What non-nephrologists should know about Kidney Transplant

1. Management of Renal Transplant Patients
What a non-nephrologist should know!
Dr.Sanjay Maitra
MD(Med),DM(PGI-CHD),Clin.Fellowship (Toronto Univ.,CANADA)
Senior Consultant Nephrologist
APOLLO HOSPITALS HYDERABAD

2. Treatment options for ESRD
(Severe CKD-GFR<15ml/min)
Dialysis
Haemodialysis
Peritoneal Dialysis
Renal Transplant
Living Donor
Cadaveric

3. History Of Renal Transplantation
Always fascinated mankind
In Hindu Mythology- Ganesha
In Ancient Greece- Chimera
Attempts of transplantation were very early
Around 1000 BC Samhita did tissue flaps
Gasparo Tagliacozzi in the 16th
century
revived and updated these techniques

4. Lord Ganesha

5. Chimera

6. History Of Renal Transplantation
Always fascinated mankind
In Hindu Mythology- Ganesha
In Ancient Greece- Chimera
Attempts of transplantation were very early
Around 1000 BC Samhita did tissue flaps
Gasparo Tagliacozzi in the 16th
century
revived and updated these techniques

7. History Of Renal Transplantation
Alexis Carrel described the techniques for
anastomosing blood vessels in animals (1902)
Awarded the Nobel Prize.
Autotransplants did well wheras allogenic organs
failed due to ‘biologic incompatibility’
In 1940 Sir Peter Medawar, Rupert Billinghan and
Leslie Brent Studied factors governing host
tolerance
Skin grafting in rabbits as in humans were rejected
When the same animal was rechallenged with grafts
from the same donor the rejection was much
quicker(amnestic response)

8. History Of Renal Transplantation
Ray Owen and colleagues noted that non-
identical twin cattle that shared a placenta
did not reject their grafts while they did
from other cattle- Exposure to shared cells
in utero induced tolerance
Medawars group confimed in animal
models that exposure to foreign cells early
in development induced tolerance ,while
later on they got sensitised
Dr. Medawar awarded the Nobel Prize in
Medicine in 1960 for his descriptions of
rejection,immunological memory and
tolerance

9. History Of Renal Transplantation
First recorded solid organ transplant was
by Emerich Ullmann (Hungary) in 1902-
implanted canine kidney into a goat
First Xenotransplant was by French
surgeon Mathieu Jaboulay (1906)-
tranplanted a pig and another a goat
kidney into a human.Both failed
First attempt of kidney transplantation
between humans was by Russian Surgeon
Yu Yu Voronoy in 1936 .Failed.

10. History Of Renal Transplantation
In Boston at Peter Bent Brigham Hospital in
1940 a lot of interest was generated for
treating renal failures
Dialysis machines were just coming to the
market making dialysis possible
Active research with animal models for kidney
transplantation
David Hume,John Merill and later John Murray
pioneered renal transplantation using both
cadaveric and living unrelated donors
Series of 9 patients,8 failed one cadaver graft lasted
5 months

11. Modern era of Transplantation
On 23rd
December,1954 at the Peter Bent Brigham
Hospital at Boston
Surgeons –John Merill, Hartwell Harrison, David
Hume, headed by Joseph Murray
Patient Richard Herrick received a kidney from his
identical twin Ron
Confirmed to be immunologically identical by demonstrating
that they do not reject each others skin grafts
Transplanted kidney placed in pelvic retroperitoneal position
Both donor and recipient were well
Kidney functioned well and worked for 9 years after surgery
Dr.Murray reproduced these results in a series of operations
using identical twins

12. Sayegh M and Carpenter C. N Engl J Med 2004;351:2761-2766
The First Identical-Twin Kidney Transplantation, Performed on December 23, 1954

13. Richard ( R ) and Ron Herrick( D )

14. Modern era of Transplantation
To overcome rejection total body irradiation
was used,most died of overwhelming sepsis
Sublethal doses of irradiation along with
corticosteroids were used
George Hutchings and Gertrude Elion
identified Azathioprine from 6
mercaptopurine ,along with Steroids used to
prevent rejection- Awarded Nobel Prize in 1988
Sir Roy Calne introduced Cyclosporine in 1979,
isolated from soil fungus

15. Modern era of Transplantation
After Cyclosporine came
Polyclonal antibodies
Tacrolimus
Monoclonal antibodies
Mycophnolate mofetil
Sirolimus/Everolimus
Besides treating and preventing rejection
drugs should also be well tolerated, easy
to use and improve long term graft
function

16. Transplant Centers – All India
Total No :180
North :25
South :100
East :20
West :35
Hyderabad

17. Transplant Trend
0
500
1000
1500
2000
2500
3000
3500
4000
All India Nort h East West Sout h
Tx Nos.
All India 3500
North 800
East + U.P 350
West 700
South 1650
Living donor-95%
Cadaveric -5%

18. How does Transplantation
compare to Dialysis?
Renal Transplant is better than long
term dialysis in terms of
Life expectancy
Quality of life
Overall cost

19. Wolfe R et al. N Engl J Med 1999;341:1725-1730
Annual Death Rates and Total Numbers of Deaths, 1991-1997

20. Wolfe R et al. N Engl J Med 1999;341:1725-1730
Adjusted Relative Risk of Death among 23,275 Recipients of a First Cadaveric
Transplant

21. How does Transplantation
compare to Dialysis?
Renal Transplant is better than long term
dialysis in terms of
Life expectancy
Quality of life
No dialysis, No dietary restrictions, can
work better
Overall cost
Cost levels out after the first year, saves
dialysis cost, better earning potential and
no attendants to accompany

22. One year Graft Survival
The progress made
In 1960’s and seventies
With azathioprine + Prednisolone - 45-50%
Living related donors were better than
cadavers
In early eighties,
With cyclosporine, OKT3- 60-80
Between 1988-96
For living donors↑from 88-94%
For cadaver donor 77-88%
According to current estimates
Cadaver donors 89% ,living donors 95 %

23. Hariharan S et al. N Engl J Med 2000;342:605-612
Projected Half-Life of Renal Transplants, 1988 to 1995, before and after the
Censoring of Data on Patients Who Died with Functioning Grafts

24. Problems plaguing transplantation
Long term graft dysfunction
Persistent threat of infections
Disparity between organ supply and demand
Commerce in organ donation
Lack of funds for transplantation and subsequent
follow up.
Non-availability of Insurance coverage
Lack of trained manpower available for follow up

25. Sayegh M and Carpenter C. N Engl J Med 2004;351:2761-2766
Mean Rates of Graft and Patient Survival for Transplantations in the
United States from 1993 through 2002

26. Transplantation-The next 50 years
Tranplantation across the blood groups
Donor tolerance
Mixed haematopoeitic chimerism
Costimulatory block, CD28/CD154
Xenotransplantation
Concerns of infection
Growth of adult organs from stem cells
From de-differentiated stem cells, if possible shall
change the whole scenario of transplantation

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28. The basics of Kidney transplantation surgery

29. Who is a candidate for Renal
transplantation?
Recipient must have confirmed ESRD
Exclude any reversible causes of renal dysfunction
Exclude patients with significant comorbidity,
LV dysfunction, Lung disease, cancers
Exclude chronic infections, HIV,HbsAg +ve
with active disease
Exclude active Vasculitis and Lupus

30. Advantages of Living donor
Kidney transplantation
Improved graft outcome
Reduced waiting time
Pre-emptive transplantation possible

31. Who can be considered as a
kidney donor?
Should have a compatible blood group with the recipient
as in blood transfusion
Should be between 25-60 years of age
Should have normal kidney functions, no proteinuria and
no focus of severe infections in the Genito-urinary tract
Should have no Hypertension,Diabetes, significant cardiac
disease ,COPD causing anaesthetic problems,
Disseminated cancer
No Viral infections –HbsAg,HIV,HCV,CMV
Should be mentally fit and willing to donate the kidney
Donation should be altruistic

32. Donor workup for renal Transplantation
Immun. screen Bl.gp./HLA type/Cross match
Haem. screen Complete bl. picture/Coag.prof
Biochem.screen Bl.sugar/LFT/ S.creat/Cl.Cr/S.Elect
Urinanalysis Routine exam/Culture& sensitivity
Cardiovascular Serial BP/ECG/Echo
Virus screen Hep.B/Hep.C/HIV/CMV/EBV
Radiology Chest X-Ray,USG abdomen
Isotope renogram, Renal angio.

33. Halloran P. N Engl J Med 2004
;351:2715-2729
Steps in T-Cell-Mediated Rejection

34. Halloran P. N Engl J Med 2004;351:2715-2729
Individual Immunosuppressive Drugs and Sites of Action in the Three-Signal Model

35. Halloran P. N Engl J Med 2004;351:2715-2729
Classification of Immunosuppressive Therapies Used in
Organ Transplantation or in Phase 2-3 Trials

36. Surgical Problems Occuring Post transplant
Occult bleeding in the immediate post-op
period
Wound complications particularly in obese
pts.
Urinary leak,most common in the immediate
post transplant period
Graft dysfunction due to graft thrombosis
Lymphocoele –may develop in upto 20 % of
patients

37. Medical Problems Occuring Post transplant
Graft dysfunction including progressive graft
loss
Recurrence and De-Novo disease
Coronary artery disease and lipid disorders
Post transplant hypertension
Post transplantant Diabetes Mellitus
Haematologic complications after transplant
Post transplant liver disease
Post transplant bone disease
Malignancies post-transplant and PTLD

38. Medical Problems Occuring Post transplant
Infections in the Post Transplant patient
Bacterial
Cytomegalovirus
Other viral infections including Polyomavirus
Fungal Infections

39. Post-Transplant monitoring
History and physical examination
Assessment of graft function
Evaluation of hematologic & immune
system
Metabolic parameters
Measurement of therapeutic drug levels
Viral screening
General health maintenance screening

40. Recommended frequency of OP visits
For adult Renal Transplant patients
Time after transplantation Freq.of visits
First 30 days 2-3/wk
1-3 months Weekly
4-12 months Every 2-4 weeks
>12 months Every 2-3 months

41. Problems post-transplant
The changing profile
First 3 months post transplantation
Rejection /Effects of Immunosuppression
Four- twelve months post transplant
Surveillance for acute rejection/
immunosuppressant toxicity/infection
Monitoring after the first year
Acute rejection less common
Check for chronic graft dysfunction and
Immunosuppressant toxicity
Manage Hypertension/Diabetes/CAD/Cancer

42. Problems Occuring Post transplant
Graft Dysfunction
Delayed Graft Function- occurring in
the immediate post Transplant
period
Early Graft Dysfunction- occurring in
the first 2-3 post transplantation
months
Late graft dysfunction

43. Causes of Graft Dysfunction
3-6 months post-Transplantation
Acute Rejection
Antibody-mediated/Cell-mediated
Urinary obstruction
Urine extravasation
Calcineurin inhibitor toxicity
Other drug induced toxicity
Thrombotic Microangiopathy-HUS/TTP
Acute pyelonephritis
Hemodynamic effect-Vol.Depletion/Low BP
Recurrent Glom.Disease

44. Causes of Graft Dysfunction
> 6months Post transplantation
Intrinsic Renal Disease
Chronic allograft nephropathy
Chronic calcineurin inhibitor nephro-toxicity
Late acute rejection
Interstitial nephritis
Recurrent or de-novo glomerular disease
BK polyoma virus nephropathy
Vascular
Renal artery stenosis
Thrombotic microangiopathy
Urologic
Obstruction/stricture/stones/BK virus
associated stricture

45. Clinical presentation of acute Rejection
Extremely variable,there is no reliable clinical
syndrome to establish the diagnosis
Most patients have mild symptoms
Slight rise in S.creatinine/low-grade fever/graft
tenderness
Some have a more dramatic presentation with rapid
deterioration of renal function and oligoanuria
Kidney Biopsy is necessary for a confirmatory
diagnosis

46. Evaluation ofAcute Rejection
Serum creatinine/24 hours creatinine clearance
Formulas estimating GFR
Serum cystatin C
Ultrasonography with doppler studies
Radionuclide imaging
Cytokines-IL-6
Urine enzymes- Ganzyme and perforin
Proteomics
Donor specific antibodies
Kidney Biopsy

47. Histology of Acute Rejection
Banff Classification
Normal
Antibody mediated Rejection
A. Immediate
B. Delayed (accelerated acute)
Borderline changes-Suspicious of acute rejection
Acute Rejection
Grades IA,IB,IIA,IIB &III depending on degree of
interstitial infiltration, tubulitis and arteritis
Chronic /Sclerosing Allograft Nephropathy
Others

48. Antibody Mediated Rejection
Addition to Banff ’97 Classification
Type I- ATN like-C4d+,minimal
inflammation
Type II-Capillary-margination and/or
thrombosis, C4d+
Type III- Arterial- transmural arteritis
and/or arterial fibrinoid change with
lymphocyte infiltrate in vessel,C4d+

49. Acute Rejection
Current estimates are that incidence is 15-20 %
3/4th
of them are within the 1st
3 months
At least half are histologically mild
Treatment is determined by histology
Initial treatment is by pulse methylprednisolone
In Higher grades of rejection or steroid resistant
rejection use antithymocyte globulin, OKT3,
Alemtuzumab (Campath-1H)
Do not try treating rejection without the transplant
physicians help, give steroids and refer
Do not modify the immunosuppressants

50. Treatment of Antibody –mediated
Rejection
Clinical features are non-specific- mild to
severe graft dysfunction
Antidonor HLA antibodies present in majority
Do not respond to Pulse steroids
Goal is to eliminate Donor specific antibodies
and prevent its resynthesis
Antilymphocyte antibodies infusion
High dose Tacrolimus +MMF+plasmapheresis
Immunoadsorption with protein A
column+Antithymocte IV
IVIG + plasmapheresis

51. Chronic Allograft Dysfunction
After the 1st
Post transplant year
Chronic allograft nephropathy
Drug toxicity
Recurrent and /or de-novo glomerular
disease
Polyoma (BK virus) infections
Late acute rejections

52. Chronic Allograft Nephropathy
Clinically presents as slow progressive decline
in renal function usually with hypertension and
proteinuria
Pathologically all 4 compartments of the kidney
are affected
Interstial fibrosis and tubular atrophy
Glomerulosclerosis
Intimal thickening of arteries and arterioles
In some ‘Transplant Glomerulopathy’-Double contours
of the Glomerular basement membrane with
mesangial interposition and expansion

53. Factors contributing to Chronic
Allograft Nephropathy
Immunologic Non-Immunologic
Cell-mediated Rejectn. Donor organ quality
Anti-body mediated
rejectn
Delayed Graft fn.
Prior rejecn. Drug toxicity
CSA/TAC
Less Immunosuppression Hypertension
HLA mismatch Hyperlipidimia
High PRA Hyperfiltration

54. Calcineurin Inhibitor Toxicity
Cyclosporin(CSA) &Tacrolimus(Tac)
Calcineurin Inhibitor Nephrotoxicity is a
significant problem: D/D of rejection
Acute –causes asymptomatic rise in S.Creat.
May be accompanied by other side effects like
hyperkalemia,tremors,worsening hypertension
Chronic- May present as Chronic Allograft
Nephropathy
Diagnosis is by Kidney Biopsy –shows patchy
striped fibrosis,peripheral nodular hyalinosis of
arterioles and tubular microcalcifications .Detected
in 90% at 10 yrs.
Drug levels play a crucial role should be
monitored

55. Recurrent / De-Novo Glomerular disease
Glom.Disease recurs in 10%-30% of cases
Caused 2.7% graft loss in one series
Causes graft loss 0.6% in 1st
year, 8% by 10 yrs
FSGS, MPGN and membranous GN are the most
common recurrent primary diseases
Diabetic nephropathy is responsible for about 20
% of recurrent glomerular diseases and have
worse outcomes

56. Commonly used Maintainence
Immunosuppression protocols
Cyclosporine +
Azathioprine+Prednisolone
Azathioprine + Prednisolone
Cyclosporine+ MMF+ steroids
Tacrolimus +MMF+steroids
MMF+ steroids
Sirolimus/Everolimus +MMF/AZA+steroids

57. Infections post-transplant
The first month- Mainly bacterial infections in
wound,lungs,urine or blood. Highest
immunosuppressive dose, no oppurtunistic
infections
1-6 months-CMV predominates causes 2/3 of
cases.UTI is the next most common cause .Co-
trimoxazole prophylaxis very useful
Later than 6 months- 10% develop Chronic liver
disease,10% have oppurtunistic infections like
Listeria,Nocardia and Mycobacteria

58. Fishman J and Rubin R. N Engl J Med 1998;338:1741-1751
Usual Sequence of Infections after Organ Transplantation

59. Post- Transplant
Mycobacterial Infections
Active TB in Transplant
1% in US ,5-15% in India and Pakistan
Incidence 36-74 times higher than gen.population
Reactivation of latent infection, newly acquired
infection,Transmission from donor.
Median time of onset is 11.5 months
Wide variety of presentation involving many
organs
Mortality as high as 30 %
Treatment is with RHZE ,PZA for 2 months rest for
6 months

60. Cytomegalovirus Infections
Post Transplant
Most concerning viral agent in transplants
Causes late graft loss ,CAN and CVD
Symptomatic infection in 20-60% pts.
Anti-lymphocyte products, High dose MMF,
MMF+ TAC increase incidence
D+/R- is most susceptible to infection during
first 3 months,
D+/R+ have poor outcomes in the long term

61. Diagnosis of Cytomegalovirus
Infections post Transplant
Method Comment
Histopathology Detects Incln.
Bodies,Insensitive
Serology Useful to detect past exposure
Culture Takes 1-3 weeks ,+ve test
means infection
Antigenemia assay Rapid semiquantifiable
PCR Best test,Rapid,Most
sensitive,Can be quantified

62. Treatment of Cytomegalovirus
infections post Transplant
In established disease
Gancyclovir 5mg/kg IV 12 hrly for 21 days
Add CMV hyperimmune globulin for severe disease
Prophylaxis –IV/oral Gancyclovir for 3 months
Val-gancyclovir- Valyl-ester prodrug of oral
gancyclovir which has a better absorption.Dose
450-900 mg/day
Foscarnet and Cidofovir for resistant cases

63. Polyomavirus Infections post
Transplant(BK Virus)
Re-activation presents as shedding of decoy cells in
urine in 10%-68% of cases.PCR in blood/histology
Presentations are of asymptomatic viruria or renal
dysfunction ,could be acute renal failure or chronic
graft dysfunction
Symptomatic Polyomavirus nephropathy present
in 1-8 % of renal transplant patients
Presents as chronic Graft dysfunction and ureteral
stenosis
D/D Rejection and CMV infection
Outcome is poor-30% graft loss
No specific treatment available.↓Immunosuppression

64. Cardiovascular mortality in kidney transplant recipients

65. Traditional and Non-traditional Risk
Factors for CVD in Renal Tx.pts.
Traditional Non-Traditional
Older age Decreased kidney Fn.
Male gender CNI
Fam.H/O CVD Proteinuria
Diabetes Anaemia
Hypertension Oxidative stress
Dyslipidemia AGE products
Physical inactivity Homocysteine
LVH Uric acid
Menopause Hyperparathyroidism
Tobacco use Thrombogenic factors

66. Hypertension Post Renal
Transplant
Incidence 80% (With cut of 120/80 mmHg)
CNI use
Prednisolone use
Pre-existing hypertension
Primary kidney disease
Transplant renal artery stenosis
Graft dysfunction

67. BP Management after the
First post transplant year

68. Djamali, A. et al. Clin J Am Soc Nephrol 2006;1:623-640
. Dyslipidemia management after the first posttransplant year

69. Risk Factors for Post Tx.Diabetes
Recipient Characterestics Donor characterestics
Older Age (>45 yrs) Deceased donor
Higher BMI(>30) Male Gender
Black race Transplant era (After
1995)
Family H/O Diabetes Tacrolimus use
Lesser education HLA Mismatch
Acute rejection
HCV infection

70. Djamali, A. et al. Clin J Am Soc Nephrol 2006;1:623-640
Diabetes management after the first posttransplant year

71. Djamali, A. et al. Clin J Am Soc Nephrol 2006;1:623-640
Common causes of posttransplantation anemia

72. Djamali, A. et al. Clin J Am Soc Nephrol 2006;1:623-640
Posttransplantation malignancies

73. Screening frequencies for malignancies
Screening 12 months Others
Skin and Lip Physical Self exam 1/mth
Anogenital Physical/pelvic/PAP
Ut.Cervix Pelvic/PAP
Sarcomas Skin/Pharyngeal/Conjun High risk gps.
PTLD Physical Self exam 1/mth
Hepatic ∝-fetoprotein
Breast Physical mammogram Self exam 1/mth
Colorectal Colonoscopy 5 yr
Prostrate Rectal PSA

74. Suggestions to the Non-nephrologists
Managing Renal Transplant Patients
Never take graft dysfunction lightly, confirm the
diagnosis,contact the transplant nephrologist,
investigate with his help ,give preliminary
treatment and refer if necessary
Transplant patients are immunocompromised
patients,even trivial infections/atypical
infections may be life threatening for them
Do not try to alter or stop immunosuppression
without the nephrologists suggestion
Be vigilant,act fast they are a difficult group to
handle

75. Thank You