This document discusses the use of renal replacement therapy (RRT) such as hemodialysis in intensive care unit (ICU) patients for non-renal indications. It describes how RRT can help treat conditions like sepsis, acute respiratory distress syndrome (ARDS), and complications from cardiopulmonary bypass by removing inflammatory mediators and excess fluid. The document also indicates that early, intensive RRT may improve outcomes for patients going into cardiogenic shock after cardiac surgery. RRT is presented as a way to support multiple organ systems beyond just the kidneys.

1. Non Renal Indication Hemodialysis in ICU
Mohammad Ruly Ardiansyah

2. INTRODUCTION
• Renal replacement therapy (RRT) is a common supportive treatment for renal
dysfunction, especially acute kidney injury or Chronic Kidney Disease ( CKD )
• There are other illnesses without renal involvement where RRT might be of
value.
• Critically ill or immunosuppressed patients with renal dysfunction often have
dysfunction in other organs as well.
• To improve patient outcomes, clinicians began to initiate kidney replacement
therapy in situations where nonrenal conditions may lead to acute kidney injury,
such as septic shock, hematopoietic stem cell transplantation, veno-occlusive
renal disease, cardiopulmonary bypass, chemotherapy, tumor lysis syndrome,
hyperammonemia, and various others.
• In this review, we discuss the use of various modes of kidney replacement
therapy in treating nonrenal complications to illustrate why kidney support
therapy is a more appropriate terminology than kidney replacement therapy.

4. SYSTEMIC INFLAMMATORY RESPONSE
SYNDROME AND SEPSIS
Sepsis and other inflammatory syndromes represent the most
popular non-renal indications for RRT

5. Sepsis is a systemic inflammatory response induced by an infection, leading to organ dysfunction and
mortality. Historically, sepsis-induced organ dysfunction and lethality were attributed to the interplay
between inflammatory and antiinflammatory responses. With advances in intensive care management and
goal-directed interventions, early sepsis mortality has diminished, only to surge later after "recovery" from
acute events, prompting a search for sepsis-induced alterations in immune function. Sepsis is well known to
alter innate and adaptive immune responses for sustained periods after clinical "recovery," with
immunosuppression being a prominent example of such alterations. Recent studies have centered on
immune-modulatory therapy. These efforts are focused on defining and reversing the persistent immune cell
dysfunction that is associated with mortality long after the acute events of sepsis have resolved.

6. ➢ The serial theory postulates an initial
systemic inflammatory process
followed by inhibition of systemic
inflammation and immune
hyporesponsiveness.
➢ In the parallel theory, both processes
occur simultaneously and parallel
synthesis of pro-and antiinflammatory
mediators coexist in different
compartments of the body.
(Reprinted from Ronco C, Bonello M, Bordoni V, et al.
Extracorporeal therapies in non-renal disease: treatment of
sepsis and the peak concentration hypothesis. Blood Purif.
2004;22:164 –174, with permission from S. Karger AG,
Basel.) CARS, compensatory antiinflammatory response
syndrome; SIRS, systemic inflammatory response
syndrome.
The serial (sequential) theory of sepsis and the parallel
theory

7. Peaks of mediators characteristic of systemic inflammatory response syndrome (SIRS) and compensated anti-
inflammatory response syndrome (CARS) may be seen in sequence or in parallel. Broad-based control of peaks
with continuous renal replacement therapy (CRRT) is hypothesized to lessen the degree of imbalance and restore
immunohomeostasis. IL-1, interleukin-1; IL-10, interleukin-10; PAF, platelet-activating factor; TNF, tumor necrosis
factor. Adapted from reference (19), with permission from Wiley-Blackwell Publishing, Ltd.
Peak concentration hypothesis

10. ACUTE RESPIRATORY DISTRESS
SYNDROME
Beside the eventual elimination of inflammatory mediators, fluid
removal with reduction of extravascular lung water (EVLW) is a
second mechanism by which hemofiltration may be beneficial in
ARDS.

11. However, what they actually
showed was a better survival
in the patients who responded
to diuretics, dialysis, or
ultrafiltration with a lowering
of PCWP compared with
patients in whom the same
treatment had no effect on the
wedge pressure. In other
words, they were probably
comparing different patients

12. Contrib Nephrol. 1991; 93: 65-70
Laggner et al compared the effect of ultrafiltration on the EVLW of
patients with cardiogenic pulmonary edema and ARDS, and showed
a decrease of the shunt fraction in both groups. However, the
reduction of EVLW was less pronounced in ARDS patients in whom
hemofiltration also induced a decrease of cardiac output and
O2 delivery55
Ultrafiltration in ARDS patients should therefore be performed only
under close hemodynamic monitoring.

13. CARDIOPULMONARY BYPASS
• Another possible indication for hemofiltration is surgery with
cardiopulmonary bypass (CPB).
• CPB, especially in children, results in tissue edema, pulmonary
dysfunction, and poor cardiac performance caused by hemodilution
and fluid overload and to activation of the inflammatory response.
Isolated ultrafiltration, during and especially after CPB, in children has
been shown to reduce weight gain, blood loss, and transfusion
requirement, to improve left ventricular systolic and diastolic
function, to decrease pulmonary vascular resistance and to improve
oxygenation. It remains unclear, however, if these beneficial effects
are due to fluid removal alone or if the removal of inflammatory
mediators also contributes to these effects.

14. Cardiopulmonary bypass and the extracorporeal circulation responses with the pathophysiologic changes resembling the
systemic inflammatory response syndrome (SIRS). The contact of blood with xenosurfaces of the extracorporeal machine device,
the ischemia/reperfusion, and the hyperbaric oxygen triggered SIRS-like pathophysiological responses. The SIRS-like response is
associated with overactivation of leukocytes, platelets (which can contribute to an increased coagulopathy), and endothelial and
cardiac cell. The secretion of proinflammatory factors by leucocytes and the increase tension and blood oxygenation stimulate
the overproduction of reactive oxygen species (ROS), which feeds a vicious cycle of inflammation ROS production.
Inflammatory Response in Patients under Coronary Artery
Bypass Grafting Surgery

15. The inflammatory response to cardiopulmonary bypass is
divided into 2 phases: “early” and “late” phases. The first phase
is induced by the contact with xenosurfaces and the late phase
is more related to oxygen reperfusion after ischemia and
endotoxemia.
Inflammatory Response in Patients under Coronary Artery
Bypass Grafting Surgery……….

16. Complex cascade of pathophysiologic phenomena associated with ischemia/reperfusion in CABG. Anaerobic metabolism causes an
increase on lactate and reduced pH with transmembrane pump impairment, which lead to an intracellular Ca2+ and Na+ increases,
and consequently cellular edema. Increase on intracellular Ca2+ activated phospholipase A2 and calpain, with arachidonic acid
degranulate and protein synthesis inhibition. Thus, caspase and neutrophil activation occur with cellular apoptosis. The neutrophils
activation induces membrane lesions and more proinflammatory mediators liberation, including nitric oxide, via nitric oxide
synthase (NOS) activation and that leads to microvascular damage and endothelial impairment, in a vicious circle.

17. Objective
Continuous renal replacement therapy (CRRT) is currently the mainstay renal support for
critically ill patients. However, the optimal intensity of CRRT remains debated owing to the
heterogeneity of the study populations and CRRT techniques across centers. The present study
investigated the beneficial effects of early and intensive continuous
venovenous hemofiltration (CVVH) on patients with shock after cardiotomy.
Methods
Patients who had received CRRT for cardiogenic shock and acute kidney injury after cardiac
surgery from January 2003 to December 2007 were retrospectively recruited. They were
divided into 2 groups according to the delivered dosage of hemofiltration.
Results
The mean duration between intensive care unit admission and initiation of CVVH was 1.4 ± 0.8
days. The all-cause mortality by day 30 was 73.3% and 45.4% in the low- and high-dose groups,
respectively (P = .002). The corresponding in-hospital mortality rate was 82.2% and 61.8%
(P = .02). No significant difference was seen in the renal recovery of the survivors between the
2 groups.
Conclusions
In patients developing postoperative cardiogenic shock and acute kidney injury after cardiac
surgery, an early higher CVVH dose was associated with better in-hospital and long-term
survival. Moreover, the beneficial effect of intensive treatment might be more critical in the
early perioperative period.

18. CONGESTIVE HEART FAILURE
• In congestive heart failure (CHF), the reduced systemic blood flow is perceived as a reduced effective circulating volume
resulting in the activation of several neurohumoral systems such as the sympathetic system and the renin-angiotensin-
aldosterone system, and in the release of vasopressin. This inappropriate activation results in arteriolar vasoconstriction (further
increasing the afterload) and in water retention caused by enhanced renal sodium reabsorption leading to an increase in filling
pressures and edema. The treatment of refractory CHF requires an interruption in the vicious neurohumoral hemodynamic
cycle, and this can mostly be achieved with diuretics, vasodilators, and βbgr blocking agents
• Some patients remain refractory to this medical treatment, and in these patients, the removal of fluids and sodium can be
achieved with simple ultrafiltration. Canaud treated 52 patients with chronic heart failure and New York Heart Association
(NYHA) class IV with isolated ultrafiltration. In 35 surviving patients, ultrafiltration resulted in an increase of diuresis and sodium
excretion, and a further decrease of body weight after interruption of the procedure. Despite fluid removal, arterial pressure
remained stable and patients recovered to NYHA class II or III
• Other authors also report a decrease of neuroendocrine factors such as norepinephrine, aldosterone, vasopressin, and plasma
renin activity, a striking increase of water and sodium excretion, a more sustained improvement in functional capacity than with
supplementary doses of loop diuretics, a re-established response to traditional medical treatment, and an improvement of the
quality of life
• Recently established guidelines for the treatment of chronic heart failure (Task Force of the Working Group on Heart Failure of
the European Society of Cardiology) mention ultrafiltration as an aid to gain time while waiting for a transplantation

19. The study indicates that: (1) hemofiltration may be a
short-term treatment for refractory cardiac
insufficiency with overhydration; (2) a filtration rate of
500 ml/hour is effective and safe; and (3) the central
venous pressure may be a reliable guide to volume
subtraction.
Kidney International, Vol. 56, Suppl. 72 (1999), pp. S-95–S-98
In severe CHF, hemofiltration is a helpful tool to treat the
decompensated patient, who is resistant to diuretics
REFERENCES and suffers from massive fluid overload.

20. Recommendations for the use of HDF in clinical practice
UF recommendations for HF from the 2013 guideline by
the American College of Cardiology
Foundation/American Heart Association Task Force are
shown in table below along with recommendations from
the Canadian Cardiovascular Society and the European
Society of Cardiology

21. INBORN ERRORS OF METABOLISM
• Children with maple syrup urine disease, urea cycle disorders,
and organic acidemia can produce high levels of branched-
chain amino acids and hyperammonemia, inducing irreversible
damage, especially in the central nervous system.
• Continuous venovenous hemofiltration (CVVH) and especially
continuous venovenous hemodialysis (CVVHD) are rapidly
effective in clearing these low molecular weight toxic
metabolites, allowing the patients to recover their neurological
status

22. LACTIC ACIDOSIS
• A few case reports suggest that continuous hemofiltration, by extracorporeal
elimination of lactate, may contribute to the correction of lactic acidosis76
• Levraut et al recently demonstrated that in patients with a normal lactate level
and stable hemodynamic and respiratory status, the contribution of continuous
bicarbonate hemodiafiltration to the total body clearance of lactate only
represents 0.5 to 3.2%
• They conclude that the reported reduction in lactate level during hemofiltration
probably reflects an improvement in acid-base and metabolic status leading to
enhanced lactate metabolism
• However, in patients with an increased lactate level and reduced endogenous
clearance caused by liver dysfunction, the contribution of extracorporeal
elimination might indeed become clinically important, especially if extracorporeal
clearance is substantial (high-volume hemofiltration or dialysis). In addition,
bicarbonate hemo(dia)filtration minimizes hypervolemia and hypernatremia, both
of which are side effects of bicarbonate administration

24. CRUSH INJURY
• Because the molecular weight of myoglobin is 17,000 Da and thus
compatible with convective removal, hemofiltration might represent a
means to prevent renal failure in crush injury and other causes of
rhabdomyolysis and myoglobin gaining access to the circulation. The
presence of myoglobin in the filtrate has indeed been demonstrated.
• Found a rapid fall in myoglobin levels, regardless of renal function or
the method of blood purification, suggesting extrarenal catabolism of
myoglobin
• Adequate fluid resuscitation combined with urinary alkalinization
remain the mainstays in the treatment of crush injury.

25. TUMOR LYSIS SYNDROME
• Tumor lysis syndrome (TLS) describes a constellation of biochemical and clinical abnormalities
resulting from rapid and massive tumor cell death.
• TLS is frequently associated with hyperuricemia, hyperkalemia, hyperphosphatemia, and secondary
hypocalcemia that may lead to serious clinical complications, including acute kidney injury and
cardiac arrest.
• Tumor lysis syndrome may lead to renal failure caused by tubular obstruction by uric acid crystals or
to hyperphosphatemia with precipitation of calcium/phosphate complexes in renal interstitium and
tubuli
• Both uric acid and phosphate are small molecules that require a highly diffusive clearance, and
conventional dialysis is certainly more effective than the continuous techniques; however, CRRT
can been used in unstable patients or in combination with intermittent dialysis
• The prevention of ARF in tumor lysis syndrome relies on the stimulation of diuresis combined with
allopurinol.
• CRRT has been used to prevent ARF in high-risk patients, who were defined based on the level of
LDH and the urine output