This document presents two case studies of patients who developed acute kidney injury (AKI) after kidney transplantation. Both patients were taking tacrolimus, which can cause salt-losing nephropathy by inhibiting sodium transport mechanisms in the kidney. This leads to increased urinary sodium excretion and volume depletion if not properly managed. The first patient's AKI resolved with fluid resuscitation, while the second patient required tacrolimus dose adjustments to prevent further injury. The document discusses the mechanisms by which tacrolimus can disrupt sodium handling and cause salt-losing nephropathy in transplant patients. Early identification and management are important to prevent potentially irreversible kidney damage from tacrolimus toxicity.

1. TUBULAR MESS
Ahad Lodhi
12/11/13

2. Case Presentation
• CC: Generalized Weakness, Dizziness, Passing
out, Weight loss
• HPI:
66 y.o Caucasian male with h/o deceased kidney
transplant 6 months ago due to unknown GN
after being on Dialysis for 3 yrs. His past history
is also significant for PUD, BPH, orthostatic
hypotension and Chronic diarrhea.

3. • He was brought in by his wife who informed
us that he has been passing out 4-5 times a
day. He has also lost about 40lbs since his
transplant. He has decrease po intake and
some trouble taking in solids. He continues to
have loose watery stools 3-5 times a day
without blood.
• Patient was last hospitalized 2 months ago
with similar complaints of passing out and
sepsis or urinary origin.
• He is advised CIC which he tries to follow most
of the time.

4. • On his previous admission he was deemed
hypovolemic and dehydrated but was found to
have high urinary Na excretion, subsequently
he was started on Fludricortisone, Salt tablets
and midodrine with mild improvement of
symptoms. He was also diagnosed with Salt
losing nephropathy.
• He was worked up for chronic diarrhea which
was –ve for infection and was attributed to
some extent to MPA. Which was stopped.
• He also had leuckopenia and his valgancyclovir
was changed to acyclovir.

5. • On discharge, he was continued on
Tacrolimus, acyclovir, low dose MPA.
• His Prednisone was stopped 5 weeks later as
part of steroid sparing regimen and 3 weeks
ago his TMP-SX and acyclovir was also
stopped.
• His Tacrilomus level has been fluctuating,
being as high as 29 due to his fluctuating
volume status.
• On Arrival he was on Tacrolimus,
Fludricortisone, Midodrine and Low dose
MPA.
• Recent Urine cx found Enterocoocus

6. ROS:
• -ve for
Fever, chills, vomiting, Hematuria, numbness,
tingling, changes in vision, rash, chest
pain, SOB, no herbal medications +ve for
Nausea.

7. Physical exam
• BP laying 165/105, Sitting 105/ 65, HR 74,
Afeb
• Cachectic looking male
• Left Arm AVF
• +Foley with clear urine
• Dry Mucous membranes
• Neuro: grossly intact
• Rest without any Positive findings.

8. Labs
Day 1
Day 3
Day 5
Cr
1.4
1.1
0.97
Tac Level
19.7
7.8
-
Fena %
1.19
0.61
0.56
Serum NA
136
136
140
Patient was treated with Normal Saline during these days

9. Day 1
Day 3
Day 5
Cr
1.4
1.1
0.97
Tac Level
19.7
7.8
-
Fena %
1.19
0.61
0.56
Serum NA
136
136
140
Does he have….
a.
b.
c.
d.
e.
AKI?
Pre-Renal due to hypovolemia?
ATN?
Salt loosing Nephropathy?
Inappropriate ADH ?

10. Case 2
• 32 yo S/P decease KP transplant 1 month ago
with discharge Cr 0.8 presents after 3-4 days
of Nausea vomiting and Dec PO intake. She
has a h/o hypertension but on presentation
she has Systolic BP of 85. She denies decrease
in Urine output, no new medication, no
NSAIDs, no fever, chills, diarrhea.
• +Thirst, dizziness and compliance with
medications

11. Meds
•
•
•
•
•
•
•
•
Tacrolimus
Cellcept
Prednisone
Amlodipine
Metoprolol
Acyclovir
Fluconazole
Bactrim MWF

12. Exam
•
•
•
•
•
•
HR 87 , BP 90/68 Afebrile
Deconditioned, Tiered
Dry Mucous membranes
RRR , Lungs CTA
No edema
Incision with staples, no signs of infection

13. Labs
Day 1
Day 2
Day 3
Cr
1.4
1.1
0.8
Tac
26.5
16.9
8.2
Fena%
-
1.3%
0.77
Serum Na
136
138
140
Patient was treated with Normal Saline during these days

14. Day 1
Day 2
Day 3
Cr
1.4
1.1
0.8
Tac
26.5
16.9
8.2
Fena%
-
1.3%
0.77
Serum Na
136
138
140
Does she have….
a.
b.
c.
d.
e.
AKI?
Pre-Renal due to Hypovolemia?
ATN?
Salt loosing Nephropathy?
Inappropriate ADH?

15. Tacrolimus induced salt loosing
nephropathy
Just a Thought…
Please don’t grill me !!

16. Tacrolimus (FK506)
• Also Known as fujimycin, Prograf, Advagraf.
• It is a Macrolide Lactone, discovered in 1984
from Fermentation broth of a japanese soil
sample that contained Streptomyces
tsukubaensis.
• It’s the first macrolide immunosuppressant to
be discovered

17. MOA
• Activation of T-cell receptor increases
intracellular Ca, which acts vis calmodulin to
activated calcineurin.
• Calciueurin, activates nuclear factor of activated T
cell that increases the activity of gene coding for
IL2 and related cytokines.
• Tac prevents dephosphorylation, hence activation
of NF-AT leading to dec IL2 production
• It binds to FKBP12 and creates a new complex,
FK506-FKBP12 thus inhibiting calcinuerin.

18. Tacrolimus nephrotoxicity

20. Na+-K+-ATPase Inhibition
• Due to inhibition of calcineurin
• Inhibition at basolateral membranes
• Decline in Na uptake which leads to decrease
in trans-membrane secretion of K
• (TMP can also cause that and Patient no 2 was
on TMP)

22. Na+-K+-2Cl--cotransporter (NKCC2)
• Tacrolimus reduces its expression at apical membrane.
• Effects are like seen in :
– Type I Bartter's syndrome (NKCC2 mutations)
(in here you don’t see Hyperkalemia and Acidosis)
– After Rx with NKCC2 inhibitors (e.g., furosemide)
Including: polyuria, nephrocalcinosis, magnesium
wasting, hyperreninemic
hyperaldosteronism, juxtaglomerular apparatus hyperplasia
And increased Na loses
(here also you don’t see Hyperkalemia and Metabolic
acidosis)

24. Aldosterone resistance
•
•
•
•
•
Binding to HSP,
Reducing transcriptional activity of hMR
Reduced effect of Aldosterone
Decreased production of Enac Channel
Pesudo-hypoaldosterone state
(last 2 explain the Hyperkalemia and Metabolic
acidosis)

26. All the above mechanisms can
also cause Na loss

27. Feb 1995

29. The numbers of days with
serum sodium <130 mmol/l
are shown, by time after
transplantation

30. Conclusion
• Post transplant, many factors lead to
increased urinary Na excretion, e.g. native
kidney CKD, ATN, DGF, IV fluids. No particular
attention is given is usually given or needed.
• Hyperkalemia in light of recovering Renal
function is usually concerning and usually
attributed to Tacrolimus.

31. Conclusions
• Salt losing nephropathy is usually not evident until
another cause of hypovolemia is present, e.g Diarrhea,
vomiting.
• This can lead to supra-physiologic level of Tacrolimus
and lead to ATN and other forms of Tac nephrotoxicity.
• If identified early, AKI can be treated, Tac levels
restored and irreversible damage can be prevented.
• This is usually not enough to prompt a change in
immunosuppression.
• If change is needed, cyclosporine (causes less Na loss)
or non Calcinuerin inhibitor can be used.

32. I hope no one has any question?
Suggestions and comments
appreciated.