By Dr. J. Stalin Roy

Prof P. Vijayaraghavan’s unit

Stanley Medical College

Dialysis - types Hemodialysis

Hemofiltration (high convective transport of substances)

Hemodialysis (high transport rates of LMW substances by diffusion)

Hemodiafiltration (both) Peritoneal dialysis

CAPD – Continuous Ambulatory Peritoneal Dialysis

APD – Automated Peritoneal Dialysis

Hemodialysis Hemodialysis relies on the principles of solute

diffusion across a semipermeable membrane. Movement of metabolic waste products takes

place down a concentration gradient from the circulation into the dialysate.

Movement is via both diffusive clearance (dialysis) and convective clearance (ultrafiltration).

The removal of small solutes occurs primarily by diffusion while larger components are effectively removed by convection.

Criteria for initiating maintenance HD Presence of uremic symptoms, Hyperkalemia unresponsive to

conservative measures, Persistent extracellular volume expansion

despite diuretic therapy, Acidosis refractory to medical therapy, Bleeding diathesis, and Creatinine clearance or estimated

glomerular filtration rate (GFR) below 10 mL/min per 1.73 m2

There are three essential components to hemodialysis: The dialyzer, The composition and delivery of the

dialysate, and The blood delivery system

Dialyzer The dialyzer consists of a plastic device

composed of bundles of capillary tubes through which blood circulates while dialysate travels on the outside of the fibre bundle.

There are four categories of dialysis membranes: cellulose, substituted cellulose, cellulo-synthetic, and synthetic.

Cellulosic membranes are bio-incompatible because of the presence of free hydroxyl groups on the membrane surface which activate compliment.

Dialyzer

Dialysate The composition of dialysate fluid:

Potassium can be varied from 0 to 4 mmol/L depending on the predialysis plasma K+ concentration.

The usual calcium concentration is 1.25 mmol/L (2.5 meq/L),

The usual dialysate sodium concentration is 140 mmol/L. Approximately 120 liters of water is used which is

processed using reverse osmosis (RO) for purification. Sodium modelling – In patients who frequently

develop hypotension during their dialysis run, to counterbalance urea-related osmolar gradients the dialysate sodium concentration is gradually lowered from the range of 145–155 meq/L to isotonic concentrations (140 meq/L)

Blood Delivery System

The blood delivery system is composed of the extracorporeal circuit in the dialysis machine and the dialysis access.

The dialysis machine consists of a blood pump, dialysis solution delivery system, and various safety monitors.

The blood pump moves blood from the access site, through the dialyzer, and back to the patient.

Dialysis machine

Dialysis access Despite the technical improvements vascular access continues

to be referred to as the “Achilles heel” of the HD procedure. The fistula, graft, or catheter through which blood is obtained for

hemodialysis is often referred to as a dialysis access. A native fistula created by the anastomosis of an artery to a vein

which results in arterialization of the vein is the ideal access. Grafts and catheters tend to be used among persons with

smaller-caliber veins or persons whose veins have been damaged by repeated venipuncture, or after prolonged hospitalization.

For persons on maintenance hemodialysis, tunneled catheters are used.

Translumbar or transhepatic approaches into the inferior vena cava may be required if the superior vena cava or other central veins draining the upper extremities are stenosed or thrombosed.

Typical forearm loop graft access along with location of stenosis in failing grafts

Goals of Dialysis The HD procedure is targeted at removing

both low- and high-molecular-weight solutes. Fractional removal of urea nitrogen and its

derivations are considered to be the standard methods by which "adequacy of dialysis" is measured.

For the majority of patients with ESRD, between 9 and 12 h of dialysis are required each week, usually divided into three equal sessions.

Several studies have suggested that longer hemodialysis session lengths and more frequent cycles may be beneficial.

Complications of HD Hypotension Muscle cramps Dialysis disequilibrium syndrome Restless leg syndrome Arrhythmia and angina hypoglycemia Hemorrhage Blood membrane interaction Intradialytic hemolysis

Peritoneal dialysis In peritoneal dialysis, 1.5–3 L of a dextrose-

containing solution is infused into the peritoneal cavity and allowed to dwell for a set period of time, usually 2–4 h.

As with hemodialysis, toxic materials are removed through a combination of convective clearance generated through ultrafiltration and diffusive clearance down a concentration gradient.

The rate of peritoneal solute transport varies from patient to patient and may be altered by the presence of infection (peritonitis), drugs, and physical factors such as position and exercise.

Forms of peritoneal dialysis PD for ESRD is nowadays delivered either as

Continuous Ambulatory Peritoneal Dialysis - CAPD or as Continuous Cyclic Peritoneal Dialysis - CCPD.

The old modality of intermittent PD whereby patients attended a PD unit two or three times a week for 10 to 24 hours of treatment at a time is now considered an inadequate therapy.

Forms of PD CAPD

Dry day APD

CCPD

APD with two Day Dwells

APD with short day Dwells

TIDAL PD with no day dwell

Access to the peritoneal cavity- Various PD catheters

PD solutions Lactate is the preferred buffer in peritoneal dialysis

solutions. Standard peritoneal solutions have, been based on the use

of glucose as the osmotic agent, however there have been increasing concerns in recent times – due to its toxic effects on the peritoneal membrane and the potentially adverse cardiovascular effects of its constant systemic absorption.

Recently, a nonabsorbable carbohydrate (icodextrin) has been introduced as an alternative osmotic agent. Studies have demonstrated more efficient ultrafiltration with icodextrin than with dextrose-containing solutions.

The most common additives to peritoneal dialysis solutions are heparin to prevent obstruction of the dialysis catheter lumen with fibrin and antibiotics during an episode of acute peritonitis.

Insulin may also be added in patients with diabetes mellitus.

Complications of PD Peritonitis

Gram positive 71% (MC-CONS, Staph aureus) Gram negative 24%(MC-E.coli)

Mechanical complications Hernias Diaphragmatic tear – hydrothorax Gastric reflux

Metabolic complications Hyperglycemia Hyperlipidemia Hypoalbuminemia Hypokalemia>hyperkalemia hyponatremia

Encapsulating Peritoneal Sclerosis Encapsulating peritoneal sclerosis (EPS), the most feared

complication of PD, is an uncommon but dramatic condition in which gross sclerosis of the peritoneal membrane occurs to a degree that causes encapsulation of the intestines with consequent obstructive ileus, leading to anorexia and weight loss.

There is typically hemorrhagic ascites, and there are often features of systemic inflammation including anemia, high serum C-reactive protein, low serum albumin. and low-grade fever.

Radiologic features include calcification of the peritoneum with formation of an encapsulating fibrotic cocoon around the bowels, loculated ascites, adherent and dilated bowel loops, and air-fluid levels.

The mortality rate is in the range of 30% to 50%.

The cause is unknown. A similar condition labeled idiopathic occurs in patients without renal failure and other cases occur in association with use of β-blockers, autoimmune disease, and malignancy

Acute Peritoneal Dialysis The use of PD to treat acute renal failure is much less

common than was the case 2 decades ago. The widespread availability of conventional hemodialysis,

combined with better strategies to avoid bleeding and maintain hemodynamic stability have led to a decrease in emergent PD use.

Nevertheless, the modality is still regularly used especially in developing countries.

Peritoneal access is via a Tenchkoff catheter. Most commonly, acute PD is delivered as exchanges

every 1 to 2 hours, done either manually or with a cycler. A recent trial comparing acute PD and hemodialysis in a

Vietnamese population in which malaria was the main cause of acute renal failure showed inferior outcomes with PD but it is unclear how much these results can be extrapolated to other settings.

Renal transplantation

Transplantation of the human kidney is the treatment of choice for advanced chronic renal failure.

Studies comparing transplant recipients to patients on the deceased donor transplant waiting list have shown that survival is better after kidney transplantation than on dialysis

Recipient Selection There are few absolute contraindications

to renal transplantation. The transplant procedure is relatively

noninvasive, as the organ is placed in the inguinal fossa without entering the peritoneal cavity.

Recipients without perioperative complications can often be discharged from the hospital in excellent condition within 5 days of the operation.

All candidates must have a thorough risk-versus-benefit evaluation prior to being approved for transplantation.

In particular, an aggressive approach to diagnosis of correctable coronary artery disease, presence of latent or indolent infection (HIV, hepatitis B or C, tuberculosis), and neoplasm should be a routine part of the candidate workup.

Most transplant centers consider overt AIDS and active hepatitis to be absolute contraindications to transplantation because of the high risk of opportunistic infection.

HLA typing: Tissue typing identifies the two alleles encoded in at each

of the three loci (A,B,DR). The term HLA matching means assigning a donor to a

recipient, after typing both, with few mismatches as possible

Cross matching test (T-cell cross match test): The serum of a potential recipient is incubated with cells

from the possible donor to see whether the recipient would destroy the transplant by anti-body mediated rejection.

Panel reactive antibodies: It is determined by testing the serum of the patient against

a panel of cells or antigens prepared from many different donors using flow-cytometry. The results are expressed as percentage of positive donors.

Cross matching prevents a transplant from being given to a recipient who has preexisting antibodies to the transplant. Usually done immediately before a cadaver transplant.

PRA measurement determines how many anti-HLA antibodies a person has which predicts whether he or she will have difficulty getting a transplant.

Long-term graft survival as a function of donor source and HLA matching

Immunosuppressive - Antibody Preparations

Depleting Antibodies They are prescribed in two situations:

○ (1) as induction therapy in the first week after transplant (especially in patients with delayed graft function (DGF) or at high risk of acute rejection) and

○ (2) for reversal of severe acute rejection. Polyclonal Antibodies

○ Polyclonal antibody preparations are manufactured by immunizing horses or rabbits with human lymphoid tissue. Rabbit thymoglobulin is probably the polyclonal agent of choice.

Anti-CD3 Monoclonal Antibodies ○ OKT3 is a mouse monoclonal antibody raised against the CD3-

receptor complex on human T cells. It is not widely used today. Anti-CD52 Monoclonal Antibody

○ Alemtuzumab (Campath 1H) is a humanized antibody directed against the CD52 antigen, which is present on all blood mononuclear cells. It causes profound and long-lasting depletion of both T and B cells.

Non-depleting:Anti-IL2R Monoclonal Antibodies

○ Unlike the polyclonals and OKT3, humanized/chimeric anti-IL2R monoclonal antibodies have the potential for more specific immunosuppression because the full IL-2 receptor is expressed only on activated T cells.

○ They are used for induction immunosuppression but not for treatment of acute rejection.

Belatacept ○ Belatacept (LEA29Y) is a novel second-generation

CTLA-4Ig that binds with higher affinity to B7-1/2 and prevents effective T cell activation by blocking the CD28 costimulation pathway.

Drug Mechanism Side effect

Glucocorticoids Binds cytosolic receptors and heat shock proteins. Blocks transcription of IL-1,-2,-3,-6, TNF-α, and IFN-γ

Hypertension, glucose intolerance, dyslipidemia, osteoporosis

Cyclosporine (CsA)

Trimolecular complex with cyclophilin and calcineurin block in cytokine (e.g., IL-2) production; however, stimulates TGF- production

Nephrotoxicity, hypertension, dyslipidemia, glucose intolerance, hirsutism/hyperplasia of gums

Tacrolimus (FK506)

Trimolecular complex with FKBP-12 and calcineurin block in cytokine (e.g., IL-2) production; may stimulate TGF- production

Similar to CsA, but hirsutism/hyperplasia of gums unusual, and diabetes more likely

Azathioprine Hepatic metabolites inhibit purine synthesis

Marrow suppression (WBC > RBC > platelets)

Mycophenolate mofetil (MMF)

Inhibits purine synthesis via inosine monophosphate dehydrogenase

Diarrhea/cramps; dose-related liver and marrow suppression is uncommon

Sirolimus Complexes with FKBP-12 and then blocks p70 S6 kinase in the IL-2 receptor pathway for proliferation

Hyperlipidemia, thrombocytopenia

Delayed graft function DGF DGF is defined as the requirement of

dialysis in the first 7 days after transplant. Occurs in 20-25% of cadaver transplants. Most commonly due to postischemic ATN

caused by donor hypovolemia, or prolonged cold or warm ischemia.

USG done to rule out technical causes. Biopsy to differentiate from acute rejection in high risk patients.

Acute rejection There are several types:

Hyperacute – is rare and caused by preformed antibodies leading to immediate graft destruction after perfusion.

Accelerated acute – occurs 2-3 days after transplant and is an antibody-mediated process that occurs in presensitized patients with prior transplants, transfusions or pregnancies.

Acute cellular rejection – T-cell mediated response occurs after 5-7 days post transplant until 4 weeks with gradual lessening of risk in the first 6 monts.

In the modern era of immunosuppression the clinical presentation of acute rejection is subtle and is rarely characterized by fever, swelling, and tenderness over the allograft.

Increase in serum creatinine 25% above baseline without and other attributable cause should raise the suspicion of acute rejection.

Calcineurin inhibitors (cyclosporine or tacrolimus) may cause deterioration in renal function in a manner similar to a rejection episode. Biopsy is usually needed to differentiate.

The first rejection episode is usually treated with IV administration of methylprednisolone, 500–1000 mg daily for 3 days.

Failure to respond is an indication for antibody therapy, usually with OKT3 or antithymocyte globulin.

Medical management of the kidney transplant recipient Cardiovascular disease

Post transplant patients are more likely to die of cardiac causes than due to graft failure.

There is 10 fold increase in CV mortality in transplant recipients.

The principle causes are○ Hypertension○ Post transplant DM○ Post transplant Dyslipidemia○ Hyperhomocysteinemia

Hypertension:Present in 50- 90% of pts.Preexisting HT, tacrolimus, cyclosporine, steroids,

Chronic Allograft Nephropathy, episodes of acute rejection, recurrent or de novo glomerulonephritis, transplant renal artery stenosis all have been implicated.

Non dihydropyridine CCBs and diuretics are used in the early post transplant period.

ACE inhibitors or ARBs have gained in popularity recently, however an increase in serum creatinine >30% above baseline should alert the clinician about the possibility of renal artery stenosis.

B blockers should be used in patients with preexisting CAD.

• Post transplant Diabetes mellitus Occurs in 4- 25% of pts. Risk factors are race –Indian, age >40, family

history, IGT prior to transplant, hypertension, HCV, CMV, immunosuppressive drugs – steroids, tacrolimus, cyclosporine(lesser extent).

Insulin may be needed in upto 40% of patients. Metformin is preferred in obese patients with normal graft function. Sulphonylurea derivatives must be used with caution as they are likely to cause hypoglycemia.

Post transplant dyslipidemia:The prevalence of hypercholesterolemia and

hypertriglyceridemia after transplant is very high. Steroids, CNIs (cyclosporine more than tacrolimus),

and sirolimus are the principal causes. The renal transplant state is considered as a

coronary heart disease risk equivalent, so the target LDL cholesterol should be less than 100 mg/dL (or perhaps less than 70 mg/dL).

Many patients require pharmacologic treatment to achieve target lipid values; usually statins are used.

Hyperhomocysteinemia:As in the general population,

hyperhomocysteinemia has been proposed as a risk factor for cardiovascular disease in renal transplant recipients.

Plasma homocysteine concentrations typically fall after transplant but do not normalize.

however interventions to lower homocysteine cannot be recommended at this time.

Infections

Peritransplant (<1 month)

Early (1–6 months) Late (>6 months)

Wound infections Pneumocystis carinii Aspergillus

Herpesvirus Cytomegalovirus Nocardia

Oral candidiasis Legionella BK virus (polyoma)

Urinary tract infection Listeria Herpes zoster

Hepatitis B Hepatitis B

Hepatitis C Hepatitis C

The Most Common Opportunistic Infections in the Renal Transplant Recipient

Prophylactic therapy for recipients of renal transplants

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Trimethoprim-sulfamethoxazole (TMP/SMX)

Routine use eliminates the incidence of pneumocysits carinii, listeria monocytogenes, nocardia asteroides and toxoplasmosis gondii.Also reduces the incidence of UTI from 30-80% to <5-10%

Monthly intravenous or aresolized pentamidine or dapsone or atovaquone

Replaces TMP/SMX for patients with sulfa allergies

Nystatin 4ml after meals and before bedtime

For fungal prophylaxis

Acyclovir, valgancyclovir, gancyclovir

For CMV prophylaxis

Recommended immunization before and after transplantation

Vaccine Before After

MMR Yes -

DPT Yes dT

Varicella Yes Controversial

Polio Yes -

Hemophillus influenzae B

Yes Yes

Influenza yes Yes

Pneumococcus Yes Yes

Hepatitis B Yes Yes

Hepatitis A Yes Yes

MalignancyThe incidence of tumors in patients on

immunosuppressive therapy is 5–6%, or approximately 100 times greater than that in the general population of the same age range.

The most common lesions are cancer of the skin and lips and carcinoma in situ of the cervix, as well as lymphomas such as non-Hodgkin's lymphoma.

ELECTROLYTE DISORDERS Hypercalcemia

Hypercalcemia is common and is due mainly to persistent hyperparathyroidism or administration of calcium and vitamin D.

Treatment is correction of hyperparathyroidism. Hypophosphatemia

Hypophosphatemia is also common in the early post-transplant period, particularly when allograft function is excellent and is mainly due to excess urinary excretion of phosphate.

This hyperphosphaturia has several causes: residual hyperparathyroidism, glucocorticoids, low vitamin D state, and a putative humoral factor, phosphatonin.

Rarely, phosphate depletion is severe enough to cause profound muscle weakness, including respiratory muscle weakness.

Treatment involves high-phosphate diet (e.g., low-fat dairy products), oral phosphate supplements, and vitamin D analogs, to achieve a tagret of 2.5 to 4.0 mg/dL.

Hyperkalemia Mild hyperkalemia is common, even with good allograft function. The principal cause is CNI-induced impairment of tubule

potassium secretion. Treatment is often not required; exacerbating factors should be

minimized. Metabolic Acidosis

Mild metabolic acidosis is often associated with hyperkalemia. In most cases, it has the features of a distal (hyperchloremic)

renal tubular acidosis. This reflects tubule dysfunction caused by CNIs, rejection, or

residual hyperparathyroidism. Oral bicarbonate is given in severe cases.

Other Electrolyte Abnormalities Hypomagnesemia is common and due to a magnesuric effect of

the CNIs. It is usually asymptomatic. Magnesium supplements are sometimes prescribed when the

plasma magnesium level is less than 1.5 mg/dL.

Bone disorders after renal transplantation:Hyperparathyroidism Gout Calcineurin inhibitor associated bone painOsteonecrosisosteoporosis

Chronic allograft nephropathy -CAN Chronic allograft dysfunction is the term used to

describe a persistent (over weeks to months) decrease in transplant GFR, with or without persistent proteinuria. The causes are most commonly CAN, recurrent disease, calcineurin inhibitor nephropathy.

CAN is the most common cause of Graft Failure in the first post transplant decade.

CAN is a histologic diagnosis characterized by glomerulosclerois, fibrointimal thickening, of large and medium sized arteries, tubulointestitial fibrosis.

When CAN is associated with evidence of inflammation it is termed chronic rejection.

Risk factors for CANAlloantigen-Dependent (immune) risk factors

Alloantigen-Independent (non-immune) risk factors

Acute rejection (incl subclinical) Kidney size mismatch

MHC antigen mismatches Proteinuria

Previous transplantation Older donor age

Cadaver donor Hypertension

Younger recipient age Dyslipidemia

Delayed graft function Smoking

CMV infection

Alloantigen dependent (oval shaded) and independent factors (rectangular shaded) thought to be involved in the pathogenesis of

chronic allograft nephropathy.

Strategies to prevent and treat CAN

Minimize acute rejectionUse adequate immunosuppressionMonitor graft function and urinary proteinBiopsy for unexplained increase in Cr or urinary protein

Minimize subclinical acute rejectionUse adequate immunosuppression

Consider elective withdrawal of calcineurin inhibitors after 1yr

Reduce proteinuriaUse ACE inhibitors or ARB

Control blood pressure<130/80 if proteinuria <1g/dl<125/75 if proteinuria >1g/dl

Treat other cardiovascular riskTarget LDL <100mg/dlSmoking cessation

Recurrence of primary disease in renal grafts

References:Brenner and rector’s The Kidney 8th ed.Comprehensive Clinical Nephrology by John Feehally 3rd ed.Harrison’s Principles of Internal Medicine 17th ed.