Medullary cystic kidney disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: nabeel ahmed

Overview

Medullary cystic kidney disease (MCKD) is an autosomal dominant kidney disorder characterized by tubulointerstitial sclerosis leading to end-stage renal disease autosomal dominant interstitial kidney disease (ADIKD) is a rare and heterogeneous genetic disorder. Medullary cystic kidney disease (MCKD) − MCKD is another term that has been used for ADIKD.

Classification

Medullary cystic kidney disease may be classified according to genetic mutation into:

• Mutations in the UMOD gene, which encodes uromodulin are present in the majority of cases of ADIKD . This condition has also called uromodulin-associated kidney disease (UAKD) , medullary cystic kidney disease type 2 (MCKD2) and familial juvenile hyperuricemic nephropathy (FJHN) .
• Mutations in the REN gene, which encodes renin.
• Mutations in the MUC1 gene, which encodes mucin 1 ,called as medullary cystic kidney disease type 1 (MCKD1).

Pathophysiology

• Uromodulin associated kidney disease ( UAKD ) :
  • UAKD is due to mutations in the UMOD gene on chromosome 16p12, which encodes uromodulin (Tamm-Horsfall mucoprotein).
  • Missense mutation in exon 4 or 5 , it very rare mutation in exons 6 or 8.
  • Uromodulin is produced exclusively in the thick ascending limb of the loop of Henle. It is an insoluble protein whose sticky, adherent properties are probably important in maintaining the watertight integrity of the thick ascending limb.
  • Uromodulin also appears to facilitate intracellular transport of both the Na-K-2Cl furosemide-sensitive transporter and the ROMK potassium channel on the apical surface of the thick ascending loop tubular cells.
  • Intracellular accumulation of abnormal uromodulin proteins can lead to tubular cell atrophy and death.
  • The abnormal uromodulin appears to impair the synthesis and secretion of normal uromodulin produced from the unaffected allele, resulting in a marked reduction in urinary uromodulin excretion.

There is two major pathophysiologic effects of uromodulin gene mutations: Hyperuricemia and progressive chronic kidney disease.

• Hyperuricemia :
  • Due to accumulation of abnormal uromodulin in thick ascending limb cells leads sequentially to impaired NaCl reabsorption, mild renal salt wasting, volume contraction, and a secondary increase in proximal urate reabsorption, which restores volume status to normal but leads to hyperuricemia.
  • Progressive chronic kidney disease  :
  • Due to tubular cell death in the thick ascending limb due to accumulation of mutant uromodulin. Renal biopsy reveals tubulointerstitial disease but no uric acid crystals.
• Mutations in the REN gene :
  • The renin gene is located on chromosome 1. Two REN gene mutations associated with autosomal dominant interstitial kidney disease (ADIKD) which is due to signal sequence of pre-prorenin.
  • Mutations in this signal sequence disrupt the translocation of pre-prorenin into the endoplasmic reticulum of renin expressing cells.
  • Renin is necessary for nephrogenesis, homozygous deletions of renin result in death during uterine development.
  • Renin is present in multiple segments of the renal tubule, also on the juxtaglomerular complex. In these cells, pre-prorenin is translocated into the endoplasmic reticulum, where it is converted to prorenin.
  • Prorenin is secreted, while the remainder is targeted to lysosomes where it is further cleaved to active renin.
  • Mutations which disrupt the signal sequence of prorenin prevent proper translocation to the endoplasmic reticulum,as a result accumulation of pre-prorenin in the cytoplasm of renin producing cells.
  • Due to accumulation of pre-prorenin in renal tubular cells leads to ultrastructural damage and apoptosis .

Epidemiology

Age

• Patients of all age groups may develop medullary cystic kidney disease.
• Medullary cystic kidney disease is more commonly observed among teenage years but end stage renal disease usually occurring between the ages of 20 and 70 years old.

Gender

• Medullary cystic kidney disease affects men and women equally.
• Male are more commonly affected with medullary cystic kidney disease than female.

Risk Factors

Medullary cystic kidney disease (MCKD) is an autosomal dominant kidney disorder.

• Characterized by tubulointerstitial sclerosis leading to end-stage renal disease. Autosomal dominant interstitial kidney disease (ADIKD) is a rare and heterogeneous genetic disorder.

Differential diagnosis

For a list of diseases that should be differentiated from medullary cystic kidney disease, click here.

Complications and Prognosis

Medullary cystic kidney disease may lead to following health problems:

• Anemia
• Cardiac tamponade
• Bone weakness and fractures
• Change in glucose metabolism
• End stage renal disease
• Congestive heart failure
• Hyponatremia
• Gastrointestinal bleeding and ulcers
• Hemorrhage
• Hyperkalemia
• Pericarditis
• Peripheral neuropathy
• Platelet dysfunction with easy bruising
• Menstrual problems
• Miscarriage
• Infertility

Symptoms

Symptoms usually begin before the age of 20, but they vary great.

• Excessive urination, caused by the reduced ability of the diseased kidneys to respond to antidiuretic (fluid-holding) hormone

• Anorexia
• Pruritus
• Enuresis
• Osteomalacia
• Pallor
• Polydipsia
• Patients with REN gene mutations develop early onset gout
• Anemia, with low erythropoietin levels
• Mild hyperkalemia
• Affected patients may be at increased risk for acute kidney injury in the setting of volume depletion and/or when nonsteroidal anti-inflammatory drugs are used.

Diagnosis

• The diagnosis medullary cystic kidney disease suspected based upon clinical manifestations and the family history, and can be confirmed through genetic testing.
• A presumptive clinical diagnosis of medullary cystic kidney disease in a young individual presenting with gout and chronic kidney disease relies upon three factors:
  • A strong family history of kidney disease in a pattern suggestive of autosomal dominant inheritance
  • Family history of gout
  • A bland urinary sediment with little or no proteinuria
• One or both of the first two factors may be missing in patients with spontaneous mutations, or if the family history is incomplete. In addition, a strong family history of gout may be absent in patients with a mutation in the MUC1 gene. It is important to include information about all family members as obtaining medical records from family members may be helpful.
• In patients with medullary cystic kidney disease, anemia beginning during childhood.
• Before the onset of severe renal dysfunction should raise suspicion for the presence of a REN gene mutation.
• Measurement of plasma renin and aldosterone is not usually helpful, since the levels of these hormones are highly variable depending upon volume status, posture, and stress.

Tests may include:

• 24-hour urine volume and electrolytes
• Blood urea nitrogen
• Creatinine blood test and creatinine clearance
• Abdominal CT scan and abdominal ultrasound
• Renal ultrasound and renal biopsy
• Genetic testing of the UMOD gene
• Genetic testing of the REN gene
• Genetic testing of the MUC1 gene

Fractional excretion of uric acid :

Patients with UAKD or a REN gene mutation, but not patients with MUC1 mutations, should have hyperuricemia and a low fractional excretion of uric acid. The fractional excretion of uric acid (FEUA) can be calculated from a random urine specimen using the same formula used to calculate the fractional excretion of sodium, substituting uric acid for sodium using either standard units

• FEUA  =  (urine uric acid concentration  x  serum creatinine)  ÷  (urine creatinine concentration  x  serum uric acid) Underexcretion is defined as an FEUA less than 6% and is often below 4% . Normal values in healthy adults are 8 ± 3 % in males and 13 ± 3 % in females.The normal fractional excretion of uric acid in healthy children is even higher (18 ± 5 percent). One caveat is that the fractional excretion of uric acid and other solutes, such as sodium, increases as renal function worsens . The expected values for FEUA cited above only apply to patients with a glomerular filtration rate above 70 mL/min . Higher values would be seen at lower filtration rates.

Treatment

• There is no cure for medullary cystic kidney disease. At first, treatment focuses on controlling symptoms, reducing complications, and slowing the progression of the disease.
• Patients who have gout are usually treated with allopurinol. It is unclear if lowering uric acid levels or initiating therapy with angiotensin inhibitors prevents the progression of CKD. The management of CKD in patients with medullary cystic kidney disease is similar to that in patients with other causes of CKD .

Prevention

• There are no primary preventive measures available for Medullary cystic kidney disease because it is an inherited disorder.It may not be preventable.