The correct answer is B

Comment: The patient underwent treatment with CVVH, because of his altered mental status, hyponatremia, metabolic acidosis, electrolyte imbalance, oliguric AKI, and increased serum creatinine and creatinine phosphokinase levels resulting from septic shock and hepatic failure.

CVVH is the simplest and most widely used CRRT in pediatric patients and is a highly effective method of solute removal and is indicated for uremia, severe metabolic acidosis, or electrolyte imbalance with or without fluid overload. CVVH is particularly efficient at removing small and large molecules (e.g., B12, tumor necrosis factor) via convection using a pre- and/or postfilter replacement solution at about 35 mL/kg/h. Solutes can be removed in large quantities while easily maintaining a net zero or even a positive fluid balance in the patient. The amount of fluid in the effluent bag is equal to the amount of fluid removed from the patient plus the volume of replacement fluids administered. No dialysis solution is used.

CVVH adds use of pumped replacement fluids, either pre- or postfilter, to enhance middle molecule clearance by convection. The maximum patient fluid removal rate is 1000 mL/h.

Replacement solutions in CVVH are infused into the blood circuit using replacement pump 1 through the purple line of the Prismaflex set and/or replacement pump 2 through the green line of the Prismaflex set. Replacement pump 1 infuses solution pre- or postfilter, and pump 2 infuses fluid postfilter only.

The primary therapeutic goal of CVVH is water and solute removal across a semipermeable membrane to provide fluid balance and to control electrolyte balance. Continuous hemofiltration with the aid of a blood pump provides solute removal by convection.

A replacement solution is required to drive convection. This type of convection uses no countercurrent dialysate solution. It offers high-volume ultrafiltration using replacement fluid, which can be administered prefilter (or postfilter). By reducing the hematocrit at the blood inlet, predilution is believed to reduce clotting. Postdilution will require less replacement fluid to achieve a given clearance (dose). A combination of predilution, for example, by the predilution pump, and postdilution by the replacement pump would provide benefits in several areas and provide the flexibility required to treat a given patient. Predilution also means a loss between 15% and 35% of clearance (dose), depending on the flow rates. The pump guarantees adequate blood flow to maintain required ultrafiltration (UF) rates. Venous blood access is usually femoral, jugular, or subclavian using a double-lumen cannula.

Replacement solutions for CVVH can be normal saline, lactated Ringer’s solution, total parenteral nutrition, routine intravenous fluids, or pharmacy-made solutions. Bicarbonate-based buffered replacement solutions are preferred for patients with hepatic failure because these patients may not be able to convert lactate to bicarbonate.

Replacement fluid is given at a rate of 2000 mL/L/1.73 m ² (35 mL/kg/h) into the circuit either before blood reaches the membrane (predilution) or after passage over the filter membrane (postdilution).

Prefilter dilution increases the hemofilter membrane filter life. It also increases convective solute transport. Prefilter dilution reduces solute clearance and lowers anticoagulation requirements. Some of the delivered replacement fluid will be lost by hemofiltration; thus, higher UF is required given the loss of replacement fluid through the filter. In postdilution, the drug clearance equals the UF rate, whereas in predilution the replacement fluid should be considered when calculating clearance.

It is recommended to base the decision when to start CRRT not only on the severity of acute renal failure but also on the severity of other organ failure.

Initiation of CRRT is to be considered in oliguric patients despite adequate fluid resuscitation and/or a persisting steep rise in serum creatinine, in addition to persisting shock.

Potential benefits of CRRT in patients with multiple organ dysfunctions include management of fluid balance, decreasing fluid overload, removal of inflammatory mediators, enhanced nutritional support, and control of electrolyte and acid-base abnormalities.

For cases involving AKI, particular attention should be paid to water and sodium retention and blood nitrogen levels, all of which have a significant impact on the treatment and survival of infants and young children, as well as the speed of progress. The characteristics of systemic disease are also important factors.

CVVH requires blood, effluent, and replacement pumps. Dialysate is not required. Plasma water and solutes are removed by convection and ultrafiltration. The convection transport mechanism removes middle and large molecular solutes as well as large volumes of fluid simultaneously. This transport mechanism is used in CVVH and CVVHDF.

Bicarbonate-based or lactate-based replacement fluids are used (pre- or postfilter) based on the patient’s clinical need. Higher replacement fluid rates increase convective clearances.

CVVHD requires the use of blood, effluent, and dialysis pump. Replacement solution is not required. Plasma water and solutes are removed by a combination of diffusion and UF. Dialysate is used to create a concentration gradient across a semipermeable membrane. This transport mechanism is used in CVVHD and CVVHDF. Through diffusion, dialysate corrects underlying metabolic imbalances. Dialysate is dependent on buffering agent, electrolytes, and glucose concentrations. Dialysate composition should reflect normal plasma values to achieve homeostasis. Bicarbonate-based solution is physiologic and replaces lost bicarbonate immediately. A bicarbonate concentration of 30 to 35 mEq/L corrects metabolic acidosis in 24 to 48 hours. It is a superior buffer in normalizing acidosis without the risk of alkalosis. Bicarbonate-based solution is also a preferred buffer for patients with liver failure. It improves hemodynamic instability with fewer cardiovascular events.

Lactate-based solution is metabolized into bicarbonate in the liver on a 1:1 in subjects with normal liver function and can sufficiently correct acidemia. However, lactate-based solution has a pH value of 5.4 and is a powerful peripheral vasodilator leading to further acidemia for patients with hypoxia, liver impairment, and preexisting lactic acidemia.

The replacement and dialysate fluids should have the same composition to reduce staff confusion and the risk for error.

CVVHDF requires the use of blood, effluent, dialysate, and replacement pumps. Both dialysate and replacement solutions are used. Plasma water and solutes are removed by diffusion, convection, and UF. In CVVHDF, removal of small molecules is achieved by diffusion through the addition of dialysate solution and removal of middle and large molecules by convection through the addition of replacement solution. This transport mechanism is used only in CVVHDF.

In general, CRRT clearance of solute is dependent on the molecule size of the solute, the sieving coefficient, and the pore size of the semipermeable membrane. The higher the UF rate, the greater the solute clearance. Small molecules easily pass through a membrane driven by diffusion and convection. Middle- and large-size molecules are cleared primarily by convection. The semipermeable membrane removes solutes with a molecular weight of up to 50,000 Da. Plasma proteins or substances that are highly protein bound will not be cleared.

The sieving coefficient of a molecule is the ability of a substance to pass through a membrane from the blood compartment of the hemofilter to the fluid compartment. A sieving coefficient of 1 will allow the free passage of a substance but a sieving coefficient of 0 indicates that the substance is unable to pass. The sieving coefficient of sodium is 0.94, potassium 1.0, creatinine 1.0, and albumin 0.

It is recommended to continue CRRT as long as the criteria defining severe oliguric AKI are present. If the clinical condition improves, it may be considered to wait before connecting a new circuit to see whether renal function recovers. CRRT should be restarted in case of clinical or metabolic deterioration.

CRRT may be postponed when the underlying disease is improving, other organ failure is recovering, and the slope in the serum creatinine rise declines to see if renal function is also recovering.

Establishing vascular access is a key factor for successful CRRT in children. The internal jugular vein is the primary site of choice because of a lower associated risk of complications and simplicity of catheter insertion. The femoral vein is optimal and constitutes the easiest site for insertion. The subclavian vein is the least preferred site given its higher risk of pneumonia/hemothorax and its association with central venous stenosis. The length of the catheter chosen will depend on the site used. Two single-lumen venous hemodialysis catheters can be used in infants. Recommended catheters by age are <6 months, 4 to 5 Fr single lumen; 6 to 12 months, 5 to 7 Fr double lumen; 1 to 3 years, 8 to 9 Fr double lumen; and >3 years, 8 to 12 Fr double lumen.

The semipermeable membrane is structurally designed to allow high fluid removal and molecular cutoff weight of 30,000 to 50,000 Da. The membrane provides an interface between the blood and dialysate compartment. The membrane biocompatibility minimizes severe patient reactions and decreases the complement activation.

Filters and tubing with a low prefilled volume should be used to reduce the blood volume in extracorporeal circulation and help ameliorate the decrease in effective circulating blood volume. Filters with a high-molecular-weight polymer membrane, high permeability, good biocompatibility, and small impact on the coagulation system should be selected. The use of AN69 membranes has been linked to bradykinin release syndrome among patients who are acidotic or taking angiotensin-converting enzyme inhibitors. Alternative membranes should be used in such cases. Generally, the blood volume in extracorporeal circulation should be maintained at <10 % of body weight (e.g., <30 mL in neonates, <50 mL in infants, <100 mL in children). For neonates weighing <2.5 kg, tubing can be prefilled with plasma, whole blood, or 5% albumin.

For continuous modes of renal replacement therapy to be effective, in terms of both effective solute clearance and fluid removal, the extracorporeal circuits must operate continuously. Thus, preventing clotting in the CRRT circuit is a key goal to effective patient management. Because these patients may also be at increased risk of bleeding, regional anticoagulation with citrate is increasing in popularity, particularly after the introduction of commercially available CRRT machines and fluids specifically designed for citrate anticoagulation. Although regional anticoagulation with citrate provides many advantages over other systemic anticoagulants, excess citrate may lead to metabolic complications, ranging from acidosis to alkalosis, and may also potentially expose patients to electrolyte disturbances from hyper- and hyponatremia and hyper- and hypocalcemia.

Transmembrane pressure should be monitored and maintained at <200 mm Hg (a transmembrane pressure >250 mm Hg may indicate clotting in the filter). Particular attention should be paid to warming the replacement fluid. The recommended flow rates are as follows: blood flow, 30 mL/min in neonates, 30 to 40 mL/min in infants/young children, 50 to 75 mL/min in children weighing <20 kg, and 75 to 100 mL/min in children weighing >20 kg; UF rate, 8 to 10 mL/min/m ² in neonates/infants and 8 to 15 mL/min/m ² in children (daily fluid input/output, cardiac function, and edema should be considered); and dialysates, 15 to 20 mL/min/m ² in neonates/infants/children.

A simple and easy method for estimating drug clearance as a function of total creatinine clearance when the information on the pharmacokinetics of a particular drug is not available is to add replacement fluid rate (CVVH) or dialysate flow rate (CVVHD), usually 2 L/1.73 m ² /h or 33 mL/1.73 m ² /min, to the patient’s native creatinine clearance (mL/1.73 m ² /min). This value is the patient’s new creatinine clearance, and drugs should be dosed accordingly.

Patients treated with continuous renal therapies in the intensive care unit are probably at risk for antibiotic underdosing and therapeutic failures.

Estimation of renal function in acute injury is very challenging, but recently short-interval creatinine clearance measurements have been demonstrated.

Widely available drug databases support individualized decision-making. There is little literature to support adjusting the loading dose of antibiotics in AKI. The sum of renal creatinine clearance and CVVH ultrafiltration provides a starting point for subsequent antibiotic dosing. When available, therapeutic drug monitoring should be used, especially for drugs with low therapeutic index. Loss of macro- and micronutrients is well documented during CRRT and, in general, requires replenishing or compensating eventual deficits.

The final aim should be to optimize the nutritional status of the patient and to reduce the so-called daily trauma induced by CRRT. Daily recommended energy requirements during CRRT fluctuate between 25 and 35 kcal/kg (60–70% carbohydrates and 30–40% lipids) and between 1.5 and 1.8 g/kg protein. Significant alterations of carbohydrate and lipid metabolism as well as severe electrolyte disturbances may be found in patients undergoing CRRT. Close monitoring of these metabolic parameters and their interactions is imperative. Energy requirements during CRRT are increased and should best be assessed by indirect calorimetry. However, this technique is not universally available and will need correction for the known bicarbonate/CO ₂ diversion induced by CRRT. The current European Society for Clinical Nutrition and Metabolism guidelines allow us to adequately supplement important micronutrients such as amino acids (glutamine), water-soluble vitamins, and trace elements. More widespread recognition of “daily trauma” and the use of an appropriate checklist may help the bedside clinician better assess and handle nutrition deficits in CRRT patients.

The correct answer is B

Comment: Several controlled studies have shown that locking the catheter with an antibiotic or antiseptic solution can reduce the incidence of bacteremia as much as 10-fold. Although the use of ultrapure water and ultrapure dialysate is recommended in general to combat a subtle inflammatory influence of dialysis, such measures will not protect against catheter-induced sepsis. Antibiotics given to the patient near the end of the dialysis treatment have little effect on catheter biofilm because the exposure is limited to both concentration and time. Replacing the catheter will resolve the problem, but it cannot be considered a prophylactic measure.

The correct answer is A

It has been well documented that with glucose (dextrose)-containing fluids, the crystalloid-induced transcapillary UF is dependent on maintaining an osmotic gradient between the peritoneum and the blood, which favors the movement of fluid from the blood to the peritoneum. The peritoneal membrane functions as an impermeable membrane and allows movement of most solutes down their concentration gradients. Unfortunately, glucose (dextrose) is readily absorbed, and eventually the concentration gradient for transcapillary UF no longer exists. At that time, UF ceases and lymphatic absorption predominates.

An ideal osmotic agent for PD solutions would either not be absorbed or would only very slowly be absorbed so that the osmotic gradient is maintained throughout the dwell. Icodextrin is such a solution. Icodextrin is a polymer that induces ultrafiltration via a colloid osmotic force. By substituting icodextrin for dextrose, one may be able to increase UF volume during long dwells (8–15 hours) when compared with dextrose-containing fluids. Because attention has returned to optimizing BP and volume control, it has been recognized that at times, the UF volume may be relatively sodium free. Crystalloid-induced UF is via small pores (salt and water removal) and transcellular aquapores (water removal only). Therefore, during short dwells, one may remove relatively less sodium than water. In contrast, colloid-induced UF is almost exclusively via small pores, so there is no discrepancy  between the relative amounts of salt and water removed during a typical dwell with a colloid osmotic agent. These differences must be appreciated when attempting to optimize BP control in PD patients.

The correct answer is A

Comment: Hemodialyzed patients are especially prone to acute volume overload after intravenous injection of radiographic contrast agents, including aortography or contrast-enhanced magnetic resonance imaging (MRI). Recent studies have shown that both gadolinium and iodinated radiographic contrast agents are rapidly and efficiently removed by hemodialysis and hemofiltration. Average removal rates of gadolinium were 78%, 95%, 98%, and after the first to third hemodialysis sessions. Physicians must also be alert to the significantly low serum calcium levels that may last up to 4.5 days after gadolinium administration. This effect of gadolinium is apparently dose related. ^,

The correct answer is D

Comment: QT dispersion, defined as the difference in duration between the longest and shortest QT interval on an electrocardiogram, is a method of approximating repolarization abnormalities. QT dispersion has been shown to independently predict cardiovascular mortality in incident dialysis patients. Intra-dialytic QT dispersion has been demonstrated to be inversely related to a dialysate calcium composition. ^,

The correct answer is D

Comment: L-carnitine is a readily dialyzed, low-molecular-weight metabolic intermediate. L-carnitine deficiency has been proposed as a contributor to myocardial dysfunction, hyperlipidemia, muscle weakness, and erythropoietin resistance in dialysis patients. The best evidence for the benefit of L-carnitine in maintenance dialysis patients is for the treatment of erythropoietin resistance.

The correct answer is D

Comment: As an index of solute clearance, Kt/V urea <1.2 serves as a generally accepted marker of inadequate dialysis doses. Patients with a large body mass are less likely to achieve an individual treatment target Kt/V urea of 1.2. Although each of the proposed solutions will increase weekly Kt/V urea, increasing the frequency of hemodialysis will have the greatest effect on weekly urea clearance by increasing the efficiency of the hemodialysis procedure. ^,

The correct answer is D

Comment: Strategies involving catheter removal coupled with a 3-week course of cefazolin intravenously have been demonstrated to be successful in achieving high cure rates. Antibiotic therapy alone results in an insufficient cure rate.

The correct answer is A

Comment: Intradialytic hypotension occurs in 15% to 25% of all hemodialysis treatments. Although many strategies to prevent this complication are at least partly successful, a recent prospective crossover study did not support the use of isolated UF followed by isovolemic dialysis. Each of the other four choices has demonstrated utility in preventing dialysis hypotension, albeit a head-to-head comparison of these four strategies has not been performed in a single study.

The correct answer is D

Comment: The management of pain in patients with CKD is challenging for many reasons. These patients have increased susceptibility to adverse drug effects from altered drug metabolism and excretion, and there are limited safety data for use in this population despite a high pain burden. NSAIDs have long been regarded as dangerous for use in patients with CKD because of the risk for nephrotoxicity; thus, alternative classes of analgesics, including opioids, have become more commonly used for pain control in this population. Given the well-established risks that opioids and other analgesics pose, further characterization of the risk posed by NSAIDs in patients with CKD is warranted. NSAID use has been associated with acute kidney injury, progressive loss of glomerular filtration rate in CKD, electrolyte derangements, and hypervolemia with worsening of heart failure and hypertension. The risk for these nephrotoxicity syndromes is modified by many comorbid conditions, risk factors, and characteristics of use, and in patients with CKD, the risk differs between levels of glomerular filtration rate. In this review, we offer recommendations for the cautious use of NSAIDs in the CKD population after careful consideration of these risk factors on an individualized basis.

The correct answer is D

Comment: The risk of analgesic nephropathy from the use of NSAIDs remains controversial.

The correct answer is D

Comment: Recent studies have shown increased patient survival (95%) and kidney graft survival (92%) at 1 year for SKP transplantation, representing a higher kidney graft survival than that for recipients with diabetes of cadaveric kidney transplants alone. SKP transplant offers the best survival advantage and represents the treatment of choice for type 1 diabetes patients with renal failure. Patients who have received 1 to 6 months of dialysis before transplantation have had at least a 15% increase in mortality risk in comparison to those who underwent preemptive transplantation. A 75% higher risk of death was seen in those patients who were on dialysis for greater than 24 months. ^,

The correct answer is B

Comment: Skin cancers are the most frequent malignant conditions seen in transplant recipients and can cause increased morbidity and mortality. Standard practice is to undergo surveillance aggressively to remove all basal and squamous cell carcinomas—thus, answer B is correct. There is no evidence that male subjects have less skin cancer than females. Reducing immunosuppression will result in an increased risk of rejection and probably not do much to prevent skin cancer after 2 years of immunosuppressive therapy. Viral warts do suggest some degree of overimmunosuppression. There is no evidence, however, that these warts need to be removed to prevent malignant transformation. They probably should be removed on their own merits. There is no evidence that MMF is better than azathioprine for the prevention of malignancy; in fact, there is some anecdotal evidence that the opposite is true.

The correct answer is E

Comment: The patient has anemia, leukopenia, thrombocytopenia, hyperkalemia, non-anion gap acidosis, and renal failure. Clarithromycin increases the levels of tacrolimus, cyclosporine, and sirolimus by decreasing their metabolism by the cytochrome P450 system; therefore, it should not be administered to transplant patients unless absolutely necessary. This is also true for erythromycin.

Azithromycin does not have the same effect on the metabolism of cyclosporine, tacrolimus, or sirolimus and may be used safely in transplant patients. Very high levels of tacrolimus can cause acute renal failure because of the vasoconstriction effect on the renal arteries and may be associated with type IV renal tubular acidosis. High levels of sirolimus may cause thrombocytopenia and leukopenia. Tacrolimus and cyclosporine may cause hemolytic uremic syndrome (HUS); sirolimus does not.

The correct answer is D

Comment: The patient is only 3 weeks postrenal transplantation. Opportunistic infections are less likely. They are, however, in the differential diagnosis. She is afebrile with a normal WBC, suggesting that this is not an infectious case.

This makes infections such as CMV and Pneumocystis pneumonia or others unlikely. So the correct answer is D.

Her LDH, which may be raised in Pneumocystis pneumonia , is normal. She has no findings on examination to suggest congestive heart failure. The patient has recently started on sirolimus. There have been several reported cases of interstitial pneumonitis in patients treated with sirolimus. The pneumonitis is not dose-related and responds to discontinuation of sirolimus, with complete resolution within 3 months in all reported cases.

The correct answer is D

Comment: Both cyclosporine and tacrolimus can cause hyperlipidemia; however, the risk is greater with cyclosporine. Hyperlipidemia has been reported as 1 of the major side effects of sirolimus therapy (35–50%) compared with azathioprine (18%). Hyperlipidemia is also a known side effect of corticosteroids. MMF has not been associated with lipid abnormalities.

The correct answer is D

Comment: Mycophenolate mofetil has been associated with leukopenia and anemia. Both ACE inhibitors and angiotensin-receptor blockers (ARB) have been shown to cause anemia in renal transplant patients. Anemia has been infrequently reported as a side effect of sirolimus, but it has been reported. There have been many reports documenting the association between paravirus B19 as a cause of anemia in renal transplant recipients. ^–

The correct answer is A

Comment: PTLD carries a high mortality of about 70%, according to various reports, and several factors—including the number of involved organs, primary central nervous system involvement, and monoclonality—suggest a poorer prognosis. Therapeutic interventions include the reduction of immunosuppression, antiviral therapy, anti–B-cell antibodies, anti-interleukin 6 antibodies, alpha-interferon, cytotoxic T cells, chemotherapy, radiation, and surgical resection. The reduction of immunosuppression forms the cornerstone of all treatment and may be sufficient by itself, with complete remission in 63% of cases in some reports. This girl is a high immunological risk patient with localized PTLD. Withdrawal of immunosuppression will almost certainly result in acute rejection in an individual who is not at a very high risk of dying from PTLD.

Currently, many transplant programs would also administer rituximab in addition to reducing immunosuppression. Rituximab has been shown to induce remission in transplant recipients, including lung, liver, small bowel, and stem cell transplants. However, there are insufficient data to maintain immunosuppression at current levels in combination with rituximab therapy. Neither acyclovir nor ganciclovir have an effect on Epstein-Barr virus persistence associated with latent infection, and their use has not been effective in the treatment of PTLD.

The correct answer is D

Comment: Unfortunately, none of the interventions has been shown to yield the listed clinical benefits in randomized controlled trials.

The correct answer is C

Comment: The two most predictive risk factors for the progression of glomerular diseases are the quantity of protein excreted in the urine and the extent of tubulointerstitial disease in a renal biopsy. There is no evidence that choice A is a predictive factor. There is no convincing evidence that the ACE genotype predicts the progression of glomerular diseases, particularly FSGS. Therefore, choice B is also incorrect. Choice D, the level of plasma renin activity, has not been demonstrated to be a predictor of renal disease progression. In fact, in most CKDs, plasma renin activity is suppressed, most likely related to volume expansion. Thus, the beneficial effects of ACE inhibitors in slowing the progression of renal disease are somewhat of a paradox. There is no evidence that a family history of hypertension predicts the progression of FSGS. Therefore, choice E is incorrect. The link between tubulointerstitial disease and progression may relate to reabsorption of proteins by proximal tubular cells, with activation of these cells and subsequent release of inflammatory mediators. ^,

The correct answer is C

Comment: This patient has stage 3 CKD. Abnormalities in calcium, phosphorous, and PTH commonly develop as GFR declines. The earliest and most sensitive marker of abnormal mineral metabolism is an elevation in serum PTH. This develops when the GFR decreases to <70 mL/min/1.73 m ² . Therefore, choice A is incorrect. Calcitriol synthesis decreases in CKD, but usually not until the GFR is <40 mL/min/1.73 m ² , and the changes are somewhat variable. Choice B is incorrect because PTH secretion occurs at an earlier stage in CKD, when the GFR is 40 to 70 mL/min/1.73 m ² . Choice C is correct because one of the mechanisms for decreased calcitriol synthesis is the inhibition of the one hydroxylase enzyme in the kidney by elevated serum phosphorous. In regard to choice D, the set point for calcium is altered in CKD, leading to increased PTH secretion for a given decrease (not increase) in serum calcium level. Choice E is incorrect because parathyroid-related bone disease (osteitis fibrosa cystica) is more common than osteomalacia.

The correct answer is D

Comment: Buffering of hydrogen by bone is associated with the release of calcium. In addition, acidosis stimulates osteoclastic activity. Metabolic acidosis occurs when the GFR falls to 60 mL/min/1.73 m ² and can have adverse consequences even when the serum bicarbonate is between 15 and 22 mEq/L. Option A is therefore incorrect. Option B is incorrect because acidosis suppresses albumin synthesis by the liver. Option C is incorrect because acidosis is associated with increased PTH release. Option E is also incorrect because acidosis-stimulated degradation of protein from skeletal muscle is mediated in part by increased cortisol release and decreased release of insulin-like growth factor 1. ¹

The correct answer is B

Comment: The patient has stage 3 CKD, and secondary hyperparathyroidism is present. Calcitriol therapy (choice B) can effectively reduce PTH secretion and is the best treatment for this patient. Dietary phosphorous restriction to 800 mg to 1000 mg should be instituted when the serum phosphorous is >4.6 mg/dL (option A is incorrect). Option C is incorrect because calcium-containing phosphate binders can be used as primary therapy but should be limited to 1500 mg/day. If vascular calcification is present, current treatment guidelines suggest the non–calcium-containing phosphate binders may be preferred. Option D is incorrect because long-term treatment with aluminum-containing phosphate binders can cause osteomalacia secondary to the deposition of aluminum in bone. Option E is incorrect because sevelamer has not been associated with osteomalacia or an increased risk of bone fractures.

The correct answer is E

Comment: The patient has stage 3 CKD secondary to diabetic nephropathy. In addition to a decrease in her GFR, she has significant proteinuria. In an analysis of the MDRD study that did not enroll those with diabetes, patients with more than 1 g of protein per 24 hours had a slower rate of progression with the lowered BP goal of a mean arterial pressure of 92 mm Hg. Based on this study, on JNC-VI recommendations, and on expert opinion, the best option is E for lowering her target BP to 125 to 130/75 to 80 mm Hg. Option A is incorrect because there are no data demonstrating that more intensive glycemic control in type 2 diabetes with established nephropathy can allow the progression of their kidney disease. HbA1c levels, however, have been independently associated with a faster rate of decline of GFR in patients with established diabetic nephropathy. Option B is incorrect because the patient has a high risk of progression to ESRD. Option C is incorrect because no J-shaped curve—that is, a worse cardiovascular or renal outcome with progressively lower BP—has been demonstrated in those with diabetes. Option D is incorrect because the addition of an ARB to an ACE inhibitor can reduce proteinuria in some studies but has never been demonstrated to slow the progression of kidney disease. In contrast, in nondiabetic kidney disease, the COOPERATE study demonstrated combination therapy can slow progression.

Additional laboratory tests performed on the patient demonstrate a hemoglobin of 10.1 g/dL with a serum iron of 92 mg/dL, a transferring saturation of 23%, and a ferritin of 130 ng/mL.

The correct answer is B

Comment: Option B is correct because studies have demonstrated that treatment of anemia can prevent the development of left ventricular hypertrophy. Option A is incorrect because treatment of anemia is associated with lower rates of hospitalization. Option C is incorrect because many studies have shown treatment with erythropoietin has no effect on the progression of kidney disease. Option D is incorrect because adverse consequences of anemia occur when hemoglobin levels are greater than 8 g/dL. Option E is incorrect but remains controversial. In a study by Hayashi et al., left ventricular mass index progressively decreased as hemoglobin was normalized, suggesting target hemoglobin should be higher than 11 g/dL. ^,

The correct answer is C

Comment: The results of clinical trials of dietary protein restriction on slowing the progression of kidney disease have been mixed. In the primary analysis of the MDRD study, no beneficial effect of dietary protein restriction was seen, although there are a number of limitations of this trial. Nonetheless, other trials have demonstrated a beneficial effect in slowing the development of ESRD. Those with diabetes tend to have a more beneficial response in comparison to those without diabetes. Therefore, option A is incorrect. Option B is also incorrect because a post hoc analysis of the MDRD study showed the greatest beneficial effect of protein restriction in the patients with the highest initial levels of GFR. Option C is incorrect because the MDRD study demonstrated that an initial reduction in proteinuria was associated with a slower rate of progression. Option D is incorrect because this level of protein restriction should not have a negative impact on nutritional parameters. ^,

The correct answer is A

Comment: This patient has stage 4 CKD secondary to membranous glomerulonephritis. Tubulointerstitial disease accompanies most glomerular disease, and its severity is a major risk for subsequent renal disease progression. Therefore, option B is incorrect because the severity of tubulointerstitial disease is a stronger predictor of progression than the low number of globally sclerosed glomeruli in this patient. Option C is incorrect because proteinuria is another major risk factor for renal disease progression in almost all studied diseases. Option D is incorrect because the patients with the highest levels of proteinuria have the greatest response to ACE inhibitor therapy.

The correct answer is C

Comment: Adaptations occur in surviving nephrons in an attempt to compensate for the loss of renal mass. One of these adaptations is increased ammoniagenesis. Ammonia can activate complement, which can be a risk factor in the development of tubulointerstitial disease. Option A is incorrect because the degree of glomerular involvement is heterogeneous and increases in single-nephron GFR is an adaptation that would occur in the less-damaged glomeruli. Option B is incorrect because reabsorption of protein in proximal tubule cells with their subsequent activation is felt to be a mechanism leading to tubulointerstitial disease. Option E is incorrect because it presents a paradox in thinking about chronic polycystic kidney disease (PKD). Plasma renin activity is suppressed in most chronic kidney diseases, yet inhibition of angiotensin II is a major renal protective strategy. The hypertension seen in kidney disease is related to mechanisms other than activation of the renin-angiotensin system.

The correct answer is B

Comment: The presence of microscopic hematuria fits the definition of CKD (stage 1). Her calculated GFR based on the Schwartz equation is 90 mL/min/2.73 m ² , consistent with stage 2 CKD. Option A is incorrect for these reasons. Option C is incorrect because there is no evidence that the Schwartz study equation is not accurate in CKD patients. Option C is incorrect because measuring GFR by 125 I-iothalamate clearance is not clinically necessary.

The correct answer is C

Comment: This patient has responded to treatment with an ACE inhibitor with a decrease in BP and urinary protein excretion. His serum creatinine, however, has increased from 2.8 to 3.2 mg/dL. This is an approximate 13% increase in serum creatinine. ACE inhibitors are commonly associated with an increase in creatinine following initiation therapy because of a preferential effect on dilating the efferent arteriole. If the increase in serum creatinine is less than 30%, the ACE inhibitor can be continued with a recheck of serum creatinine. Option A is incorrect, for the reasons discussed previously. In patients with bilateral renal artery disease, serum creatinine can certainly go up on an ACE inhibitor, but it is usually more than a 30% increase, and it tends to be persistent. Option B is incorrect because it is unlikely that the loop diuretic is causing the increase in serum creatinine in the absence of evidence of volume depletion. Option D is incorrect because ARB and an ACE inhibitor are both likely to have a similar effect on an increase in serum creatinine. Option E is incorrect because there is no evidence that steroids and cyclophosphamides are indicated in the treatment of this disease.

The correct answer is C

Comment: Treatment with a statin can lower both serum cholesterol, as well as LDL cholesterol, and is indicated in this patient with significant CKD.

There is evidence that the addition of ezetimibe cholesterol absorption inhibitor to a statin does have additional benefits in lowering LDL compared with the already being treated with an ACE inhibitor or ARB can decrease proteinuria and statin alone (SHARP study). Treatment with a statin in patients with CKD who are already being treated with ACE inhibitor or ARB can decrease proteinuria and stabilize creatinine clearance.

The correct answer is D

Comment: The patient’s spot urine protein-to-creatinine ratio is misleading because the patient is cachectic and produces only approximately 453 mg of creatinine per day. Other mechanisms besides nephritic syndrome (such as malnutrition) are needed to account for this patient’s low albumin and creatinine.

The correct answer is C

Comment: Previous studies examined the effects of BP lowering on the progression of hypertensive kidney disease. Patients were treated with either a beta-blocker, ACE inhibitor, or a dihydropyridine CCB. None of the drugs was associated with a difference in GFR slope. ACE inhibitors, however, decreased the risk of developing the clinical composite outcome by 22% compared with the beta-blocker and by 38% compared with the CCB. Thus, answers A, D, and E are incorrect. Answer B is incorrect because biopsies have demonstrated typical hypertensive nephrocalcinosis in patients with a clinical diagnosis of hypertension.

The correct answer is B

Comment: The presence of CKD is an independent predictor of CVD. The risk holds even mild elevation in the serum creatinine, or small decreases in GFR, and not for a serum creatinine greater than 3 mg/dL. Therefore, answer D is incorrect. Microalbuminuria is an independent risk factor for CVD and may be a more general marker of disordered function of the vascular endothelium. In a study of the Medicare population, Collins et al. demonstrated that patients with a diagnosis of CKD were 5 to 10 times more likely to die than to reach ESRD. Therefore, answer B is incorrect. Not only is CKD a risk factor for CVD, but recent analyses have also shown that the presence of CKD is a risk for both cerebral and peripheral vascular disease. ^,

The correct answer is B

Comment: This patient has stage 4 CKD secondary to FSGS. Significant proteinuria is present and his BP is elevated. Controlling BP can slow the progression of kidney failure, although the exact target BP remains somewhat controversial. In a meta-analysis of 11 randomized control trials that compared the efficacy of antihypertensive treatment with or without an ACE inhibitor for patients with nondiabetic kidney disease, it was demonstrated that a systolic BP between 110 and 129 mm Hg was associated with the lowest risk of kidney disease progression. In this analysis, the systolic BP was not predictive of progression. Systolic BP less than 110 mm Hg was associated with a higher risk for kidney disease progression, making answers A and C incorrect. Dihydropyridine CCBs should not be the drugs of first choice in the setting of CKD because these drugs have been associated with greater amounts of proteinuria compared with ACE inhibitors or ARBs. When used in combination with an ACE or ARB, however, dihydropyridine CCBs can effectively lower BP and do not limit the antiproteinuric effects of the ACE inhibitor or ARB.

The correct answer is E

Comment: Evaluation of proteinuria should begin with a careful history and thorough physical examination, urine microscopic examination, and determination of the amount of protein excretion rate. The protein excretion rate has been traditionally measured using 24-hour urine collections. However, the collection of 24-hour urine is often cumbersome, and spot urinary protein-to-creatinine ratio (PCR), expressed in g/g or mg/mg, has become a simple and attractive yet reliable alternative. A spot urine PCR has been found to have a significant linear correlation with a 24-hour urine PCR. Furthermore, because the PCR compares urinary protein concentration with urinary creatinine concentration, urinary dilution or concentration does not influence this value.

Orthostatic proteinuria is diagnosed when the PCR is greater than 0.3 in a urine specimen tested during daytime activity but less than 0.3 when the urine is collected after the nighttime recumbent position.

Isolated persistent proteinuria lasting more than 6 months or proteinuria complicated with hematuria, hypertension, or abnormal renal function usually associated with glomerular lesions or congenital kidney and urinary tract anomalies such as unilateral kidney agenesis, obstructive hydronephrosis, and reflux nephropathy, which often require further evaluations including renal ultrasonography and voiding cystourethrogram.

If proteinuria is associated with glomerulonephritis, then referral to a pediatric nephrologist is warranted for possible renal biopsy indication.

Isolated persistent proteinuria (<1.0 g/day) not associated with hypertension, hematuria, or renal dysfunction can be treated with ACE inhibitors or ARBs with close follow-up.

The correct answer is A

Comment: Renin-angiotensin system inhibitors are considered first-line agents for hypertensive patients with progressive CKD.

Stopping renin-angiotensin system inhibition in patients with CKD increases GFR and is associated with higher absolute risks of mortality and major adverse cardiovascular events, but also with a lower absolute risk of initiating renal replacement therapy.

The correct answer is A

Comment: Rapidly progressive glomerulonephritis (RPGN), characterized by a rapid development of nephritis with loss of kidney function in days or weeks, is typically associated histologically, with crescents in most glomeruli, and is a challenging problem, particularly in low-resource settings. RPGN is a diagnostic and therapeutic emergency requiring prompt evaluation and treatment to prevent poor outcomes. Histopathologically, RPGN consists of four major categories, anti-glomerular basement membrane (GBM) disease, immune complex mediated, pauci-immune disorders, and idiopathic/overlap disorders. Clinical manifestations include gross hematuria, proteinuria, oliguria, hypertension, and edema. Diagnostic evaluation, including renal function tests, electrolytes, urinalysis/microscopy, and serology including (anti-GBM antibody, antineutrophil cytoplasmic antibody) starts simultaneously with management. An urgent renal biopsy is required to allow specific pathologic diagnosis as well as to assess disease activity and chronicity to guide specific treatment. The current guidelines for the management of pediatric RPGN are adopted from adult experience and consist of induction and maintenance therapy. Aggressive combination immunosuppression has markedly improved outcomes; however, nephrotic syndrome, severe acute kidney injury requiring dialysis, presence of fibrous crescents, and chronicity are predictors of poor renal survival. RPGN-associated with postinfectious glomerulonephritis usually has a good prognosis in children without immunosuppression, whereas immune-complex-mediated glomerulonephritis and lupus nephritis are associated with poor prognosis with development of end-stage kidney disease in more than 50% and 30%, respectively.

The correct answer is B

Comment: In recent years, major genome-wide association studies have provided significant insight into the genetic basis of IgA nephropathy. Patients typically have high levels of aberrantly O-glycosylated IgA1 molecules, which become targets of an autoantibody response, leading to immune complex formation. These deposit in the mesangium and spark off an unhindered immune response, ultimately leading to fibrosis and kidney failure.

To date, genome-wide association studies for IgA nephropathy have successfully identified many risk loci with candidate genes involved in antigen processing and presentation, gut mucosal immunity, IgA biology, and dysregulation of the alternative complement pathway.

An overall genetic risk can be computed with these genome-wide significant susceptibility variants and has been shown to inversely correlate with age of diagnosis. Interestingly, the IgA nephropathy genetic risk score is strongly associated with global pathogen diversity, suggesting that the selective pressure from environmental factors may account for variation in risk allele frequency and the geographic variation in disease prevalence among world populations.

There is significant variability of up to 30% in the incidence of recurrence of IgA nephropathy after transplantation. Recurrence is associated with a higher risk of graft failure and is more common in younger patients with rapidly progressive, crescentic disease in their native kidneys.

Because the risk of allele frequency in disease prevalence among the general population is considerably lower than related donors, kidney transplantation from the adopted sibling is preferred for transplantation in IgA patients with ESRD. ^,

The correct answers are A, B, and E

Comment: The initial treatment of symptomatic hypercalcemia should have three elements to provide some efficacy, both initially and several days later. Virtually all patients with significant hypercalcemia have some element of extracellular fluid volume contraction. For this reason, it is important to start therapy with intravenous saline (option B). ^,

Calcitonin is effective in approximately 70% of patients. It is safe and relatively nontoxic, and it acts to lower serum calcium within several hours. For this reason, it should be the initial agent of choice to provide some benefit before the more potent bisphosphonates become maximally effective (option A). It typically loses its effectiveness within hours in most patients. For this reason, it is important to begin therapy with a bisphosphonate at this time, as well (option E).

Bisphosphonates block the hypocalciuric effect of PTH. They act by interfering with the metabolic activity of osteoclasts; they are cytotoxic to osteoclasts. Pamidronate, zoledronic acid, and etidronate are the currently available agents that are recommended for the treatment of malignancy-associated hypercalcemia. Zoledronate appears to be the most efficacious, with a maximum effect occurring in 48 to 72 hours. ^,

The correct answers are F and G

Comment: A recent systematic review on the evaluation and management of pediatrics examined 317 citations, of which 132 papers were selected for analysis and 62 were included in final analysis. The studies are categorized on the basis of GRADE. The overall quality of evidence is categorized as high (A), moderate (B), low (C), or poor (D). The strength of a recommendation was determined as level 1 (recommended) or level 2 (suggested). The ungraded statements were determined on the basis of common sense to provide general advice on the basis of study design and all intervention outcomes of interest are as follows: A, B, C, or D translating to high, moderate, low, and very low, respectively.

Of 115 statements, 56 (48.6%) were graded 1 (we recommend), 34 (29.5%) were graded 2 (we suggest), and 25 (21.7%) were ungraded statements. Altogether, only 22 (19.1%) of the recommendations achieved the “A” or “B” level.

Using the GRADE system, in our clinical presentation, options A, B, C, D, and E are categorized as A and highly recommended. Options F and G are categorized as poor (D) and are not recommended. Options H and I are categorized as moderate (B) and are suggested.

The correct answer is D

Comment: The indications for parathyroidectomy include: (1) hypercalcemia and hyperphosphatemia in the presence of very high PTH level (>800 pg/mL) with failure to lower PTH levels after 6 to 8 weeks of vitamin D analog and/or calcimimetics therapy; (2) fractures and tendon avulsions; (3) calcific arteriolopathy; and (4) hypertrophied gland and weight >4.0 g as determined by ultrasonography.

The correct answer is A

Comment: Gadodiamide binds with colorimetric agents used in assaying serum calcium and produces spurious hypocalcemia. Parathyroid infarct is a rare event. Gadopentetate does not produce the same effect. Barium administration is associated with hypokalemia, and barium sulfate used in radiologic studies does not enter the circulation. A defective laboratory instrument is always possible, but gadodiamide predictably produces this artificial finding.

The correct answer is D

Comment: In its most florid form, calcific vasculopathy may be manifested as calciphylaxis. A small fraction of patients with ESRD, particularly those treated with dialysis, develop deep skin ulcerations in association with calcification of subcutaneous arterioles. Uremic peripheral neuropathy is a distal, symmetrical, mixed sensorimotor. It occurs more commonly in men, and it is independent of the underlying disease. There is no specific myopathy associated with uremia.

Arthralgia and myalgias characterize diffuse scleroderma. Early diffuse cutaneous systemic sclerosis includes arthritic symptoms. A specific myopathy is not seen. Recurrent HSP does not manifest a specific myopathic picture, as seen in this case.

The correct answer is D

Comment: Sevelamer hydrochloride (Renagel) significantly lowers serum phosphorous in hemodialysis patients but with minimal effects on serum calcium in comparison to treatment with standard calcium-based phosphate binders. Patients with the highest PTH levels (>300 pg/mL) experienced the greatest reduction in PTH. The effect on PTH levels, however, may be inconsistent.

The correct answer is D

Comment: Hyperphosphatemia is the strongest predictor of calciphylaxis in patients receiving hemodialysis treatment. There is a 3.5-fold increase in the risk of calciphylaxis associated with each 1-mg/dL increase in the serum phosphate concentrations. Body mass index, diabetes, hypertension, hypomagnesemia, aluminum, and higher dosages of erythropoietin and iron dextran are not independent predictors of calciphylaxis.

The correct answer is A

Comment: This patient’s clinical picture is consistent with low turnover bone disease; therefore, aluminum toxicity must be considered. In the presence of significant aluminum exposure, bone biopsy seems indicated in the following cases: before parathyroidectomy and before starting long desferrioxamine treatment, given the risks of deafness and fatal mucormycosis as complications of treatment. Bone alkaline phosphatase is not sensitive enough to distinguish between low and normal turnover. Procollagen-carboxy-terminal propeptide is not a specific indicator of bone disease because it is not well-controlled with bone histology.

The correct answer is C

Comment: The indications for parathyroidectomy, 2 of which apply to this patient, have classically included (1) hypercalcemia and hyperphosphatemia in the presence of very high PTH levels (>800 pg/mL), as in this patient, with concurrent resistance to pharmacologic control; (2) fractures and tendon avulsions; (3) when the estimated weight of a parathyroid gland exceeds 1 g; and (4) calcific arteriolopathy, which some experts have considered to be an absolute indication.

The correct answer is C

Comment: Green et al. studied the mechanism of posttransplant hypophosphatemia and found that sera from hypophosphatemic posttransplant patients inhibited PO ₄ transport in vitro in a PTH-independent mechanism. This finding is consistent with the concept that there are PTH-independent humoral agents (phosphating) that dramatically reduce PO ₄ reabsorption, and they may underline disorders of phosphate transport, as seen in oncogenic osteomalacia.

Cyclosporine does not produce phosphate wasting, nor does 1,25 (OH)2 D3. Glucocorticoids are phosphaturic but do not produce the severe degree of phosphate wasting seen in this case.

The correct answer is C

Comment: Any evaluation of dietary phosphorus adequacy should consider not only the content of phosphorus in food but also the bioavailability of phosphorus because most phosphorus in plants is in the form of phytate. Because humans do not have the phytase enzyme that is required to degrade phytate and to release phosphorus, phytate is poorly digested in the human gastrointestinal tract and therefore limits phosphorus absorption from plant sources. Phosphorus in meat is well-absorbed because it is found mostly as intracellular organic compounds that are easily hydrolyzed in the gastrointestinal tract, releasing inorganic phosphorus for absorption.

The correct answer is B

Comment: Recent evidence suggests that the tumor product responsible for the phosphaturic action is FGF-23, a member of a large family of proteins involved in regulating fibroblast function. In oncogenic osteomalacia, there is an overproduction of FGF-23. In hereditary X-linked hypophosphatemic rickets, there is a mutation in an endopeptidase that normally inactivates FGF-23 and prevents high levels of the cytokine from migrating from bone to act systemically and in the kidney. In autosomal dominant hypophosphatemic rickets, there are mutations in the gene encoding FGF-23 so that it is functional.