A 35-year-old man with a strong family history of polycystic kidney disease sees his primary care physician for mild abdominal discomfort for 10 days. He is found to have ablood pressure (BP) of 144/96 mmHg. An ultrasound of the abdomen shows bilateral large kidneys (>13.6 cm). He is subsequently referred to a nephrologist who confirms the diagnosis of autosomal dominant polycystic kidney disease (ADPKD) . The patient asks about the relationship between the large kidneys (total kidney volume) and subsequent complications of ADPKD. Which one of the following statements is FALSE regarding total kidney volume (TKV) and pathophysiologic changes?

Determination of TKV with magnetic resonance imaging (MRI) has become an important prognostic factor in patients with ADPKD. It associates with the development of ESRD. It was shown initially that a fall in GFR occurred at TKV of approximately 600 mL in adult women and at 1100 mL in adult men, and the progression to ESRD is faster in men than women. Patients with HTN have larger kidneys and TKV as compared with those patients who have normal BP. Also, there is an inverse correlation between increasing TKV and decreasing GFR. ADPKD is genetically determined by two genes: PKD1 and PKD2. About 85 % of patients have PKD1 genotype, and the remaining 15 % have PKD2 genotype . The TKV is much higher in PKD1 than PKD2 patients. The kidneys start enlarging even in childhood, but the GFR remains within normal range for 3–5 decades. Thus, option E is false.

The abdominal pain in the above patient is related to several factors. Which one of the following factors is the LEAST likely cause of his pain?

Abdominal pain occurs in approximately 60 % of patients with ADPKD. At times, rupture of the cyst causing pain and hematuria is rather common. Patients with ADP KD are at risk for uric acid and calcium oxalate stone formation. Low urine pH, low citrate and NH ₄ ⁺ excretion, and urinary stasis account for predisposition to kidney stone formation . Urinary tract infection is also a common cause of abdominal pain . Some patients have chronic pain due to growth of the cyst or distension of the abdomen due to large kidneys. Renal cell carcinoma in this young patient is very unlikely. However, in a patient older than 50 years of age, renal cell carcinoma should be considered as one of the causes of abdominal pain. Thus, option D is very unlikely cause of pain in this patient.

Which one of the following statements regarding HTN in ADPKD patients is FALSE?

Treatment of HTN is highly beneficial in the prevention of renal and extrarenal complications of ADPKD. Long-term therapy with ACE-Is is found to reduce albuminuria and LV H as well as LVMI. Hemodynamic effects of ACE-Is include an increase in renal blood flow and a reduction in FF so that renal Na ⁺ absorption is decreased. Thus, ACE-Is or angiotensin receptor blockers seems to be the first choice for ADPKD patients with or without target organ damage. The goal BP for patients with LVH, renal dysfunction, or proteinuria is <130/80 mmHg. For those with only HTN and without complications, the BP goal is <140/80 mmHg. Thus, option D is false.

It should be noted that rigorous control of BP (MAP <93 mmHg) than moderate control of BP (MAP 100–107 mmHg) in MDRD study, which enrolled a large number of ADPKD patients, demonstrated reduction in LVMI independent of the type of antihypertensive agent used.

Besides total kidney volume (TKV) , which one of the following modifiable predictors is ASSOCIATED with deterioration in renal function in ADPKD patients?

The National Institutes of Health sponsored a Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease ( CRISP) to develop imaging techniques to analyze and follow disease progression in ADPKD patients. In the CRISP I study, higher TKV and cyst volumes are associated with faster decline in GFR. The participants in this study were followed up for 3 years. The follow-up of these patients was extended up to 6 years. During this follow-up, higher body surface area, 24-h urine osmolality (a surrogate marker of vasopressin effect on kidney), 24-h Na ²⁺ excretion (a surrogate marker of salt intake), and low HDL cholesterol (a possible surrogate marker of vascular disease) were found to be risk factors for decline in renal function. Correction of these abnormalities may be important in preventing progression of renal disease in patients with ADPKD.

Several drugs that inhibit the growth of cysts in patients with autosomal polycyst ic kidney disease (ADPKD) are being investigated throughout the world. Which one of the following drugs has been tried in a large cohort of patients in the United States and NOT approved for clinical use?

A 3-year trial using tolvaptan showed that this drug slowed the increase in total kidney volume (TKV) and the decline in renal function in ADPKD patients as compared with those on placebo. However, elevations in liver enzymes and bilirubin were higher in tolvaptan than placebo group. Despite these beneficial effects, tolvaptan is not approved for use in ADPKD patients by the Food and Drug Administration. Thus, option B is correct.

Overactivation of mTOR is implicated in cell proliferation and growth. As a result, the inhibitors of mTOR have been tried in ADPKD patients. Although mTOR inhibitors have slowed the progression of TKV, the results on slowing the decline in GFR are unclear. A meta-analysis has shown no long-term benefit of mTOR use in ADPKD patients.

Tyrosine kinase inhibitors are also antiproliferative, and are being investigated in animal models of ADPKD, but not approved for human use.

A 34-year-old woman with autosomal polycystic kidney disease (ADPKD) is referred to a nephrologist for evaluation and management of HTN. She asks you whether she needs a CT of head for possible aneurysms. Regarding screening for the presence of intracranial aneurysms (ICA) in patients with ADPKD, which one of the following choices is FALSE?

Another concern regarding ICA is the risk of rupture of asymptomatic ICA and its management. It has been suggested that the risk of growth or rupture of aneurysms <7 mm in diameter is small. For those with aneurysms ≥10 mm in diameter or aneurysms in the posterior circulation, endovascular management may be the treatment of choice in patients over 50 years of age. Control of HTN and hyperlipidemia as well as smoking cessation is recommended to reduce the risk of aneurysmal rupture.

A 50-year-old man on maintenancehemodialysis (HD) for over 10 years is found to have gross hematuria, fever, flank pain, and rising hematocrit level. Physical exam shows bilateral flank pain and palpable masses. A tentative diagnosis of acquired cystic disease (ACKD) is made. Which one of the following statements is FALSE in patients with ACKD?

ACKD develops in the remnant kidneys in >90 % of patients who are maintained on HD for more than 8 years. ACKD is a clinically recognized complication of long-term HD and PD therapy. The incidence approximates >90 % after 8 years of HD. ACKD occurs even in CKD patients without dialysis . Clinical manifestations include gross hematuria, flank pain, fever, palpable renal mass, and rising hematocrit.

An important complication of ACKD is the development of renal cell carcinoma , which is due to the pronounced epithelial hyperplasia lining the cyst. A CT scan with or without contrast is the preferred technique in suspect patients with renal cell carcinoma. This CT can distinguish simple cysts from multiple acquired cysts. An ultrasound or MRI can be used in CKD patients to prevent contrast induced further deterioration in renal function.

ACKD has been shown to regress after successful renal transplantation. Therefore, option C is false.

An 18-year-old African American female student comes to the Emergency Department with complaints of weakness, dizziness, and poor appetite. On physical exam, she is a thin female with normal growth, but tachypnic. History reveals nocturia and polydipsia. Her BP is 100/60 mmHg with a pulse rate of 102 (supine) and 80/40 mmHg with a pulse rate of 120 (standing). She weighs 52 kg. The rest of the physical exam is unremarkable except for a pericardial friction rub . Initial labs:

Which one of the following is the MOST likely diagnosis ?

The clinical history and lab data are consistent with the diagnosis of autosomal dominant MCD. MCD manifests as both autosomal recessive and dominant disease. Autosomal recessive disease occurs in infants and children and the disease is called nephronophthisis (NPH) . Children with NPH progress to ESRD at an early age (around 12–13 years of age). Furthermore, NPH is associated with retinal degeneration, optic atrophy, and retinitis pigmentosa. For this reason, NPH is also termed renal-retinal dysplasia.

Autosomal dominant MCD is a progressive disease with onset of ESRD usually in the second and third decade of life. Despite renal failure, patients develop relative hypotension due to renal salt wasting and volume depletion. Inability to concentrate urine is also an early finding. Flank pain, hematuria, nephrolithiasis, and HTN are uncommon, and distinguish this disease from polycystic kidney disease and medullary sponge kidney. The kidneys tend to be small and open renal biopsy is needed to make the definitive diagnosis in patients with MCD. Both kidneys are involved. The kidney surface has granular appearance, and cysts are located preferentially at the corticomedullary junction. Cysts are not present in organs other than the kidney.

A 35-year-old woman is referred to a nephrologist for frequent urinary tract infections (UTIs) , hematuria, and a renal stone. There is no weight loss . Physical exam is otherwise unremarkable. Labs are as follows:

An IVP showed pronounced tubular ectasia of all papillae. Which one of the following statements characterizes the patient’s condition?

Clinically, patients with MSK present with microscopic or gross hematuria alone or in association with UTIs, nephrolithiasis or nephrocalcinosis. Both UTI and nephrolithiasis are frequent complications of MSK. Sterile pyuria is occasionally observed in patients with MSK without UTI. The incidence of UTI is higher in women than in men.

Renal stones are mostly composed of calcium oxalate and calcium phosphate. Renal colic is a frequent clinical manifestation. The risk factors for stone formation include urine stasis in ectatic tubules, absorptive hypercalciuria, hypocitraturia, and defective urinary acidification due to distal form of RTA. Therefore, recurrent UTIs are not responsible for renal stone formation. Renal tubular ectasia, resulting in abnormal precalycial opacification, is also seen in renal TB, renal papillary necrosis, and medullary nephrocalcinosis in primary hyperparathyroidism . These diseases should be included in the differential diagnosis of MSK and can be excluded based upon the associated clinical signs and etiologic conditions.

Match the following clinical histories of patients with the molecular defects:

The patient described in choice A has Liddle syndrome, which is an autosomal dominant disorder. It is caused by mutations in the cytoplasmic COOH-terminus of the β-and γ- subunits of the EN aC. Activation of this channel results in increased Na ⁺ reabsorption with blunted Na ⁺ excretion, hypokalemia, and low-renin-aldosterone HTN. However, HTN responds to triamterene or amiloride, but not to spironolactone. Affected patients are at increased risk for cerebrovascular and cardiovascular disease.

The child described in choice B carries the diagnosis of the syndrome of apparent mineralocorticoid excess (AME) , which is a rare autosomal recessive disorder. It is due to a loss-of-function mutation in the gene encoding the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). This enzyme converts cortisol to the inactive cortisone. As a consequence of the mutation, the 11β-HSD2 enzyme activity is decreased with resultant accumulation of cortisol. Cortisol acts like a mineralocorticoid by occupying its receptor, causing Na ⁺ reabsorption, hypokalemic metabolic alkalosis, and low-renin-aldosterone HTN. Suppression of renin and aldosterone is due to volume excess caused by Na ⁺ and water retention. Children with AME demonstrate low birth weight and nephrocalcinosis, the latter is due to hypokalemic nephropathy. HTN responds to salt restriction, amiloride or triamterene but not to regular doses of spironolactone. Licorice ingestion induces a similar syndrome. Complications include cardiac events, including stroke and renal failure.

The clinical history described in choice C is consistent with the diagnosis of glucocorticoid-remediable hyperaldosteronism (GRA). This disorder, also called familial hyperaldosteronism type 1, is caused by a chimeric gene duplication from unequal crossover between 11β-hydroxylase and aldosterone synthase. Some patients with GRA may have severe HTN, hypokalemia, and metabolic alkalosis. Some other patients may have mild HTN, normal to low serum [K ⁺ ], and mild increase in serum [HCO ₃ ⁻ ]. Plasma renin is suppressed, but aldosterone levels are increased. Aldosterone secretion is stimulated by ACTH and not by angiotensin II. Therefore, administration of glucocorticoid suppresses excessive aldosterone secretion and improves HTN.

The possible diagnosis of the patient presented in choice D is a case of early-onset HTN with severe exacerbation during pregnancy. This disorder is caused by an activating heterozygous missense mutation in the mineralocorticoid receptor (MR) gene called S810L mutation. Clinically, the patient presents with HTN before age 20 years with low plasma K ⁺ , renin, and aldosterone levels. Pregnancy exacerbates HTN without proteinuria, edema, or neurologic changes. Aldosterone levels, which are elevated during pregnancy, are extremely low in MR gene mutation. MR antagonists such as spironolactone become agonists and increase BP in patients with mutation in MR gene. Therefore, spironolactone is contraindicated in these patients. Progesterone also increases BP in patients with MR gene mutation, since this hormone levels are extremely high in these patients. It should be remembered that heterozygous loss-of-function mutations in the MR gene (locus symbol NR3C2) results in pseudohypoaldosteronism type I (PHA I), an autosomal disorder, that causes salt wasting and hypotension. This disease remits with age.

The clinical history present in choice E is similar to PHA I, but it is an autosomal recessive disorder. It is caused by mutations in any of the three (α, β, γ) subunits of the ENaC. This autosomal recessive disorder can manifest in the neonate as failure to thrive or in childhood which is a rare disease. It is characterized by salt-wasting, hypotension, hyperkalemia, and metabolic acidosis. Other biochemical abnormalities include hyponatremia, high plasma and urine aldosterone levels despite hyperkalemia, and high plasma renin activity. Treatment includes life-long high salt supplementation (at least 50 mEq/kg/day) and K ⁺ restriction as well as cation exchange resin (kayexalate).

The case in choice F represents pseudohypoaldosteronism type II (PHA II). It is called familial hyperkalemia and HTN or Gordon syndrome. The disease is caused by mutations in the genes that encode WNK family of serine-threonine kinases, WNK1 and WNK4. Both mutated kinases are present in the distal nephron, and promote transcellular or paracellular Cl ⁻ conductance. As a result, more salt is absorbed, causing an increase in intravascular volume. This expansion in intravascular volume suppresses renin activity, but increases BP. At the same time, both K ⁺ and H ⁺ secretion are reduced, resulting in hyperkalemia and metabolic acidosis. Aldosterone levels vary from low to high concentrations depending on the severity of hyperkalemia. Thus, patients with PHA II disorder, which may present in the neonate or adult, is characterized by hyperkalemia, metabolic acidosis, low-renin and low- to high aldosterone levels and volume-dependent HTN. Thiazide diuretics correct both metabolic abnormalities and HTN.

Match the following disease conditions with the molecular defects:

Cystinosis is an important cause of Fanconi syndrome in children. It is caused by inactivating mutations in CTNS which encodes a lysosomal membrane protein called cystinosin . It is a membrane transporter that is responsible for cystine export from lysosomes. Because of this mutation, transport of cystine is impaired, with resultant accumulation of cystine in renal tubules and other organs. Nephropathic cystinosis manifests in the first year of life with failure to thrive, increased thirst, polyuria, and hypophosphatemic rickets. Increased urinary loss of Na ⁺ , Ca ²⁺ , and Mg ²⁺ occurs in cystinosis. ESRD occurs by 10 years of age and cystinosis does not recur in transplanted kidney.

Cystinuria is an autosomal recessive disorder with a defective transport of cystine and the dibasic amino acids (lysine, ornithine, and arginine) in the renal tubules and GI tract. Three types of cystinuria have been described: type A, type B, and type AB. All three types are classified based on cystine excretion. Type A cystinuria is due to mutations in the SLC3A1 gene, which encodes the proximal tubule S3 segment and intestinal dibasic amino acid transporter. Cystinuria presents as nephrolithiasis usually during the first and third decades of life, but may occur in infants. Urinalysis shows cystine (hexagonal) crystals in the sediment. Type B cystinuria is secondary to mutations in SLC7A9 gene, whereas type AB cystinuria is caused by mutations in both SLC3A and SLC7A9 genes.

Primary hyperoxaluria type 1, the most common and severe form of the primary hyperoxalurias, is due to absolute or functional deficiency of the gene AGTX. This gene encodes the liver-specific enzyme AGT (alanine-glyoxylate aminotransferase). AGT is a pyridoxal-PO ₄ -dependent enzyme, which catalyzes the conversion of glyoxylate to glycine which is deposited in the kidney and other organs. The deficiency of the enzyme results in accumulation of glycolate and oxalate. Excess production of oxalate presents as calcium oxalate nephrolithiasis and progressive renal failure. ESRD may occur in 80 % of patients by 30 years of age. In the absence of this enzyme, the result is high levels of glycolic and oxalic acids, which readily convert to oxalate.

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is an autosomal recessive disease caused by mutations in paracellin-1, a protein that is present in tight junctions of the thick ascending limb of Henle’s loop. The disease is characterized by renal Mg ²⁺ wasting and hypomagnesemia. Hypercalciuria is also present, resulting in bilateral nephrocalcinosis and progressive renal failure. Serum PTH levels are abnormally increased with normal serum concentrations of Ca ²⁺ , phosphate, and K ⁺ . Hypomagnesemia is unresponsive to oral or IV magnesium administration. Renal transplantation normalizes renal tubular handling of Mg ²⁺ and Ca ²⁺ .

X-linked hypophosphatemic rickets, a dominant disorder, is caused by a mutation in the PHEX gene . This gene encodes a protein that has similarities with neutral endopeptidases. Patients with this disease are characterized by short stature, femoral or tibial bowing and evidence of rickets and osteomalacia. Biochemically, these patients have hypophosphatemia, phosphaturia, normal plasma Ca ²⁺ and PTH, and increased alkaline phosphatase levels. The most important serum abnormality is inappropriately normal 1,25(OH) ₂ D ₃ levels in the presence of hypophosphatemia (<2.5 mg/dL). Males are affected more severely than females. Treatment includes calcitriol and phosphate therapy.

Which one of the following observations is LEAST likely in patients with Fabry’s disease?

Fabry’s disease is an X-linked disorder of abnormal glycosphingolipid metabolism . It is caused by deficient activity of lysosomal α-galactosidase A, resulting in accumulation of globotriaosylceramide in various organs, including the kidney, skin, brain, and vascular tissue. Male hemizygotes are affected more severely than female heterozygotes whose clinical manifestations vary from asymptomatic to severe disease.

In male hemizygotes, the clinical manifestations may begin in childhood with pain in extremities and acroparasthesias. LVH and coronary artery disease and stroke may occur at a younger age. Accumulation of globotriaosylceramide in podocytes rather than deficient nephrin and podocin causes proteinuria and renal failure. Therefore, statement E is false.

The diagnosis of Fabry’s disease is usually made by measuring plasma or leukocyte levels of α-galactosidase activity in affected males. Prenatal diagnosis can also be made by measuring the enzyme activity in amniotic fluid.

Treatment of the disease includes replacement of recombinant human α-galactosidase (Fabrazyme). Studies have shown improvement in clinical manifestation of the disease.

A 30-year-old woman is referred to a nephrologist for proteinuria, hematuria, and elevation in serum creatinine level. She complained of eye pain and limping. She has a family history of glaucoma and proteinuria, but none on dialysis. Her serum creatinine is 3.6 mg/dL and serum ANA is negative. Her serum complement levels are normal. A 24-h urine collection reveals 3.6 g of proteinuria. The renal biopsy findings are as follows:

Based upon the above information, which one of the following is the MOST likely diagnosis?