16 after transplantation and every 4 weeks (plus or minus 3 days) thereafter: 5 mg per
kg
Side Effects: Anemia, Diarrhea, Urinary transfection peripheral, Edema, Hypertension, Pyrexia, graft
dysfunctin
• Mechanism of Action:
It binds to CD80 and CD86 on antigen-presenting cells, thereby blocking CD28

32. Ravulizumab-cwvz
• Humanized monoclonal antibody
• Treatment of atypical hemolytic uremic syndrome (aHUS)
Side Effects:
Diarrhea nausea vomiting
Mechanism of Action:
Inhibiting its cleavage to C5a (the proinflammatory anaphylatoxin) and C5b
(the initiating subunit of the terminal complement complex [C5b-9]) and preventing
the generation of the terminal complement complex C5b9.

33. Everolimus
Macrolide immunosuppressant. It inhibits the mammalian Target Of Rapamycin
(mTOR)
Initial dose 0.75 mg orally twice daily (1.5 mg/day)
Side Effects:
Peripheral edema Constipation Hypertension
Mechanism of Action:
Everolimus binds to the immunophilin FK Binding Protein-12 (FKBP-12) to
generate an immunosuppressive complex that binds to inhibits activation of
mammalian Target of Rapamycin (mTOR), a key regulatory kinase
Inhibition of mTOR activation results in inhibition of T lymphocyte activation and
proliferation associated with antigen and cytokine (IL-2, IL-4, and IL-15)
stimulation and the inhibition of antibody production

34. Tolvaptan
• A selective vasopressin V2-receptor antagonist. Decreased binding of
vasopressincauses an increase in urine water excretion, increase in free water
clearance
• Dose is 60 mg orally per day as 45 mg taken on waking and 15 mg taken 8 hours
later
• Titrate to 60 mg plus 30 mg then to 90 mg plus 30 mg per day if tolerated with at
least weekly intervals between titrations
• Patients may down-titrate based on tolerability.
• Side Effects: Thirst polyuria nocturia pollakiuria polydipsia

35. Peginesatide
Peptide-based erythropoiesis stimulating agent (ESA) anemia due to chronic kidney disease
0.04 mg/kg body weight
Side effects: Dyspnea diarrhea nausea Cough
Mechanism of Action
Peginesatide is a peptide-based erythropoiesis stimulating agent (ESA). It is comprised of two identical, 21-amino
acid chains covalently bonded to a linker derived from iminodiacetic acid and ß-alanine. Binds to and activates the
human erythropoietin receptor and stimulates erythropoiesis in human red cell precursors in vitro
Etelcalcetide
Calcium-sensing receptor agonist
Chronic kidney disease on hemodialysis
Starting dose of 5 mg
Side Effects: muscle spasms diarrhea nausea
Mechanism of Action: Binds to the CaSR and enhances activation of the receptor by
extracellular calcium.

36. References
• Brenner and Rector's The Kidney 9th ed.
• Harrison's Principles of Internal Medicine, 19th edition
• Kidney Disease: Improving Global Outcomes (KDIGO)
• The Washington manual of Critical care 2nd edition