polycystic kidney disease solution for everyone

Polycystic kidney disease (PKD or PCKD, also known as polycystic kidney syndrome) is a cystic genetic disorder of the kidneys.^[1]There are two types of PKD: autosomal dominant polycystic kidney disease (ADPKD) and the less-common autosomal recessive polycystic kidney disease (ARPKD).

It occurs in humans and some other animals. PKD is characterized by the presence of multiple cysts (hence, "polycystic") typically in both kidneys; however 17% of cases initially present with observable disease in one kidney, with most cases progressing to bilateral disease in adulthood.^[2] The cysts are numerous and are fluid-filled, resulting in massive enlargement of the kidneys. The disease can also damage the liver, pancreas and, in some rare cases, the heart and brain. The two major forms of polycystic kidney disease are distinguished by their patterns of inheritance.

Polycystic kidney disease is one of the most common life-threatening genetic diseases, affecting an estimated 12.5 million people worldwide.^[3]

Polycystic Kidney Disease, or PKD, is a blanket term for the two types of PKD, each having their own pathology and causes. These two types of PKD are Autosomal dominant polycystic kidney disease (ADPKD) and Autosomal recessive polycystic kidney disease (ARPKD)

Autosomal dominant[edit]

CT scan showing autosomal dominant polycystic kidney disease

Autosomal dominant polycystic kidney disease (ADPKD) is the most common of all the hereditary cystic kidney diseases^[2][4][5] with an incidence of 1:500 live births.^[2][5] Studies show that 10% of end-stage renal disease (ESRD) patients being treated with hemodialysis in Europe and the U.S. were initially diagnosed and treated for ADPKD.^[2] ADPKD does not appear to demonstrate a preference for any particular ethnicity.

ADPKD is characterized by progressive cyst development and bilaterally enlarged kidneys with multiple cysts. There are three geneticmutations in the PKD-1, PKD-2, and PKD3 gene with similar phenotypical presentations. Gene PKD-1 is located on chromosome 16 and codes for a protein involved in regulation of cell cycle and intracellular calcium transport in epithelial cells, and is responsible for 85% of the cases of ADPKD. A group of voltage-linked calcium channels are coded for by PKD-2 on chromosome 4. PKD3 recently appeared in research papers as a postulated 3rd gene. At this time, PKD3 has not been proven.^[2][4] Fewer than 10% of cases of ADPKD appear in non-ADPKD families.

Cyst formation begins in utero from any point along the nephron, although fewer than 5% of nephrons are thought to be involved. As the cysts accumulate fluid, they enlarge, separate entirely from the nephron, compress the neighboring renal parenchyma, and progressively compromise renal function.

Under the function of gene defect, epithelial cells of renal tubule turn into epithelial cells of cyst wall after phenotype change, and begin to have the function of secreting cyst fluid, which leads to continuous cysts enlargement.^[6]

Autosomal recessive[edit]

Autosomal recessive polycystic kidney disease (ARPKD) (OMIM #263200) is the lesser common of the two types of PKD, with an incidence of 1:20,000 live births and is typically identified in the first few weeks after birth. Unfortunately, resulting hypoplasia results in a 30% death rate in neonates with ARPKD.^[2] In ARPKD kidneys retain their shape but are larger than the normal anatomical range with dilated collecting ducts from the medulla to the cortex.

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End stage kidney disease overview.

Chronic kidney disease (CKD), also known as chronic renal disease (CRD), is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are non-specific, and might include feeling generally unwell and experiencing a reduced appetite. Often, chronic kidney disease is diagnosed as a result of screening of people known to be at risk of kidney problems, such as those with high blood pressure or diabetes and those with a blood relative with chronic kidney disease. Chronic kidney disease may also be identified when it leads to one of its recognized complications, such as cardiovascular disease, anemia or pericarditis.^[1] It is differentiated from acute kidney disease in that the reduction in kidney function must be present for over 3 months.
Chronic kidney disease is identified by a blood test for creatinine. Higher levels of creatinine indicate a lower glomerular filtration rate and as a result a decreased capability of the kidneys to excrete waste products. Creatinine levels may be normal in the early stages of CKD, and the condition is discovered if urinalysis (testing of a urine sample) shows that the kidney is allowing the loss of protein or red blood cells into the urine. To fully investigate the underlying cause of kidney damage, various forms of medical imaging, blood tests and often renal biopsy (removing a small sample of kidney tissue) are employed to find out if there is a reversible cause for the kidney malfunction.^[1] Recent professional guidelines classify the severity of chronic kidney disease in five stages, with stage 1 being the mildest and usually causing few symptoms and stage 5 being a severe illness with poor life expectancy if untreated. Stage 5 CKD is often called end stage renal disease (ESRD), end stage renal failure (ESRF), or end-stage kidney disease (ESKD) and is synonymous with the now outdated terms chronic kidney failure (CKF) or chronic renal failure (CRF).^[1]
There is no specific treatment unequivocally shown to slow the worsening of chronic kidney disease. If there is an underlying cause to CKD, such as vasculitis, this may be treated directly to slow the damage. In more advanced stages, treatments may be required for anemia and bone disease. Severe CKD requires renal replacement therapy, which may involve a form of dialysis, but ideally constitutes a kidney transplant.<sup>[1]


Symptoms</sup>

CKD is initially without specific symptoms and is generally only detected as an increase in serum creatinine or protein in the urine. As the kidney function decreases:

• Blood pressure is increased due to fluid overload and production of vasoactive hormones created by the kidney via the RAS (renin-angiotensin system), increasing one's risk of developing hypertension and/or suffering from congestive heart failure
• Urea accumulates, leading to azotemia and ultimately uremia (symptoms ranging from lethargy to pericarditis and encephalopathy). Urea is excreted by sweating and crystallizes on skin ("uremic frost").
• Potassium accumulates in the blood (known as hyperkalemia with a range of symptoms including malaise and potentially fatal cardiac arrhythmias). Hyperkalemia usually does not develop until the GFR falls to less than 20-25 mL/min/1.73 m², at which point the kidneys have decreased ability to excrete potassium. Hyperkalemia in CKD can be exacerbated by acidemia (which leads to extracellular shift of potassium) and from lack of insulin.^[2]
• Erythropoietin synthesis is decreased
• Fluid volume overload — symptoms may range from mild edema to life-threatening pulmonary edema
• Hyperphosphatemia — due to reduced phosphate excretion, which follows the decrease in glomerular filtration. Hyperphosphatemia is associated to increased cardiovascular risk, being a direct stimulus to vascular calcification.^[3]
• Hypocalcemia — due to 1,25 dihydroxyvitamin D₃ deficiency. The 1,25 dihydroxyvitamin D₃ deficiency is due to stimulation of fibroblast growth factor-23.^[4] Osteocytes are responsible for the increased production of FGF23, which is a potent inhibitor of the enzyme 1-alpha-hydroxylase (responsible for the conversion of 25-hydroxycholecalciferol into 1,25 dihydroxyvitamin D₃).^[5]
  • Later this progresses to secondary hyperparathyroidism, renal osteodystrophy and vascular calcification that further impairs cardiac function.
• Metabolic acidosis, due to accumulation of sulfates, phosphates, uric acid etc. This may cause altered enzyme activity by excess acid acting on enzymes and also increased excitability of cardiac and neuronal membranes by the promotion of hyperkalemia due to excess acid (acidemia).^[6] Acidosis is also due to decreased capacity of generating enough ammonia from the cells of the proximal tubule.^[2]
• Iron deficiency anemia, which increases in prevalence as kidney function decreases, and is especially prevalent in those requiring haemodialysis. It is multifactoral in cause but includes increased inflammation, reduction in Erythropoietin, hyperuricemia leading to bone marrow suppression.

People with chronic kidney disease suffer from accelerated atherosclerosis and are more likely to develop cardiovascular disease than the general population. Patients afflicted with chronic kidney disease and cardiovascular disease tend to have significantly worse prognoses than those suffering only from the latter.^{[citation needed]}
Sexual dysfunction is very common in both men and women with chronic kidney disease. A majority of men have a reduced sex drive, difficulty obtaining an erection and reaching orgasm, and the problems get worse with age. A majority of women have trouble with sexual arousal, and painful periods and problems with performing and enjoying sex are common.<sup>[7]

Cause</sup>

The three most common causes of CKD are diabetes mellitus, hypertension, and glomerulonephritis.^[8] Together, these cause approximately 75% of all adult cases.
Historically, kidney disease has been classified according to the part of the renal anatomy that is involved.^{[citation needed]}

• Vascular, includes large vessel disease such as bilateral renal artery stenosis and small vessel disease such as ischemic nephropathy, hemolytic-uremic syndrome and vasculitis
• Glomerular, comprising a diverse group and subclassified into
  • Primary Glomerular disease such as focal segmental glomerulosclerosis and IgA nephropathy (or nephritis)
  • Secondary Glomerular disease such as diabetic nephropathy and lupus nephritis
• Tubulointerstitial including polycystic kidney disease, drug and toxin-induced chronic tubulointerstitial nephritis and reflux nephropathy
• Obstructive such as with bilateral kidney stones and diseases of the prostate
• On rare cases, pinworms infecting the kidney can also cause nephropathy.
• non traditional causes of CKD are denoted if the common causes of CKD are not present, e.g. in El Salvador, Nicaragua, ... in rural communities with agriculture.

Stages
All individuals with a glomerular filtration rate (GFR) <60 mL/min/1.73 m² for 3 months are classified as having chronic kidney disease, irrespective of the presence or absence of kidney damage. The rationale for including these individuals is that reduction in kidney function to this level or lower represents loss of half or more of the adult level of normal kidney function, which may be associated with a number of complications.^[1]
All individuals with kidney damage are classified as having chronic kidney disease, irrespective of the level of GFR. The rationale for including individuals with GFR > 60 mL/min/1.73 m² is that GFR may be sustained at normal or increased levels despite substantial kidney damage and that patients with kidney damage are at increased risk of the two major outcomes of chronic kidney disease: loss of kidney function and development of cardiovascular disease.^[1]
The loss of protein in the urine is regarded as an independent marker for worsening of renal function and cardiovascular disease. Hence, British guidelines append the letter "P" to the stage of chronic kidney disease if there is significant protein loss.^[9]

Stage 1

Slightly diminished function; kidney damage with normal or relatively high GFR (≥90 mL/min/1.73 m²). Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine test or imaging studies.^[1]

Stage 2

Mild reduction in GFR (60–89 mL/min/1.73 m²) with kidney damage. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine test or imaging studies.^[1]

Stage 3

Moderate reduction in GFR (30–59 mL/min/1.73 m²).^[1] British guidelines distinguish between stage 3A (GFR 45–59) and stage 3B (GFR 30–44) for purposes of screening and referral.^[9]

Stage 4

Severe reduction in GFR (15–29 mL/min/1.73 m²)^[1] Preparation for renal replacement therapy

Stage 5

Established kidney failure (GFR <15 mL/min/1.73 m², permanent renal replacement therapy (RRT),^[1] or end stage renal disease (ESRD)

For more details on this topic, see End Stage Renal Disease (US Federal Program).

NDD-CKD vs. ESRD

The term non-dialysis dependent CKD, also abbreviated as NDD-CKD, is a designation used to encompass the status of those persons with an established CKD who do not yet require the life-supporting treatments for renal failure known as renal replacement therapy (including maintenance dialysis or renal transplantation). The condition of individuals with CKD, who require either of the 2 types of renal replacement therapy (dialysis or transplantation), is referred to as the end-stage renal disease (ESRD). Hence, the start of the ESRD is practically the irreversible conclusion of the NDD-CKD. Even though the non-dialysis dependent status refers to the status of persons with earlier stages of CKD (stages 1 to 4), patients with advanced stage of CKD (Stage 5), who have not yet started renal replacement therapy are also referred to as NDD-CKD.

Screening

Screening those who neither have symptoms nor risk factors for chronic kidney disease is not recommended.^[10] Those who should be screened include: those with hypertension or history of cardiovascular disease, those with diabetes or marked obesity, those aged > 60 years, subjects with indigenous racial origin, those with a history of renal disease in the past, as well as subjects who have relatives who had kidney disease requiring dialysis. Screening should include calculation of estimated GFR/1.73 m² from the serum creatinine level, and measurement of urine-to-albumin creatinine ratio in a first-morning urine specimen as well as dipstick screen for hematuria.^[11] Guidelines for nephrologist referral vary among different countries. Nephrology referral is useful when eGFR/1.73m² is less than 30 or decreasing by more than 3 mL/min/year, when urine albumin-to-creatinine ratio is more than 30 mg/g, when blood pressure is difficult to control, or when hematuria or other findings suggest either a primarily glomerular disorder or secondary disease amenable to specific treatment. Other benefits of early nephrology referral include proper patient education regarding options for renal replacement therapy as well as pre-emptive transplantation, and timely workup and placement of an arteriovenous fistula in those patients opting for future hemodialysis.

Treatment
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