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Five patients with polycystic disease of the kidney were examined with gray-scale ultrasonography. It was found that bilateral involvement may be demonstrated by ultrasound even when it cannot be seen on excretory urography. It is suggested that this technique be used in screening families in whom a history of polycystic kidney disease has been shown.
Two patients with polycystic kidney disease and renal failure developed profound hypotension within 30 minutes after starting hemodialysis. After ruling out all recognized causes of hypotension during early dialysis, we found that their vena cavas were obstructed by compression of the vessels against the spinal column by the greatly enlarged polycystic kidneys. Immediately after bilateral nephrectomy, the patients had dialysis, with removal of large amounts of fluid without causing hypotension. We speculate that compression of the vena cava by massively enlarged polycystic kidneys may significantly contribute to the renal insufficiency by greatly increasing renal venous pressure.
Adult polycystic kidney disease is recognized as the traditional form of cystic kidney disease in man. It was the first described. It is the best studied. It is the most common among adults, affecting roughly one of every 500 persons. It accounts for renal failure in some 5% of patients coming to renal transplantation and ranks third as a cause of end-stage renal disease. Its cause(s) and prevention (other than genetic control through counseling) remain unknown, although some evidence of a preliminary nature is beginning to accumulate.
Autosomal dominant polycystic kidney disease (ADPKD) accounts for 5%-10% of prevalent end-stage kidney failure (ESKD). ADPKD cysts result from a loss of sufficient functional expression of PKD1/Polycystin-1 (PC1) in approximately 80% of families. Kidney disease severity correlates with the extent to which PC1 dosage is reduced below a critical level, and evidence suggests therapeutic benefit from increasing PC1 expression in these conditions. Upstream open reading frame (uORF) translation can reduce translation of a protein's coding sequence. Ribosome profiling data and bioinformatic predictions suggested the presence of conserved PKD1 uORFs, so we sought to explore their biological role. We generated luciferase reporters and two humanized PKD1 5' UTR mouse models with or without single nucleotide edits removing uORF start codons (ΔuORF) to define active uORFs and test their impact on PC1 translation. PKD1 uORF start codons can robustly initiate translation, and ΔuORF conveys a 2-4 fold increase in PC1 protein expression and resultant prevention of kidney cysts in Dnajb11 as well as in Pkd1 missense models. PKD1 uORF1-blocking steric antisense oligonucleotides (ASOs) substantially increase PC1 expression in vitro. PKD1 uORFs play an important role in the low basal expression of WT PKD1, and their inhibition represents an opportunity to therapeutically increase PC1 translation in polycystic kidney and liver disease resulting from reduced dosage of PC1.
Congenital hepatic fibrosis is nearly always associated with ectasia of collecting tubules of the kidneys. This abnormality usually remains silent. In this study we report three cases of adult's CHF with associated renal failure treated by hemodialysis. In all three cases, renal injuries were indistinguishable from those found in adult-type of polycystic disease. The kidneys of our third patient, who underwent two nephrectomies at a 14-years interval, showed ectasia of the collecting tubules with only a few cortical cysts. The second one showed numerous large cysts and only a few ectatic tubules. Our data indicate that: renal failure can complicate the CHF course in adults. Uremia can be the pressenting feature; polycystic kidneys in CHF are microscopically different from those found in adult-type, they might be considered as the final stage in ectasia of collecting tubules.
Adult polycystic kidney disease treatment at Howard University Hospital is summarized. The cases are taken from autopsies performed between January 1955 and November 1975 and from the Hospital's dialysis population. Polycystic kidney disease was identified in six adults and four infants. Only two dialysis patients were clinically thought to have the disease. A review of the major clinical features of the disease is presented.
In 5 patients with polycystic kidney disease and creatinine clearances ranging from 4 to 40 ml/min, relationships between changes in blood pressure, sodium balance, body fluid compartments, plasma renin activity (PRA), urinary aldosterone excretion, and plasma aldosterone concentrations were studied during periods of low, medium, and high sodium intake. Total body water (TBW), total exchangeable body sodium (TEBS), and extracellular volume (ECV) were measured by isotope dilution techniques, plasma volume with Evan's blue dye, and PRA and aldosterone by radioimmunoassay. Low sodium intake reduced kidney function, blood pressure, and serum sodium, while PRA reached its highest levels. Subsequent increases in sodium intake improved kidney function and increased blood pressure. Plasma volume increased slightly and ECV markedly, while PRA dropped to 15 percent of the value noted after the low sodium intake. TBW and TEBS showed inconsistent changes. Aldosterone changes correlated closely with PRA. Blood pressure showed a negative correlation with PRA, but a positive one with body weight and cumulative sodium balance, and with plasma and extracellular volumes.it is suggested that whereas renin and aldosterone are involved in the maintenance of circulatory homeostasis during sodium loss, sodium retention causes an increase in blood pressure by concomitant changes in body fluids.
KEY POINTS: A novel nonsense variant ( mcy ) in ankyrin repeat and sterile alpha motif domain-containing 6 ( Anks6 ) promotes rapid disease progression in the Han:SPRD- Cy rat carrying a missense variant in Anks6 . mcy-/- rats exhibit prenatal lethality characterized by laterality and cardiovascular abnormalities. These findings indicate that ANKS6 nonfunction in rats leads to prenatal lethality, whereas misfunction leads to polycystic kidney disease development. BACKGROUND: Polycystic kidney disease (PKD) encompasses a group of genetic disorders characterized by the proliferation of fluid-filled renal cysts, leading to progressive renal failure and death. A key feature of PKD is its variable expressivity across patients, even when caused by the same variant, highlighting the importance of genetic background in PKD expression. METHODS: We identified an ostensibly healthy Sprague Dawley rat line with a variant that modifies PKD expressivity in Han:SPRD- Cy rats (caused by a missense variant [p.Arg717Trp] in the ankyrin repeat and sterile alpha motif domain-containing 6 [ Anks6 ] gene), which we named mcy (modifier of Cy ). We used whole-genome sequencing and segregation analysis to identify the mcy variant, quantitative PCR and mRNA sequencing to evaluate its effects on gene expression, western blotting and immunohistochemistry to assess its protein consequences, and ultrasound and histology to examine its impact on rat embryonic development. RESULTS: We identified a nonsense variant in the Anks6 gene as the genetic basis of the mcy phenotype (c.1126G>T [p.Glu376X]). Although mcy+/- rats are ostensibly healthy and do not develop PKD, mcy-/- rats exhibit laterality defects and die prenatally at E16.5 because of apparent perturbations in cardiovascular development. Notably, mcy+/-Cy+/- rats develop PKD much more rapidly than Cy+/- rats, and in a timeframe consistent with Cy-/-rats . Transcripts with the mcy variant allele seem to undergo nonsense-mediated decay, and no ANKS6 protein is detected. However, gene expression patterns in the kidneys did not differ significantly between age-matched mcy+/+ and mcy+/- rats, indicating that ANKS6 insufficiency does not cause PKD. CONCLUSIONS: We identified a novel nonsense variant in Anks6 . The findings indicate that the absence of wild-type ANKS6 accelerates PKD development in the Han:SPRD- Cy rat and that complete ANKS6 deficiency prevents normal embryonic development in rats.
A case of polycystic kidney disease in a newborn child is reported. Renal cortical necrosis due to asphyxia was the cause of death. The histopathological picture and a heavy family history support the rare diagnosis of polycystic kidney disease of adult type in a new-born child.
Seventeen adult patients with end stage polycystic kidney disease underwent renal transplantation. Two groups were identified: (1) those transplanted with retained polycystic kidneys, (2) those prepared with preliminary bilateral nephrectomy. Although there was a shockingly higher incidence in the mortality rate in the non-nephrectomized group, no specific cause could be identified. The results do indicate, however, that bilateral nephrectomy is essential in all patients with a history of pyelonephritis or gross hematuria. Substantial benefit from retained kidneys was noted only during the initial period of hemodialysis.
We evaluated an adult with polycystic kidney disease that had been present since birth. Our evidence indicates that this patient is a unique example of survival into adult life of the recessively inherited, infantile form of polycystic kidney disease.
5 patients with polycystic kidney disease undergoing chronic hemodialysis who developed perinephric abscesses are described. Gallium-67 scintigraphy was helpful in making a diagnosis in 2 of these patients. All 5 patients initially presented with urinary tract infections. Perinephric abscess became evident over a variable period of time (2--28 days) following completion of antibiotic therapy for their urinary tract infection. Gallium-67 scintigraphy appears useful in detecting this complication, and nephrectomy should be considered once the diagnosis is confirmed.
Thirty-one renal transplantations were performed in 25 patients with end-stage polycystic disease of the kidneys. Of the 14 recipients transplanted with both polycystic kidneys in situ and followed for at least 6 months, 10 had a previous history of urinary tract infection. Four of these 14 recipients had relapsing urinary tract infection after transplantation, the other 10 have been at risk on immunosuppressive therapy for a total of 152 months and have had no trouble that could be attributed to the presence of the polycystic kidneys. Despite the potentiality of polycystic kidneys to be a source of post-transplant infection when left in situ, a good outcome of renal transplatation could be achieved without preparative bilateral nephrectomy. The one-year patient and graft survivals are comparable to those obtained in our total transplantation series and renal transplantation is considered to be an acceptable therapy in polycystic disease.
Results of an ongoing prospective study of progeny of patients with adult-onset polycystic kidney disease using grey-scale ultrasound and high-dose nephrotomography are reported. Six asymptomatic subjects out of 17 at risk for polycystic kidney disease were found by ultrasonography to have multiple renal cysts; this included two unrelated children aged 18 months and 6 y who had normal high-dose nephrotomography. We suggest that ultrasonography may be the method of choice for presymptomatic detection of polycystic kidney disease. Serial studies of at-risk individuals by sonography will be useful in determining the earliest age of detection, the latest age of ultrasonography presentation, and in following the natural history of polycystic kidney disease.
Sixteen patients with adult polycystic kidney disease (PKD) were studied by gray scale B mode ultrasonography. The nephrosonographic appearance of adult PKD is a spectrum ranging from kidneys of normal size to enlarged kidneys with multiple variable-sized cysts. Strong focal cortical echoes were present in patients with only small cysts in the renal cortex. Hepatic cysts, which appeared as sharply marginated anechoic regions within the liver parenchyma, were detected by ultrasound in 50% of our patients. Hepatic and renal cysts appeared on computed tomograms as sharply defined, ovoid areas of low attenuation. There was good diagnostic correlation between ultrasonography and computed tomograms as sharply defined, ovoid areas of low attenuation. There was good diagnostic correlation between ultrasonography and computed tomography. Ultrasound and computed tomography are accurate methods for diagnosis of adult PKD; however, the ability to diagnose quickly and noninvasively both renal involvement and associated extrarenal involvement makes ultrasound the procedure of choice for diagnosis, screening, and followup.
A multigeneration family with polycystic kidney disease (PCKD) was studied by personal interviews of all affected and most suspected-affected adults. A clear pattern of denial was identified, which strongly influenced individuals' awareness of PCKD and individuals' taking actions appropriate to that awareness, as well as family cohesion and communication. Time lags--in fact, availability, awareness and action-taking had serious consequences in terms of continued genetic transmission, future "burden" to the family and society, and the psychological stability of individual family members. The potentially important roles of the family physician in this type of familial disease are discussed as: a source of information, a facilitator of awareness and appropriate action, and a counselor in assisting adaptation to this major life stress.
Thirty patients with chronic renal diease -10 with polycystic kidney disease (PKD) and normal GFR; 10 with PKD and GFR is less than 30 ml+min; 10 with chronic glomerulonephritis (CGN) and GFR is less than 30 ml+min -and 10 normal subjects were investigated. The ability to concentrate urine maximally (T-CH2O) after water deprivation and the renal handling of water and electrolytes following hypertonic volume expansion were studied. A defect in T-CH2O was common in PKD patients even with normal GFR. In PKD patients with normal GFR, volume expansion was not followed by a natriuretic effect of the same magnitude as in controls. This ""inadequate natriuresis after volume expansion"" may be explained partly by chronic hyponatremia and partly by a functional defect, i.e. the incomplete arterial vasodilation in the kidney. At comparable degrees of renal insufficiency, T-CH2O was lower in PKD than in CGN patients. It seems likely that in PKD patients the increased endogenous osmotic load has exaggerated the tubular defect in urine concentration already present at normal GFR. Furthermore, volume expansion was followed by a significant increase in fractional sodium excretion only in PKD patients with renal insufficiency.
Kidney fragments from two cases of hereditary polycystic kidney disease (adult form) at an early stage were examined by microdissection. Localized cystic cystic dilatations were found in proximal and distal tubules, loops of Henle, and collecting tubules. Entirely normal nephrons and collecting tubules were also observed. Abnormal branching of collecting tubules or the abnormal attachment of nephrons, as described in other microdissection studies, were not found. Our observations do not confirm the hypothesis that the adult form of hereditary polycystic kidney disease is the consequence of ampullary dysfunction during early development.